Synthetic intermediate of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine, synthetic intermediate of thionucleoside, and method for producing the same

Abstract

A compound represented by a formula [1D] as shown below (wherein R.sup.1A, R.sup.1B, R.sup.2A, R.sup.2B, R.sup.3A and R.sup.3B represent a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, and the like) is useful as an intermediate for producing a thionucleoside, and the production method of the present invention is useful as a method for producing a thionucleoside. ##STR00001##

Claims

1. A compound represented by the following formula [1F]: ##STR00349## (wherein R.sup.1 represents a hydroxyl-protecting group; R.sup.2 represents a hydroxyl-protecting group; or R.sup.1 and R.sup.2 may together form an optionally substituted C.sub.1-3 alkylene group; and R.sup.3C represents a hydrogen atom, a halogen atom, a group represented by the following formula [16]:
OR.sup.3a[16] (wherein R.sup.3a represents a hydroxyl-protecting group), or an optionally substituted C.sub.1-6 alkyl group; R.sup.3D represents a hydrogen atom, a halogen atom, a group represented by the following formula [16]
OR.sup.3a[16] (wherein R.sup.3a has the same meanings as those described above), or an optionally substituted C.sub.1-6 alkyl group; R.sup.4 represents a halogen atom, a hydroxyl group, an optionally substituted C.sub.1-6 alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group; R.sup.5 and R.sup.6 together represent a group represented by the following formula [2]:
Y[2] (wherein Y represents an oxygen atom or a group represented by the following formula [3]:
NOR.sup.7[3] (wherein R.sup.7 represents a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted silyl group)); provided that, when R.sup.5 and R.sup.6 together represent a group represented by the following formula [2a]:
O[2a] one of R.sup.3C and R.sup.3D represents a halogen atom, the other represents a hydrogen atom, and R.sup.4 represents a halogen atom, an optionally substituted C.sub.1-6 alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group; when R.sup.5 and R.sup.6 together represent a group represented by the following formula [3]:
NOR.sup.7[3] (wherein R.sup.7 has the same meanings as those described above), one of R.sup.3C and R.sup.3D represents a group represented by the following formula [16]:
OR.sup.3a[16] (wherein R.sup.3a has the same meanings as those described above), the other represents a hydrogen atom, and R.sup.4 represents an iodine atom, a hydroxyl group, an optionally substituted C.sub.1-6 alkylsulfonyloxy group or an optionally substituted arylsulfonyloxy group, R.sup.1 represents an optionally substituted acyl group, and R.sup.2 represents an optionally substituted acyl group; or when R.sup.5 and R.sup.6 together represent a group represented by the following formula [3]:
NOR.sup.7[3] (wherein R.sup.7 has the same meanings as those described above), one of R.sup.3C and R.sup.3D represents a hydrogen atom, the other represents a hydrogen atom, and R.sup.4 represents a hydroxyl group, R.sup.1 represents an optionally substituted aroyl group, and R.sup.2 represents an optionally substituted aroyl group).

Description

EXAMPLES

(1) Unless otherwise specified, SNAP KP-Sil Cartridge (Biotage Japan Ltd.), FR-260 Hi-Flash Column (YAMAZEN), or Wakogel C-200 were used for silica gel column chromatography.

(2) The mixing ratio used regarding eluent indicates a volume ratio.

(3) For instance, the phrase hexane/ethyl acetate=90/10 to 50/50 means that an eluent consisting of hexane:ethyl acetate=90:10 was changed to an eluent consisting of hexane:ethyl acetate=50:50.

(4) The .sup.1H-NMR spectra were measured employing Bruker AV400N (Bruker) or Bruker AV300 (Bruker), using tetramethylsilane as an internal standard. The total value was indicated with ppm.

(5) The .sup.19F-NMR spectra were measured employing Bruker AV400N (Bruker), and the total value was indicated with ppm.

(6) The LC/MS analysis was carried out under the following conditions.

(7) Measurement apparatus: Waters SQD

(8) Column: Waters BEHC 18, 1.7 m, 2.130 mm

(9) Solvent: Liquid A: 0.1% formic acid/water

(10) Liquid B: 0.1% formic acid/acetonitrile

(11) Gradient cycle: 0.00 min (liquid A/liquid B=95/5), 2.00 min (liquid A/liquid B=5/95), 3.00 min (liquid A/liquid B=5/95), 3.01 min (liquid A/liquid B=100/0), 3.80 min (liquid A/liquid B=100/0)

(12) Flow rate: 0.5 mL/min

(13) Column temperature: room temperature

(14) Ionization method: electron spray ionization (ESI) method (in which positive and negative ion peaks are detected)

(15) Detection wavelength: 254 nm

(16) Individual abbreviations used in the Examples have the following meanings.

(17) Ac: acetyl

(18) Bn: benzyl

(19) Bz: benzoyl

(20) Cbz: benzyloxycarbonyl

(21) Et: ethyl

(22) Me: methyl

(23) Ms: methylsulfonyl

(24) Ph: phenyl

(25) PMB: 4-methoxybenzyl

(26) .sup.iPr: isopropyl

(27) TBDPS: tert-butyl(diphenyl)silyl

(28) THP: tetrahydropyranyl

(29) TIPS: tris(propan-2-yl)silyl

(30) Tol: (4-methylphenyl)carbonyl

(31) DMSO-d.sub.6: deuterated dimethyl sulfoxide

(32) RT (min): retention time (min)

Example 1

(33) ##STR00044##

(34) 474 mL of methanol and 21.4 g of O-methylhydroxylamine hydrochloride were added to 119 g of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=benzoate. Thereafter, 35.7 mL of triethylamine was added dropwise to the mixture at a temperature of 0 C. to 10 C., and the thus obtained mixture was then stirred at room temperature for 5 hours. Thereafter, 400 mL of ethyl acetate and 400 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain 92.6 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoate in the form of a colorless oily product. .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 78:22.

(35) .sup.1H-NMR (CDCl.sub.3) value:

(36) 3.05 (0.22H, d, J=5.6 Hz), 3.11 (0.78H, d, J=6.0 Hz), 3.83 (2.34H, s), 3.92 (0.66H, s), 4.35-4.49 (m, 2H), 4.55-4.68 (m, 1H), 5.42-5.54 (m, 0.78H), 5.48-5.67 (m, 0.78H), 5.74 (0.22H, ddd, J=28.0, 8.0, 1.6 Hz), 6.06 (0.22H, ddd, J=46.4, 4.8, 1.6 Hz), 6.84 (0.22H, dd, J=11.2, 4.8 Hz), 7.38-7.48 (4.78H, m), 7.54-7.63 (2H, m), 8.00-8.10 (4H, m)

(37) ##STR00045##

(38) 64.4 g of 4-nitrobenzenesulfonyl chloride was added to a solution of 87.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoate in 300 mL of an ethyl acetate at a temperature of 0 C. to 10 C. Thereafter, 40.5 mL of triethylamine was added dropwise to the mixture at 15 C. or lower over 30 minutes, and the thus obtained mixture was then stirred at 26 C. for 5 hours. Thereafter, 300 mL of a 5% sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the obtained mixture was then stirred at the same temperature as described above for 2 hours, Thereafter, the water layer was removed, and the organic layer was successively washed with a mixed solution of 100 mL of 1 mol/L hydrochloric acid and 100 mL of a 10% sodium chloride aqueous solution, and with a mixed solution of 100 mL of a 5% sodium hydrogen carbonate aqueous solution and 100 mL of a 10% sodium chloride aqueous solution. The resultant was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain 126 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((4-nitrobenzene)sulfonyl)oxy)pentan-3-yl=benzoate in the form of a light yellow solid. Thereafter, .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 1:2.

(39) .sup.1H-NMR (CDCl.sub.3) value:

(40) 8.20-8.15 (2H, m), 8.10-8.05 (2H, m), 8.03-7.96 (2H, m), 7.92-7.86 (2H, m), 7.64-7.54 (2H, m), 7.48-7.38 (4.23H, m), 6.82 (0.77H, dd, J=11.2, 4.4 Hz), 5.94 (0.77H, ddd, J=26.4, 6.0, 2.4 Hz), 5.84 (0.77H, ddd, J=46.8, 4.4, 2.4 Hz), 5.77 (0.23H, ddd, J=23.2, 5.6, 2.8 Hz), 5.43 (0.23H, ddd, J=6.8, 5.6, 2.8 Hz), 5.40 (0.77H, ddd, J=7.2, 6.0, 2.8 Hz), 5.34 (0.23H, ddd, J=46.0, 6.8, 2.8 Hz), 4.76 (0.23H, dd, J=12.4, 2.8 Hz), 4.75 (0.77H, dd, J=12.4, 2.8 Hz), 4.52 (0.77H, dd, J=12.4, 7.2 Hz), 4.51 (0.23H, dd, J=12.4, 6.8 Hz), 3.89 (2.31H, s), 3.85 (0.69H, s)

(41) .sup.19F-NMR (CDCl.sub.3) value:

(42) 204.4-204.7 (0.77 F, m), 196.4-196.6 (0.23 F, m)

(43) ##STR00046##

(44) 153.4 g of anhydrous lithium bromide was added to a solution of 101.5 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((4-nitrobenzene)sulfonyl)oxy)pentan-3-yl=benzoate in 350 mL of an N,N-dimethylformamide dividedly over six times at a temperature of 50 C. to 60 C. The obtained mixture was stirred at 57 C. for 4 hours 30 minutes. Thereafter, 400 mL of ethyl acetate and 250 mL of 1 mol/L hydrochloric acid were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with 250 mL of 1 mol/L hydrochloric acid and 250 mL of a 10% sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 79.9 g of a brown oily product.

(45) As a result of the measurement of .sup.1H-NMR, it was found that the brown oily product was a mixture of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate and (2R,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate (87:13), and that the syn-anti ratio of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate was 82:18.

(46) (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate

(47) .sup.1H-NMR (CDCl.sub.3) value:

(48) 8.15-8.00 (4H, m), 7.65-7.55 (2H, m), 7.51-7.40 (4.82H, m), 6.87 (0.18H, dd, J=11.2, 4.8 Hz), 6.07 (0.18H, ddd, J=46.8, 4.4, 3.2 Hz), 5.94 (0.18H, ddd, J=24.4, 6.0, 3.2 Hz), 5.82 (0.82H, ddd, J=16.4, 6.0, 2.8 Hz), 5.52 (0.82H, dt, J=46.8, 6.0 Hz), 4.84-4.71 (1H, m), 4.64-4.55 (2H, m), 3.89 (2.46H, s), 3.85 (0.54H, s)

(49) .sup.19F-NMR (CDCl.sub.3) value:

(50) 193.3-193.5 (0.82 F, m), 203.1-203.4 (0.18 F, m)

(51) ##STR00047##

(52) 170 mL of a 50% glyoxylic acid aqueous solution was added to a solution of 79.9 g of the brown oily product obtained in Example 1(3) in 255 mL of tetrahydrofuran, and the obtained mixture was then stirred at 56 C. for 12 hours. Thereafter, the reaction mixture was cooled to room temperature, and 255 mL of ethyl acetate and 170 mL of a 10% sodium chloride aqueous solution were added to the mixture, and the water layer was then removed. The organic layer was successively washed with 170 mL of a 10% sodium chloride aqueous solution, and with a mixed solution of 170 mL of a 5% sodium hydrogen carbonate aqueous solution and 170 mL of a 10% sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 70.4 g of a brown oily product.

(53) The obtained oily product was a mixture of (2S,3S,4S)-1-(benzoyloxy)-2-bromo-4-fluoro-5-oxopentan-3-yl=benzoate and a water adduct thereof.

(54) ##STR00048##

(55) 26.7 g of a sodium hydrogen sulfide x-hydrate (Wako Pure Chemical Industries, Ltd.) was added to a solution of 70.4 g of the brown oily product obtained in Example 1(4) in 700 mL of N-methylpyrrolidone at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 2 hours. Thereafter, 13.4 g of a sodium hydrogen sulfide x-hydrate was added to the reaction mixture, and the thus obtained mixture was then stirred at 0 C. to 10 C. for 3 hours. Thereafter, 1050 mL of ethyl acetate and 700 mL of a 10% sodium chloride aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with a mixed solution of 700 mL of 1 mol/L hydrochloric acid and 350 mL of a 10% sodium chloride aqueous solution, and with a mixed solution of 350 mL of a 5% sodium hydrogen carbonate aqueous solution and 350 mL of a 10% sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 52.1 g of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=benzoate in the form of a light brown oily product.

(56) .sup.1H-NMR (CDCl.sub.3) value:

(57) 8.08-7.97 (4H, m), 7.63-7.31 (6H, m), 6.05 (0.61H, ddd, J=12.0, 7.2, 5.6 Hz), 5.83 (0.39H, ddd, J=12.4, 2.8, 2.0 Hz), 5.64 (0.39H, ddd, J=9.6, 8.4, 2.0 Hz), 5.49 (0.61H, m), 5.31 (0.39H, dt, J=47.6, 2.0 Hz), 5.20 (0.61H, ddd, J=51.2, 7.2, 4.0 Hz), 4.67 (0.61H, dd, J=11.6, 6.8 Hz), 4.60 (0.61H, dd, J=11.6, 6.8 Hz), 4.53-4.47 (0.78H, m), 4.21 (0.39H, tdd, J=8.0, 2.8, 1.2 Hz), 3.75 (0.61H, td, J=6.8, 5.6 Hz), 3.01 (0.61H, d, J=4.8 Hz, OH), 2.64 (0.39H, d, J=8.4 Hz, OH)

(58) .sup.19F-NMR (CDCl.sub.3) value:

(59) 183.6-183.9 (0.61 F, m), 192.3-192.6 (0.39 F, m)

(60) ##STR00049##

(61) 26.0 mL of acetic anhydride was added to a solution of 52.1 g of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=benzoate in 210 mL of tetrahydrofuran, and 58.0 mL of triethylamine was then added dropwise to the mixture at 10 C. or lower. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, 100 mL of ethyl acetate, 210 mL of a 5% sodium hydrogen carbonate aqueous solution and 100 mL of a 10% sodium chloride aqueous solution were added to the reaction mixture, and the obtained mixture was then stirred for 1 hour. Thereafter, the water layer was removed, and the organic layer was successively washed with a mixed solution of 150 mL of 1 mol/L hydrochloric acid and 100 mL of a 10% sodium chloride aqueous solution, and with a mixed solution of 50 mL of a 5% sodium hydrogen carbonate aqueous solution and 100 mL of a 10% sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was recrystallized from methanol, so as to obtain 29.3 g of ((2R,3S,4S)-5-(acetyloxy)-3-(benzoyloxy)-4-fluorothiolan-2-yl)methyl=benzoate in the form of a white solid.

(62) ##STR00050##

(63) 9.2 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 5.0 g of ((2R,3S,4S)-5-(acetyloxy)-3-(benzoyloxy)-4-fluorothiolan-2-yl)methyl=benzoate in 20 mL of methylene chloride in a nitrogen atmosphere under cooling on ice, and the obtained mixture was then stirred at a temperature of 5 C. to 7 C. for 3 hours. Thereafter, 10 mL of a 30% sodium acetate aqueous solution was added dropwise to the reaction mixture. The organic layer was fractionated, and the water layer was extracted with methylene chloride. The organic layer was combined with the extract, and the obtained mixture was then washed with a 25% sodium hydrogen carbonate aqueous solution. The water layer was extracted with methylene chloride twice. The organic layer was combined with the extract, and the obtained mixture was then washed with a 3% sodium hydrogen carbonate aqueous solution. The water layer was extracted with methylene chloride. The organic layer was combined with the extract, and the obtained mixture was then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, so as to obtain 15 mL of a methylene chloride solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorothiolan-2-yl)methy=benzoate.

(64) Separately, in a nitrogen atmosphere, 7.7 g of 1,1,1,3,3,3-hexamethyldisilazane and 15.8 mg of ammonium sulfate were added to a suspension of 3.66 g of acetylcytosine in 15 mL of ethylbenzene, and the obtained mixture was then stirred at a temperature of 110 C. to 115 C. for 2 hours. Thereafter, the reaction mixture was cooled to room temperature, and the solvent was then distilled away under reduced pressure, so as to obtain 7.5 g of a white solid.

(65) 1.25 mL of N-ethylpyrrolidone was added to the obtained white solid, and 15 mL of the above-described methylene chloride solution was then added dropwise to the mixture at a temperature of 70 C. to 75 C. The thus obtained mixture was stirred at the same temperature as described above for 1 hour. Thereafter, the reaction mixture was cooled to room temperature, and 75 mL of methylene chloride, 4 mL of water and 5 g of Celite were then added to the mixture, followed by stirring at a temperature of 27 C. to 28 C. for 2 hours. Thereafter, insoluble matters were removed by filtration, and the residue was then washed with methylene chloride. The filtrate was combined with the wash liquid, and the mixture was then washed with a solution of 2.85 g of dipotassium hydrogen phosphate and 0.38 g of potassium dihydrogen phosphate in 14.3 mL of water. The water layer was extracted with methylene chloride. The organic layer was combined with the extract, and insoluble matters were then removed by filtration. The solvent was replaced with propyl acetate. The precipitated solid was collected by filtration, and was then washed with propyl acetate, so as to obtain 1.53 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=4-benzoate in the form of a white solid.

(66) ##STR00051##

(67) 20 mL of 25% ammonia water was added to a solution of 2.03 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=4-benzoate in 40 mL of methanol, and the obtained mixture was then stirred at room temperature for 12 hours. Thereafter, the solvent was concentrated under reduced pressure, and the precipitated solid was then washed with methanol, so as to obtain 374 mg of (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane in the form of a white solid.

(68) The wash liquid was concentrated under reduced pressure, and the precipitated solid was then dissolved in 150 mL of ethyl acetate. 80 mL of the solvent was distilled away under reduced pressure. The precipitated solid was collected by filtration, and was then washed with ethyl acetate, so as to obtain 491 mg of (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane in the form of a white solid.

(69) .sup.1H-NMR (DMSO-d.sub.6) value:

(70) 7.99 (1H, d, J=7.9 Hz), 7.28-7.20 (2H, brs), 6.46 (1H, dd, J=14.5, 5.3 Hz), 5.88 (1H, d, J=4.6 Hz), 5.77 (1H, d, J=7.9 Hz), 5.25 (1H, t, J=5.3 Hz), 4.92 (1H, dt, J=50.9, 5.3 Hz), 4.30-4.19 (1H, m), 3.78-3.54 (2H, m), 3.23 (1H, q, J=5.9 Hz)

Example 2

(71) ##STR00052##

(72) In a nitrogen atmosphere, 76 mL of 30% hydrogen bromide/acetic acid was added dropwise to a suspension of 150 g of (3S,4R,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3-fluorooxolan-2-yl=benzoate in 105 mL of acetic acid at room temperature, and the obtained mixture was then stirred at 25 C. for 8 hours. Thereafter, 450 mL of toluene and 450 mL of water were added to the reaction mixture, and the thus obtained mixture was then stirred for 5 minutes. After that, the water layer was removed. The obtained organic layer was successively washed with 450 mL of water and 450 mL of a 5% sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 136 g of ((2R,3R,4S)-3-(benzoyloxy)-5-bromo-4-fluorooxolan-2-yl)methyl=benzoate in the form of a colorless oily product.

(73) As a result of the measurement of .sup.1H-NMR, it was found that the obtained compounds were all forms.

(74) .sup.1H-NMR (CDCl.sub.3) value:

(75) 8.11 (2H, dd, J=8.0, 0.8 Hz), 8.07 (2H, dd, J=8.0, 0.8 Hz), 7.63 (1H, tt, J=8.0, 0.8 Hz), 7.56 (1H, tt, J=8.0, 0.8 Hz), 7.49 (2H, t, J=8.0 Hz), 7.43 (2H, t, J=8.0 Hz), 6.64 (1H, d, J=12.4 Hz), 5.60 (1H, d, J=50.0 Hz), 5.54 (1H, dd, J=22.0, 3.0 Hz), 4.68-4.86 (3H, m)

(76) .sup.19F-NMR (CDCl.sub.3) value:

(77) 165.8-166.1 (1 F, m)

(78) ##STR00053##

(79) 270 mL of acetonitrile and 300 mL of a 10% sodium hydrogen carbonate aqueous solution were added to 136 g of ((2R,3R,4S)-3-(benzoyloxy)-5-bromo-4-fluorooxolan-2-yl)methyl=benzoate, and the obtained mixture was then stirred at 50 C. for 4 hours. Thereafter, 150 mL of toluene was added to the reaction mixture, and the water layer was then removed. Thereafter, the residue was cooled to 25 C. to obtain a toluene/acetonitrile solution of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=benzoate.

(80) The obtained ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=benzoate was used in the form of a solution for the subsequent reaction, without being isolated.

(81) ##STR00054##

(82) 135 mL of water and 40.2 g of O-methylhydroxylamine hydrochloride were added to a toluene/acetonitrile solution of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=benzoate. Subsequently, 58.2 mL of triethylamine was added dropwise to the mixture at a temperature of 25 C. to 30 C., and the obtained mixture was then stirred for 6 hours. Thereafter, 150 mL of toluene and 300 mL of a 10% sodium chloride aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain 122 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoate in the form of a colorless oily product.

(83) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 3:1.

(84) .sup.1H-NMR (CDCl.sub.3) value:

(85) 8.10-8.00 (4H, m), 7.63-7.54 (2H, m), 7.48-7.38 (4.75H, m), 6.84 (0.25H, dd, J=11.2, 4.8 Hz), 6.06 (0.25H, ddd, J=46.4, 4.8, 1.6 Hz), 5.74 (0.25H, ddd, J=28.0, 8.0, 1.6 Hz), 5.75 (0.75H, ddd, J=45.6, 6.8, 2.4 Hz), 5.49 (0.75H, ddd, J=26.0, 8.4, 2.4 Hz), 4.64 (0.75H, dd, J=12.0, 2.4 Hz), 4.60 (0.25H, dd, J=11.2, 2.4 Hz), 4.50-4.35 (2H, m), 3.91 (0.75H, s), 3.82 (2.25H, s), 3.11 (0.75H, d, J=6.0 Hz), 3.05 (0.25H, d, J=5.6 Hz)

(86) .sup.19F-NMR (CDCl.sub.3) value:

(87) 199.9-200.2 (0.75 F, m), 207.3-207.5 (0.25 F, m)

Example 3

(88) ##STR00055##

(89) In a nitrogen atmosphere, 6.50 g of lithium chloride was added to a mixed solution of 30.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoate in 150 mL of N,N-dimethylacetamide and 30 mL of pyridine. Subsequently, 6.40 mL of sulfuryl chloride was added dropwise to the mixture at a temperature of 20 C. to 0 C. over 20 minutes, and the thus obtained mixture was then stirred at room temperature for 3 hours. Thereafter, 300 mL of ethyl acetate, 150 mL of a 20% sodium chloride aqueous solution and 100 mL of water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with 150 mL of 1 mol/L hydrochloric acid twice, and then with 150 mL of a saturated sodium hydrogen carbonate aqueous solution, and it was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 34.2 g of (2S,3S,4R)-1-(benzoyloxy)-2-chloro-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate in the form of a colorless oily product.

(90) The obtained (2S,3S,4R)-1-(benzoyloxy)-2-chloro-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate was directly used in the subsequent reaction without being isolated.

(91) A small amount of reaction solution was diluted with deuterated chloroform, and .sup.1H-NMR was then measured. As a result, the syn/anti ratio was found to be 85:15.

(92) .sup.1H-NMR (CDCl.sub.3) value:

(93) 3.84 (0.45H, s), 3.88 (2.55H, s), 4.54-4.74 (3H, m), 5.52 (0.85H, dt, J=46.4, 6.4 Hz), 5.85 (0.85H, d dd, J=17.2, 5.9, 3.2 Hz), 5.88-6.00 (0.15H, m), 5.95-6.12 (0.15H, m), 6.88 (0.15H, dd, J=11.2, 4.8 Hz), 7.40-7.53 (4.85H, m), 7.55-7.66 (2H, m), 8.01-8.15 (4H, m)

(94) ##STR00056##

(95) In a nitrogen atmosphere, a mixture of 30.6 g of the (2S,3S,4R)-1-(benzoyloxy)-2-chloro-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate obtained in Example 3(1), 183 mL of tetrahydrofuran and 133 mL of glyoxylic acid was stirred at 60 C. for 10 hours. Thereafter, 300 mL of ethyl acetate, 200 mL of a 20% sodium chloride aqueous solution, 300 mL of water and 65.1 g of sodium hydrogen carbonate were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain 27.3 g of a colorless oily product.

(96) The obtained oily product was a mixture of (2S,3S,4S)-1-(benzoyloxy)-2-chloro-4-fluoro-5-oxopentan-3-yl=benzoate and a water adduct thereof.

(97) .sup.1H-NMR (CDCl.sub.3) value:

(98) 4.69-4.78 (3H, m), 5.37 (1H, dd, J=46.8, 4.0 Hz), 5.85 (1H, dt, J=20.8, 3.6 Hz), 7.39-7.53 (4H, m), 7.54-7.66 (2H, m), 8.01-8.12 (4H, m), 9.83 (1H, d, J=6.4 Hz)

(99) ##STR00057##

(100) In a nitrogen atmosphere, 96.2 mg of a sodium monohydrogen sulfide n-hydrate was added to a solution of 350 mg of the colorless oily product obtained in Example 3 (2) in 5.25 mL of N-methylpyrrolidone, and the obtained mixture was then stirred at room temperature for 5 hours. Thereafter, 7.90 mL of ethyl acetate, 5.25 mL of a 20% sodium chloride aqueous solution and 5.25 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1), so as to obtain 80.0 mg of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=benzoate in the form of a colorless oily product.

(101) .sup.1H-NMR (CDCl.sub.3) value:

(102) 3.74 (0.55H, q, J=6.8 Hz), 4.17-4.23 (0.45H, m), 4.44-4.55 (0.90H, m), 4.56-4.64 (0.55H, m), 4.64-4.72 (0.55H, m), 5.20 (0.55H, ddd, J=51.5, 7.6, 4.0 Hz), 5.32 (0.45H, dt, J=47.6, 2.4 Hz), 5.48 (0.55H, t, J=4.4 Hz), 5.64 (0.45H, dd, J=8.411.2, 1.6 Hz), 5.82 (0.45H, dt, J=12.8, 3.2 Hz), 6.04-6.12 (0.55H, m), 7.28-7.65 (6H, m), 7.94-8.16 (4H, m)

(103) ##STR00058##

(104) In a nitrogen atmosphere, 39.5 mL of triethylamine and 17.9 mL of acetic anhydride were added dropwise to a solution of 10.3 g of ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=benzoate in 20 mL of ethyl acetate, and the obtained mixture was then stirred at room temperature for 4 hours. Thereafter, 50 mL of ethyl acetate, 20 mL of a 20% sodium chloride aqueous solution and 30 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. Thereafter, 30 mL of saturated ammonium chloride water was added to the organic layer, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), so as to obtain 8.35 g of ((2R,3S,4S)-5-(acetyloxy)-3-(benzoyloxy)-4-fluorothiolan-2-yl)methyl=benzoate in the form of a brown oily product.

(105) .sup.1H-NMR (CDCl.sub.3) value:

(106) 2.12 (1.29H, s), 2.13 (1.71H, s), 3.74 (0.57H, q, J=6.8 Hz), 4.11 (0.43H, q, J=6.8 Hz), 4.43-4.59 (1.43H, m), 4.69 (0.57H, dd, J=11.1, 6.0 Hz), 5.31 (0.57H, ddd, J=50.8, 9.1, 4.8 Hz), 5.39 (0.43H, dt, J=47.6, 3.2 Hz), 5.85 (0.43H, dt, J=12.0, 4.0 Hz), 6.08 (0.57H, dt, J=11.6, 8.4 Hz), 6.18 (0.57H, d, J=4.8 Hz), 6.24 (0.43H, dd, J=13.6, 2.0 Hz), 7.28-7.36 (1.14H, m), 7.37-7.65 (4.86H, m), 7.92-7.98 (1.14H, m), 8.00-8.09 (2.86H, m)

Example 4

(107) ##STR00059##

(108) 200 mL of a 5% sodium hydrogen carbonate aqueous solution was added to a suspension of 17.2 g of O-benzylhydroxylamine hydrochloride in 86 mL of ethyl acetate, and the water layer was then removed. Thereafter, the solvent was concentrated under reduced pressure. To the obtained residue, 130 mL of methylene chloride, 19.4 g of ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=benzoate, 13.6 g of sodium hydrogen carbonate and 1.36 g of pyridinium p-toluenesulfonate were added, and the obtained mixture was then stirred at 50 C. for 1 hour. Thereafter, the reaction mixture was cooled to room temperature. Subsequently, 100 mL of ethyl acetate, 100 mL of a 20% sodium chloride aqueous solution and 50 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), so as to obtain 36.4 g of (2R,3R,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-4-fluoro-2-hydroxypentyl=benzoate in the form of a colorless oily product.

(109) .sup.1H-NMR (CDCl.sub.3) value:

(110) 2.88 (0.31H, s), 2.91 (0.69H, s), 4.33-4.46 (2H, m), 4.55-4.64 (1H, m), 5.06 (1.38H, s), 5.16 (0.62H, dd, J=6.8, 5.5 Hz), 5.49 (0.69H, ddd, J=25.9, 7.6, 1.6 Hz), 5.58 (0.69H, ddd, J=46.7, 6.4, 2.4 Hz), 5.79 (0.31H, dd, J=27.5, 7.9 Hz), 6.10 (0.31H, ddd, J=46.7, 4.8, 2.0 Hz), 6.90 (0.31H, dd, J=11.2, 4.8 Hz), 7.24 (5H, m), 7.38-7.53 (4.69H, m), 7.54-7.64 (2H, m), 7.99-8.10 (4H, m)

(111) ##STR00060##

(112) In a nitrogen atmosphere, a mixture of 1.00 g of (2R,3R,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-4-fluoro-2-hydroxypentyl=benzoate, 5.00 mL of N,N-dimethylformamide and 1.00 mL of pyridine was cooled to 20 C. While the internal temperature was kept at 0 C. or lower, 0.210 mL of sulfuryl chloride was added dropwise to the reaction mixture over 20 minutes, and the thus obtained mixture was then stirred at room temperature for 3 hours. Thereafter, 10 mL of ethyl acetate, 5 mL of a 20% sodium chloride aqueous solution and 5 mL of water were added to the reaction mixture, and the water layer was then removed. 5 mL of 1 mol/L hydrochloric acid was added to the organic layer, and the water layer was then removed. This operation was repeated twice. Subsequently, 5 mL of a saturated sodium hydrogen carbonate aqueous solution was added to the organic layer, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), so as to obtain 1.01 g of (2S,3S,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-2-chloro-4-fluoropentyl=benzoate in the form of a colorless oily product.

(113) .sup.1H-NMR (CDCl.sub.3) value:

(114) 4.48-4.75 (3H, m), 5.07 (0.4H, s), 5.11 (1.6H, s), 5.52 (0.8H, dt, J=46.8, 6.0 Hz), 5.84 (0.8H, ddd, J=16.4, 6.0, 3.2 Hz), 5.89-6.00 (0.2H, m), 6.01-6.18 (0.2H, m), 6.92 (0.2H, dd, J=8.1, 3.6 Hz), 7.25-7.34 (5H, m), 7.39-7.51 (4.8H, m), 7.53-7.64 (2H, m), 8.00-8.12 (4H, m)

(115) ##STR00061##

(116) In a nitrogen atmosphere, a mixture of 0.610 g of (2S,3S,4R)-3-(benzoyloxy)-5-((benzyloxy)imino)-2-chloro-4-fluoropentyl=benzoate, 3.00 mL of benzaldehyde and 0.300 mL of concentrated sulfuric acid was stirred at room temperature for 1 hour. Thereafter, 5 mL of ethyl acetate, 5 mL of a 20% sodium chloride aqueous solution and 5 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), so as to obtain 0.260 g of a colorless oily product.

(117) The obtained oily product was a mixture of (2S,3S,4S)-1-(benzoyloxy)-2-chloro-4-fluoro-5-oxopentan-3-yl=benzoate and a water adduct thereof.

(118) .sup.1H-NMR (CDCl.sub.3) value:

(119) 4.69-4.78 (3H, m), 5.37 (1H, dd, J=46.8, 4.0 Hz), 5.85 (1H, dt, J=20.8, 3.6 Hz, 7.39-7.53 (4H, m), 7.54-7.66 (2H, m), 8.01-8.12 (4H, m), 9.83 (1H, d, J=6.4 Hz)

Example 5

(120) ##STR00062##

(121) A mixture of 1.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol, 30 mL of tetrahydrofuran, 4.24 mL of triethylamine, 2.8 mL of acetic anhydride and 0.01 g of 4-dimethylaminopyridine was stirred at 25 C. for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, was then washed with a sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 2.2 g of ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=acetate in the form of a colorless oily product.

(122) .sup.1H-NMR (DMSO-d.sub.6) value:

(123) 5.28-5.12 (2H, m), 5.01 (1H, d, J=4.0 Hz), 4.31 (1H, dd, J=3.6, 11.2 Hz), 4.10-4.02 (2H, m), 3.34 (3H, s), 2.09 (3H, s), 2.23 (3H, s)

(124) ##STR00063##

(125) A mixture of 2.1 g of ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=acetate, 9 mL of trifluoroacetic acid and 1 mL of water was stirred at 50 C. for 8 hours. Thereafter, ethyl acetate and a sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=acetate in the form of a colorless oily product.

(126) A mixture of the obtained ((2R,3R,4S)-3-(acetyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=acetate, 10 mL of methanol, 0.85 g of O-methylhydroxylamine hydrochloride and 0.7 mL of triethylamine was stirred at 25 C. for 0.5 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1), so as to obtain 0.35 g of (2R,3R,4R)-1-(acetyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=acetate in the form of a colorless oily product.

(127) .sup.1H-NMR (DMSO-d.sub.6) value: 7.51 (0.75H, dd, J=6.8, 7.2 Hz), 7.02 (0.25H, dd, J=4.8, 10.4 Hz), 5.93-5.73 (1.25H, m), 5.36 (0.75H, ddd, J=2.8, 6.8, 45.6 Hz), 5.12 (0.25H, ddd, J=2.4, 8.4, 26.4 Hz), 4.05-3.85 (3H, m), 3.83 (0.75H, s), 3.80 (2.25H, s), 2.06 (2.25H, s), 2.04 (0.75H, s), 1.99 (3H, m)

(128) ##STR00064##

(129) A mixture of 0.35 g of the (2R,3R,4R)-1-(acetyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=acetate, 5 mL of acetonitrile, 0.15 mL of N-methylimidazole and 0.41 g of 2,4,5-trichlorobenzenesulfonyl chloride was stirred at 25 C. for 5 hours. Further, 0.10 g of 2,4,5-trichlorobenzenesulfonyl chloride was added to the reaction mixture, and the thus obtained mixture was then left at 25 C. for 3 days. Subsequently, 1.0 mL of N-methylimidazole was added to the reaction mixture, and the thus obtained mixture was then left at 25 C. for 1 day. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with diluted hydrochloric acid twice, and then with a sodium hydrogen carbonate aqueous solution. The resultant was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), so as to obtain 0.44 g of a colorless solid. The obtained solid was recrystallized from methanol, so as to obtain 0.29 g of (2R,3R,4R)-1-(acetyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfon yl)oxy)pentan-3-yl=acetate in the form of a colorless solid.

(130) .sup.1H-NMR (DMSO-d.sub.6) value:

(131) 8.33 (1.0H, m), 8.23 (1.0H, m), 7.55 (0.75H, dd, J=6.0, 7.2 Hz), 7.05 (0.25H, dd, J=4.8, 11.2 Hz), 5.81 (0.25H, ddd, J=2.0, 4.8, 46.4 Hz), 5.53 (0.25H, ddd, J=2.4, 5.2, 28.4 Hz), 5.49-5.33 (1.5H, m), 5.18-5.11 (1H, m), 4.35-4.12 (2H, m), 3.81 (3H, m), 2.07 (3H, m), 1.86-1.85 (3H, m)

Example 6

(132) ##STR00065##

(133) In a nitrogen atmosphere, 0.53 mL of pentafluorobenzenesulfonyl chloride was added dropwise to a solution of 1.3 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoatein 4 mL of an ethyl acetate and 4.0 mL of triethylamine at a temperature of 0 C. to 4 C., and the obtained mixture was then stirred at 0 C. for 2 hours 40 minutes. Thereafter, 0.27 mL of triethylamine and 0.26 mL of pentafluorobenzenesulfonyl chloride were added dropwise to the reaction mixture, and the thus obtained mixture was then stirred for 1 hour. Thereafter, 5.4 mL of a saturated sodium hydrogen carbonate aqueous solution and dimethylaminopyridine were added to the reaction mixture. The obtained mixture was stirred at room temperature for 30 minutes, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 1.8 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((pentafluorobenzene)sulfonyl)oxy)pentyl=benzoate in the form of a colorless oily product.

(134) .sup.1H-NMR (CDCl.sub.3) value:

(135) 3.86 (2.16H, s), 3.92 (0.84H, s), 4.57 (1H, dd, J=13.2, 7.2 Hz), 4.80 (0.72H, dd, J=12.8, 2.8 Hz), 4.81 (0.28H, dd, J=12.8, 2.8 Hz), 5.42 (0.72H, ddd, J=45.6, 6.4, 3.2 Hz), 5.51-5.60 (1H, m), 5.83 (0.72H, ddd, J=22.8, 5.6, 3.2 Hz), 5.90 (0.28H, ddd, J=46.8, 4.4, 2.4 Hz), 6.00 (0.28H, ddd, J=26.0, 5.6, 2.4 Hz), 6.84 (0.28H, dd, J=11.2, 4.4 Hz), 7.38-8.07 (10.72H, m)

(136) .sup.19F-NMR (CDCl.sub.3) value:

(137) 133.79 (2 F, m), 142.45 (1 F, m), 157.66 (2 F, m), 196.43 (0.72 F, ddd, J=45.6, 22.8, 6.8 Hz), 204.90 (0.28 F, ddd, J=46.8, 26.0, 11.2 Hz)

(138) ##STR00066##

(139) In a nitrogen atmosphere, 430 mg of anhydrous lithium bromide was added to a solution of 615 mg of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((pentafluorobenzene)sulfonyl)oxy)pentyl=benzoate in 2.2 mL of dimethylimidazolidinone, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 3 mL of water and 3 mL of ethyl acetate were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 379 mg of (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate in the form of a colorless oily product.

(140) .sup.1H-NMR (CDCl.sub.3) value:

(141) 3.85 (0.51H, s), 3.88 (2.49H, s), 4.52-4.65 (2H, m), 4.70-4.85 (1H, m), 5.52 (0.83H, ddd, J=46.8, 6.4, 6.4 Hz), 5.82 (0.83H, ddd, J=16.4, 6.4, 2.8 Hz), 5.94 (0.17H, ddd, J=24.4, 6.0, 2.8 Hz), 6.07 (0.17H, ddd, J=47.2, 4.4, 2.8 Hz), 6.87 (0.17H, dd, J=10.8, 4.4 Hz), 7.41-8.16 (10.83H, m)

(142) .sup.19F-NMR (CDCl.sub.3) value:

(143) 193.45 (0.83 F, ddd, J=46.8, 16.4, 6.4 Hz), 203.28 (0.17 F, ddd, J=47.2, 24.4, 10.8 Hz)

Example 7

(144) ##STR00067##

(145) In a nitrogen atmosphere, 5.1 mL of 1-methylimidazole was added dropwise to a solution of 20.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoate and 17.3 g of 2,4,5-trichlorobenzenesulfonyl chloride in 50 mL of acetonitrile at a temperature of 0 C. to 4 C., and the obtained mixture was then stirred at room temperature for 22 hours. Thereafter, 50 mL of a saturated sodium hydrogen carbonate aqueous solution and 50 mL of water were added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 1 hour. A solid was collected by filtration, and it was washed with 50 mL of water twice, and then with 25 mL of methanol twice, so as to obtain 28.3 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentyl=benzoate in the form of a white solid.

(146) .sup.1H-NMR (CDCl.sub.3) value:

(147) 3.85 (2.22H, s), 3.91 (0.78H, s), 4.54 (1H, dd, J=12.8, 6.4 Hz), 4.73 (0.74H, dd, J=12.8, 3.2 Hz), 4.75 (0.26H, dd, J=12.8, 2.8 Hz), 5.37-5.52 (1.74H, m), 5.82 (0.74H, ddd, J=22.8, 5.6, 2.8 Hz), 5.90 (0.26H, brs, J=48.0 Hz), 6.00 (0.26H, ddd, J=26.0, 5.6, 2.0 Hz), 6.83 (0.26H, dd, J=11.2, 4.4 Hz), 7.38-8.11 (12.74H, m)

(148) .sup.19F-NMR (CDCl.sub.3) value:

(149) 196.70 (0.74 F, ddd, J=45.6, 22.8, 6.8 Hz), 204.90 (0.26 F, ddd, J=48.0, 26.0, 11.2 Hz)

(150) ##STR00068##

(151) In a nitrogen atmosphere, 291 mg of anhydrous lithium bromide was added to a solution of 421 mg of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentyl=benzoate in 1.34 mL of dimethylimidazolidinone, and the obtained mixture was then stirred at 40 C. for 4 hours. Thereafter, the reaction mixture was analyzed by high performance liquid chromatography. As a result, the reaction percentage was found to be 98%, and (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate was generated.

Example 8

(152) ##STR00069##

(153) In a nitrogen atmosphere, 0.30 mL of 1-methylimidazole was added dropwise to a solution of 1.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoate and 857 mg of 3-nitrobenzenesulfonyl chloride in 5.0 mL of acetonitrile at a temperature of 0 C. to 4 C., and the obtained mixture was then stirred at room temperature for 15 hours 30 minutes. Thereafter, 5 mL of a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 5.0 mL of ethyl acetate was added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 1.59 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((3-nitrobenzene)sulfonyl)oxy)pentyl=benzoate in the form of a colorless oily product.

(154) .sup.1H-NMR (CDCl.sub.3) value:

(155) 3.84 (2.01H, s), 3.89 (0.99H, s), 4.50 (1H, dd, J=12.8, 6.4 Hz), 4.73-4.80 (1H, m), 5.33 (0.67H, ddd, J=45.6, 6.8, 3.2 Hz), 5.39-5.48 (1H, m), 5.73-5.87 (1H, m), 5.95 (0.33H, ddd, J=26.4, 6.0, 2.4 Hz), 6.80 (0.33H, dd, J=11.2, 4.4 Hz), 7.30-8.75 (14.67H, m)

(156) .sup.19F-NMR (CDCl.sub.3) value:

(157) 196.64 (0.67 F, ddd, J=45.6, 23.3, 6.8 Hz), 204.77 (0.33 F, ddd, J=46.7, 26.4, 11.2 Hz)

(158) ##STR00070##

(159) In a nitrogen atmosphere, 73.6 mg of anhydrous lithium bromide was added to a solution of 103 mg of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((3-nitrobenzene)sulfonyl)oxy)pentyl=benzoate in 0.34 mL of N,N-dimethylformamide, and the obtained mixture was then stirred at 60 C. for 5 hours 30 minute. Thereafter, the reaction mixture was analyzed by high performance liquid chromatography. As a result, the reaction percentage was found to be 98%, and (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate was generated.

Example 9

(160) ##STR00071##

(161) In a nitrogen atmosphere, 0.30 mL of 1-methylimidazole was added dropwise to a solution of 1.0 g of (2R,3R,4R)-1-(benzoyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentan-3-yl=benzoate and 857 mg of 2-nitrobenzenesulfonyl chloride in 5.0 mL of acetonitrile at a temperature of 0 C. to 4 C., and the obtained mixture was then stirred at room temperature for 15 hours 30 minutes. Thereafter, 5 mL of a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 5.0 mL of ethyl acetate was added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 1.44 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2-nitrobenzene)sulfonyl)oxy)pentyl=benzoate in the form of a colorless oily product.

(162) .sup.1H-NMR (CDCl.sub.3) value:

(163) 3.83 (2.13H, s), 3.90 (0.87H, s), 4.56 (1H, dd, J=12.8, 6.0 Hz), 4.84 (1H, dd, J=12.8, 2.8 Hz), 5.42 (0.71H, ddd, J=45.6, 6.4, 3.2 Hz), 5.39-5.55 (1.71H, m), 5.87 (0.71H, ddd, J=23.6, 6.0, 2.8 Hz), 5.93 (0.29H, ddd, J=49.2, 4.4, 2.4 Hz), 6.80 (0.29H, dd, J=11.2, 4.4 Hz), 7.35-8.15 (14.71H, m)

(164) .sup.19F-NMR (CDCl.sub.3) value:

(165) 197.12 (0.71 F, ddd, J=45.6, 23.6, 6.8 Hz), 205.10 (0.29 F, ddd, J=49.2, 26.4, 11.2 Hz)

(166) ##STR00072##

(167) In a nitrogen atmosphere, 875 mg of anhydrous lithium bromide was added to a solution of 1.15 g of (2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-(methoxyimino)-2-(((2-nitrobenzene)sulfonyl)oxy)pentyl=benzoate in 4 mL of N,N-dimethylformamide, and the obtained mixture was then stirred at 60 C. for 3 hours. Thereafter, the reaction mixture was analyzed by high performance liquid chromatography. As a result, the reaction percentage was found to be 98%, and (2S,3S,4R)-1-(benzoyloxy)-2-bromo-4-fluoro-5-(methoxyimino)pentan-3-yl=benzoate was generated.

Example 10

(168) ##STR00073##

(169) A mixture of 800 mg of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol, 67 mg of tetrabutylammonium chloride, 4 mL of toluene, 481 mg of sodium hydroxide, 4 mL of water and 1.56 g of 4-methylbenzoyl chloride was stirred at 5 C. for 1 hour, and then at room temperature for 2.5 hours. Thereafter, the organic layer was fractionated, it was then washed with a saturated sodium chloride aqueous solution twice, and it was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate/hexane=1/10 to 1/2), so as to obtain 1.61 g of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-methylphenyl)carbonyloxy)oxolan-2-yl)methyl=4-methylbenzoate in the form of a white solid.

(170) .sup.1H-NMR (CDCl.sub.3) value:

(171) 7.98-7.93 (4H, m), 7.25-7.20 (4H, m), 5.79 (1H, ddd, J=17.2, 6.0, 6.0 Hz), 5.25 (1H, ddd, J=52.4, 6.4, 4.4 Hz), 5.07 (1H, d, J=4.4 Hz), 4.72 (1H, dd, J=11.6, 6.4 Hz), 4.56 (1H, dd, J=11.6, 6.4 Hz), 4.38-4.34 (1H, m), 3.48 (3H, s), 2.43 (3H, s)

(172) 19F-NMR (CDCl.sub.3) value:

(173) 206.73 (1 F, dd, J=52.1, 17.5 Hz)

(174) ##STR00074##

(175) A mixture of 800 mg of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-methylphenyl)carbonyloxy)oxolan-2-yl)methyl=4-methylbenzoate, 2.2 mL of trifluoroacetic acid and 268 mg of water was stirred at 50 C. for 7 hours. Thereafter, 50 mL of ethyl acetate was added to the reaction mixture, and the thus obtained mixture was washed with a saturated sodium hydrogen carbonate aqueous solution three times, and then with a saturated sodium chloride aqueous solution once. The organic layer was fractionated, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate/hexane=1/10 to 1/2), so as to obtain 720 mg of ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-methylphenyl)carbonyloxy)oxolan-2-yl)methyl=4-methylbenzoate in the form of a colorless oily product.

(176) .sup.1H-NMR (CDCl.sub.3) value:

(177) 7.97-7.93 (4H, m), 7.24-7.21 (4H, m), 5.68 (1H, dd, J=10.0, 3.6 Hz), 5.47 (1H, dd, J=22.0, 4.4 Hz), 5.16 (1H, d, J=49.2 Hz), 4.74-4.67 (2H, m), 4.60-4.56 (1H, m), 2.93 (1H, dd, J=3.4, 3.4 Hz), 2.42 (3H, s), 2.40 (3H, s)

(178) .sup.19F-NMR (CDCl.sub.3) value: 190.09 (1 F, ddd, J=49.3, 22.4, 10.4 Hz)

(179) ##STR00075##

(180) (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-((4-methylphenyl)carbonyloxy)pentyl=4-methylbenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(181) .sup.1H-NMR (CDCl.sub.3) value:

(182) 7.97-7.89 (4H, m), 7.39 (0.80H, dd, J=6.8, 6.8 Hz), 7.26-7.21 (4H, m), 6.83 (0.20H, dd, J=11.1, 4.7 Hz), 6.05 (0.20H, ddd, J=46.4, 4.2, 1.5 Hz), 5.70 (0.20H, dd, J=28.2, 1.9 Hz), 5.56 (0.80H, ddd, J=45.4, 6.9, 2.3 Hz), 5.44 (0.80H, ddd, J=26.0, 8.4, 2.4 Hz), 4.61 (0.80H, dd, J=12.4, 3.2 Hz), 4.57 (0.20H, dd, J=11.1, 1.9 Hz), 4.45-4.34 (2H, m), 3.91 (0.60H, s), 3.83 (2.40H, s), 3.03 (0.80H, d, J=5.8 Hz), 2.98 (0.20H, d, J=2.4 Hz), 2.42-2.41 (6H, m)

(183) .sup.19F-NMR (CDCl.sub.3) value:

(184) 200.06 (0.8 F, ddd, J=45.2, 25.7, 6.9 Hz), 207.4 (0.2 F, ddd, J=46.5, 28.2, 11.1 Hz)

(185) ##STR00076##

(186) (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-((4-methylphenyl)carbonyloxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=4-methylbenzoate was obtained in the form of a white solid in the same manner as that of Example 7(1).

(187) .sup.1H-NMR (CDCl.sub.3) value:

(188) 8.06 (1H, s), 7.83 (4H, dd, J=45.8, 8.2 Hz), 7.41-7.39 (1.18H, m), 7.26-7.20 (4H, m), 6.83 (0.82H, dd, J=11.0, 4.6 Hz), 6.00-5.91 (1.41H, m), 5.85-5.83 (0.41H, m), 5.77 (0.18H, ddd, 22.8, 5.9, 3.1 Hz), 5.46 (0.09H, ddd, J=28.5, 6.5, 2.9 Hz), 5.41-5.36 (0.91H, m), 4.72-4.65 (1H, m), 4.56-4.51 (1H, m), 3.90 (2.46H, s), 3.86 (0.54H, s), 2.42 (6H, s)

(189) .sup.19F-NMR (CDCl.sub.3) value:

(190) 196.58 (0.18 F, ddd, J=45.6, 22.6, 6.7 Hz), 204.85 (0.82 F, ddd, J=46.5, 26.3, 11.0 Hz)

(191) ##STR00077##

(192) (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-((4-methylphenyl)carbonyloxy)pentyl=4-methylbenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(193) .sup.1H-NMR (CDCl.sub.3) value:

(194) 8.02-7.88 (4H, m), 7.47 (0.86H, dd, J=6.4, 6.4 Hz), 7.28-7.19 (4H, m), 6.86 (0.14H, dd, J=11.2.4.8 Hz), 6.05 (0.14H, ddd, J=47.0, 4.7, 3.0 Hz), 5.91 (0.14H, ddd, J=24.8, 5.7, 3.1 Hz), 5.79 (0.86H, ddd, J=17.2, 5.7, 3.1 Hz), 5.51 (0.86H, ddd, J=46.8, 5.2, 5.3 Hz), 4.79-4.70 (1.14H, m), 4.62-4.54 (1.86H, m), 3.88 (2.58H, m), 3.85 (0.42H, m), 2.43-2.40 (6H, m)

(195) .sup.19F-NMR (CDCl.sub.3) value:

(196) 193.52 (0.86 F, ddd, J=46.7, 16.8, 6.3 Hz), 203.30 (0.14 F, ddd, J=46.9, 24.6, 10.8 Hz)

(197) ##STR00078##

(198) A mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-((4-methylphenyl)carbonyloxy)-5-oxopentyl=4-methylbenzoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4).

(199) .sup.1H-NMR (CDCl.sub.3) value:

(200) 9.81 (1H, d, J=6.0 Hz), 8.01-7.88 (4H, m), 7.26-7.18 (4H, m), 5.80-4.61 (5H, m), 2.42-2.34 (6H, m)

(201) .sup.19F-NMR (CDCl.sub.3) value:

(202) 210.08 (1 F, ddd, J=47.1, 20.8, 6.5 Hz)

(203) ##STR00079##

(204) ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-methylphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate was obtained in the form of a white solid in the same manner as that of Example 1(5).

(205) .sup.1H-NMR (CDCl.sub.3) value:

(206) 8.01-7.87 (4H, m), 7.26-7.14 (4H, m), 6.03-5.97 (0.54H, m), 5.81 (0.46H, dt, J=12.1, 4.6 Hz), 5.62 (0.46H, dd, J=9.6 Hz), 5.49 (0.54H, dd, J=9.6, 5.2 Hz), 5.37 (0.23H, m), 5.25 (0.50H, m), 5.12 (0.27H, m), 4.68-4.56 (1.1H, m), 4.48-4.46 (0.92H, m), 4.19-4.15 (0.46H, m), 3.74 (0.54H, dd, J=12.0, 6.8 Hz), 2.81 (0.54H, dd, J=5.8, 1.4 Hz), 2.45-2.37 (6.46H, m)

(207) .sup.19F-NMR (CDCl.sub.3) value:

(208) 183.63 (0.54 F, dd, J=47.4, 11.4 Hz), 192.74 (0.46 F, ddd, J=51.2, 11.5, 5.1 Hz)

(209) ##STR00080##

(210) 12 mg of dimethylaminopyridine and 622 mg of 2-picoline were added to a solution of 1.35 g of ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-methylphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate in 8.1 mL of tetrahydrofuran, and 511 mg of acetic anhydride was then added to the mixture at a temperature of 10 C. or lower. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate was added to the reaction mixture. The thus obtained mixture was washed with a saturated sodium chloride aqueous solution three times, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. Methanol was added to the obtained residue, and a solid was collected by filtration, so as to obtain 546 mg of ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((4-methylphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate in the form of a white solid.

(211) .sup.1H-NMR (CDCl.sub.3) value:

(212) 7.88 (4H, dd, J=28.0, 8.0 Hz), 7.16 (4H, dd, J=32.0, 8.0 Hz), 6.17 (1H, d, J=4.4 Hz), 6.08-6.01 (1H, m), 5.30 (1H, ddd, J=50.8, 9.6, 4.5 Hz), 4.66 (1H, dd, J=11.2, 6.0 Hz), 4.47 (1H, dd, J=11.4, 6.6 Hz), 3.72 (1H, dd, J=13.4, 6.6 Hz), 2.42 (3H, s), 2.36 (3H, s), 2.12 (3H, s)

(213) .sup.19F-NMR (CDCl.sub.3) value: 191.83 (1 F, dd, J=50.8, 11.7 Hz)

(214) ##STR00081##

(215) ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methylphenyl)carbonyloxy)thiolan-2-yl) methyl=4-methylbenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(7).

(216) .sup.1H-NMR (CDCl.sub.3) value:

(217) 8.01-7.86 (4H, m), 7.27-7.20 (4H, m), 5.82-5.80 (0.5H, m), 5.77-5.75 (0.5H, m), 5.73-5.71 (1H, m), 5.68-5.67 (0.5H, m), 5.58-5.56 (0.5H, m), 4.66-4.60 (1H, m), 4.57-4.49 (1H, m), 4.34-4.28 (1H, m), 2.42 (3H, s), 2.40 (3H, s)

(218) .sup.19F-NMR (CDCl.sub.3) value: 163.52 (1 F, dd, J=46.9, 14.4 Hz)

(219) ##STR00082##

(220) Using a methylene chloride solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methylphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate, ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((4-methyl phenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate was obtained in the form of a yellow-brown solid in the same manner as that of Example 22(2).

(221) m/z (ESI-positive): 540.5 [M+H].sup.+

(222) .sup.19F-NMR (CDCl.sub.3) value: 195.82 (1 F, ddd, J=49.0, 23.5, 9.2 Hz)

(223) ##STR00083##

(224) (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane was obtained in the same manner as that of Example 1(8).

Example 11

(225) ##STR00084##

(226) ((2R,3R,4S)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=4-chlorobenzoate was obtained in the form of a white solid in the same manner as that of Example 10(1), with the exception that the reaction time was set at 8 hours.

(227) .sup.1H-NMR (CDCl.sub.3) value:

(228) 8.02-7.96 (4H, m), 7.45-7.26 (4H, m), 5.83 (1H, ddd, J=17.2, 6.0, 6.0 Hz), 5.25 (1H, ddd, J=52.0, 6.4, 4.4 Hz), 5.07 (1H, d, J=4.4 Hz), 4.73 (1H, dd, J=11.6, 4.0 Hz), 4.56 (1H, dd, J=11.6, 6.4 Hz), 4.37-4.33 (1H, m), 3.48 (3H, s)

(229) .sup.19F-NMR (CDCl.sub.3) value: 191.75 (1 F, dd, J=50.6, 11.9 Hz)

(230) ##STR00085##

(231) ((2R,3R,4S)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=4-chlorobenzoate was obtained in the form of a white solid in the same manner as that of Example 10(2).

(232) .sup.1H-NMR (CDCl.sub.3) value:

(233) 8.01-7.97 (4H, m), 7.45-7.39 (4H, m), 5.69 (1H, d, J=10.0 Hz), 5.46 (1H, dd, J=21.8, 4.2 Hz), 5.16 (1H, d, J=49.2 Hz), 4.76-4.59 (3H, m), 2.92 (1H, brs)

(234) .sup.19F-NMR (CDCl.sub.3) value: 190.45 (1 F, ddd, J=49.1, 21.9, 10.1 Hz)

(235) ##STR00086##

(236) (2R,3R,4R)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl=4-chlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(237) .sup.1H-NMR (CDCl.sub.3) value:

(238) 7.98-7.92 (4H, m), 7.58 (0.86H, dd, J=6.0, 6.0 Hz), 7.45-7.39 (4H, m), 6.82 (0.14H, dd, J=11.2, 4.6 Hz), 6.04 (0.14H, ddd, J=46.4, 4.6, 2.0 Hz), 5.75 (0.14H, dd, J=8.2, 2.0 Hz), 5.55-5.50 (1.72H, m), 4.63-4.54 (1H, m), 4.46-4.35 (2H, m), 3.91 (0.42H, s), 3.85 (2.58H, s), 3.08 (0.86H, d, J=6.6, 1.1 Hz), 2.91 (0.25H, d, J=6.0 Hz)

(239) .sup.19F-NMR (CDCl.sub.3) value:

(240) 200.31 (0.86 F, ddd, J=46.5, 23.6, 5.7 Hz), 207.35 (0.14 F, ddd, J=45.2, 29.2, 10.4 Hz)

(241) ##STR00087##

(242) (2R,3R,4R)-1-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=4-chlorobenzoate was obtained in the form of a white solid in the same manner as that of Example 7(1).

(243) 1H-NMR (CDCl.sub.3) value:

(244) 7.99 (1H, s), 7.96-7.89 (4H, m), 7.65 (1H, s), 7.44-7.40 (4H, m), 7.35 (1H, m), 5.62-5.58 (1H, m), 5.37-5.22 (2H, m), 4.84-4.79 (1H, m), 4.68-4.63 (1H, m), 3.83 (3H, s)

(245) .sup.19F-NMR (CDCl.sub.3) value: 190.52 (1 F, ddd, J=47.4, 17.4, 6.5 Hz)

(246) ##STR00088##

(247) (2S,3S,4R)-2-bromo-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)pentyl=4-chlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(248) .sup.1H-NMR (CDCl.sub.3) value:

(249) 8.02-7.91 (4H, m), 7.46-7.40 (5H, m), 5.87 (1H, ddd, J=6.1, 6.1, 1.7 Hz), 5.14 (1H, ddd, J=46.8, 27.2, 11.7 Hz), 4.65-4.64 (2H, m), 4.53-4.48 (1H, m), 3.81 (3H, s)

(250) .sup.19F-NMR (CDCl.sub.3) value: 171.64 (1 F, ddd, J=46.6, 8.7, 5.2 Hz)

(251) ##STR00089##

(252) A mixture of (2S,3S,4S)-2-bromo-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-oxopentyl=4-chlorobenzoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 60 C. for 7 hours and then at room temperature for 3 days.

(253) .sup.1H-NMR (CDCl.sub.3) value:

(254) 9.80-9.78 (1H, m), 8.02-7.90 (4H, m), 7.48-7.39 (4H, m), 5.80-4.54 (5H, m)

(255) .sup.19F-NMR (CDCl.sub.3) value: 194.14 (1 F, ddd, J=47.3, 18.5, 4.4 Hz)

(256) ##STR00090##

(257) ((2R,3S,4S)-3-((4-chlorophenyl)carbonyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=4-chlorobenzoate was obtained in the form of a yellow-brown solid in the same manner as that of Example 1(5), with the exception that the reaction was carried out at room temperature for 24 hours.

(258) .sup.1H-NMR (CDCl.sub.3) value:

(259) 8.00-7.90 (4H, m), 7.44-7.31 (4H, m), 6.04-6.01 (0.56H, m), 5.79 (0.44H, dt, J=12.6, 5.3 Hz), 5.68-5.62 (0.44H, m), 5.48 (0.54H, dd, J=8.8, 4.4 Hz), 5.37-5.36 (0.22H, m), 5.27-5.24 (0.50H, m), 5.12-5.11 (0.28H, m), 4.65-4.59 (1.3H, m), 4.49-4.47 (0.7H, m), 4.20-4.15 (0.44H, m), 2.79 (0.54H, d, J=4.0 Hz), 2.37 (0.54H, d, J=8.0 Hz)

(260) .sup.19F-NMR (CDCl.sub.3) value:

(261) 183.81 (0.54 F, dd, J=46.7, 11.8 Hz), 192.29 (0.46 F, ddd, J=51.6, 11.8, 4.2 Hz)

(262) ##STR00091##

(263) ((2R,3S,4S,5R)-5-acetyloxy-3-((4-chlorophenyl)carbonyloxy)-4-fluorothiolan-2-yl)methyl=4-chlorobenzoate was obtained in the form of a white solid in the same manner as that of Example 10(8).

(264) .sup.1H-NMR (CDCl.sub.3) value:

(265) 7.96 (4H, dd, J=14.0, 2.4 Hz), 7.41 (4H, dd, J=18.8, 8.4 Hz), 6.23 (1H, dd, J=14.0, 2.0 Hz), 5.82 (1H, ddd, J=12.0, 8.0, 3.0 Hz), 5.38 (1H, ddd, J=44.8, 3.4, 2.3 Hz), 4.55-4.43 (2H, m), 4.10-4.07 (1H, m), 2.12 (3H, s)

(266) 19F-NMR (CDCl.sub.3) value: 191.76 (1 F, dd, J=50.8, 11.7 Hz)

(267) ##STR00092##

(268) ((2R,3S,4S,5R)-5-bromo-3-((4-chlorophenyl)carbonyloxy)-4-fluorothiolan-2-yl) methyl=4-chlorobenzoate was obtained in the form of a yellow-brown oily product in the same manner as that of Example 1(7).

(269) .sup.1H-NMR (CDCl.sub.3) value:

(270) 8.01 (4H, dd, J=16.8, 8.4 Hz), 7.42 (4H, dd, J=10.8, 8.4 Hz), 5.82-5.80 (0.5H, m), 5.77-5.76 (0.5H, m), 5.74-5.73 (1H, m), 5.69 (0.5H, brs), 5.58-5.56 (0.5H, m), 4.65-4.50 (1H, m), 4.32-4.26 (1H, m)

(271) .sup.19F-NMR (CDCl.sub.3) value: 163.51 (1 F, dd, J=47.2, 14.5 Hz)

(272) ##STR00093##

(273) ((2R,3S,4S,5R)-3-((4-chlorophenyl)carbonyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=4-chlorobenzoate was obtained in the form of a light yellow solid in the same manner as that of Example 22(2).

(274) m/z (ESI-positive): 580.4[M+H].sup.+

(275) .sup.19F-NMR (CDCl.sub.3) value: 196.19 (1 F, ddd, J=49.1, 23.9, 8.7 Hz)

(276) ##STR00094##

(277) (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane was obtained in the same manner as that of Example 1(8).

Example 12

(278) ##STR00095##

(279) ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-methoxyphenyl)carbonyloxy)oxolan-2-yl)methyl=4-methoxybenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 10(1).

(280) .sup.1H-NMR (CDCl.sub.3) value:

(281) 8.03-7.98 (4H, m), 6.93-6.88 (4H, m), 5.45 (1H, dd, J=23.2, 4.8 Hz), 5.21-5.03 (2H, m), 4.71 (1H, dd, J=12.0, 3.6 Hz), 4.60 (1H, dd, J=12.0, 4.4 Hz), 4.47-4.50 (1H, m), 3.87 (3H, s), 3.85 (3H, s), 3.45 (3H, s)

(282) .sup.19F-NMR (CDCl.sub.3) value: 190.34 (1 F, ddd, J=49.3, 23.1, 10.5 Hz)

(283) ##STR00096##

(284) ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-methoxyphenyl)carbonyloxy)oxolan-2-yl) methyl=4-methoxybenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 10(2).

(285) 1H-NMR (CDCl.sub.3) value:

(286) 8.03-7.97 (4H, m), 6.94-6.88 (4H, m), 5.68 (1H, dd, J=10.4, 3.6 Hz), 5.45 (1H, dd, J=22.2, 4.2 Hz), 5.15 (1H, d, J=49.2 Hz), 4.72-4.55 (3H, m), 3.34 (1H, dd, J=3.4 Hz)

(287) .sup.19F-NMR (CDCl.sub.3) value: 189.89-190.10 (1 F, m)

(288) ##STR00097##

(289) (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-((4-methoxyphenyl)carbonyloxy)pentyl=4-methoxybenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(290) 1H-NMR (CDCl.sub.3) value:

(291) 8.04-7.96 (4H, m), 7.39 (0.70H, dd, J=6.0, 6.0 Hz), 6.94-6.89 (4H, m), 6.83 (0.30H, dd, J=11.0, 4.8 Hz), 6.05 (0.30H, ddd, J=46.5, 4.8, 1.9 Hz), 5.71-5.62 (0.30H, m), 5.56 (0.70H, ddd, J=45.4, 6.9, 2.3 Hz), 5.42 (0.70H, ddd, J=26.0, 8.4, 2.3 Hz), 4.62-4.54 (1H, m), 4.42-4.32 (2H, m), 3.91 (0.9H, s), 3.87-3.85 (6H, m), 3.83 (2.1H, s), 3.06 (0.7H, d, J=2.4 Hz), 3.01 (0.3H, d, J=2.4 Hz)

(292) .sup.19F-NMR (CDCl.sub.3) value:

(293) 200.11 (0.7 F, ddd, J=45.2, 26.0, 6.8 Hz), 207.36 (0.3 F, ddd, J=46.5, 28.4, 10.9 Hz)

(294) ##STR00098##

(295) (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-((4-methoxyphenyl)carbonyloxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=4-methoxybenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(296) .sup.1H-NMR (CDCl.sub.3) value:

(297) 8.07-8.06 (1H, s), 7.98-7.82 (4H, m), 7.43-7.39 (1.73H, m), 6.93-6.88 (4H, m), 6.82 (0.27H, dd, J=11.0, 4.5 Hz), 5.96-5.95 (0.27H, m), 5.87 (0.27H, ddd, 22.7, 5.3, 2.3 Hz), 5.75 (0.73H, ddd, 22.9, 5.9, 3.1 Hz), 5.50-5.47 (0.36H, m), 5.42-5.36 (1.36H, m), 4.70-4.64 (1H, m), 4.53-4.48 (1H, m), 3.90-3.83 (9H, m)

(298) .sup.19F-NMR (CDCl.sub.3) value:

(299) 196.63 (0.73 F, ddd, J=45.6, 23.0, 6.8 Hz), 204.89 (0.27 F, ddd, J=46.5, 26.3, 11.0 Hz)

(300) ##STR00099##

(301) (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-((4-methoxyphenyl)carbonyl oxy)pentyl=4-methoxybenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(302) .sup.1H-NMR (CDCl.sub.3) value:

(303) 8.08-7.94 (4H, m), 7.46 (1H, dd, J=6.5, 6.5 Hz), 6.96-6.89 (4H, m), 5.77 (1H, ddd, J=16.8, 6.0, 3.2 Hz), 5.50 (1H, ddd, J=46.8, 6.3, 6.3 Hz), 4.75-4.69 (1H, m), 4.57-4.53 (2H, m), 3.88-3.84 (9H, m)

(304) .sup.19F-NMR (CDCl.sub.3) value: 193.50 (1 F, ddd, J=46.1, 16.9, 6.2 Hz)

(305) ##STR00100##

(306) A mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)-5-oxopentyl=4-methoxybenzoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 60 C. for 14 hours.

(307) .sup.1H-NMR (CDCl.sub.3) value:

(308) 9.85-9.70 (1H, m), 8.02-7.91 (4H, m), 6.94-6.86 (4H, m), 6.07-4.38 (5H, m), 3.87-3.84 (6H, m)

(309) .sup.19F-NMR (CDCl.sub.3) value: 210.07 (1 F, ddd, J=47.3, 20.9, 6.4 Hz)

(310) ##STR00101##

(311) ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-methoxyphenyl)carbonyloxy)thiolan-2-yl) methyl=4-methoxybenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(5), with the exception that the reaction was carried out at room temperature for 5 hours.

(312) .sup.1H-NMR (CDCl.sub.3) value:

(313) 8.02-7.93 (4H, m), 6.93-6.82 (4H, m), 6.32-5.97 (0.54H, m), 5.80 (0.46H, dt, J=12.2, 4.9 Hz), 5.61 (0.46H, dt, J=9.7, 9.7 Hz), 5.48 (0.54H, dd, J=9.5, 5.0 Hz), 5.36-5.35 (0.23H, m), 5.25-5.23 (0.50H, m), 5.14-5.09 (0.27H, m), 4.65-4.54 (1.3H, m), 4.47-4.45 (0.7H, m), 4.25-4.17 (0.46H, m), 3.87-3.83 (6H, m), 3.73 (0.54H, d, J=12.3, 6.7 Hz), 2.78 (0.54H, d, J=5.3 Hz), 2.69 (0.46H, d, J=8.6 Hz)

(314) .sup.19F-NMR (CDCl.sub.3) value:

(315) 183.54 (0.54 F, dd, J=47.1, 11.4 Hz), 192.82 (0.46 F, ddd, J=51.4, 11.7, 5.1 Hz)

(316) ##STR00102##

(317) ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methoxybenzoate was obtained in the form of a white solid in the same manner as that of Example 10(8).

(318) .sup.1H-NMR (CDCl.sub.3) value:

(319) 7.98 (4H, dd, J=9.8, 9.8 Hz), 6.89 (4H, dd, J=16.4, 8.8 Hz), 6.22 (1H, dd, J=13.6, 1.8 Hz), 5.81 (1H, d dd, J=12.3, 8.2, 3.0 Hz), 5.37 (1H, ddd, J=45.0, 3.5, 2.2 Hz), 4.54-4.40 (2H, m), 4.15-4.03 (1H, m), 3.87 (3H, s), 3.85 (3H, s), 2.11 (3H, s)

(320) .sup.19F-NMR (CDCl.sub.3) value: 191.95 (1 F, dd, J=50.8, 11.7 Hz)

(321) ##STR00103##

(322) ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methoxybenzoate was obtained in the form of a white solid in the same manner as that of Example 1(7).

(323) .sup.1H-NMR (CDCl.sub.3) value:

(324) 8.03 (4H, dd, J=20.9, 8.9 Hz), 6.91 (4H, dd, J=11.3, 8.9 Hz), 5.81-5.79 (0.5H, m), 5.76-5.74 (0.5H, m), 5.72-5.71 (1H, m), 5.68 (0.5H, brs), 5.58-5.56 (0.5H, m), 4.64-4.47 (1H, m), 4.33-4.27 (1H, m), 3.87 (3H, s), 3.85 (3H, s)

(325) .sup.19F-NMR (CDCl.sub.3) value: 163.56 (1 F, dd, J=47.2, 14.8 Hz)

(326) ##STR00104##

(327) Using a methylene chloride solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methoxybenzoate, ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((4-methoxyphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methoxybenzoate was obtained in the form of a light yellow solid in the same manner as that of Example 22(2).

(328) m/z (ESI-positive): 572.5 [M+H].sup.+

(329) .sup.19F-NMR (CDCl.sub.3) value: 196.14 (1 F, ddd, J=49.6, 23.7, 8.9 Hz)

(330) ##STR00105##

(331) (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane was obtained in the same manner as that of Example 1(8).

Example 13

(332) ##STR00106##

(333) ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-(trifluoromethyl)phenyl)carbonyloxy)oxolan-2-yl)methyl=4-(trifluoromethyl)benzoate was obtained in the form of a white solid in the same manner as that of Example 10(1).

(334) .sup.1H-NMR (CDCl.sub.3) value:

(335) 8.21-8.15 (4H, m), 7.68-7.75 (4H, m), 5.83 (1H, ddd, J=17.2, 6.0, 6.0 Hz), 5.28 (1H, ddd, J=52.0, 6.4, 4.4 Hz), 5.09 (1H, d, J=4.4 Hz), 4.78 (1H, dd, J=12.0, 4.0 Hz), 4.62 (1H, dd, J=12.0, 6.4 Hz), 4.41-4.37 (1H, m), 3.49 (3H, s)

(336) .sup.19F-NMR (CDCl.sub.3) value: 63.16 (3F, s), 63.23 (3F, s), 206.61 (1 F, dd, J=52.3, 16.9 Hz)

(337) ##STR00107##

(338) ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-(trifluoromethyl)phenyl)carbonyloxy)oxolan-2-yl)methyl=4-(trifluoromethyl)benzoate was obtained in the form of a colorless oily product in the same manner as that of Example 10(2).

(339) .sup.1H-NMR (CDCl.sub.3) value:

(340) 8.18 (4H, dd, J=7.8, 7.8 Hz), 7.73 (4H, dd, J=12.4, 4.4 Hz), 5.72 (1H, dd, J=9.8, 2.6 Hz), 5.51 (1H, dd, J=21.6, 4.0 Hz), 5.19 (1H, d, J=49.2 Hz), 4.82-4.78 (1H, m), 4.72-4.64 (2H, m), 2.85 (1H, dd, J=3.2, 3.2 Hz)

(341) .sup.19F-NMR (CDCl.sub.3) value:

(342) 63.16 (3F, s), 63.24 (3F, s), 190.66 (1 F, dddd, J=49.0, 21.7, 9.6, 2.4 Hz)

(343) ##STR00108##

(344) (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-((4-(trifluoromethyl)phenyl)carbonyloxy)pentyl=4-(trifluoromethyl)benzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(345) .sup.1H-NMR (CDCl.sub.3) value:

(346) 8.19-8.11 (4H, m), 7.74-7.69 (4H, m), 7.40 (0.64H, dd, J=6.4, 6.4 Hz), 6.83 (0.36H, dd, J=11.2, 4.4 Hz), 6.10 (0.36H, ddd, J=46.4, 4.5, 2.0 Hz), 5.82 (0.36H, dd, J=8.1, 1.9 Hz), 5.65 (0.32H, dd, J=6.4.2.4 Hz), 5.57-5.48 (0.96H, m), 4.67-4.60 (1H, m), 4.51-4.41 (2H, m), 3.93 (1.08H, s), 3.82 (1.92H, s), 2.88 (0.64H, d, J=5.8 Hz), 2.83 (0.36H, d, J=5.9 Hz),

(347) .sup.19F-NMR (CDCl.sub.3) value:

(348) 63.23 (3F, s), 63.28 (3F, s), 200.2 (0.64 F, ddd, J=45.2, 25.3, 7.2 Hz), 207.4 (0.36 F, ddd, J=46.3, 27.5, 11.3 Hz)

(349) ##STR00109##

(350) (2R,3R,4R)-2-fluoro-1-(methoxyimino)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)-5-((4-(trifluoromethyl)phenyl)carbonyloxy)pentan-3-yl=4-(trifluoromethyl)benzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(351) .sup.1H-NMR (CDCl.sub.3) value:

(352) 8.15-8.05 (5H, m), 7.75-7.70 (4H, m), 7.50 (1H, s), 7.41 (0.65H, dd, J=6.6, 6.6 Hz), 6.81 (0.35H, dd, J=11.3, 4.4 Hz), 6.02 (0.35H, ddd, J=25.7, 5.9, 2.5 Hz), 5.95-5.93 (0.17H, m), 5.86-5.78 (0.82H, m), 5.51-5.38 (1.65H, m), 4.81-4.74 (1H, m), 4.63-4.57 (1H, m), 3.92 (1.95H, s), 3.83 (1.05H, s)

(353) .sup.19F-NMR (CDCl.sub.3) value:

(354) 63.23 (3F, s), 63.30 (3F, s), 196.6 (0.65 F, ddd, J=45.6, 21.9, 6.9 Hz), 204.9 (0.35 F, ddd, J=46.9, 25.9, 11.4 Hz)

(355) ##STR00110##

(356) (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-((4-(trifluoromethyl)phenyl)carbonyloxy)pentyl=4-(trifluoromethyl)benzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(357) .sup.1H-NMR (CDCl.sub.3) value:

(358) 8.23-8.08 (4H, m), 7.76-7.66 (4H, m), 7.49 (0.82H, dd, J=6.4, 6.4 Hz), 6.87 (0.18H, dd, J=11.2, 4.8 Hz), 6.07 (0.18H, ddd, 47.0, 4.6, 3.3 Hz), 5.93 (0.18H, ddd, 23.8, 5.7, 3.2 Hz), 5.83 (0.82H, ddd, 15.6, 6.2, 3.0 Hz), 5.53 (0.82H, ddd, 46.8, 6.3, 6.3 Hz), 4.81-4.70 (1H, m), 4.81-4.74 (1H, m), 4.65-4.58 (1H, m), 3.90 (2.46H, s), 3.88 (0.54H, s)

(359) .sup.19F-NMR (CDCl.sub.3) value:

(360) 63.24 (3F, s), 63.27 (3F, s), 193.37 (0.82 F, ddd, J=46.7, 15.4, 6.4 Hz), 202.98 (0.18 F, ddd, J=47.1, 23.5, 10.7 Hz)

(361) ##STR00111##

(362) A mixture of (2S,3S,4S)-2-bromo-4-fluoro-5-oxo-3-((4-(trifluoromethyl)phenyl)carbonyloxy)pentyl=4-(trifluoromethyl)benzoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 60 C. for 8 hours, and then at 70 C. for 2 hours.

(363) .sup.1H-NMR (CDCl.sub.3) value:

(364) 9.84 (1H, d, J=5.6 Hz), 8.23-8.03 (4H, m), 7.78-7.57 (4H, m), 5.89-4.09 (5H, m)

(365) .sup.19F-NMR (CDCl.sub.3) value: 63.28 (3F, s), 63.36 (3F, s), 210.07 (1 F, ddd, J=47.1, 20.1, 5.8 Hz)

(366) ##STR00112##

(367) ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((4-(trifluoromethyl)phenyl)carbonyloxy)thiolan-2-yl)methyl=4-(trifluoromethyl)benzoate was obtained in the form of a white solid in the same manner as that of Example 1(5), with the exception that the reaction was carried out for 6 hours.

(368) .sup.1H-NMR (CDCl.sub.3) value:

(369) 8.18-8.07 (4H, m), 7.75-7.58 (4H, m), 6.10-6.06 (0.53H, m), 5.84 (0.47H, dt, 13.0, 6.0 Hz), 5.67 (00.47H, dd, J=10.2, 7.1 Hz), 5.49 (0.53H, dd, J=8.4, 4.1 Hz), 5.40-5.39 (0.23H, m), 5.30-5.27 (0.50H, m), 5.17-5.14 (0.27H, m), 5.17-4.65 (1.3H, m), 4.55-4.53 (0.7H, m), 4.22 (0.47H, m), 3.78 (0.53H, dd, J=13.0, 6.2 Hz), 2.91 (0.53H, d, J=4.4 Hz), 2.45 (0.47H, d, J=7.0 Hz)

(370) .sup.19F-NMR (CDCl.sub.3) value:

(371) 63.28 (3F, s), 63.30 (3F, s), 184.00 (0.47 F, dd, J=47.4, 11.9 Hz), 192.00 (0.53 F, ddd, J=51.4, 11.8, 3.7 Hz)

(372) ##STR00113##

(373) ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)thiolan-2-yl)methyl=4-(trifluoromethyl)benzoate was obtained in the form of a white solid in the same manner as that of Example 10(8), with the exception that hexane was used instead of methanol as a solvent to be added to the obtained residue.

(374) .sup.1H-NMR (CDCl.sub.3) value:

(375) 8.05 (4H, dd, J=22.0, 8.0 Hz), 7.62 (4H, dd, J=48.2, 8.2 Hz), 6.19 (1H, d, J=4.4 Hz), 6.11-6.04 (1H, m), 5.32 (1H, ddd, J=50.6, 9.1, 4.5 Hz), 4.62 (1H, ddd, J=55.6, 11.4, 6.6 Hz), 3.78 (1H, dd, J=13.6, 6.8 Hz), 2.16 (3H, s)

(376) .sup.19F-NMR (CDCl.sub.3) value: 63.32 (3F, s), 63.33 (3F, s), 191.78 (1 F, dd, J=50.6, 11.9 Hz)

(377) ##STR00114##

(378) ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)thiolan-2-yl)methyl=4-(trifluoromethyl)benzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(7).

(379) .sup.1H-NMR (CDCl.sub.3) value:

(380) 8.19 (4H, dd, J=15.8, 8.0 Hz), 7.72 (4H, dd, J=9.0, 9.0 Hz), 5.87-5.85 (0.5H, m), 5.82-5.80 (0.5H, m), 5.76 (1H, brs), 5.71 (0.5H, brs), 5.61 (0.5H, brs), 4.68-4.59 (2H, m), 4.36-4.30 (1H, m)

(381) .sup.19F-NMR (CDCl.sub.3) value: 63.20 (3F, s), 63.28 (3F, s), 163.52 (1 F, dd, J=46.9, 14.4 Hz)

(382) ##STR00115##

(383) Using a methylene chloride solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)thiolan-2-yl)methyl=4-(trifluoromethyl)benzoate, ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((4-(trifluoromethyl)phenyl)carbonyloxy)thiolan-2-yl)methyl=4-(trifluoromethyl)benzoate was obtained in the form of a light yellow solid in the same manner as that of Example 22(2).

(384) m/z (ESI-positive): 648.5 [M+H].sup.+

(385) .sup.19F-NMR (CDCl.sub.3) value: 196.23 (1H, ddd, J=49.7, 24.5, 8.7 Hz)

(386) ##STR00116##

(387) (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane was obtained in the same manner as that of Example 1(8).

Example 14

(388) ##STR00117##

(389) ((2R,3R,4S)-4-fluoro-5-methoxy-3-((3-phenyl-2-propenoyl)oxy)oxolan-2-yl)methyl=3-phenyl-2-propenoate was obtained in the form of a white solid in the same manner as that of Example 10(1).

(390) .sup.1H-NMR (CDCl.sub.3) value:

(391) 7.74 (2H, dd, J=16.0, 5.6), 7.54-7.51 (4H, m), 7.42-7.36 (6H, m), 6.47 (2H, dd, J=16.0, 6.8 Hz), 5.63 (1H, ddd, J=17.2, 6.0, 6.0 Hz), 5.20 (1H, ddd, J=52.4, 6.4, 4.4 Hz), 5.05 (1H, d, J=4.4 Hz), 4.62 (1H, dd, J=11.6, 4.0 Hz), 4.40 (1H, dd, J=11.6, 7.2 Hz), 4.31-4.24 (1H, m), 3.52 (3H, s)

(392) .sup.19F-NMR (CDCl.sub.3) value: 206.91 (1 F, dd, J=52.3, 16.9 Hz)

(393) ##STR00118##

(394) ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((3-phenyl-2-propenoyl)oxy)oxolan-2-yl)methyl=3-phenyl-2-propenoate was obtained in the form of a colorless oily product in the same manner as that of Example 10(2), with the exceptions that the reaction temperature was set at 70 C. and that the reaction time was set at 4 hours.

(395) .sup.1H-NMR (CDCl.sub.3) value:

(396) 7.75 (2H, dd, J=16.0, 8.0 Hz), 7.54-7.51 (4H, m), 7.41-7.37 (6H, m), 6.48 (2H, dd, J=16.0, 4.4 Hz), 5.67 (1H, dd, J=10.4, 2.8 Hz), 5.51 (1H, dd, J=21.6, 4.0 Hz), 5.32 (1H, dd, J=22.2, 4.2 Hz), 5.09 (1H, d, J=49.2 Hz), 4.65-4.58 (2H, m), 4.48-4.42 (1H, m), 3.15 (1H, brs)

(397) .sup.19F-NMR (CDCl.sub.3) value: 190.06 (1 F, ddd, J=49.1, 22.1, 10.3 Hz)

(398) ##STR00119##

(399) (2R,3R,4R)-2-fluoro-4-hydroxy-1-(methoxyimino)-5-((3-phenyl-2-propenoyl)oxy)pentan-3-yl=3-phenyl-2-propenoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(400) .sup.1H-NMR (CDCl.sub.3) value:

(401) 7.75 (2H, dd, J=19.7, 16.1 Hz), 7.53-7.50 (4H, m), 7.41-7.37 (6.77H, m), 6.85 (0.23H, dd, J=11.2, 4.8 Hz), 6.48 (2H, dd, J=16.0, 14.8 Hz), 6.01 (ddd, J=46.4, 4.8, 2.0 Hz), 5.57 (ddd, J=28.4, 8.0, 2.0 Hz), 5.53 (ddd, J=45.4, 6.6, 2.4 Hz), 5.33 (ddd, J=26.0, 8.1, 2.5 Hz), 4.50-4.40 (1H, m), 4.32-4.28 (2H, m), 3.94 (0.7H, s), 3.02-2.99 (1H, m)

(402) .sup.19F-NMR (CDCl.sub.3) value:

(403) 200.15 (0.77 F, ddd, J=45.6, 26.0, 7.2 Hz), 207.29 (0.23 F, ddd, J=46.7, 28.2, 11.3 Hz)

(404) ##STR00120##

(405) (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-((3-phenyl-2-propenoyl)oxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=3-phenyl-2-propenoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(406) .sup.1H-NMR (CDCl.sub.3) value:

(407) 8.17 (1H, s), 7.78-7.63 (3H, m), 7.54-7.50 (4H, m), 7.41-7.36 (6.77H, m), 6.81 (0.23H, dd, J=11.1, 4.4 Hz), 6.33 (1.54H, dd, J=77.6, 16.0 Hz), 6.32 (0.46H, dd, J=65.2, 16.0 Hz), 5.89 (0.23H, m), 5.79 (0.23H, ddd, 19.0, 5.5, 2.4 Hz), 5.66 (0.77H, ddd, 23.6, 6.4, 3.2 Hz), 5.37 (0.77H, ddd, 45.8, 6.5, 3.1 Hz), 5.29-5.25 (1H, m), 4.59-4.55 (1H, m), 4.43-4.38 (1H, m), 3.94 (0.69H, s), 3.89 (2.31H, s)

(408) .sup.19F-NMR (CDCl.sub.3) value:

(409) 197.2 (0.77 F, ddd, J=45.6, 23.4, 6.9 Hz), 205.2 (0.23 F, ddd, J=46.7, 26.4, 11.3 Hz)

(410) ##STR00121##

(411) (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-1-((3-phenyl-2-propenoyl)oxy) pentan-3-yl=3-phenyl-2-propenoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(412) .sup.1H-NMR (CDCl.sub.3) value:

(413) 7.78 (2H, dd, J=28.0, 16.0 Hz), 7.57-7.51 (4H, m), 7.46 (0.87H, dd, J=6.5, 6.5 Hz), 7.41-7.37 (6H, m), 6.87 (0.13H, dd, J=11.0, 4.8 Hz), 6.50 (2H, dd, J=29.6, 16.0 Hz), 6.03 (0.13H, dd, J=47.2, 4.6, 3.3 Hz), 5.75 (0.13H, dd, J=25.1, 5.8, 3.1 Hz), 5.65 (0.87H, ddd, 17.6, 5.6, 3.6 Hz), 5.53 (0.82H, ddd, 46.8, 6.3, 6.3 Hz), 4.66-4.44 (3H, m), 3.92 (3H, s)

(414) .sup.19F-NMR (CDCl.sub.3) value: 193.71 (1 F, ddd, J=46.7, 17.3, 6.4 Hz)

(415) ##STR00122##

(416) A mixture of (2S,3S,4S)-2-bromo-4-fluoro-5-oxo-1-((3-phenyl-2-propenoyl)oxy)pentan-3-yl 3-phenyl-2-propenoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 40 C. for 2 hours, and then at 70 C. for 13 hours.

(417) .sup.1H-NMR (CDCl.sub.3) value:

(418) 9.86-9.79 (1H, m), 8.86-7.67 (2H, m), 7.58-7.26 (10H, m), 6.53-6.45 (2H, m), 5.79-4.11 (5H, m)

(419) .sup.19F-NMR (CDCl.sub.3) value: 210.09-210.34 (1 F, m)

(420) ##STR00123##

(421) ((2R,3S,4S)-4-fluoro-5-hydroxy-3-((3-phenyl-2-propenoyl)oxy)thiolan-2-yl)methyl=3-phenyl-2-propenoate was obtained in the form of a brown oily product in the same manner as that of Example 1(5), with the exception that the reaction was carried out for 4 hours.

(422) .sup.1H-NMR (CDCl.sub.3) value:

(423) 7.76-7.69 (2H, m), 7.53-7.46 (4H, m), 7.41-7.31 (6H, m), 6.45 (0.94H, dd, J=15.8, 6.2 Hz), 6.43 (1.06H, dd, J=22.8, 16.0 Hz), 5.91-5.84 (0.53H, m), 5.70 (0.47H, dt, 11.9, 4.8 Hz), 5.59 (0.47H, dd, 9.8, 9.8 Hz), 5.45 (0.53H, dd, J=9.6, 4.8 Hz), 5.30-5.29 (0.23H, m), 5.19-5.16 (0.50H, m), 5.06-5.04 (0.27H, m), 4.53-4.50 (1.3H, m), 4.55-4.53 (0.7H, m), 4.09-4.05 (0.47H, m), 3.62 (0.53H, dd, J=1 2.3, 6.7 Hz), 2.88 (0.53H, d, J=5.4 Hz), 2.52 (0.47H, d, J=9.0 Hz)

(424) .sup.19F-NMR (CDCl.sub.3) value:

(425) 183.75 (0.48 F, dd, J=47.1, 11.5 Hz), 192.65 (0.52 F, ddd, J=51.2, 11.8, 4.6 Hz)

(426) ##STR00124##

(427) ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((3-phenyl-2-propenoyl)oxy)thiolan-2-yl)methyl=3-phenyl-2-propenoate was obtained in the form of a white solid in the same manner as that of Example 10(8).

(428) .sup.1H-NMR (CDCl.sub.3) value:

(429) 7.71 (2H, dd, J=33.8, 16.2 Hz), 7.49-7.29 (10H, m), 6.42 (2H, dd, J=43.2, 16.0 Hz), 6.15 (1H, d, J=40.0 Hz), 5.23-5.86 (1H, m), 5.22 (1H, ddd, J=50.8, 8.9, 4.5 Hz), 4.46 (1H, ddd, J=58.4, 11.3, 6.9 Hz), 3.61 (1H, dd, J=13.8, 7.0 Hz), 2.18 (3H, s)

(430) .sup.19F-NMR (CDCl.sub.3) value: 192.04 (1 F, dd, J=50.5, 12.0 Hz)

(431) ##STR00125##

(432) ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((3-phenyl-2-propenoyl)oxy)thiolan-2-yl)methyl=3-phenyl-2-propenoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(7).

(433) .sup.1H-NMR (CDCl.sub.3) value:

(434) 7.83-7.69 (2H, m), 7.55-7.45 (4H, m), 7.42-7.31 (6H, m), 6.51-6.38 (2H, m), 5.67-5.66 (1.5H, m), 5.63-5.61 (0.5H, m), 4.65-4.59 (1H, m), 4.54-4.38 (2H, m), 4.23-4.18 (1H, m)

(435) .sup.19F-NMR (CDCl.sub.3) value: 163.52 (1 F, dd, J=49.1, 15.0 Hz)

(436) ##STR00126##

(437) Using a methylene chloride solution of ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((3-phenyl-2-propenoyl)oxy)thiolan-2-yl)methyl=3-phenyl-2-propenoate, ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((3-phenyl-2-propenoyl)oxy)thiolan-2-yl)methyl=3-phenyl-2-propenoate was obtained in the form of a yellow-brown solid in the same manner as that of Example 22(2).

(438) m/z (ESI-positive): 564.5 [M+H].sup.+

(439) .sup.19F-NMR (CDCl.sub.3) value: 195.90 (1 F, ddd, J=49.0, 23.5, 9.2 Hz)

(440) ##STR00127##

(441) (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane was obtained in the same manner as that of Example 1(8).

Example 15

(442) ##STR00128##

(443) ((2R,3R,4S)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=2,4-dichlorobenzoate was obtained in the form of a white solid in the same manner as that of Example 10(1), with the exception that the reaction time was set at 1 hour.

(444) .sup.1H-NMR (CDCl.sub.3) value:

(445) 7.89-7.81 (2H, m), 7.50-7.47 (2H, m), 7.34-7.29 (2H, m), 5.44 (1H, dd, J=22.8, 4.8 Hz), 5.20-5.02 (2H, m), 4.77 (1H, dd, J=12.0, 3.6 Hz), 4.61 (1H, dd, J=12.0, 3.6 Hz), 4.49 (1H, dd, J=8.4, 3.6 Hz), 3.44 (3H, s)

(446) .sup.19F-NMR (CDCl.sub.3) value: 190.42 (1 F, ddd, J=48.9, 22.0, 10.0 Hz)

(447) ##STR00129##

(448) ((2R,3R,4S)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=2,4-dichlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 10(2).

(449) .sup.1H-NMR (CDCl.sub.3) value:

(450) 7.87 (2H, dd, J=15.6, 8.4 Hz), 7.50 (2H, dd, J=11.6, 2.0 Hz), 7.35-7.29 (2H, m), 5.68 (1H, d, J=10.0 Hz), 5.46 (1H, dd, J=21.2, 4.0 Hz), 5.15 (1H, d, J=48.8 Hz), 4.77-4.67 (2H, m), 4.62-4.58 (1H, m), 20.87 (1H, brs)

(451) .sup.19F-NMR (CDCl.sub.3) value: 190.37 (1 F, ddd, J=48.9, 21.4, 10.1 Hz)

(452) ##STR00130##

(453) (2R,3R,4R)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl=2,4-dichlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(454) .sup.1H-NMR (CDCl.sub.3) value:

(455) 7.84 (2H, dd, J=12.0, 8.4 Hz), 7.50-7.48 (2H, m), 7.44 (0.74H, dd, J=7.4, 6.2 Hz), 7.33-7.30 (2H, m), 6.87 (0.26H, dd, J=11.3, 4.4 Hz), 6.03 (ddd, J=46.4, 4.4, 2.0 Hz), 5.82 (dd, J=8.4, 2.0 Hz), 5.63-5.61 (0.37H, m), 5.54-5.45 (1.1H, m), 4.60-4.55 (1H, m), 4.48-4.39 (2H, m), 3.94 (0.8H, s), 3.86 (2.2H, m)

(456) .sup.19F-NMR (CDCl.sub.3) value:

(457) 200.08 (0.74 F, ddd, J=44.8, 25.0, 7.3 Hz), 207.25 (0.26 F, ddd, J=46.3, 28.0, 11.5 Hz)

(458) ##STR00131##

(459) (2R,3R,4R)-1-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=2,4-dichlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(460) .sup.1H-NMR (CDCl.sub.3) value:

(461) 8.07 (1H, s), 7.83-7.75 (2H, m), 7.51-7.42 (3.76H, m), 7.35-7.26 (2H, m), 6.85 (0.24H, dd, J=11.3, 4.4 Hz), 6.00 (0.24H, ddd, J=25.8, 5.8, 2.4 Hz), 5.93-5.91 (0.12H, m) 5.84-5.76 (0.88H, m), 5.49-50.47 (0.38H, m), 5.38-5.29 (1.14H, m), 4.74-4.55 (2H, m), 3.93 (0.72H, s), 3.88 (2.28H, s)

(462) .sup.19F-NMR (CDCl.sub.3) value:

(463) 197.30 (0.88 F, ddd, J=45.6, 21.6, 7.0 Hz), 204.36 (0.12 F, ddd, J=46.7, 25.7, 11.4 Hz)

(464) (5)

(465) ##STR00132##

(466) (2S,3S,4R)-2-bromo-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)pentyl=2,4-dichlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(467) .sup.1H-NMR (CDCl.sub.3) value:

(468) 7.88 (2H, dd, J=16.0, 9.6 Hz), 7.51-7.45 (2.77H, m), 7.35-7.30 (2H, m), 6.88 (0.23H, dd, J=11.4, 4.6 Hz), 6.11-6.09 (0.12H, m), 5.99-5.94 (0.23H, m), 5.90-5.88 (0.12H, m), 5.82 (0.77H, ddd, 16.0, 5.8, 3.4 Hz), 5.50 (0.77H, ddd, 46.4, 6.2, 6.2 Hz), 4.79-4.70 (1H, m), 4.60-4.54 (2H, m), 3.93 (0.7H, s), 3.90 (2.3H, s)

(469) .sup.19F-NMR (CDCl.sub.3) value:

(470) 193.48 (0.77 F, ddd, J=46.7, 15.9, 6.1 Hz), 202.59 (0.23 F, ddd, J=47.1, 24.4, 11.2 Hz)

(471) ##STR00133##

(472) A mixture of (2S,3S,4S)-2-bromo-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-oxopentyl=2,4-dichlorobenzoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 70 C. for 6 hours.

(473) .sup.1H-NMR (CDCl.sub.3) value:

(474) 9.84 (1H, d, J=6.0 Hz), 7.90-7.82 (2H, m), 7.50-7.45 (2H, m), 7.34-7.27 (2H, m), 5.89-4.05 (5H, m)

(475) .sup.19F-NMR (CDCl.sub.3) value: 209.92 (1 F, ddd, J=46.5, 20.6, 5.7 Hz)

(476) ##STR00134##

(477) ((2R,3S,4S)-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=2,4-dichlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(5), with the exception that the reaction was carried out for 4 hours.

(478) .sup.1H-NMR (CDCl.sub.3) value:

(479) 7.93-7.78 (2H, m), 7.50-7.44 (2H, m), 7.35-7.30 (2H, m), 6.01-5.95 (0.59H, m), 5.84 (0.41H, dt, 11.6, 4.3 Hz), 5.63 (0.41H, dd, J=6.0, 6.0 Hz), 5.49 (0.59H, dd, J=7.8, 3.8 Hz), 5.37-5.36 (0.21H, m), 5.26-5.23 (0.50H, m), 5.13-5.10 (0.29H, m), 4.71-4.58 (1.2H, m), 4.53-4.43 (0.8H, m), 4.20-4.16 (0.41H, m), 3.74 (0.59H, dd, J=12.2, 6.7 Hz), 2.84 (0.59H, dd, J=5.5, 1.2 Hz), 2.56 (0.41H, d, J=9.0 Hz)

(480) .sup.19F-NMR (CDCl.sub.3) value:

(481) 183.85 (0.41 F, dd, J=47.1, 11.1 Hz), 192.53 (0.59 F, ddd, J=51.2, 11.3, 4.9 Hz)

(482) ##STR00135##

(483) ((2R,3S,4S,5R)-5-acetyloxy-3-((2,4-dichlorophenyl)carbonyloxy)-4-fluorothiolan-2-yl)methyl=2,4-dichlorobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 10(8).

(484) .sup.1H-NMR (CDCl.sub.3) value:

(485) 7.79 (2H, d, J=8.4 Hz), 7.46 (2H, dd, J=22.8, 2.0 Hz), 7.27 (2H, ddd, J=30.4, 8.4, 2.0 Hz), 6.16 (1H, d, J=4.4 Hz), 6.03-5.98 (1H, m), 5.29 (1H, ddd, J=50.6, 8.8, 4.6 Hz), 4.40 (1H, ddd, J=7.06, 11.4, 6.4 Hz), 3.73 (1H, dd, J=13.6, 6.4 Hz), 2.15 (3H, s)

(486) .sup.19F-NMR (CDCl.sub.3) value: 192.62 (1 F, dd, J=50.6, 11.5 Hz)

Example 16

(487) ##STR00136##

(488) 2.2 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol was dissolved in 26.4 mL of pyridine, and 6.1 g of 4-nitrobenzoyl chloride was then added to the obtained solution under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate was added to the reaction mixture. The thus obtained mixture was washed with water twice, and then with a saturated sodium chloride aqueous solution once, and it was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. Ethyl acetate was added to the obtained residue, and a solid was collected by filtration, so as to obtain 4.0 g of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((4-nitrophenyl)carbonyloxy)oxolan-2-yl)methyl=4-nitrobenzoate in the form of a white solid.

(489) .sup.1H-NMR (DMSO-d.sub.6) value:

(490) 8.38 (4H, d, J=8.6 Hz), 8.25 (2H, d, J=8.9 Hz), 8.22 (2H, d, J=8.9 Hz), 5.72 (1H, td, J=11.5, 5.8 Hz), 50.52 (1H, ddd, J=51.6, 6.5, 4.4 Hz), 5.16 (1H, d, J=4.3 Hz), 4.70 (1H, d, J=7.9 Hz), 4.54-4.50 (2H, m), 3.35 (3H, s)

(491) ##STR00137##

(492) ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((4-nitrophenyl)carbonyloxy)oxolan-2-yl)methyl=4-nitrobenzoate was obtained in the form of a white solid in the same manner as that of Example 10(2).

(493) .sup.1H-NMR (DMSO-d.sub.6) value:

(494) 8.39 (2H, d, J=5.9 Hz), 8.36 (2H, d, J=5.9 Hz), 8.21 (2H, d, J=5.9 Hz), 8.19 (2H, d, J=5.9 Hz), 5.53 (1H, d, J=10.9 Hz), 5.43 (1H, dd, J=23.1, 5.0 Hz), 5.18 (1H, d, J=49.2 Hz), 4.67 (3H, tdd, J=19.2, 9.9, 4.0 Hz), 3.31 (1H, s)

(495) ##STR00138##

(496) (2R,3R,4R)-3-((4-nitrophenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl=4-nitrobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(497) .sup.1H-NMR (DMSO-d.sub.6) value:

(498) 8.33 (2H, d, J=2.3 Hz), 8.30 (2H, d, J=2.6 Hz), 8.17 (2H, d, J=4.6 Hz), 8.14 (2H, t, J=3.8 Hz), 7.63 (1 H, dd, J=8.3, 5.9 Hz), 6.20 (1H, dd, J=22.0, 7.1 Hz), 6.10 (1H, d, J=6.6 Hz), 5.46 (1H, dd, J=24.9, 8.4 Hz), 4.40 (2H, dt, J=14.0, 4.8 Hz), 3.86 (1H, s), 3.71 (3H, s)

(499) ##STR00139##

(500) (2R,3R,4R)-3-((4-nitrophenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentyl=4-nitrobenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(501) .sup.1H-NMR (DMSO-d.sub.6) value:

(502) 8.36 (2H, d, J=5.0 Hz), 8.33 (2H, d, J=5.0 Hz), 8.23 (0.75H, s), 8.22 (0.25H, s), 8.18 (0.75H, s), 8.15 (0.25H, s), 8.11-8.06 (4H, m), 7.71 (0.25H, dd, J=8.1, 5.8 Hz), 7.51 (0.75H, dd, J=8.9, 5.6 Hz), 7.00 (0.25H, dd, J=11.6, 4.6 Hz), 6.14 (0.25H, dd, J=45.2, 4.3 Hz), 5.75-5.67 (1.50H, m), 4.85 (1H, dd, J=12.4, 3.1 Hz), 4.68 (2H, dt, J=26.4, 9.1 Hz), 3.79 (0.75H, s), 3.75 (2.25H, s)

(503) ##STR00140##

(504) (2S,3S,4R)-3-((4-nitrophenyl)carbonyloxy)-2-bromo-4-fluoro-5-(methoxyimino) pentyl=4-nitrobenzoate was obtained in the form of a white solid in the same manner as that of Example 7(2).

(505) .sup.1H-NMR (DMSO-d.sub.6) value:

(506) 8.39 (2H, d, J=8.9 Hz), 8.34 (2H, d, J=8.9 Hz), 8.20 (2H, d, J=8.9 Hz), 8.13 (2H, d, J=8.9 Hz), 7.78 (0.2H, t, J=6.4 Hz), 7.64 (0.8H, dd, J=7.6, 5.0 Hz), 5.92-5.88 (1H, m), 5.35 (1H, dt, J=46.0, 7.3 Hz), 5.15 (1H, dt, J=11.3, 4.0 Hz), 4.72 (2H, dt, J=20.0, 8.8 Hz), 3.84 (0.6H, s), 3.63 (2.4H, s)

(507) ##STR00141##

(508) A mixture of (2S,3S,4S)-3-((4-nitrophenyl)carbonyloxy)-2-bromo-4-fluoro-5-oxopentyl=4-nitrobenzoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4).

(509) .sup.1H-NMR (DMSO-d.sub.6) value:

(510) 9.67 (1H, d, J=8.3 Hz), 8.38 (2H, d, J=6.9 Hz), 8.34 (2H, d, J=8.9 Hz), 8.21 (2H, d, J=8.9 Hz), 8.12 (2H, d, J=8.9 Hz), 6.55 (1H, dd, J=21.3, 6.4 Hz), 5.61 (1H, dd, J=45.4, 4.8 Hz), 4.79 (2H, ddd, J=42.4, 21.1, 8.8 Hz), 4.59-4.40 (1H, m)

Example 17

(511) ##STR00142##

(512) 4.0 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol was dissolved in 40 mL of pyridine, and 10.1 g of 2-naphthoyl chloride was then added to the obtained solution under cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. Thereafter, water and ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was washed with 1 mol/L hydrochloric acid three times, and then with a saturated sodium chloride aqueous solution once, and it was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate/hexane=1/9 to 5/5), so as to obtain 5.7 g of ((2R,3R,4S)-4-fluoro-5-methoxy-3-((2-naphthoyloxy)oxolan-2-yl)methyl=2-naphthoate in the form of a white solid.

(513) .sup.1H-NMR (DMSO-d.sub.6) value:

(514) 8.67 (1H, s), 8.63 (1H, s), 8.14 (1H, d, J=7.9 Hz), 8.07-8.00 (6H, m), 7.69-7.59 (5H, m), 5.55 (1H, dd, J=23.9, 4.8 Hz), 5.38 (1H, d, J=18.2 Hz), 5.28 (1H, d, J=20.5 Hz), 4.76-4.68 (3H, m), 3.42 (3H, s)

(515) ##STR00143##

(516) ((2R,3R,4S)-4-fluoro-5-hydroxy-3-((2-naphthoyl)oxy)oxolan-2-yl)methyl=2-naphthoate was obtained in the form of a colorless oily product in the same manner as that of Example 10(2).

(517) .sup.1H-NMR (CDCl.sub.3) value:

(518) 8.63 (2H, d, J=7.3 Hz), 8.10-8.03 (2H, m), 7.90 (6H, m), 7.56 (4H, m), 5.76 (1H, d, J=10.9 Hz), 5.61 (1H, dd, J=22.1, 4.3 Hz), 5.27 (1H, d, J=49.2 Hz), 4.83 (2H, dt, J=11.7, 4.0 Hz), 4.72 (1H, dd, J=12.9, 6.3 Hz), 3.09 (1H, s)

(519) ##STR00144##

(520) (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-(2-naphthoyloxy)pentyl=2-naphthoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(521) .sup.1H-NMR (DMSO-d.sub.6) value:

(522) 8.33 (2H, d, J=2.3 Hz), 8.30 (2H, d, J=2.6 Hz), 8.17 (2H, d, J=4.6 Hz), 8.14 (2H, t, J=3.8 Hz), 7.63 (1H, dd, J=8.3, 5.9 Hz), 6.20 (1H, dd, J=22.0, 7.1 Hz), 6.10 (1H, d, J=6.6 Hz), 5.46 (1H, dd, J=24.9, 8.4 Hz), 4.40 (2H, dt, J=14.0, 4.8 Hz), 3.86 (1H, s), 3.71 (3H, s)

(523) ##STR00145##

(524) (2R,3R,4R)-4-fluoro-5-(methoxyimino)-3-(2-naphthoyloxy)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentyl=2-naphthoate was obtained in the form of a white solid in the same manner as that of Example 7(1).

(525) .sup.1H-NMR (CDCl.sub.3) value:

(526) 8.61 (1H, s), 8.49 (1H, s), 8.09 (0.3H, s), 8.08 (0.7H, s), 8.03-7.83 (8H, m), 7.65-7.53 (4H, m), 7.47 (0.7H, t, J=6.8 Hz), 7.32 (0.3H, s), 6.89 (0.3H, dd, J=11.1, 4.5 Hz), 6.11 (0.7H, ddd, J=26.3, 5.7, 2.7 Hz), 5.92 (1H, dq, J=22.9, 3.0 Hz), 5.57 (1H, dq, J=16.0, 3.1 Hz), 5.48 (1H, dq, J=20.2, 3.2 Hz), 4.84 (1H, ddd, J=12.6, 7.9, 3.0 Hz), 4.67 (1H, dd, J=12.9, 6.3 Hz), 3.94 (0.9H, s), 3.86 (2.1H, s)

(527) ##STR00146##

(528) (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-(2-naphthoyloxy)pentyl=2-naphthoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(529) .sup.1H-NMR (CDCl.sub.3) value:

(530) 8.67 (0.2H, s), 8.61 (0.8H, s), 8.57 (0.2H, s), 8.11 (0.8H, t, J=4.3 Hz), 8.04 (1H, dd, J=8.6, 1.7 Hz), 7.92-7.87 (7H, m), 7.61-7.54 (5H, m), 6.93 (0.2H, dd, J=11.2, 4.6 Hz), 6.04 (0.8H, dq, J=21.1, 3.1 Hz), 5.92 (1H, dq, J=16.8, 3.0 Hz), 5.61 (1H, dt, J=46.7, 6.2 Hz), 4.88-4.82 (1H, m), 4.78-4.66 (2H, m), 3.89 (2.4H, s), 3.86 (0.6H, s)

(531) ##STR00147##

(532) A mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-(2-naphthoyloxy)-5-oxopentyl=2-naphthoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4).

(533) .sup.1H-NMR (CDCl.sub.3) value:

(534) 9.88 (1H, d, J=6.3 Hz), 8.60 (2H, d, J=14.5 Hz), 8.02 (2H, td, J=8.8, 1.8 Hz), 7.92-7.84 (5H, m), 7.59-7.51 (5H, m), 5.95 (1H, dt, J=21.4, 3.8 Hz), 5.56 (1H, d, J=4.0 Hz), 5.41 (1H, d, J=4.0 Hz), 4.81-4.69 (2H, m)

(535) ##STR00148##

(536) ((2R,3S,4S,5R)-4-fluoro-5-hydroxy-3-((2-naphthoyl)oxy)thiolan-2-yl)methyl=2-naphthoate was obtained in the form of a white solid in the same manner as that of Example 1(5).

(537) .sup.1H-NMR (CDCl.sub.3) value:

(538) 8.58 (1H, d, J=20.8 Hz), 8.49 (1H, d, J=13.5 Hz), 8.05 (0.5H, dd, J=8.6, 1.7 Hz), 7.97 (1H, dt, J=8.3, 2.1 Hz), 7.90-7.82 (4H, m), 7.71 (2H, td, J=13.8, 5.9 Hz), 7.60-7.46 (4H, m), 7.38 (0.5H, t, J=7.6 Hz), 6.23-6.14 (0.5H, m), 5.96-5.91 (0.5H, m), 5.67 (0.5H, d, J=10.6 Hz), 5.42 (0.5H, dt, J=32.3, 3.1 Hz), 5.32 (0.5H, t, J=6.4 Hz), 5.19 (0.5H, dd, J=7.3, 4.0 Hz), 4.75-4.67 (1H, m), 4.62 (1H, dd, J=14.5, 6.3 Hz), 4.34 (0.5H, dd, J=7.8, 4.1 Hz), 3.88 (0.5H, dd, J=13.4, 6.1 Hz), 3.05 (0.5H, s), 2.67 (0.5H, s)

(539) ##STR00149##

(540) ((2R,3S,4S,5R)-5-acetyloxy-4-fluoro-3-((2-naphthoyl)oxy)thiolan-2-yl)methyl=2-naphthoate was obtained in the form of a white solid in the same manner as that of Example 10(8).

(541) .sup.1H-NMR (CDCl.sub.3) value:

(542) 8.60 (0.35H, s), 8.58 (0.35H, s), 8.53 (0.65H, s), 8.42 (0.65H, s), 8.03 (0.70H, d, J=8.6 Hz), 7.94 (1.30H, ddd, J=13.2, 8.6, 1.7 Hz), 7.87-7.47 (9.35H, m), 7.35 (0.65H, t, J=6.9 Hz), 6.19-6.08 (2H, m), 5.56-5.28 (1H, m), 4.75 (0.70H, dd, J=11.4, 7.1 Hz), 4.60 (1.30H, t, J=8.1 Hz), 4.24-4.21 (0.35H, m), 3.88 (0.65H, q, J=6.8 Hz), 2.16 (1.05H, s), 2.16 (1.95H, s)

(543) ##STR00150##

(544) ((2R,3S,4S,5R)-5-bromo-4-fluoro-3-((2-naphthoyl)oxy)thiolan-2-yl)methyl=2-naphthoate was obtained in the form of a white solid in the same manner as that of Example 1(7).

(545) .sup.1H-NMR (CDCl.sub.3) value:

(546) 8.65 (2H, d, J=27.6 Hz), 8.11-7.80 (8H, m), 7.64-7.47 (4H, m), 5.96 (0.5H, brs), 5.91 (0.5H, brs), 5.82 (0.5H, brs), 5.78 (0.5H, brs), 5.74 (0.5H, brs), 5.66 (0.5H, brs), 4.76-4.62 (2H, m), 4.48-4.42 (1 H, m)

(547) .sup.19F-NMR (CDCl.sub.3) value: 163.66 (1 F, dd, J=48.0, 14.5 Hz)

(548) ##STR00151##

(549) ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-((2-naphthoyl)oxy)thiolan-2-yl)methyl=2-naphthoate was obtained in the form of a white solid in the same manner as that of Example 22(2).

(550) m/z (ESI-positive): 664.6[M+H].sup.+

(551) .sup.19F-NMR (CDCl.sub.3) value: 195.71 (1 F, ddd, J=49.6, 22.7, 9.0 Hz)

(552) ##STR00152##

(553) (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane was obtained in the same manner as that of Example 1(8).

Example 18

(554) ##STR00153##

(555) 2.5 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol was dissolved in 25 mL of pyridine, and 7.2 g of 4-phenylbenzoyl chloride was then added to the obtained solution under cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. Thereafter, ethyl acetate was added to the reaction mixture. The thus obtained mixture was washed with water twice, and then with a saturated sodium chloride aqueous solution once, and it was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate/hexane=1/9 to 6/4), so as to obtain 3.3 g of ((2R,3R,4S)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=(1,1-biphenyl)-4-carboxylate in the form of a white solid.

(556) .sup.1H-NMR (DMSO-d.sub.6) value:

(557) 8.05 (4H, dd, J=8.4, 1.8 Hz), 7.86 (2H, d, J=8.6 Hz), 7.82 (2H, d, J=8.6 Hz), 7.76-7.72 (4H, m), 7.50-7.45 (6H, m), 5.48 (1H, dd, J=23.8, 5.0 Hz), 5.34 (1H, d, J=9.6 Hz), 5.24 (1H, d, J=28.7 Hz), 4.71-40.59 (3H, m), 3.40 (3H, s)

(558) ##STR00154##

(559) ((2R,3R,4S)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a white solid in the same manner as that of Example 10(2).

(560) .sup.1H-NMR (DMSO-d.sub.6) value:

(561) 8.06 (4H, t, J=8.6 Hz), 7.86 (2H, d, J=8.6 Hz), 7.81 (2H, d, J=8.6 Hz), 7.77-7.72 (4H, m), 7.52-7.45 (6H, m), 7.07 (1H, dd, J=4.0, 2.6 Hz), 5.54 (1H, dd, J=10.6, 4.3 Hz), 5.44 (1H, dd, J=23.4, 4.6 Hz), 5.15 (1H, d, J=49.9 Hz), 4.68-4.58 (3H, m)

(562) ##STR00155##

(563) (2R,3R,4R)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-4-fluoro-2-hydroxy-5-(methoxy imino)pentyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a white solid in the same manner as that of Example 1(1).

(564) .sup.1H-NMR (DMSO-d.sub.6) value:

(565) 8.09-7.98 (4H, m), 7.88-7.68 (8H, m), 7.50-7.44 (6H, m), 7.12 (0.3H, dd, J=10.6, 4.6 Hz), 6.06 (1.7H, ddd, J=32.5, 14.2, 5.6 Hz), 5.54 (2H, tt, J=39.1, 7.7 Hz), 5.15 (0.3H, d, J=48.9 Hz), 4.69-4.57 (0.7H, m), 4.41-4.26 (2H, m), 3.88 (0.9H, s), 3.75 (2.1H, s)

(566) ##STR00156##

(567) (2R,3R,4R)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(568) .sup.1H-NMR (DMSO-d.sub.6) value:

(569) 8.14 (1H, s), 8.05 (2H, dd, J=19.7, 11.1 Hz), 7.97 (1H, s), 7.81 (8H, m), 7.50 (8H, m), 7.20 (0.5H, dd, J=11.2, 4.6 Hz), 6.09 (0.5H, dq, J=48.2, 3.1 Hz), 5.86 (1H, dt, J=23.1, 3.8 Hz), 5.68 (2H, tt, J=29.9, 9.4 Hz), 4.70 (2H, dt, J=27.4, 9.7 Hz), 3.79 (3H, s)

(570) ##STR00157##

(571) (2S,3S,4R)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-2-bromo-4-fluoro-5-(methoxyimino)pentyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(572) .sup.1H-NMR (DMSO-d.sub.6) value:

(573) 8.10-8.01 (2H, m), 7.95 (1H, d, J=8.6 Hz), 7.88-7.83 (3H, m), 7.80 (1H, d, J=6.6 Hz), 7.68 (5H, m), 7.47 (6H, m), 6.01-5.93 (1H, m), 5.46 (1H, dt, J=47.4, 6.9 Hz), 5.05 (1H, t, J=45.2 Hz), 4.71 (3H, ddd, J=25.6, 14.5, 7.8 Hz), 3.86 (3H, s)

(574) ##STR00158##

(575) A mixture of (2S,3S,4S)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-2-bromo-4-fluoro-5-oxopentyl=(1,1-biphenyl)-4-carboxylate and a water adduct thereof was obtained in the form of a white solid in the same manner as that of Example 1(4).

(576) .sup.1H-NMR (DMSO-d.sub.6) value:

(577) 9.69 (1H, d, J=9.9 Hz), 8.06 (2H, m), 8.00 (2H, d, J=7.3 Hz), 7.86 (2H, dd, J=8.6, 2.6 Hz), 7.77 (2H, dd, J=8.4, 4.1 Hz), 7.70 (3H, d, J=12.6 Hz), 7.53-7.43 (7H, m), 6.55 (1H, dd, J=20.1, 5.9 Hz), 6.06 (1H, ddd, J=22.1, 5.0, 3.3 Hz), 5.82 (1H, dq, J=14.9, 4.0 Hz), 5.01-4.95 (1H, m), 4.77-4.67 (1H, m)

(578) ##STR00159##

(579) ((2R,3S,4S)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a white solid in the same manner as that of Example 1(5).

(580) .sup.1H-NMR (DMSO-d.sub.6) value:

(581) 8.04 (2H, dd, J=8.6, 2.3 Hz), 7.87 (2H, t, J=8.4 Hz), 7.79 (2H, dd, J=8.6, 3.0 Hz), 7.71-7.67 (2H, m), 7.63-7.39 (10H, m), 6.84 (1H, dd, J=6.1, 1.8 Hz), 6.09 (0.5H, dt, J=14.2, 5.9 Hz), 5.76 (0.5H, dd, J=14.5, 6.9 Hz), 5.66 (0.5H, dt, J=14.4, 5.4 Hz), 5.39-5.30 (1H, m), 5.18 (0.5H, dt, J=17.2, 5.1 Hz), 4.48 (2H, ddd, J=29.3, 15.8, 9.3 Hz), 4.18 (0.5H, dd, J=12.9, 7.3 Hz), 3.83 (0.5H, dd, J=13.2, 7.3 Hz)

(582) ##STR00160##

(583) ((2R,3S,4S)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-5-acetyloxy-4-fluorothiolan-2-yl)methyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a white solid in the same manner as that of Example 10(8).

(584) .sup.1H-NMR (CDCl.sub.3) value:

(585) 8.11 (0.5H, d, J=8.6 Hz), 8.07 (2H, d, J=8.6 Hz), 7.98 (1.5H, d, J=8.6 Hz), 7.67-7.38 (14H, m), 6.25 (0.25H, t, J=6.9 Hz), 6.14 (1.5H, tt, J=10.7, 3.7 Hz), 5.89 (0.25H, td, J=8.5, 4.2 Hz), 5.42 (0.25H, ddd, J=48.0, 4.0, 2.6 Hz), 5.33 (0.75H, ddd, J=50.7, 9.1, 4.5 Hz), 4.69 (1H, dd, J=11.4, 6.8 Hz), 4.54 (1H, dd, J=10.9, 6.6 Hz), 4.15 (0.25H, ddd, J=13.2, 6.8, 2.1 Hz), 3.79 (0.75H, q, J=6.8 Hz), 2.17 (2.25H, d, J=2.3 Hz), 2.14 (0.75H, s)

(586) ##STR00161##

(587) ((2R,3S,4S,5R)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-5-bromo-4-fluorothiolan-2-yl)methyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a colorless oily product in the same manner as that of Example 1(7).

(588) .sup.1H-NMR (CDCl.sub.3) value:

(589) 8.14 (2H, dd, J=21.0, 8.4 Hz), 7.69-7.37 (16H, m), 5.89-5.70 (0.5H, m), 5.84-5.82 (0.5H, m), 5.78-5.77 (0.5H, m), 5.75 (0.5H, brs), 5.71 (0.5H, brs), 5.62-5.61 (0.5H, m), 4.70-4.56 (2H, m), 4.40-4.34 (1H, m)

(590) .sup.19F-NMR (282.37 MHz, CDCl.sub.3) value: 163.62 (1 F, dd, J=48.9, 14.3 Hz)

(591) ##STR00162##

(592) Using a methylene chloride solution of ((2R,3S,4S,5R)-3-(((1,1-biphenyl)-4-carbonyl)oxy)-5-bromo-4-fluorothiolan-2-yl)methyl=(1,1-biphenyl)-4-carboxylate, ((2R,3S,4S,5R)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-3-(((1,1-biphenyl)-4-carbonyl)oxy)thiolan-2-yl)methyl=(1,1-biphenyl)-4-carboxylate was obtained in the form of a white solid in the same manner as that of Example 22(2).

(593) m/z (ESI-positive): 612.6[M+H].sup.+

(594) .sup.19F-NMR (CDCl.sub.3) value: 195.70 (1 F, ddd, J=49.6, 22.7, 9.0 Hz)

(595) ##STR00163##

(596) (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane was obtained in the same manner as that of Example 1(8).

Example 19

(597) ##STR00164##

(598) ((2R,3R,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=trimethylacetate was obtained in the form of a white solid in the same manner as that of Example 10(1), with the exception that the reaction time was set at 2 hours.

(599) .sup.1H-NMR (CDCl.sub.3) value:

(600) 5.11-5.04 (2H, m), 4.80 (1H, d, J=47.6 Hz), 4.42 (1H, dd, J=12.0, 3.6 Hz), 4.27 (1H, dd, J=12.0, 4.4 Hz), 4.17 (1H, m), 3.39 (3H, s), 1.21 (18H, m)

(601) .sup.19F-NMR (CDCl.sub.3) value: 190.55 (1 F, ddd, J=49.5, 23.0, 10.5 Hz)

(602) ##STR00165##

(603) ((2R,3R,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=trimethylacetate was obtained in the form of a colorless oily product in the same manner as that of Example 10(2).

(604) .sup.1H-NMR (CDCl.sub.3) value:

(605) 5.57 (1H, dd, J=10.4, 4.0 Hz), 5.11 (1H, dd, J=22.0, 3.6 Hz), 4.92 (1H, d, J=49.6 Hz), 4.42-4.35 (2H, m), 4.27-4.23 (1H, m), 2.96 (1H, dd, J=11.8, 3.2 Hz), 1.21 (9H, s), 1.20 (9H, s)

(606) .sup.19F-NMR (CDCl.sub.3) value: 190.09 (1 F, ddd, J=49.8, 22.6, 11.2 Hz)

(607) ##STR00166##

(608) (2R,3R,4R)-3-(2,2-dimethylpropionyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl=trimethylacetate was obtained in the form of a white solid in the same manner as that of Example 1(1).

(609) .sup.1H-NMR (CDCl.sub.3) value:

(610) 7.29 (0.73H, dd, J=8.1, 6.4 Hz), 6.75 (0.27H, dd, J=11.3, 4.6 Hz), 5.91 (0.27H, ddd, J=46.5, 4.6, 1.8 Hz), 5.43 (0.73H, ddd, J=45.3, 6.4, 2.3 Hz), 5.38 (0.27H, ddd, J=28.6, 8.7, 1.8 Hz), 4.74 (0.73H, ddd, J=25.7, 8.8, 2.4 Hz), 4.27-3.91 (3H, m), 3.91 (0.80H, s), 3.88 (2.20H, s), 2.78 (0.73H, d, J=6.4 Hz), 2.73 (0.27H, d, J=6.4 Hz), 1.23 (9H, s), 1.22 (9H, s)

(611) .sup.19F-NMR (CDCl.sub.3) value:

(612) 201.5 (0.7 F, ddd, J=43.5, 23.8, 6.2 Hz), 208.1 (0.3 F, ddd, J=46.5, 28.7, 11.6 Hz)

(613) ##STR00167##

(614) (2R,3R,4R)-5-(2,2-dimethylpropionyloxy)-2-fluoro-1-(methoxyimino)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=trimethylacetate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(615) .sup.1H-NMR (CDCl.sub.3) value:

(616) 8.16 (1H, s), 7.69 (1H, s), 7.22 (0.67H, dd, J=7.8, 6.4 Hz), 6.64 (0.33H, dd, J=11.3, 4.4 Hz), 5.73-5.67 (0.33H, m), 5.63-5.60 (0.33H, m), 5.36 (0.67H, ddd, J=51.9, 6.4, 3.6), 5.38-5.35 (0.34H, m), 5.19-5.53 (1H, m), 5.13-5.09 (0.33H, m), 4.44-4.40 (1H, m), 4.21-4.16 (1H, m), 3.90 (2.01H, s), 3.89 (0.99H, s), 1.19 (9H, s), 1.17 (9H, s)

(617) .sup.19F-NMR (CDCl.sub.3) value:

(618) 199.40 (0.71 F, ddd, J=48.0, 26.2, 8.0 Hz), 206.33 (0.29 F, ddd, J=49.9, 30.1, 12.4 Hz)

(619) ##STR00168##

(620) (2S,3S,4R)-2-bromo-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-(methoxyimino)pentyl=trimethylacetate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(621) .sup.1H-NMR (CDCl.sub.3) value:

(622) 7.38 (0.83H, dd, J=6.5, 6.5 Hz), 6.75 (0.17H, dd, J=11.2, 4.7), 5.85 (0.17H, ddd, J=47.4, 4.7, 3.0), 50.64 (0.17H, m), 5.37-5.47 (2.25H, m), 5.23 (0.41H, m), 4.57-4.18 (2H, m), 3.91 (2.49H, s), 3.89 (0.51H, s), 1.27 (9H, s), 1.23 (9H, s)

(623) .sup.19F-NMR (CDCl.sub.3) value:

(624) 194.50 (0.84 F, ddd, J=46.6, 16.6, 6.6 Hz), 203.81 (0.16 F, ddd, J=47.3, 25.7, 11.2 Hz)

(625) ##STR00169##

(626) A mixture of (2S,3S,4S)-2-bromo-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-oxopentyl=trimethylacetate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 60 C. for 8 hours.

(627) .sup.1H-NMR (CDCl.sub.3) value: 9.72 (1H, d, J=6.6 Hz), 5.58-4.56 (5H, m), 1.27-1.23 (18H, m)

(628) .sup.19F-NMR (CDCl.sub.3) value: 210.77 (1 F, ddd, J=46.8, 20.9, 6.5 Hz)

(629) ##STR00170##

(630) ((2R,3S,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=trimethylacetate was obtained in the form of a colorless oily product in the same manner as that of Example 1(5).

(631) .sup.1H-NMR (CDCl.sub.3) value:

(632) 5.62-5.44 (1.5H, m), 5.41 (0.5H, m), 5.16 (0.25H, m), 5.06-5.03 (0.5H, m), 4.94-4.90 (0.25H, m), 4.38-4.28 (1H, m), 4.16-4.10 (1H, m), 3.85 (0.5H, dd, J=7.4, 7.4), 3.42 (0.5H, dd, J=13.1, 5.7), 2.97 (0.5H, brs), 2.46 (0.5H, brs), 1.23-1.21 (18H, m)

(633) .sup.19F-NMR (CDCl.sub.3) value:

(634) 184.20 (0.54 F, ddd, J=47.1, 11.1, 11.1 Hz), 193.48 (0.46 F, ddd, J=51.8, 10.9, 5.4 Hz)

(635) ##STR00171##

(636) 14 mg of acetic anhydride was added to a solution of 40 mg of ((2R,3S,4S)-3-(2,2-dimethylpropionyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=trimethylacetate, 0.3 mg of dimethylaminopyridine and 19 mg of 2-picoline in 1.0 mL of tetrahydrofuran at a temperature of 10 C. or lower, and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with a saturated sodium chloride aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution. After that, the organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by column chromatography, so as to obtain 44 mg of ((2R,3S,4S)-5-acetyloxy-3-(2,2-dimethylpropionyloxy)-4-fluorothiolan-2-yl)methyl=trimethylacetate in the form of a colorless oily product.

(637) .sup.1H-NMR (CDCl.sub.3) value:

(638) 6.14 (0.41H, dd, J=13.8, 2.1 Hz), 6.10 (0.59H, d, J=4.5), 5.64 (0.59H, ddd, J=16.5, 9.0, 7.7), 5.43 (0.41H, ddd, J=12.2, 3.4, 3.4), 5.18 (0.41H, ddd, J=47.4, 3.4, 2.1), 5.10 (0.59H, ddd, J=50.8, 9.0, 4.5), 4.36 (0.59H, dd, J=11.5, 4.7), 4.23 (0.41H, dd, J=11.2, 7.4), 4.12-4.07 (1H, m), 3.78 (0.41H, m), 3.42 (0.59H, ddd, J=7.7, 4.7, 4.7), 2.16 (1.77H, s), 2.10 (1.23H, s), 1.25 (5.31H, s), 1.23 (3.69H, s), 1.21 (5.31H, s), 1.20 (3.96H, s)

(639) .sup.19F-NMR (CDCl.sub.3) value:

(640) 187.09 (0.44 F, ddd, J=50.5, 13.9, 13.9 Hz), 192.57 (0.56 F, dd, J=50.9, 11.8 Hz)

Example 20

(641) ##STR00172##

(642) ((2R,3R,4S)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=3,5-dimethylbenzoate was obtained in the form of a white solid in the same manner as that of Example 10(1), with the exception that the reaction time was set at 1 hour.

(643) .sup.1H-NMR (CDCl.sub.3) value:

(644) 7.67-7.64 (4H, m), 7.22-7.17 (2H, m), 5.46 (1H, dd, J=23.8, 4.8 Hz), 5.22-5.03 (2H, m), 4.70 (1H, dd, J=12.0, 4.0 Hz), 4.62 (1H, dd, J=12.0, 4.8 Hz), 4.52-4.49 (1H, m), 3.46 (3H, s), 2.36 (6H, s), 2.32 (6H, s)

(645) .sup.19F-NMR (CDCl.sub.3) value: 190.21 (1 F, ddd, J=49.1, 23.1, 10.7 Hz)

(646) ##STR00173##

(647) ((2R,3R,4S)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=3,5-dimethylbenzoate was obtained in the form of a white solid in the same manner as that of Example 10(2).

(648) .sup.1H-NMR (CDCl.sub.3) value:

(649) 7.68 (2H, s), 7.65 (2H, s), 7.22 (1H, s), 7.17 (1H, s), 5.69 (1H, dd, J=10.4, 3.8 Hz), 5.46 (1H, dd, J=210.8, 3.8 Hz), 5.16 (1H, d, J=49.2 Hz), 4.71-4.69 (3H, m), 2.36 (6H, s), 2.32 (6H, s)

(650) .sup.19F-NMR (CDCl.sub.3) value: 190.45 (1 F, dddd, J=49.3, 22.3, 10.9, 2.4 Hz)

(651) ##STR00174##

(652) (2R,3R,4R)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-2-hydroxy-5-(methoxyimino)pentyl=3,5-dimethylbenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(653) .sup.1H-NMR (CDCl.sub.3) value:

(654) 7.67 (2H, s), 7.62 (2H, s), 7.40 (0.80H, dd, J=6.8, 6.8 Hz), 7.23 (1H, s), 7.20 (1H, s), 6.84 (0.20H, dd, J=11.1, 4.6 Hz), 6.06 (0.20H, ddd, J=46.4, 4.6, 2.0 Hz), 5.70 (0.20H, ddd, J=28.5, 8.2, 1.9 Hz), 5.57 (0.80H, ddd, J=45.2, 6.8, 2.4 Hz), 5.43 (0.80H, ddd, J=26.0, 8.4, 2.4 Hz), 4.60-4.51 (1H, m), 4.48-4.34 (2H, m), 3.92 (0.60H, s), 3.84 (2.40H, s), 3.03 (0.80H, d, J=6.2 Hz), 2.98 (0.20H, d, J=13.7 Hz), 2.36 (6H, s), 2.35 (6H, s)

(655) .sup.19F-NMR (CDCl.sub.3) value:

(656) 200.07 (0.86 F, ddd, J=45.3, 26.0, 7.0 Hz), 207.47 (0.14 F, ddd, J=46.3, 28.4, 4.6 Hz)

(657) ##STR00175##

(658) (2R,3R,4R)-1-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=3,5-dimethylbenzoate was obtained in the form of a white solid in the same manner as that of Example 7(1).

(659) .sup.1H-NMR (CDCl.sub.3) value:

(660) 8.05 (1H, s), 7.65 (2H, s), 7.51 (2H, s), 7.41 (1H, dd, J=6.6, 6.6 Hz), 7.37 (1H, s), 7.23 (1H, s), 7.20 (1H, s), 5.78 (1H, ddd, J=23.2, 6.1, 3.0 Hz), 5.52-5.50 (0.50H, m), 5.44-5.38 (1.50H, m), 4.67 (1H, dd, J=12.8, 2.9 Hz), 4.53 (1H, dd, J=12.9, 6.2 Hz), 3.87 (3H, s), 2.36 (12H, m)

(661) .sup.19F-NMR (CDCl.sub.3) value: 196.79 (1 F, ddd, J=45.7, 23.3, 6.7 Hz)

(662) ##STR00176##

(663) (2S,3S,4R)-2-bromo-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-(methoxyimino)pentyl=3,5-dimethylbenzoate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(664) .sup.1H-NMR (CDCl.sub.3) value:

(665) 7.72 (2H, s), 7.65 (2H, s), 7.48 (1H, dd, J=6.4, 6.4 Hz), 7.23 (1H, s), 7.20 (1H, s), 5.80-5.75 (1H, m), 5.53 (1H, ddd, J=46.8, 6.4, 6.2 Hz), 4.76-4.69 (1H, m), 4.63-4.56 (2H, m), 3.89 (3H, s), 2.40 (6H, s), 2.35 (6H, s)

(666) .sup.19F-NMR (CDCl.sub.3) value: 193.60 (1 F, ddd, J=46.7, 17.3, 6.2 Hz)

(667) ##STR00177##

(668) A mixture of (2S,3S,4S)-2-bromo-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-oxopentyl=3,5-dimethylbenzoate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 60 C. for 11 hours.

(669) .sup.1H-NMR (CDCl.sub.3) value:

(670) 9.82 (1H, d, J=6.3 Hz), 7.65 (2H, s), 7.29 (2H, s), 7.23 (1H, s), 7.20 (1H, s), 5.82 (1H, ddd, J=21.7, 3.5, 3.5 Hz), 5.41 (1H, dd, J=46.9, 3.5, Hz), 4.61-4.19 (3H, m), 2.37-2.34 (12H, m)

(671) .sup.19F-NMR (CDCl.sub.3) value: 210.09 (1 F, ddd, J=46.8, 21.9, 6.7 Hz)

(672) ##STR00178##

(673) ((2R,3S,4S)-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=3,5-dimethylbenzoate was obtained in the form of a yellow oily product in the same manner as that of Example 1(5).

(674) .sup.1H-NMR (CDCl.sub.3) value:

(675) 7.65 (1H, s), 7.61 (1H, s), 7.59 (1H, s), 7.57 (1H, s), 7.21 (0.50H, s), 7.19 (0.50H, s), 7.17 (0.50H, s), 7.12 (0.50H, s), 6.07-6.00 (0.50H, m), 5.80 (0.50H, ddd, J=12.4, 2.5, 2.5 Hz), 5.61 (0.50H, ddd, J=9.3, 9.3, 6.1 Hz), 5.48-5.46 (0.50H, m), 5.37-5.36 (0.25H, m), 5.26-5.23 (0.50H, m), 5.14-5.11 (0.25 H, m), 4.65-4.56 (1.25H, m), 4.48-4.46 (0.75H, m), 4.22-4.16 (0.50H, m), 3.77-3.72 (0.50H, m), 2.34-2.33 (6H, m), 2.32 (3H, s), 2.25 (3H, s)

(676) .sup.19F-NMR (CDCl.sub.3) value:

(677) 183.72 (0.50 F, ddd, J=47.7, 12.0, 12.0 Hz), 192.40 (0.50 F, ddd, J=51.2, 11.3, 3.7 Hz)

(678) ##STR00179##

(679) ((2R,3S,4S)-5-acetyloxy-3-((3,5-dimethylphenyl)carbonyloxy)-4-fluorothiolan-2-yl)methyl=3,5-dimethylbenzoate was obtained in the form of a yellow oily product in the same manner as that of Example 19 (8).

(680) .sup.1H-NMR (CDCl.sub.3) value:

(681) 7.64-7.61 (2.9H, m), 7.53 (1.1H, s), 7.45 (0.45H, s), 7.19 (0.55H, s), 7.16 (0.45H, s), 7.08 (0.55H, s), 6.23 (0.45H, dd, J=13.8, 2.3 Hz), 6.16 (0.55H, d, J=4.5 Hz), 6.05 (0.55H, ddd, J=16.2, 9.0, 7.3 Hz), 5.82 (0.45H, ddd, J=12.4, 4.0, 3.8 Hz), 5.38 (0.45H, ddd, J=47.7, 3.8, 2.3 Hz), 5.29 (0.55H, ddd, J=50.7, 9.0, 4.5 Hz), 4.66-4.62 (1H, m), 4.54-4.41 (1.55H, m), 4.13-4.07 (0.45H, m), 2.34-2.31 (9H, m), 2.23 (3H, m) 2.17-2.13 (3H, m)

(682) .sup.19F-NMR (CDCl.sub.3) value:

(683) 187.11 (0.5 F, ddd, J=48.1, 13.2, 13.2 Hz), 191.86 (0.5 F, dd, J=53.8, 12.3 Hz)

Example 21

(684) ##STR00180##

(685) ((2R,3R,4S)-4-fluoro-5-methoxy-3-(methoxycarbonyloxy)oxolan-2-yl)methyl=methylformate was obtained in the form of a white solid in the same manner as that of Example 10(1), with the exception that the reaction time was set at 5 hours.

(686) .sup.1H-NMR (CDCl.sub.3) value:

(687) 5.11 (1H, d, J=10.0 Hz), 5.03-4.91 (2H, m), 4.50 (1H, dd, J=11.6, 7.2 Hz), 4.33 (1H, dd, J=11.6, 5.2 Hz), 4.31-4.29 (1H, m), 3.83 (3H, s), 3.81 (3H, s), 3.41 (3H, s)

(688) .sup.19F-NMR (CDCl.sub.3) value: 191.20 (1 F, ddd, J=49.1, 22.2, 10.5 Hz)

(689) ##STR00181##

(690) ((2R,3R,4S)-4-fluoro-5-hydroxy-3-(methoxycarbonyloxy)oxolan-2-yl)methyl=methylformate was obtained in the form of a colorless oily product in the same manner as that of Example 10(2).

(691) .sup.1H-NMR (CDCl.sub.3) value:

(692) 5.59 (0.84H, dd, J=10.0, 3.6 Hz), 5.47-5.42 (0.16H, m), 5.20 (0.16H, ddd, J=17.2, 4.0, 4.0 Hz), 5.02 (0.84H, d, J=48.8 Hz), 5.05-4.98 (16H, m), 4.31-4.15 (2H, m), 4.36-4.32 (1H, m), 3.84 (3H, s), 3.80 (3H, s), 3.50 (1H, brs)

(693) .sup.19F-NMR (CDCl.sub.3) value:

(694) 191.10 (0.88 F, ddd, J=48.9, 21.1, 10.2 Hz), 206.53 (0.12 F, ddd, J=51.2, 16.9, 6.0 Hz)

(695) ##STR00182##

(696) (2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)-3-(methoxycarbonyloxy)pentyl=methylformate was obtained in the form of a colorless oily product in the same manner as that of Example 1(1).

(697) .sup.1H-NMR (CDCl.sub.3) value:

(698) 7.42 (0.78H, dd, J=6.8, 6.8 Hz), 6.85 (0.22H, dd, J=11.2, 4.8 Hz), 5.91 (0.22H, ddd, J=46.4, 4.8, 2.0 Hz), 5.41 (0.78H, ddd, J=45.2, 6.8, 2.8 Hz), 5.25-5.15 (0.22H, m), 5.00 (0.78H, ddd, J=24.2, 8.2, 2.8 Hz), 4.52-4.19 (3H, m), 3.89 (3H, s), 3.83 (3H, s), 3.81 (3H, s), 3.08 (1H, brs)

(699) .sup.19F-NMR (CDCl.sub.3) value:

(700) 199.93 (0.75 F, ddd, J=45.2, 24.3, 4.9 Hz), 207.93 (0.25 F, ddd, J=46.3, 27.1, 10.5 Hz)

(701) ##STR00183##

(702) (2R,3R,4R)-2-fluoro-1-(methoxyimino)-5-(methoxycarbonyloxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=methylformate was obtained in the form of a colorless oily product in the same manner as that of Example 7(1).

(703) .sup.1H-NMR (CDCl.sub.3) value:

(704) 8.13-8.08 (1H, m), 7.70-7.68 (1H, m), 7.39-7.30 (0.87H, m), 6.83-6.75 (0.13H, m), 5.80-5.66 (0.24H, m), 5.54-5.45 (0.13H, m), 5.36-5.27 (0.76H, m), 5.19-5.15 (0.50H, m), 5.12-5.01 (1.37H, m), 4.54-4.42 (1.13H, m), 4.34-4.26 (0.87H, m), 3.93-3.73 (9H, m)

(705) .sup.19F-NMR (CDCl.sub.3) value:

(706) 196.34 (0.74 F, ddd, J=45.3, 20.9, 6.4 Hz), 205.27 (0.26 F, ddd, J=46.7, 25.2, 11.1 Hz)

(707) ##STR00184##

(708) (2S,3S,4R)-2-bromo-4-fluoro-5-(methoxyimino)-3-(methoxycarbonyloxy)pentyl=methylformate was obtained in the form of a colorless oily product in the same manner as that of Example 7(2).

(709) .sup.1H-NMR (CDCl.sub.3) value:

(710) 7.48-7.41 (0.80H, m), 6.96-6.83 (0.20H, m), 5.95 (0.12H, ddd, J=47.0, 4.8, 3.4 Hz), 5.45-5.09 (1.88H, m), 4.56-4.31 (3H, m), 3.94-3.80 (9H, m)

(711) .sup.19F-NMR (CDCl.sub.3) value:

(712) 193.89 (0.71 F, ddd, J=46.1, 16.6, 6.0 Hz), 203.12 (0.29 F, ddd, J=47.1, 24.5, 10.9 Hz)

(713) ##STR00185##

(714) A mixture of (2S,3S,4S)-2-bromo-4-fluoro-3-(methoxycarbonyloxy)-5-oxopentyl=methylformate and a water adduct thereof was obtained in the form of a colorless oily product in the same manner as that of Example 1(4), with the exception that the reaction was carried out at 60 C. for 9 hours.

(715) .sup.1H-NMR (CDCl.sub.3) value:

(716) 9.78 (1H, m), 5.48-5.18 (2H, m), 4.57-4.34 (3H, m), 3.84-3.80 (6H, m)

(717) .sup.19F-NMR (CDCl.sub.3) value: 210.73 (1 F, ddd, J=47.3, 21.8, 6.2 Hz)

(718) ##STR00186##

(719) ((2R,3S,4S)-4-fluoro-5-hydroxy-3-(methoxycarbonyloxy)thiolan-2-yl)methyl=methylformate was obtained in the form of a colorless oily product in the same manner as that of Example 1(5).

(720) .sup.1H-NMR (CDCl.sub.3) value:

(721) 5.57-5.46 (1H, m), 5.38-5.35 (0.80H, m), 5.25-5.23 (0.20H, m), 5.12-5.09 (0.70H, m), 4.99-4.97 (0.30H, m), 4.71-4.31 (1.30H, m), 4.23-4.19 (0.70H, m), 3.84 (3H, s), 3.81 (3H, s), 3.77-3.73 (1H, m)

(722) .sup.19F-NMR (CDCl.sub.3) value: 185.10 (0.43F, d, J=46.7 Hz), 192.12 (0.57 F, dd, J=51.5, 12.0 Hz)

(723) ##STR00187##

(724) ((2R,3S,4S)-5-acetyloxy-4-fluoro-3-(methoxycarbonyloxy)thiolan-2-yl)methyl=methylformate was obtained in the form of a colorless oily product in the same manner as that of Example 19 (8).

(725) .sup.1H-NMR (CDCl.sub.3) value:

(726) 6.12-6.06 (1H, m), 5.51 (0.60H, ddd, J=15.6, 8.8, 6.8 Hz), 5.38-5.31 (0.60H, m), 5.23-5.19 (0.50H, m), 5.10-5.07 (0.30H, m), 4.45 (0.60H, dd, J=11.2, 5.6 Hz), 4.32-4.20 (1.40, m), 3.95-3.84 (3.40H, m), 3.80-3.79 (3H, m), 3.54-3.51 (0.60H, m), 2.17 (1.80H, s), 2.12 (1.20H, s)

(727) .sup.19F-NMR (CDCl.sub.3) value:

(728) 187.31 (0.37 F, ddd, J=47.8, 14.1, 14.1 Hz), 191.72 (0.63 F, dd, J=50.5, 11.3 Hz)

Example 22

(729) ##STR00188##

(730) 94 mL of a 30% hydrobromic acid/acetic acid solution was added to a solution of 100 g of ((2R,3S,4S)-5-acetyloxy-3-(benzoyloxy)-4-fluorothiolan-2-yl)methyl=benzoate in 600 mL of methylene chloride at room temperature, and the obtained mixture was then stirred for 3 hours. Thereafter, 500 mL of water was added to the reaction mixture, and the thus obtained mixture was then stirred for 10 minutes. Thereafter, the organic layer was fractionated, and was then washed with 600 mL of a 7% sodium hydrogen carbonate aqueous solution, so as to obtain 620 mL of a methylene chloride solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorothiolan-2-yl)methyl=benzoate.

(731) ##STR00189##

(732) Under a nitrogen gas current, 193 g of 1,1,1,3,3,3-hexamethyldisilazane was added to a suspension of 66.4 g of cytosine and 316 mg of ammonium sulfate in 200 mL of toluene, and the obtained mixture was then stirred under heating to reflux, until the reaction mixture became a homogeneous solution. Thereafter, 620 mL of the methylene chloride solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorothiolan-2-yl)methyl=benzoate obtained in (1) above was added dropwise to the reaction mixture at 70 C., and the thus obtained mixture was then stirred at 70 C. for 12 hours, while methylene chloride was distilled away. Thereafter, the reaction mixture was cooled to room temperature, and 146 mg of 4-dimethylaminopyridine was added to the mixture. Subsequently, 122 g of acetic anhydride was added dropwise to the reaction mixture at 60 C., and the thus obtained mixture was then stirred at a temperature of 60 C. or higher for 1 hour. Thereafter, the reaction mixture was cooled to room temperature, and 2000 mL of methylene chloride and 600 mL of 2 mol/L hydrochloric acid were then added thereto. The organic layer was fractionated, and methylene chloride was then distilled away in an external bath at 45 C. After that, 1500 mL of propyl acetate was added to the obtained residue, and the obtained mixture was then heated to 80 C. Thereafter, the mixture was stirred until distillation of distillate components was terminated. Thereafter, the reaction mixture was cooled to 10 C., and a solid was then collected by filtration, so as to obtain 78.0 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=benzoate.

(733) ##STR00190##

(734) 60 mg of a 28% sodium methoxide/methanol solution was added to a suspension of 800 mg of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=benzoate in 10 mL of methanol at 22 C., and the obtained mixture was then stirred for 5 hours. Thereafter, the reaction mixture was cooled to 5 C., and 140 L of methanesulfonic acid and 2.4 mL of water were then added thereto, so that a solid was dissolved therein. After that, the solvent was distilled away under reduced pressure, and 12.6 mL of acetone was then added to the obtained residue. The thus obtained mixture was stirred at 20 C. for 90 minutes, and then at 5 C. for 1 hour. A solid was collected by filtration, so as to obtain 478 mg of (2R,3S,4S,5R)-3-hydroxy-2-hydroxymethyl-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolane methanesulfonate in the form of a white solid.

Example 23

(735) ##STR00191##

(736) 9.4 mL of a 30% hydrobromic acid/acetic acid solution was added to a solution of 10 g of ((2R,3S,4S)-5-acetyloxy-3-(benzoyloxy)-4-fluorothiolan-2-yl)methyl=benzoate in 60 mL of methylene chloride at room temperature, and the obtained mixture was then stirred for 3 hours. Thereafter, 70 mL of water was added to the reaction mixture, and the thus obtained mixture was then stirred for 10 minutes. Thereafter, the organic layer was fractionated, and was then washed with 70 mL of a 7% sodium hydrogen carbonate aqueous solution, so as to obtain 58 mL of a methylene chloride solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorothiolan-2-yl)methyl=benzoate.

(737) ##STR00192##

(738) Under a nitrogen gas current, 19.3 g of 1,1,1,3,3,3-hexamethyldisilazane was added to a suspension of 6.6 g of cytosine and 32 mg of ammonium sulfate in 20 mL of toluene, and the obtained mixture was then stirred while heating to reflux, until the reaction mixture became a homogeneous solution. Thereafter, 58 mL of the methylene chloride solution of ((2R,3S,4S)-3-(benzoyloxy)-5-bromo-4-fluorothiolan-2-yl)methyl=benzoate obtained in (1) above was added dropwise to the reaction mixture at 70 C., and the thus obtained mixture was then stirred at 70 C. for 10 hours, while methylene chloride was distilled away. Thereafter, the reaction mixture was cooled to room temperature, and 15 mg of 4-dimethylaminopyridine was then added to the mixture. After that, 20 mL of isobutyric anhydride was added to the mixture at 60 C., and the thus obtained mixture was then stirred at a temperature of 70 C. to 80 C. for 1 hour. Thereafter, the reaction mixture was cooled to room temperature, and 30 mL of methylene chloride and 30 mL of 2 mol/L hydrochloric acid were added to the mixture. The organic layer was fractionated, 6 mL of triethylamine was then added thereto, and methylene chloride was then distilled away. The reaction mixture was cooled to 5 C., and a solid was then collected by filtration, so as to obtain 5.7 g of ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-(2-methylpropanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=benzoate.

(739) .sup.1H-NMR (DMSO-d.sub.6) value:

(740) 1.07 (dd, J=6.8, 1.2 Hz, 6H), 2.71 (hept, J=6.8 Hz, 1H), 4.07 (dd, J=12.0, 7.0 Hz, 1H), 4.65 (dd, J=9.9, 6.5 Hz, 1H), 4.74 (dd, 11.3, 7.5 Hz, 1H), 5.71 (ddd, J=49.4, 5.4, 5.4 Hz, 1H), 5.99 (ddd, J=11.1, 5.4, 5.4 Hz, 1H), 6.63 (dd, J=13.5, 5.4 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.48 (dd, J=7.8, 7.8 Hz, 2H), 7.57 (dd, J=7.7, 7.7 Hz, 2H), 7.66 (dd, J=7.5, 7.5 Hz, 1H), 7.72 (dd, J=7.4, 7.4 Hz, 1H), 7.95 (dd, J=1.3, 8.4 Hz, 2H), 8.01 (dd, J=1.3, 8.4 Hz, 2H), 8.45 (d, J=7.4 Hz, 1H), 10.98 (brs, 1H)

Example 24

(741) ##STR00193##

(742) ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-(propanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=benzoate was obtained in the same manner as that of Example 23.

(743) .sup.1H-NMR (DMSO-d.sub.6) value:

(744) 1.04 (t, J=7.4 Hz, 3H), 2.43 (q, J=7.4 Hz, 2H), 4.07 (dd, J=11.9, 6.7 Hz, 1H), 4.65 (dd, J=10.5, 6.8 Hz, 1H), 4.74 (dd, 11.3, 7.4 Hz, 1H), 5.72 (ddd, J=49.3, 5.5, 5.5 Hz, 1H), 5.99 (ddd, J=11.1, 5.4, 5.4 Hz, 1H), 6.62 (dd, J=13.1, 5.6 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.48 (dd, J=7.8, 7.8 Hz, 2H), 7.57 (dd, J=7.8, 7.8 Hz, 2H), 7.66 (dd, J=7.4, 7.4 Hz, 1H), 7.72 (dd, J=7.6, 7.6 Hz, 1H), 7.95 (d, J=7.2 Hz, 2H), 8.01 (d, J=7.3 Hz, 2H), 8.48 (d, J=7.6 Hz, 1H), 10.96 (brs, 1H)

Example 25

(745) ##STR00194##

(746) ((2R,3S,4S,5R)-3-(benzoyloxy)-5-(4-(butanamido)-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluorothiolan-2-yl)methyl=benzoate was obtained in the same manner as that of Example 23.

(747) .sup.1H-NMR (DMSO-d.sub.6) value:

(748) 0.89 (t, J=7.4 Hz, 3H), 1.58 (qt, J=7.4, 7.4 Hz, 2H), 2.39 (t, J=7.3 Hz, 2H), 4.08 (dd, J=11.9, 7.0 Hz, 1H), 4.65 (dd, J=10.1, 6.7 Hz, 1H), 4.74 (dd, 11.4, 7.4 Hz, 1H), 5.72 (ddd, J=49.3, 5.5, 5.5 Hz, 1H), 5.99 (ddd, J=11.2, 5.5, 5.5 Hz, 1H), 6.62 (dd, J=13.2, 5.5 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.48 (dd, J=70.8, 7.8 Hz, 2H), 7.57 (dd, J=7.8, 7.8 Hz, 2H), 7.66 (dd, J=7.4, 7.4 Hz, 1H), 7.72 (dd, J=7.5, 7.5 Hz, 1H), 7.95 (dd, J=1.3, 8.3 Hz, 2H), 8.01 (dd, J=1.3, 8.4 Hz, 2H), 8.48 (d, J=7.7 Hz, 1H), 10.97 (brs, 1H)

Example 26

(749) ##STR00195##

(750) 438 mg of 60% sodium hydride was added to a solution of 727 mg of 2-deoxy-2-fluoro-1-O-methyl-D-arabinofuranoside in 15 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at the same temperature as described above for 15 minutes. Thereafter, 1.20 mL of benzyl bromide was added to the reaction mixture, and the thus obtained mixture was then stirred for 5 minutes. The mixture was further stirred at room temperature for 1.5 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 1.35 g of 2-deoxy-2-fluoro-1-O-methyl-3,5-bis-O-benzyl-D-arabinofuranoside in the form of a colorless oily product.

(751) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 1:1.

(752) RT (min): 1.80.

(753) .sup.1H-NMR (CDCl.sub.3) value:

(754) 7.38-7.25 (10H, m), 5.11 (0.5H, dd, J=6.3, 4.3 Hz), 4.96-4.92 (1.5H, m), 4.64 (2H, ABq, J=21.9, 110.2 Hz), 4.57 (2H, s), 4.28-4.11 (2H, m), 3.62-3.50 (2H, m), 3.40 (3H, s)

(755) ##STR00196##

(756) 1.26 mL of trifluoroacetic acid and 0.14 mL of water were added to 1.35 g of 2-deoxy-2-fluoro-1-O-methyl-3,5-bis-O-benzyl-D-arabinofuranoside, and the obtained mixture was then stirred at a temperature of 55 C. to 60 C. for 3 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was washed with water once and then with a saturated sodium hydrogen carbonate aqueous solution twice, and it was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 65/35), so as to obtain 954 mg of 2-deoxy-2-fluoro-3,5-bis-O-benzyl-D-arabinofuranoside in the form of a colorless oily product.

(757) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 8/2.

(758) RT (min): 1.54.

(759) .sup.1H-NMR (CDCl.sub.3) value:

(760) 7.40-7.25 (10H, m), 5.48 (0.8H, dd, J=9.9, 6.6 Hz), 5.30 (0.2H, dq, J=10.4, 2.1 Hz), 4.96 (0.2H, dt, J=52.8, 4.6 Hz), 4.95 (0.8H, dd, J=50.1, 1.3 Hz), 4.69 (0.4H, dd, J=11.2, 2.6 Hz), 4.62 (1H, d, 5.3 Hz), 4.60 (0.6H, dd, J=3.3, 11.2 Hz), 4.55 (2H, s), 4.52-4.43 (1H, m), 4.38-4.27 (0.2H, m), 4.07-3.97 (0.8H, m), 3.64-3.44 (2H, m), 2.99 (1H, m)

(761) ##STR00197##

(762) 325 mg of O-methylhydroxylammonium chloride and 0.415 mL of triethylamine were added to a solution of 954 mg of 2-deoxy-2-fluoro-3,5-bis-O-benzyl-D-arabinofuranoside in 10 mL of methanol, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, the solvent was distilled away under reduced pressure, and ethyl acetate and water were then added to the obtained residue. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 70/30), so as to obtain 1.09 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis(benzyloxy)pentanal O-methyloxime in the form of a colorless oily product.

(763) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 63:37.

(764) RT (min): 1.66.

(765) .sup.1H-NMR (CDCl.sub.3) value:

(766) 7.51 (0.63H, t, J=6.9 Hz), 7.40-7.20 (10H, m), 7.01 (0.37H, dd, J=11.9, 4.6 Hz), 5.82 (0.37H, ddd, J=46.9, 4.6, 1.3 Hz), 5.31 (0.63H, ddd, J=46.1.6.6, 3.3 Hz), 4.72-4.42 (4H, m), 3.97 (1H, brs), 3.91-3.56 (1H, m), 3.90 (1.11H, s), 3.87 (1.89H, s), 3.71-3.64 (2H, m), 2.47 (1H, brs)

(767) ##STR00198##

(768) 1.26 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.430 mL of 1-methylimidazole were added to a solution of 1.09 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis(benzyloxy)pentanal O-methyloxime in 10.4 mL of acetonitrile at room temperature, and the obtained mixture was then stirred at room temperature for 14.5 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. A solid was removed by filtration, and the organic layer was then fractionated. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.50 g of (2R,3R,4R)-2-fluoro-3,5-bis(benzyloxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in the form of a colorless oily product.

(769) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 68:32.

(770) RT (min): 2.22.

(771) .sup.1H-NMR (CDCl.sub.3) value:

(772) 8.09 (0.32H, s), 8.09 (0.68H, s), 7.43 (1H, s), 7.40 (0.68H, t, J=7.7 Hz), 7.37-7.15 (10H, m), 6.88 (0.32H, dd, J=11.2, 4.6 Hz), 5.61 (0.32H, ddd, J=47.6, 4.6, 2.4 Hz), 5.14 (0.68H, ddd, J=46.4, 6.6, 4.0 Hz), 4.88-4.75 (1H, m), 4.72-4.54 (2H, m), 4.45-4.25 (2.32H, m), 4.20-4.07 (0.68H, ddd, J=22.5, 5.3, 4.0 Hz), 3.88 (3H, s), 3.86-3.75 (2H, m)

(773) ##STR00199##

(774) 430 mg of lithium bromide was added to a solution of 1.50 g of (2R,3R,4R)-2-fluoro-3,5-bis(benzyloxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in 6 mL of tetrahydrofuran and 5.4 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 60 C. for 6 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 662 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal O-methyloxime in the form of a colorless oily product.

(775) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 86:14.

(776) RT (min): 2.00.

(777) .sup.1H-NMR (CDCl.sub.3) value:

(778) 7.42 (0.86H, t, J=6.9 Hz), 7.33 (10H, m), 6.90 (0.14H, dd, J=11.2, 5.3 Hz), 5.81 (0.14H, dq, J=47.6, 2.6 Hz), 5.32 (0.86H, dt, J=46.9, 6.6 Hz), 4.75 (1.72H, ABq, 40.3, 11.2 Hz), 4.68 (0.28H, ABq, 19.8, 8.6 Hz), 4.55 (0.28H, ABq, 12.6, 10.6 Hz), 4.48 (1.72H, s), 4.33-4.21 (0.14H, m), 4.19-4.10 (1H, m), 4.09-3.98 (0.86H, m), 3.91 (2.58H, s), 3.90 (0.42H, m), 3.93-3.83 (1H, m), 3.83-3.76 (0.14H, m), 3.71 (0.86H, m)

(779) ##STR00200##

(780) 3.3 mL of a 50% glyoxylic acid aqueous solution was added to a solution of 662 mg of the (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal O-methyloxime in 6.6 mL of tetrahydrofuran, and the obtained mixture was then stirred at 70 C. for 4.83 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 655 mg of colorless oily (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal and a water adduct thereof.

(781) RT (min): 1.54

(782) ##STR00201##

(783) 289 mg of a sodium monohydrogen sulfide n-hydrate was added to a solution of 655 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal and a water adduct thereof in 6 mL of 1-methylpyrrolidone under cooling on ice, and the obtained mixture was then stirred at the same temperature as described above for 1.25 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain a 1-methylpyrrolidone solution of 2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinofuranoside in the form of a colorless oily product.

(784) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 57/43.

(785) RT (min): 1.66, 1.68.

(786) .sup.1H-NMR (CDCl.sub.3) value:

(787) 7.39-7.21 (10H, m), 6.14 (0.57H, d, J=5.9 Hz), 5.77 (0.43H, d, J=7.9 Hz), 5.51-5.40 (0.43H, m), 5.29-5.23 (0.57H, m), 5.08 (0.43H, ddd, J=50.2, 4.6, 3.3 Hz), 4.96 (0.57H, ddd, J=52.2, 7.9, 4.0 Hz), 4.77-4.57 (2H, m), 4.54 (1.14H, s), 4.50 (0.86, s), 4.42-4.31 (0.57H, m), 4.17-1.06 (0.43H, m), 3.88-3.51 (2H, m), 3.19-3.15 (1H, m), 3.08 (2H, t, J=5.0 Hz), 2.99 (1H, t, J=6.6 Hz)

(788) ##STR00202##

(789) 5.4 mL of tetrahydrofuran, 0.293 mL of acetic anhydride, 0.541 mL of triethylamine and a piece of 4-dimethylaminopyridine were added to the 1-methylpyrrolidone solution of 2-deoxy-2-fluoro-3,5-bis(benzyloxy)-4-thio-D-arabinofuranoside obtained in Example 26 (7), and the obtained mixture was then stirred at room temperature for 1.25 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 60/40), so as to obtain 394 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinofuranoside in the form of a colorless oily product.

(790) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 55/45.

(791) RT (min): 1.89.

(792) .sup.1H-NMR (CDCl.sub.3) value:

(793) 7.39-7.22 (10H, m), 6.05 (0.55H, t, J=4.5 Hz), 6.02 (0.45H, dd, J=10.6, 3.3 Hz), 5.20 (0.45H, ddd, J=50.1, 5.3, 3.3 Hz), 5.14 (0.55H, ddd, J=51.0, 8.6, 4.6 Hz), 4.80-4.46 (4H, m), 4.36-4.23 (0.55H, m), 4.21-4.09 (0.45H, m), 3.81-3.37 (3H, m), 2.11 (1.65H, s), 2.06 (1.35H, s)

(794) ##STR00203##

(795) 0.119 mL of a 30% hydrogen bromide-acetic acid solution was added to a solution of 116.2 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-benzyl-4-thio-D-arabinofuranoside in 2.3 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, water was added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium hydrogen carbonate aqueous solution and was then dried over magnesium sulfate, so as to obtain a dichloromethane solution of 1-bromo-2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinofuranoside.

(796) 0.521 mL of N,O-bistrimethylsilyl acetamide was added to 83 mg of cytosine at room temperature, and the obtained mixture was then stirred in a nitrogen atmosphere at 80 C. for 1.5 hours. Thereafter, a dichloromethane solution of 1-bromo-2-deoxy-2-fluoro-3,5-bis-O-benzyl-4-thio-D-arabinofuranoside was added to the reaction mixture, and the solvent was then distilled away. After that, the obtained residue was further stirred at 80 C. for 2.5 hours. Thereafter, ethyl acetate and 2 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was fractionated, and it was washed with water and was then dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol), so as to obtain 61.3 mg of 1-(3,5-bis-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a colorless oily product.

(797) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 31/69.

(798) RT (min): 1.30.

(799) .sup.1H-NMR (CDCl.sub.3) value:

(800) 7.99 (0.69H, dd, J=7.6, 1.7 Hz), 7.83 (0.31H, d, J=7.3 Hz), 7.40-7.24 (10H, m), 7.21-7.16 (1H, m), 6.68 (0.69H, dd, J=18.5, 4.6 Hz), 6.34 (0.31H, dd, J=15.9, 2.0 Hz), 6.20-5.80 (1H, brs), 5.69 (0.31H, d, J=7.3 Hz), 5.60 (0.69H, d, J=7.3 Hz), 5.15 (0.31H, dt, J=47.4, 2.5 Hz), 5.11 (0.69H, dt, J=51.0, 4.5 Hz), 4.61 (1.38H, ABq, J=12.6, 11.7), 4.52 (1.24H, brs), 4.48 (1.38H, ABq, 12.9, 4.8 Hz), 4.26 (1H, m), 3.93 (0.31H, t, J=5.9 Hz), 3.70-3.55 (2.38H, m), 3.53-3.47 (0.31H, m)

(801) ##STR00204##

(802) 0.065 mL of a 1 mol/L boron tribromide-dichloromethane solution was added to a solution of 9.6 mg of 1-(3,5-bis-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in 1 mL of dichloromethane under cooling on ice. While the temperature was gradually increased to room temperature, the obtained mixture was stirred for 2 hours. Thereafter, hexane was added to the reaction mixture, and a solid was then collected by filtration. The obtained solid was washed with toluene and ethyl acetate, so as to obtain 5.3 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a white solid.

(803) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 36/64.

(804) RT (min): 0.22, 0.27.

(805) .sup.1H-NMR (DMSO-d.sub.6) value:

(806) 8.02-7.93 (1H, m), 7.40-7.15 (2H, m), 6.46 (0.64H, dd, J=14.5, 5.3 Hz), 6.15 (0.36H, dd, J=17.2, 5.9 Hz), 5.93 (0.36H, d, J=4.6 Hz), 5.84 (0.64H, d, J=4.6 Hz), 5.82-5.71 (1H, m), 5.26 (0.64H, t, J=5.3 Hz), 5.06 (0.36H, dt, J=52.2, 5.9 Hz), 5.03 (1H, dd, J=11.2, 4.6 Hz), 4.91 (0.64H, dt, J=46.2, 5.3 Hz), 4.29-4.18 (0.64H, m), 4.15-4.02 (0.36H, m), 3.82-3.67 (0.36H, m), 3.65-3.54 (1H, m), 3.51-3.28 (1H, m), 3.26-3.15 (0.64H, m)

Example 27

(807) ##STR00205##

(808) 0.941 mL of 3,4-dihydro-2H-pyran was added to a solution of 1.87 g of 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranoside in 37.5 mL of dichloromethane at room temperature, and thereafter, 49 mg of p-toluenesulfonic acid monohydrate was added to the obtained mixture under cooling on ice. The thus obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 2.33 g of 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinofuranoside in the form of a colorless oily product.

(809) RT (min): 1.96.

(810) .sup.1H-NMR (CDCl.sub.3) value:

(811) 8.06 (4H, m), 7.51 (6H, m), 5.68 (1H, d, J=10.6 Hz), 5.59-5.48 (1H, dd, 21.9, 4.5 Hz), 5.20 (1H, d, J=49.5 Hz), 5.06-5.02 (1H, m), 4.77-4.59 (2H, m), 4.53 (1H, q, 4.2 Hz), 3.94-3.84 (1H, m), 3.64-3.53 (1H, m), 1.90-1.40 (6H, m)

(812) ##STR00206##

(813) A 28% sodium methoxide/methanol solution was added to a methanol solution of 2.33 g of the 3,5-bis-O-benzoyl-2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinofuranoside, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the solvent was distilled away, and ethyl acetate and water were then added to the obtained residue. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50 to 0/100), so as to obtain 1.08 g of 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinofuranoside in the form of a colorless oily product.

(814) RT (min): 0.69.

(815) .sup.1H-NMR (CDCl.sub.3) value:

(816) 5.58-5.50 (1H, m), 5.03 (1H, brs), 4.94 (1H, dd, 44.7, 2.7 Hz), 4.30-4.07 (3H, m), 3.92-3.52 (3H, m), 2.33 (1H, d, J=9.2 Hz), 2.14-2.08 (1H, m), 1.84-1.54 (7H, m)

(817) ##STR00207##

(818) 456 mg of 60% sodium hydride was added to a solution of 1.08 g of the 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-D-arabinofuranoside in 20 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at the same temperature as described above for 25 minutes. Thereafter, 1.43 mL of 4-methoxybenzyl chloride was added to the reaction mixture, and the thus obtained mixture was then stirred for 1 hour. The reaction mixture was further stirred at room temperature for 1 hour, and it was then left at rest overnight at room temperature. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 1.42 g of 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-3,5-bis-O-(4-methoxybenzyl)-D-arabinofuranoside in the form of a colorless oily product.

(819) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 8:2.

(820) RT (min): 1.92.

(821) .sup.1H-NMR (CDCl.sub.3) value:

(822) 7.25-7.20 (4H, m), 6.90-6.83 (4H, m), 5.49 (0.8H, d, J=12.6 Hz), 5.40-5.34 (0.2H, m), 5.12 (0.4H, d, J=2.0 Hz), 4.99-4.89 (1.6H, m), 4.64-4.62 (4H, m), 4.22-4.15 (1H, m), 4.12-3.84 (2H, m), 3.81 (3H, s), 3.80 (3H, s), 3.75-3.63 (3H, m), 1.89-1.43 (6H, m)

(823) ##STR00208##

(824) 1.42 mL of 2 mol/L hydrochloric acid was added to a solution of 1.42 g of the 2-deoxy-2-fluoro-1-O-(tetrahydro-2H-pyran-2-yl)-3,5-bis-O-(4-methoxybenzyl)-D-arabinofuranoside in 14.2 mL of acetone, and the obtained mixture was then stirred at 50 C. for 1.25 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 50/50), so as to obtain 1.14 g of 2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-D-arabinofuranoside in the form of a colorless oily product.

(825) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 8:2.

(826) RT (min): 1.50.

(827) .sup.1H-NMR (CDCl.sub.3) value:

(828) 7.29-7.17 (4H, m), 6.92-6.83 (4H, m), 5.46 (0.8H, dd, J=0.2, 7.6 Hz), 5.28 (0.2H, ddd, J=11.4, 3.9, 1.2 Hz), 4.94 (0.2H, dt, J=52.8, 4.8 Hz), 4.91 (0.8H, dd, J=50.4, 1.3 Hz), 4.93-4.87 (0.2H, d, J=1.3 Hz), 4.62-4.39 (4.8H, m), 4.10-3.91 (1H, m), 3.81 (3H, s), 3.81 (3H, s), 3.77-3.67 (0.8H, m), 3.58-3.43 (2.2H, m)

(829) ##STR00209##

(830) 315 mg of O-methylhydroxylammonium chloride and 0.403 mL of triethylamine were added to a solution of 1.14 g of 2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-D-arabinofuranoside in 11 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the solvent was distilled away under reduced pressure, and ethyl acetate and water were then added to the obtained residue. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 50/50), so as to obtain 1.02 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in the form of a colorless oily product.

(831) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 69:31.

(832) RT (min): 1.58.

(833) .sup.1H-NMR (CDCl.sub.3) value:

(834) 7.47 (0.69H, t, J=6.9 Hz), 7.29-7.21 (2H, m), 7.18-7.10 (2H, m), 7.00 (0.31H, dd, J=11.2, 4.6 Hz), 60.87 (4H, m), 5.80 (0.31H, ddd, J=47.1, 4.6, 2.0 Hz), 5.35 (0.69H, ddd, J=46.2, 6.9, 3.0 Hz), 4.56-4.34 (4H, m), 3.95-3.90 (1H, m), 3.90 (0.93H, m), 3.86 (2.07H, s), 3.82-3.78 (1H, m), 3.81 (3H, s), 3.80 (3H, s), 3.71 (0.31H, dd, J=7.8, 3.3 Hz), 3.64-3.56 (1.69H, m)

(835) ##STR00210##

(836) 2.03 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.772 mL of 1-methylimidazole were added to a solution of 1.02 g of the (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 20 mL of acetonitrile at room temperature, and the obtained mixture was stirred at room temperature for 1.75 hours, and then at 40 C. for 1.25 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and a solid was removed by filtration. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in the form of a colorless oily product.

(837) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 65:35.

(838) RT (min): 2.15.

(839) .sup.1H-NMR (CDCl.sub.3) value:

(840) 8.08 (0.35H, s), 8.08 (0.65H, s), 7.43 (1H, s), 7.36 (0.65H, t, J=6.9 Hz), 7.18-7.10 (4H, m), 6.92-6.80 (4.35H, m), 5.58 (0.35H, dq, J=47.6, 2.4 Hz), 5.10 (0.65H, dq, J=46.6, 3.5 Hz), 4.85-4.72 (1H, m), 4.62-4.46 (2H, m), 4.40-4.21 (2.35H, m), 4.08 (0.65H, dq, J=23.8, 2.9 Hz), 3.87 (1.95H, s), 3.87 (1.05H, s), 3.81 (3.90H, s), 3.80 (2.10H, s), 3.81-3.72 (2H, m)

(841) ##STR00211##

(842) 451 mg of lithium bromide was added to a solution of 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in 6 mL of tetrahydrofuran and 6 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 65 C. for 7 hours. Thereafter, ethyl acetate and a 25% lithium bromide aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a 12% lithium bromide aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in the form of a colorless oily product.

(843) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 82:18.

(844) RT (min): 1.92.

(845) .sup.1H-NMR (CDCl.sub.3) value:

(846) 7.40 (0.82H, t, J=6.9 Hz), 7.24 (4H, m), 6.92-6.83 (4.18H, m), 5.79 (0.18H, ddd, J=50.9, 6.0, 2.4 Hz), 5.29 (0.82H, dt, J=46.9, 6.6 Hz), 4.66 (1.64H, ABq, J=10.5, 24.3 Hz), 4.58 (0.36H, ABq, J=18.0, 10.5 Hz), 4.48 (0.36H, s), 4.42 (1.64H, ABq, J=12.0, 1.3 Hz), 4.29-4.06 (1H, m), 3.98 (0.82H, dq, J=17.3, 3.3 Hz), 3.90 (3H, s), 3.88-3.70 (0.18H, m), 3.81 (1H, s), 3.81 (3H, s), 3.80 (3H, s), 3.71-3.63 (1H, m)

(847) ##STR00212##

(848) 4.2 mL of a 35% formaldehyde solution and 4.2 mL of 2 mol/L hydrochloric acid were added to a solution of 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 17 mL of acetone at room temperature, and the obtained mixture was then stirred at room temperature for 1.75 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 598 mg of colorless oily (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal and a water adduct thereof.

(849) RT (min): 1.66.

(850) ##STR00213##

(851) 210 mg of a sodium monohydrogen sulfide n-hydrate was added to a solution of 598 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal in 6 mL of 1-methylpyrrolidone and the water adduct thereof under cooling on ice, and the obtained mixture was then stirred at the same temperature as described above for 1.5 hours. Thereafter, ethyl acetate and a saturated saline were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 30/70), so as to obtain 453 mg of 2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranoside in the form of a colorless oily product.

(852) RT (min): 1.58, 1.61.

(853) m/z (ESI-positive): 409.3 [M+H].sup.+

(854) ##STR00214##

(855) 0.210 mL of acetic anhydride, 0.462 mL of triethylamine and 5 mg of 4-dimethylaminopyridine were added to a solution of 453 mg of 2-deoxy-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-thio-D-arabinofuranoside in 9 mL of tetrahydrofuran at room temperature, and the obtained mixture was then stirred at the same temperature as described above for 1.5 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), so as to obtain 447 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranoside in the form of a colorless oily product.

(856) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 1/1.

(857) RT (min): 1.79, 1.81.

(858) .sup.1H-NMR (CDCl.sub.3) value:

(859) 7.25-7.18 (4H, m), 6.90-6.83 (4H, m), 6.03 (0.5H, t, J=3.3 Hz), 6.01 (0.5H, J=13.8, 3.3 Hz), 5.25 (00.5H, ddd, J=50.1, 5.1, 3.3 Hz), 5.09 (0.5H, ddd, J=51.0, 8.4, 4.8 Hz), 4.73-4.46 (2H, m), 4.46 (1H, s), 4.42 (1H, ABq, J=12.0, 3.3 Hz), 4.30-4.07 (1H, m), 3.80 (6H, s), 3.79-3.55 (1.5H, m), 3.50-3.31 (1.5H, m), 2.10 (1.5H, s), 2.07 (1.5H, s)

(860) ##STR00215##

(861) 0.277 mL of N,O-bistrimethylsilyl acetamide was added to a solution of 47.2 mg of cytosine and 95.7 mg of 1-acetyl-2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranoside in 1 mL of acetonitrile at room temperature, and the obtained mixture was then stirred in a nitrogen atmosphere at 75 C. for 2 hours. Thereafter, 0.154 mL of trimethylsilyl trifluoromethanesulfonate was added to the reaction mixture, and the thus obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, dichloromethane and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 to 50/50), and then by silica gel column chromatography (NH column, chloroform/methanol=100/0 to 90/10), so as to obtain 8.8 mg of 1-(2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranosyl)cytosine in the form of a colorless oily product.

(862) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 53/47.

(863) RT (min): 1.30.

(864) .sup.1H-NMR (CDCl.sub.3) value:

(865) 8.04 (0.47H, dd, J=7.3, 1.3 Hz), 7.90 (0.53H, d, J=7.3 Hz), 7.25-7.19 (3H, m), 7.13-7.07 (1H, m), 6.92-6.79 (4H, m), 6.68 (0.47H, dd, J=17.8, 4.6 Hz), 6.36 (0.53H, dd, J=15.5, 2.3 Hz), 5.58 (0.53H, d, J=7.9 Hz), 5.52 (0.47H, d, J=7.3 Hz), 5.13 (0.53H, dt, J=46.9, 2.6 Hz), 5.09 (0.47H, dt, J=50.2, 4.6 Hz), 4.47-4.36 (3H, m), 4.28-4.19 (1H, m), 3.89 (1H, q, J=6.8 Hz), 3.83-3.75 (1H, m), 3.82 (1.41H, s), 3.81 (1.59H, s), 3.79 (3H, s), 3.64-3.42 (2H, m)

(866) ##STR00216##

(867) 0.2 mL of trifluoroacetic acid was added to a solution of 8.8 mg of 1-(2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranosyl)cytosine in 2 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, the solvent was distilled away from the reaction mixture under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH column, chloroform/methanol=90/10 to 60/40), so as to obtain 3.1 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a white solid.

(868) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 56/44.

(869) RT (min): 0.22.

(870) .sup.1H-NMR (DMSO-d.sub.6) value:

(871) 8.02-7.94 (1H, m), 7.34-7.15 (2H, m), 6.46 (0.44H, dd, J=14.5, 5.3 Hz), 6.15 (0.56H, dd, J=17.8, 5.9 Hz), 5.92 (0.56H, d, J=5.3 Hz), 5.87 (0.44H, d, J=4.6 Hz), 5.79 (0.56H, d, J=7.3 Hz), 5.77 (0.44H, d, J=7.3 Hz), 5.24 (1H, t, J=5.6 Hz), 5.06 (0.56H, dt, J=52.2, 5.9 Hz), 5.03 (1H, dd, J=11.2, 4.6 Hz), 4.91 (0.44H, dt, J=46.2, 5.3 Hz), 4.24 (0.44H, dt, J=10.7, 5.3 Hz), 4.09 (0.56H, dt, J=2.7, 6.4 Hz), 3.82-3.67 (0.66H, m), 3.65-3.54 (1H, m), 3.51-3.28 (1H, m), 3.26-3.15 (0.44H, m)

Example 28

(872) ##STR00217##

(873) In a nitrogen atmosphere, 0.44 g of sodium hydride and 2.03 g of 4-methylbenzyl bromide were added to a solution of 0.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 7.0 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 2.5 mL of methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate and hexane were then added thereto. The reaction mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40), so as to obtain 1.33 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolane in the form of a colorless oily product.

(874) .sup.1H-NMR (CDCl.sub.3) value:

(875) 7.23-7.11 (8H, m), 5.10 (0.5H, dd, J=5.9, 4.3 Hz), 4.93-4.91 (1.5H, m), 4.66-4.52 (4H, m), 4.23-4.09 (2H, m), 3.57-3.48 (2H, m), 3.40 (3H, s), 2.35 (3H, s), 2.34 (3H, s)

(876) ##STR00218##

(877) 9.8 mL of acetic acid, 3.3 mL of water and 0.56 mL of concentrated sulfuric acid were added to 1.31 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)meth yl)oxolane, and the obtained mixture was then stirred at 70 C. for 2 hours. Thereafter, ethyl acetate and hexane were added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 30/70), so as to obtain 0.74 g of (3S,4R,5R)-3-fluoro-4-((4-methylbenzyl)oxy)oxy)methyl)oxolan-2-ol in the form of a colorless oily product.

(878) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 2278.

(879) .sup.1H-NMR (CDCl.sub.3) value:

(880) 7.21-7.12 (8H, m), 5.46 (0.78H, dd, J=10.1, 7.1 Hz), 5.28 (0.22H, dd, J=10.6, 2.1 Hz), 4.94 (0.22H, dt, J=52.6, 4.8 Hz), 4.92 (0.78H, dd, J=50.4, 1.0 Hz), 4.67-4.42 (5H, m), 4.30 (0.22H, dt, J=17.8, 4.8 Hz), 4.00 (0.78H, ddt, J=19.0, 3.8, 1.0 Hz), 3.92 (0.22H, dd, J=10.6, 1.3 Hz), 3.57-3.42 (2H, m), 2.97 (0.78H, dd, J=7.1, 1.00 Hz), 2.35 (6H, s)

(881) ##STR00219##

(882) In a nitrogen atmosphere, 3.6 mL of methanol and 0.20 g of O-methylhydroxylamine hydrochloride were added to 0.72 g of (3S,4R,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolan-2-ol, and thereafter, 0.34 mL of triethylamine was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 16 hours. Thereafter, 0.10 g of O-methylhydroxylamine hydrochloride and 0.25 mL of triethylamine were added to the reaction mixture, and the thus obtained mixture was further stirred at 50 C. for 2 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), so as to obtain 0.65 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methylbenzyl)oxy)pentanal=O-methyl=oxime in the form of a colorless oily product.

(883) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 67:33.

(884) .sup.1H-NMR (CDCl.sub.3) value:

(885) 7.48 (0.67H, t, J=7.1 Hz), 7.23-7.11 (8H, m), 7.00 (0.33H, dd, J=11.6, 4.6 Hz), 5.81 (0.33H, ddd, J=46.2, 4.6, 1.8 Hz), 5.28 (0.67H, ddd, J=46.2, 7.1, 3.1 Hz), 4.58-4.28 (4H, m), 3.97-3.82 (4.33H, m), 3.74-3.60 (2.67H, m), 2.45 (0.33H, d, J=6.9 Hz), 2.43 (0.67H, d, J=6.9 Hz), 2.35 (3H, s), 2.34 (3H, s)

(886) ##STR00220##

(887) In a nitrogen atmosphere, 6.4 mL of acetonitrile, 0.60 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.21 mL of N-methylimidazole were added to 0.64 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methylbenzyl)oxy)pentanal=O-methyl=oxime, and the obtained mixture was then stirred at room temperature for 16 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 70/30), so as to obtain 1.01 g of (2R,3R,4R)-4-fluoro-5-(methoxyimino)-1,3-bis((4-methylbenzyl)oxy)pentan-2-yl=2,4,5-trichlorobenzenesulfonate in the form of a colorless oily product.

(888) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 66:34.

(889) .sup.1H-NMR (CDCl.sub.3) value:

(890) 8.08 (0.34H, s), 8.07 (0.66H, s), 7.40 (1H, s), 7.38 (0.66H, t, J=6.9 Hz), 7.14-7.05 (8H, m), 6.88 (0.34H, dd, J=11.6, 4.6 Hz), 5.59 (0.34H, ddd, J=47.6, 4.6, 2.6 Hz), 5.12 (0.66H, ddd, J=46.5, 6.9, 3.8 Hz), 4.82 (0.66H, td, J=5.3, 3.3 Hz), 4.77 (0.34H, td, J=5.6, 2.4 Hz), 4.65-4.49 (2H, m), 4.40-4.23 (2.34H, m), 4.10 (0.66H, ddd, J=23.7, 5.3, 3.8 Hz), 3.87 (3H, s), 3.85-3.82 (2H, m), 2.35-2.33 (6H, m)

(891) ##STR00221##

(892) In a nitrogen atmosphere, 10 mL of 1,3-dimethyl-2-imidazolidinone and 0.82 g of anhydrous lithium bromide were added to 1.00 g of (2R,3R,4R)-4-fluoro-5-(methoxyimino)-1,3-bis((4-methylbenzyl)oxy)pentan-2-yl=2,4,5-trichlorobenzenesulfonate, and the obtained mixture was then stirred at 50 C. for 17 hours. Thereafter, ethyl acetate and n-hexane were added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 0.56 g of (2R,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methylbenzyl)oxy)pentanal=O-methyl=oxime in the form of a light yellow oily product.

(893) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 84:16.

(894) .sup.1H-NMR (CDCl.sub.3) value:

(895) 7.40 (0.84H, t, J=6.6 Hz), 7.23-7.11 (8H, m), 6.89 (0.16H, dd, J=11.2, 5.0 Hz), 5.79 (0.16H, ddd, J=47.7, 5.0, 3.00 Hz), 5.29 (0.84H, dt, J=47.2, 6.6 Hz), 4.77-4.43 (4H, m), 4.28-4.08 (1.16H, m), 4.00 (0.84H, ddd, J=17.2, 6.6, 3.3 Hz), 3.92-3.87 (3.16H, m), 3.83 (0.84H, dd, J=10.2, 7.3 Hz), 3.77 (0.16H, ddd, J=11.2, 5.9, 2.3 Hz), 3.69 (0.84H, ddd, J=10.2.5.9, 2.3 Hz), 2.35 (3H, s), 2.34 (3H, s)

(896) ##STR00222##

(897) In a nitrogen atmosphere, 11 mL of acetone, 2.7 mL of 2 mol/L hydrochloric acid and 1.0 mL of a 37% formaldehyde aqueous solution were added to 0.55 g of (2R,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methylbenzyl)oxy)pentanal=O-methyl=oxime, and the obtained mixture was then stirred at room temperature for 4 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), to obtain 0.50 g of a colorless oily product.

(898) The obtained oily product was a mixture of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methylbenzyl)oxy)pentanal and a water adduct thereof.

(899) .sup.1H-NMR (CDCl.sub.3) value:

(900) 9.76 (1H, d, J=6.6 Hz), 7.23-7.13 (8H, m), 5.06 (1H, dd, J=47.7, 3.8 Hz), 4.66-4.48 (4H, m), 4.34 (1H, td, J=5.9, 4.8 Hz), 4.22 (1H, ddd, J=22.6, 4.8, 3.8 Hz), 3.94 (1H, dd, J=10.9, 5.4 Hz), 3.76 (1H, ddd, J=10.9, 6.4, 2.5 Hz), 2.35 (3H, s), 2.34 (3H, s)

(901) ##STR00223##

(902) 0.19 g of a sodium hydrogen sulfide x-hydrate was added to a solution of 0.50 g of the colorless oily product obtained in Example 28 (6) in 4.8 mL of 1-methyl-2-pyrrolidone under cooling on ice, and the obtained mixture was then stirred under cooling on ice for 2 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, 0.5 M hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), so as to obtain 0.36 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolan-2-ol in the form of a light yellow oily product.

(903) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 40:60.

(904) .sup.1H-NMR (CDCl.sub.3) value:

(905) 7.23-7.13 (8H, m), 5.43 (0.40H, ddt, J=12.2, 8.9, 1.3 Hz), 5.20-5.03 (1.30H, m), 4.90 (0.30H, dd, J=7.3, 4.0 Hz), 4.72-4.46 (4H, m), 4.36 (0.60H, dd, J=7.4, 1.8 Hz), 4.31 (0.40H, dd, J=7.1, 4.6 Hz), 30.95 (0.40H, t, J=7.9 Hz), 3.66-3.37 (3.20H, m), 3.03 (0.40H, dd, J=12.2, 1.3 Hz), 2.35 (6H, s)

(906) ##STR00224##

(907) In a nitrogen atmosphere, 0.17 mL of acetic anhydride and 0.38 mL of triethylamine were added to a solution of 0.34 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolan-2-ol in 3.4 mL of tetrahydrofuran under cooling on ice, and the obtained mixture was then stirred at room temperature for 21 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40), so as to obtain 0.31 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolan-2-yl=acetate in the form of a colorless oily product.

(908) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 40:60.

(909) .sup.1H-NMR (CDCl.sub.3) value:

(910) 7.21-7.12 (8H, m), 6.03 (0.40H, d, J=4.6 Hz), 6.02 (0.60H, dd, J=16.7, 3.2 Hz), 5.17 (0.60H, ddd, J=50.1, 5.4, 3.2 Hz), 5.09 (0.40H, ddd, J=50.9, 8.6, 4.6 Hz), 4.74-4.41 (4H, m), 4.26 (0.40H, ddd, J=12.6, 8.6, 4.9 Hz), 4.12 (0.60H, ddd, J=15.4, 6.9, 5.4), 3.74 (0.60H, ddd, J=6.9, 5.3, 1.1 Hz), 3.66-3.60 (1H, m), 3.51-3.34 (1.40H, m), 2.35 (6H, s), 2.10 (1.80H, s), 2.06 (1.20H, s)

(911) ##STR00225##

(912) In a nitrogen atmosphere, 0.14 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 0.15 g of (3S,4S,5R)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolan-2-yl=acetate in 0.60 mL of methylene chloride, and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous sodium sulfate, to obtain a methylene chloride solution containing (3S,4S,5R)-2-bromo-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl) thiolane.

(913) To another reaction vessel, 0.10 g of cytosine and 0.58 mL of N,O-bis(trimethylsilyl)acetamide were added in a nitrogen atmosphere, and the obtained mixture was then stirred at 80 C. for 1.5 hours. After cooling in air, the methylene chloride solution containing (3S,4S,5R)-2-bromo-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl) thiolane was added to the reaction mixture, and the obtained mixture was then stirred at 60 C. for 2.5 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was washed with a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10), so as to obtain 72 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolane in the form of a light yellow solid.

(914) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 3862.

(915) .sup.1H-NMR (CDCl.sub.3) value:

(916) 8.08 (0.62H, dd, J=7.3, 1.7 Hz), 7.95 (0.38H, d, J=7.3 Hz), 7.23-7.05 (8H, m), 6.69 (0.62H, dd, J=18.0, 4.5 Hz), 6.39 (0.38H, dd, J=15.2, 2.0 Hz), 5.56 (0.38H, d, J=7.3 Hz), 5.50 (0.62H, d, J=7.3 Hz), 5.14 (0.38H, dt, J=46.6, 2.0 Hz), 5.11 (0.62H, dt, J=50.5, 4.5 Hz), 4.63-4.40 (4H, m), 4.29-4.15 (1H, m), 3.92 (0.38H, t, J=7.6 Hz), 3.65-3.56 (2.24H, m), 3.49 (0.38H, ddd, J=9.2, 6.8, 2.0 Hz), 2.37-2.34 (6H, m)

(917) ##STR00226##

(918) In a nitrogen atmosphere, 3.0 mL of a methylene chloride solution of 1 mol/L boron trichloride was added to a solution of 70 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolane in 4.6 mL of methylene chloride under cooling on dry ice/acetone, and the obtained mixture was then stirred at the same temperature as described above for 3.5 hours. Thereafter, the temperature of the reaction mixture was increased to 0 C., and the mixture was then stirred for 30 minutes. Thereafter, 3.0 mL of methanol was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, a solid was then collected by filtration, and it was then purified by silica gel column chromatography (chloroform/methanol=100/0 to 60/40), so as to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)thiolan-3-ol in the form of a white solid.

(919) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 24:76.

(920) .sup.1H-NMR (DMSO-d.sub.6) value:

(921) 7.99 (0.76H, dd, J=7.3, 1.3 Hz), 7.97 (0.24H, d, J=7.3 Hz), 7.31-7.20 (2H, br), 6.46 (0.76H, dd, J=14.5, 5.0 Hz), 6.15 (0.24H, dd, J=17.5, 5.9 Hz), 5.95 (0.24H, d, J=5.0 Hz), 5.90 (0.76H, d, J=5.0 Hz), 5.80 (0.24H, d, J=7.3 Hz), 5.78 (0.76H, d, J=7.3 Hz), 5.26 (0.76H, t, J=5.3 Hz), 5.18-4.82 (1.24H, m), 4.29-4.20 (0.76H, m), 4.14-4.03 (0.27H, m), 3.80-3.56 (2H, m), 3.25-3.19 (1H, m)

Example 29

(922) ##STR00227##

(923) In a nitrogen atmosphere, 0.97 g of sodium hydride and 4.66 g of 4-chlorobenzyl bromide were added to a solution of 1.35 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 13 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 5 mL of methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate and hexane were then added to the mixture. The thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 3.32 g of (2R,3R,4S)-3-((4-chlorobenzyl)oxy)-2-(((4-chlorobenzyl)oxy)methyl)-4-fluoro-5-methoxyoxolane in the form of a colorless oily product.

(924) .sup.1H-NMR (CDCl.sub.3) value:

(925) 7.33-7.20 (8H, m), 5.10 (0.5H, dd, J=6.1, 4.5 Hz), 4.93-4.91 (1.5H, m), 4.68-4.52 (4H, m), 4.13-4.07 (2H, m), 3.59-3.49 (2H, m), 3.40 (3H, s)

(926) ##STR00228##

(927) 27 mL of acetic acid, 6.6 mL of water and 1.06 mL of concentrated sulfuric acid were added to 3.32 g of (2R,3R,4S)-3-((4-chlorobenzyl)oxy)-2-(((4-chlorobenzyl)oxy)methyl)-4-fluoro-5-methoxyoxolane, and the obtained mixture was then stirred at 70 C. for 2 hours. Thereafter, 4.5 mL of water and 0.53 mL of concentrated sulfuric acid were added to the reaction mixture, and the obtained mixture was then stirred at 70 C. for 5 hours. Thereafter, ethyl acetate and hexane were added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 30/70), so as to obtain 2.92 g of (3S,4R,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorooxolan-2-ol in the form of a colorless oily product.

(928) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 18:82.

(929) .sup.1H-NMR (CDCl.sub.3) value:

(930) 7.35-7.29 (4H, m), 7.25-7.20 (4H, m), 5.49 (0.82H, dd, J=10.2, 6.3 Hz), 5.31 (0.18H, ddd, J=10.2, 3.8, 2.3 Hz), 4.95 (0.18H, dt, J=52.8, 4.6 Hz), 4.95 (0.82H, dd, J=50.2, 0.3 Hz), 4.68-4.48 (4H, m), 40.43 (0.82H, td, J=5.6, 4.3 Hz), 4.26 (0.18H, dt, J=17.6, 4.6 Hz), 4.10 (0.18H, dt, J=5.0, 3.8 Hz), 3.99 (0.82H, ddt, J=19.8, 4.3, 0.9 Hz), 3.70 (0.18H, dd, J=10.2, 1.5 Hz), 3.62-3.48 (2H, m), 2.88 (0.82H, dd, J=6.6, 1.3 Hz)

(931) ##STR00229##

(932) In a nitrogen atmosphere, 14 mL of methanol and 0.72 g of O-methylhydroxylamine hydrochloride were added to 2.89 g of (3S,4R,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorooxolan-2-ol, and thereafter, 1.21 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 12 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), so as to obtain 3.09 g of (2R,3R,4R)-3,5-bis((4-chlorobenzyl)oxy)-2-fluoro-4-hydroxypentanal=O-methyl=oxime in the form of a white solid.

(933) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 65:35.

(934) .sup.1H-NMR (CDCl.sub.3) value:

(935) 7.47 (0.65H, t, J=6.9 Hz), 7.35-7.13 (8H, m), 6.99 (0.35H, dd, J=11.6, 4.6 Hz), 5.80 (0.35H, ddd, J=46.9, 4.6, 1.7 Hz), 5.28 (0.65H, ddd, J=45.9, 6.9, 3.3 Hz), 4.62-4.39 (4H, m), 4.00-3.83 (4.35H, m), 3.76-3.56 (2.65H, m), 2.42 (0.35H, d, J=6.6 Hz), 2.40 (0.65H, d, J=6.6 Hz)

(936) ##STR00230##

(937) In a nitrogen atmosphere, 31 mL of acetonitrile, 2.81 g of 2,4,5-trichlorobenzenesulfonyl chloride and 1.02 mL of N-methylimidazole were added to 3.08 g of (2R,3R,4R)-3,5-bis((4-chlorobenzyl)oxy)-2-fluoro-4-hydroxypentanal=O-methyl=oxime, and the obtained mixture was then stirred at room temperature for 4.5 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 70/30), so as to obtain 4.72 g of (2R,3R,4R)-1,3-bis((4-chlorobenzyl)oxy)-4-fluoro-5-(methoxyimino)pentan-2-yl=2,4,5-trichlorobenzenesulfonate in the form of a colorless oily product.

(938) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 68:32.

(939) .sup.1H-NMR (CDCl.sub.3) value:

(940) 8.08 (0.32H, s), 8.07 (0.68H, s), 7.42 (1H, s), 7.37 (0.68H, t, J=6.7 Hz), 7.33-7.27 (4H, m), 7.21-7.08 (4H, m), 6.87 (0.32H, dd, J=11.6, 4.6 Hz), 5.58 (0.32H, ddd, J=47.6, 4.6, 3.0 Hz), 5.12 (0.68H, ddd, J=46.5, 6.7, 4.2 Hz), 4.84 (0.68H, ddd, J=5.6, 4.8, 3.0 Hz), 4.77 (0.32H, td, J=5.6, 2.3 Hz), 4.68-40.53 (2H, m), 4.41-4.29 (2.16H, m), 4.25 (0.16H, dd, J=5.6, 2.3 Hz), 4.10 (0.68H, td, J=23.1, 4.5 Hz), 3.88 (3H, s), 3.86-3.73 (2H, m)

(941) ##STR00231##

(942) In a nitrogen atmosphere, 47 mL of 1,3-dimethyl-2-imidazolidinone and 3.64 g of anhydrous lithium bromide were added to 4.71 g of (2R,3R,4R)-1,3-bis((4-chlorobenzyl)oxy)-4-fluoro-5-(methoxyimino)pentan-2-yl=2,4,5-trichlorobenzenesulfonate, and the obtained mixture was then stirred at 50 C. for 14 hours. Thereafter, ethyl acetate and hexane were added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 2.78 g of (2R,3S,4S)-4-bromo-3,5-bis((4-chlorobenzyl)oxy)-2-fluoropentanal=O-methyl=oxime in the form of a light yellow oily product.

(943) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 81:19.

(944) .sup.1H-NMR (CDCl.sub.3) value:

(945) 7.42 (0.81H, t, J=6.6 Hz), 7.34-7.21 (8H, m), 6.89 (0.19H, dd, J=11.6, 4.8 Hz), 5.79 (0.19H, ddd, J=47.6, 4.8, 3.0 Hz), 5.31 (0.81H, dt, J=47.2, 6.6 Hz), 4.80-4.39 (4H, m), 4.30-4.11 (1.19H, m), 4.00 (0.81H, ddd, J=16.8, 6.6, 3.3 Hz), 3.913 (2.43H, s), 3.905 (0.57H, s), 3.89-3.77 (1.19H, m), 3.70 (0.81H, ddd, J=10.2, 5.9, 2.3 Hz)

(946) ##STR00232##

(947) In a nitrogen atmosphere, 55 mL of acetone, 14 mL of 2 mol/L hydrochloric acid and 4.80 mL of a 37% formaldehyde aqueous solution were added to 2.75 g of (2R,3S,4S)-4-bromo-3,5-bis((4-chlorobenzyl)oxy)-2-fluoropentanal=O-methyl=oxime, and the obtained mixture was then stirred at room temperature for 5.5 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 20/80), so as to obtain 2.56 g of a light yellow oily product.

(948) The obtained oily product was a mixture of (2S,3S,4S)-4-bromo-3,5-bis((4-chlorobenzyl)oxy)-2-fluoropentanal and a water adduct thereof.

(949) .sup.1H-NMR (CDCl.sub.3) value:

(950) 9.80 (1H, d, J=5.9 Hz), 7.35-7.15 (8H, m), 5.13 (1H, dd, J=47.6, 3.6 Hz), 4.66-4.44 (4H, m), 4.37 (1H, dt, J=5.9, 5.1 Hz), 4.22 (1H, ddd, J=23.0, 5.1, 3.6 Hz), 3.94 (1H, dd, J=10.9, 5.3 Hz), 3.78 (1H, ddd, J=10.9, 5.9, 2.5 Hz)

(951) ##STR00233##

(952) 0.91 g of a sodium hydrogen sulfide x-hydrate was added to a solution of 2.50 g of the light yellow oily product obtained in Example 29 (6) in 25 mL of 1-methyl-2-pyrrolidone under cooling on ice, and the obtained mixture was then stirred under cooling on ice for 1.5 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, 0.5 mol/L hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50), so as to obtain 1.92 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolan-2-ol in the form of a light yellow oily product.

(953) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 63:37.

(954) .sup.1H-NMR (CDCl.sub.3) value:

(955) 7.42-7.19 (8H, m), 5.45 (0.37H, ddd, J=11.6, 9.2, 1.2 Hz), 5.15 (0.63H, ddd, J=8.3, 3.6, 3.0 Hz), 5.13 (0.37H, dt, J=47.9, 1.2 Hz), 5.01 (0.63H, ddd, J=52.2, 7.1, 4.1 Hz), 4.72-4.41 (4H, m), 4.35-4.36 (1H, m), 3.93 (0.37H, t, J=7.8 Hz), 3.59-3.34 (3.26H, m), 2.89 (0.37H, dd, J=11.6, 1.0 Hz)

(956) ##STR00234##

(957) 0.86 mL of acetic anhydride and 1.90 mL of triethylamine were added to a solution of 1.89 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolan-2-ol in 19 mL of tetrahydrofuran under cooling on ice, and the obtained mixture was then stirred at room temperature for 24 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40), so as to obtain 1.77 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolan-2-yl=acetate in the form of a light yellow oily product.

(958) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 40:60.

(959) .sup.1H-NMR (CDCl.sub.3) value:

(960) 7.33-7.20 (8H, m), 6.04 (0.40H, d, J=4.3 Hz), 6.02 (0.60H, dd, J=16.8, 3.0 Hz), 5.19 (0.60H, ddd, J=50.0, 5.4, 3.0 Hz), 5.11 (0.40H, ddd, J=50.9, 8.3, 4.3 Hz), 4.76-4.41 (4H, m), 4.24 (0.40H, ddd, J=12.2, 8.3, 6.6 Hz), 4.12 (0.60H, ddd, J=15.4, 6.6, 5.4), 3.75 (0.60H, qd, J=6.6, 1.0 Hz), 3.65-3.60 (1H, m), 3.50 (0.60H, dd, J=9.6, 6.6 Hz), 3.47 (0.40H, ddd, J=9.7, 6.6, 1.0 Hz), 3.37 (0.40H, q, J=6.6 Hz), 2.11 (1.8H, s), 2.08 (1.2H, s)

(961) ##STR00235##

(962) In a nitrogen atmosphere, 0.17 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 0.20 g of (3S,4S,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolan-2-yl=acetate in 0.80 mL of methylene chloride, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate, to obtain a methylene chloride solution containing (3S,4S,5R)-2-bromo-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane.

(963) To another reaction vessel, 0.12 g of cytosine and 0.53 mL of N,O-bis(trimethylsilyl)acetamide were added in a nitrogen atmosphere, and the obtained mixture was then stirred at 80 C. for 2 hours. After cooling in air, a methylene chloride solution containing (3S,4S,5R)-2-bromo-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane was added to the reaction mixture, and the obtained mixture was then stirred 60 C. for 2 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was washed with a a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 80/20), so as to obtain 0.18 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane in the form of a light yellow solid.

(964) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 36:64.

(965) .sup.1H-NMR (CDCl.sub.3) value:

(966) 8.01 (0.64H, dd, J=7.6, 1.8 Hz), 7.93 (0.36H, d, J=7.6 Hz), 7.36-7.09 (8H, m), 6.73 (0.64H, dd, J=1 9.2, 4.3 Hz), 6.38 (0.36H, dd, J=15.0, 2.3 Hz), 5.54 (0.36H, d, J=7.6 Hz), 5.53 (0.64H, d, J=7.6 Hz), 5.20 (0.36H, dt, J=47.2, 2.3 Hz), 5.14 (0.64H, dt, J=50.5, 4.3 Hz), 4.65-4.41 (4H, m), 4.28-4.21 (1H, m), 3.95-3.89 (0.36H, m), 3.66-3.60 (2.28H, m), 3.54-3.48 (0.36H, m)

(967) ##STR00236##

(968) In a nitrogen atmosphere, 6.8 mL of a methylene chloride solution of 1 mol/L boron trichloride was added to a solution of 0.17 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane in 11 mL of methylene chloride under cooling on dry ice/acetone, and the obtained mixture was then stirred at the same temperature as described above for 3.5 hours. Thereafter, the temperature of the reaction mixture was increased to 0 C., and the reaction mixture was then stirred for 30 minutes. Thereafter, 7.5 mL of methanol was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, a solid was collected by filtration, and it was successively washed with ethyl acetate and hexane. The obtained solid was purified by silica gel column chromatography (chloroform/methanol=100/0 to 60/40), so as to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)thiolan-3-ol in the form of a white solid.

(969) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 2773.

(970) .sup.1H-NMR (DMSO-d.sub.6) value:

(971) 7.99 (0.73H, dd, J=7.3, 1.3 Hz), 7.97 (0.27H, d, J=7.3 Hz), 7.31-7.20 (2H, br), 6.46 (0.73H, dd, J=14.7, 5.3 Hz), 6.15 (0.27H, dd, J=17.5, 5.9 Hz), 5.95 (0.27H, d, J=5.3 Hz), 5.89 (0.73H, d, J=5.3 Hz), 5.80 (0.27H, d, J=7.3 Hz), 5.78 (0.73H, d, J=7.3 Hz), 5.26 (0.73H, t, J=5.3 Hz), 5.18-4.82 (1.27H, m), 4.29-4.20 (0.73H, m), 4.14-4.03 (0.27H, m), 3.80-3.54 (2H, m), 3.25-3.19 (1H, m)

Example 30

(972) ##STR00237##

(973) In a nitrogen atmosphere, 55 mL of methylene chloride and 2.60 mL of 1-methylimidazole were added to 1.37 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol, and thereafter, 3.52 mL of (benzyloxy)carbonyl chloride was added dropwise to the mixture under cooling on ice. The obtained mixture was stirred at room temperature for 3 hours. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then dissolved in ethyl acetate. The resultant was successively washed with water and a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 70/30), so as to obtain 2.91 g of benzyl=((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=carbonate in the form of a colorless oily product.

(974) .sup.1H-NMR (CDCl.sub.3) value:

(975) 7.40-7.33 (10H, m), 5.33-5.22 (1H, m), 5.14 (0.5H, dd, J=5.6, 4.3 Hz), 4.97-4.96 (1.5H, m), 4.53 (1H, dd, J=11.2, 4.0 Hz), 4.31 (1H, dd, J=11.2, 7.6 Hz), 4.21 (1H, ddd, J=7.6, 5.1, 4.0 Hz), 3.45 (3H, s)

(976) ##STR00238##

(977) 21 mL of acetic acid, 5.2 mL of water and 0.67 mL of concentrated sulfuric acid were added to 2.58 g of benzyl=((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-methoxyoxolan-2-yl)methyl=carbonate, and the obtained mixture was then stirred at 70 C. for 8 hours. Thereafter, 0.30 mL of concentrated sulfuric acid was added to the reaction mixture, and the obtained mixture was further stirred at 70 C. for 7 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 50/50), so as to obtain 1.69 g of benzyl=((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=carbonate in the form of a colorless oily product.

(978) As a result of the measurement of .sup.1H-NMR, the cap ratio was found to be 20:80.

(979) .sup.1H-NMR (CDCl.sub.3) value:

(980) 7.40-7.33 (10H, m), 5.56 (0.80H, dd, J=10.2, 4.0 Hz), 5.42 (0.20H, ddd, J=8.6, 6.6, 3.6 Hz), 5.23-5.14 (4.20H, m), 5.03 (0.80H, dd, J=21.3, 4.1 Hz), 5.02 (0.80H, dd, J=48.2, 1.0 Hz), 4.96 (0.20H, dt, J=50.9, 3.6 Hz), 4.53-4.43 (2H, m), 4.34 (0.80H, dd, J=12.4, 6.8 Hz), 4.17 (0.20H, dd, J=5.9, 4.1 Hz), 3.34 (0.20H, dd, J=8.6, 2.0 Hz), 2.70 (0.80H, dd, J=4.0, 2.8 Hz)

(981) ##STR00239##

(982) 8.4 mL of methanol and 0.37 g of O-methylhydroxylamine hydrochloride were added to 1.68 g of benzyl=((2R,3R,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxyoxolan-2-yl)methyl=carbonate, and thereafter, 0.61 mL of triethylamine was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 2 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 60/40), so as to obtain 1.66 g of dibenzyl=((2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl)=dicarbonate in the form of a colorless oily product.

(983) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 77:23.

(984) .sup.1H-NMR (CDCl.sub.3) value:

(985) 7.41-7.33 (10.77H, m), 6.82 (0.23H, dd, J=11.2, 4.6 Hz), 5.89 (0.23H, ddd, J=46.2, 4.6, 2.1 Hz), 5.39 (0.77H, ddd, J=45.2, 6.4, 2.8 Hz), 5.29-5.13 (4.23H, m), 5.01 (0.77H, ddd, J=24.0, 8.0, 2.9 Hz), 4.35-4.09 (3H, m), 3.89 (0.69H, s), 3.84 (2.31H, s), 2.62 (0.77H, d, J=5.9 Hz), 2.60 (0.23H, d, J=6.9 Hz)

(986) ##STR00240##

(987) In a nitrogen atmosphere, 10 mL of acetonitrile, 1.55 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.87 mL of N-methylimidazole were added to 1.66 g of the dibenzyl=((2R,3R,4R)-4-fluoro-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl)=dicarbonate, and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 2.40 g of dibenzyl=((2R,3R,4R)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentane-1,3-diyl)=dicarbonate in the form of a colorless oily product.

(988) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 78:22.

(989) .sup.1H-NMR (CDCl.sub.3) value:

(990) 8.11 (0.22H, s), 8.10 (0.78H, s), 7.51 (1H, s), 7.43-7.33 (10.78H, m), 6.78 (0.22H, dd, J=11.4, 4.5 Hz), 5.71 (0.22H, ddd, J=46.9, 4.5, 2.8 Hz), 5.54 (0.22H, ddd, J=25.1, 5.8, 2.8 Hz), 5.37 (0.78H, ddd, J=21.5, 5.6, 4.0 Hz), 5.31 (0.39H, dd, J=6.3, 4.0 Hz), 5.22-5.03 (5.17H, m), 5.00 (0.22H, td, J=5.8, 2.6 Hz), 4.46-4.39 (1H, m), 4.36-4.30 (1H, m), 3.87 (0.66H, s), 3.85 (2.34H, s)

(991) ##STR00241##

(992) In a nitrogen atmosphere, 24 mL of 1,3-dimethyl-2-imidazolidinone and 1.65 g of anhydrous lithium bromide were added to 2.40 g of the dibenzyl=((2R,3R,4R)-4-fluoro-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentane-1,3-diyl)=dicarbonate, and the obtained mixture was then stirred at 50 C. for 9 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 80/20), so as to obtain 1.25 g of dibenzyl=((2R,3S,4S)-2-bromo-4-fluoro-5-(methoxyimino)pentane-1,3-diyl)=dicarbonate in the form of a colorless oily product.

(993) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 79:21.

(994) .sup.1H-NMR (CDCl.sub.3) value:

(995) 7.42-7.34 (10.79H, m), 6.82 (0.21H, dd, J=11.2, 4.8 Hz), 5.94 (0.21H, ddd, J=46.9, 4.8, 3.1 Hz), 5.47-5.16 (5.79H, m), 4.59-4.31 (3H, m), 3.89 (3H, s)

(996) ##STR00242##

(997) In a nitrogen atmosphere, 22 mL of acetone, 5.6 mL of 2 mol/L hydrochloric acid and 1.87 mL of a 37% formaldehyde aqueous solution were added to 1.11 g of dibenzyl=((2R,3S,4S)-2-bromo-4-fluoro-5-(methoxyimino)pentane-1,3-diyl)=dicarbonate, and the obtained mixture was then stirred at room temperature for 4 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 20/80), so as to obtain 1.07 g of a colorless oily product.

(998) The obtained oily product was a mixture of dibenzyl=((2R,3S,4S)-2-bromo-4-fluoro-5-oxopentane-1,3-diyl)=dicarbonate and a water adduct thereof.

(999) .sup.1H-NMR (CDCl.sub.3) value:

(1000) 9.74 (1H, d, J=5.6 Hz), 7.39-7.31 (10H, m), 5.38 (1H, dt, J=22.0, 4.0 Hz), 5.20-5.13 (5H, m), 4.62-4.31 (3H, m)

(1001) ##STR00243##

(1002) 0.37 g of a sodium hydrogen sulfide x-hydrate was added to a solution of 1.05 g of the colorless oily product obtained in Example 30 (6) in 11 mL of 1-methyl-2-pyrrolidone under cooling on ice, and the obtained mixture was then stirred under cooling on ice for 1.5 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with water, 0.5 mol/L hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 40/60), so as to obtain 0.64 g of benzyl=((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=carbonate in the form of a light yellow oily product.

(1003) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 36:64.

(1004) .sup.1H-NMR (CDCl.sub.3) value:

(1005) 7.40-7.31 (10H, m), 5.53-5.45 (1H, m), 5.40 (0.36H, dtd, J=10.2, 2.0, 1.0 Hz), 5.34 (0.64H, t, J=4.0 Hz), 5.27-5.10 (4.68H, m), 4.95 (0.32H, dd, J=7.3, 4.0 Hz), 4.46 (0.64H, dd, J=10.6, 6.4 Hz), 4.37 (0.64H, dd, J=10.6, 6.4 Hz), 4.22 (0.72H, dd, J=7.3, 1.0 Hz), 4.03-3.97 (0.36H, m), 3.54 (0.64H, td, J=6.4, 5.3 Hz)

(1006) ##STR00244##

(1007) 0.28 mL of acetic anhydride and 0.61 mL of triethylamine were added to a solution of 0.64 g of benzyl=((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-5-hydroxythiolan-2-yl)methyl=carbonate in 6.4 mL of tetrahydrofuran under cooling on ice, and the obtained mixture was then stirred at room temperature for 4 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was successively washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 40/60), so as to obtain 0.58 g of (3S,4S,5R)-4-(((benzyloxy)carbonyl)oxy)-5-((((benzyloxy)carbonyl)oxy)methyl)-3-fluorothiolan-2-yl=acetate in the form of a light yellow oily product.

(1008) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 40:60.

(1009) .sup.1H-NMR (CDCl.sub.3) value:

(1010) 7.39-7.34 (10H, m), 6.08 (0.60H, dd, J=14.5, 1.7 Hz), 6.05 (0.40H, d, J=4.3 Hz), 5.51 (0.40H, ddd, J=11.9, 8.8, 7.1 Hz), 5.38-5.03 (5.60H, m), 4.47 (0.40H, dd, J=11.1, 5.8 Hz), 4.34-4.20 (1.60H, m), 3.89 (0.60H, q, J=6.4 Hz), 3.51 (0.40H, q, J=6.5 Hz), 2.11 (1.20H, s), 2.07 (1.80H, s)

(1011) ##STR00245##

(1012) In a nitrogen atmosphere, 0.08 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 100 mg of (3S,4S,5R)-4-(((benzyloxy)carbonyl)oxy)-5-((((benzyloxy)carbonyl)oxy)methyl)-3-fluorothiolan-2-yl=acetate in 0.40 mL of methylene chloride, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous sodium sulfate, to obtain a methylene chloride solution containing benzyl=((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-5-bromo-4-fluorothiolan-2-yl)methyl=carbonate.

(1013) To another reaction vessel, 59 mg of cytosine and 0.36 mL of N,O-bis(trimethylsilyl)acetamide were added in a nitrogen atmosphere, and the obtained mixture was then stirred at 80 C. for 1.5 hours. After cooling in air, the methylene chloride solution containing benzyl=((2R,3S,4S)-3-(((benzyloxy)carbonyl)oxy)-5-bromo-4-fluorothiolan-2-yl)methyl=carbonate was added to the reaction mixture, and the obtained mixture was then stirred at 60 C. for 3 hours. Thereafter, methylene chloride was added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 80/20), so as to obtain 15 mg of benzyl=((2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-(((benzyloxy)carbonyl)oxy)-4-fluorothiolan-2-yl)methyl=carbonate in the form of a white solid.

(1014) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 24:76.

(1015) .sup.1H-NMR (CDCl.sub.3) value:

(1016) 7.96 (0.76H, dd, J=7.3, 2.1 Hz), 7.96 (0.24H, d, J=7.3 Hz), 7.41-7.34 (10H, m), 6.82 (0.76H, dd, J=23.8, 4.0 Hz), 6.35 (0.24H, dd, J=15.2, 2.3 Hz), 5.77-5.66 (1.24H, m), 5.43-5.07 (5.76H, m), 4.45-4.30 (2H, m), 4.08 (0.24H, t, J=7.6 Hz), 3.80 (0.76H, t, J=7.6 Hz)

(1017) ##STR00246##

(1018) 1.0 mL of a 7 mol/L ammonia/methanol solution was added to 15 mg of benzyl=((2R,3S,4S)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((benzyloxy)carbonyl)oxy)-4-fluorothiolan-2-yl)methyl=carbonate, and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (chloroform/methanol=100/0 to 65/35), so as to obtain 6.6 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)thiolan-3-ol in the form of a white solid.

(1019) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 26:74.

(1020) .sup.1H-NMR (DMSO-d.sub.6) value:

(1021) 7.99 (0.74H, dd, J=7.3, 1.3 Hz), 7.97 (0.26H, d, J=7.3 Hz), 7.29-7.19 (2H, br), 6.46 (0.74H, dd, J=14.5, 5.0 Hz), 6.15 (0.26H, dd, J=17.5, 5.9 Hz), 5.94 (0.26H, d, J=5.0 Hz), 5.88 (0.74H, d, J=5.0 Hz), 5.79 (0.26H, d, J=7.3 Hz), 5.78 (0.74H, d, J=7.3 Hz), 5.26 (0.74H, t, J=5.3 Hz), 5.17-4.82 (1.26H, m), 4.29-4.20 (0.74H, m), 4.14-4.03 (0.26H, m), 3.79-3.56 (2H, m), 3.25-3.19 (1H, m)

Example 31

(1022) ##STR00247##

(1023) A mixture of 1.15 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol, 20 mL of N,N-dimethylformamide, 5.33 mL of tert-butyl diphenylchlorosilane and 2.83 g of imidazole was stirred at room temperature for 1 hour, and the reaction mixture was then left at room temperature for 1 day. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 9/1), so as to obtain 3.15 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluoro-2-methoxyoxolane in the form of a colorless oily product.

(1024) .sup.1H-NMR (CDCl.sub.3) value:

(1025) 7.59-7.51 (8H, m), 7.41-7.24 (12H, m), 4.94 (1H, d, J=5.3 Hz), 4.92 (1H, ddd, J=52.8, 5.9, 4.6 Hz), 4.32 (1H, dt, J=16.5, 5.3 Hz), 4.13-4.07 (1H, m), 3.38 (2H, d, J=5.3 Hz), 3.29 (3H, s), 1.06 (9H, s), 0.97 (9H, s)

(1026) ##STR00248##

(1027) 1.0 mL of 30% hydrogen bromide/acetic acid was added dropwise to a solution of 1.66 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluoro-2-methoxyoxolane in 10 mL of methylene chloride at room temperature, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, ethyl acetate and water were added to the reaction mixture, and the obtained mixture was then stirred for 5 minutes. Thereafter, the organic layer was fractionated, and it was washed with a 10% sodium hydrogen carbonate aqueous solution. After that, the solvent was distilled away under reduced pressure. 10 mL of acetonitrile and 10 mL of a 10% sodium hydrogen carbonate aqueous solution were added to the obtained residue, and the obtained mixture was then stirred at room temperature for 3 hours. Subsequently, the reaction mixture was left overnight. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 9/1), so as to obtain 0.65 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorooxolan-2-ol in the form of a colorless oily product.

(1028) .sup.1H-NMR (CDCl.sub.3) value:

(1029) 7.65-7.24 (20H, m), 5.37 (1H, t, J=9.2 Hz), 4.76 (1H, dd, J=50.2, 1.3 Hz), 4.45 (1H, td, J=5.4, 2.9 Hz), 4.38-4.32 (1H, m), 3.47-4.43 (2H, m), 3.15 (1H, d, J=8.6 z), 1.07 (9H, s), 0.91 (9H, s)

(1030) ##STR00249##

(1031) 0.13 g of O-methylhydroxylamine hydrochloride and 1.0 mL of methanol were added to 0.65 g of (3S,4R,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorooxolan-2-ol, and thereafter, 0.19 mL of triethylamine was added dropwise to the mixture under cooling on ice. The obtained mixture was stirred at room temperature for 3 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 9/1), so as to obtain 0.32 g of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-hydroxypentanal=O-methyloxime in the form of a colorless oily product.

(1032) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 4:1.

(1033) .sup.1H-NMR (CDCl.sub.3) value:

(1034) 7.63-7.50 (8H, m), 7.46-7.28 (12.75H, m), 6.72 (0.25H, dd, J=11.2, 4.6 Hz), 5.73 (0.25H, ddd, J=46.6, 4.6, 2.0 Hz), 5.10 (0.75H, ddd, J=46.1, 7.3, 4.0 Hz), 4.10 (0.25H, ddd, J=28.1, 6.3, 1.7 Hz), 3.98-3.77 (2.75H, m), 3.76 (2.25H, s), 3.60-3.50 (1.75H, m), 2.66 (0.25H, dd, J=4.0, 1.3 Hz), 2.55 (0.25H, ddd, J=28.1, 6.3, 1.7 Hz), 1.01 (9H, s), 0.97 (6.75H, s), 0.94 (2.25H, s)

(1035) ##STR00250##

(1036) A mixture of 0.32 g of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-hydroxypentanal=O-methyloxime, 2 mL of acetonitrile, 1 mL of tetrahydrofuran 0.1 mL of N-methylimidazole and 0.15 g of 2,4,5-trichlorobenzenesulfonyl chloride was stirred at room temperature for 8 hours, and the reaction mixture was then left at room temperature for 3 days. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 19/1), so as to obtain 0.24 g of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentanal=O-methyloxime in the form of a colorless oily product.

(1037) .sup.1H-NMR (CDCl.sub.3) value:

(1038) 8.01 (1H, s), 7.63-7.56 (8H, m), 7.46-7.28 (13H, m), 7.15 (1H, t, J=6.9 Hz), 5.01 (1H, dt, J=47.6, 7.3 Hz), 4.90 (1H, t, J=7.3 Hz), 4.32 (1H, ddd, J=13.2, 6.6, 1.3 Hz), 4.03 (1H, dd, J=11.2, 5.9 Hz), 3.83 (1H, dd, J=11.2, 6.6 Hz), 3.79 (3H, s), 0.99 (9H, s), 0.97 (9H, s)

(1039) ##STR00251##

(1040) 114 mg of anhydrous lithium bromide and 1.0 mL of 1,3-dimethyl-2-imidazolidinone were added to a solution of 236 mg of (2R,3R,4R)-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoro-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentanal=O-methyloxime in 1.0 mL of tetrahydrofuran, and the obtained mixture was then stirred at 50 C. for 10 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 19/1), so as to obtain 173 mg of (2R,3S,4S)-4-bromo-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoropentanal=O-methyloxime in the form of a colorless oily product.

(1041) .sup.1H-NMR (CDCl.sub.3) value:

(1042) 7.71-7.53 (8H, m), 7.46-7.29 (12H, m), 7.17 (0.86H, t, J=7.3 Hz), 6.57 (0.14H, dd, J=10.6, 5.3 Hz), 5.75 (0.14H, dt, J=47.3, 4.6 Hz), 5.13 (0.86H, dt, J=46.9, 6.6 Hz), 4.26-4.19 (1H, m), 4.08-4.00 (1H, m), 3.87-3.78 (4.58H, m), 3.65 (0.42H, s), 1.03 (9H, s), 1.00 (9H, s)

(1043) ##STR00252##

(1044) 0.18 mL of a 37% formaldehyde aqueous solution, 0.20 mL of water and 0.04 mL of concentrated hydrochloric acid were added to a solution of 173 mg of (2R,3S,4S)-4-bromo-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoropentanal O-methyloxime in 1.0 mL of acetone, and the obtained mixture was then stirred at room temperature for 48 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 7/3), so as to obtain 114 mg of a colorless oily product.

(1045) The obtained oily product was a mixture of (2R,3S,4S)-4-bromo-3,5-bis((tert-butyldiphenylsilyl)oxy)-2-fluoropentanal and a water adduct thereof.

(1046) .sup.1H-NMR (CDCl.sub.3) value:

(1047) 9.59 (1H, d, J=7.9 Hz), 7.66-7.57 (8H, m), 7.44-7.27 (12H, m), 4.93 (1H, dd, J=46.9, 4.0 Hz), 4.42 (1H, ddd, J=18.5, 4.0, 2.6 Hz), 4.16-4.09 (2H, m), 3.88 (1H, ddd, J=12.9, 8.9, 2.6 Hz), 1.03 (9H, s), 1.01 (9H, s)

(1048) ##STR00253##

(1049) 87 mg of a 15%-18% sodium hydrogen sulfide aqueous solution 87 mg was added to a solution of 114 mg of the colorless oily product obtained in Example 31 (6) in 0.5 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 30 minutes. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was then washed with a 10% sodium chloride aqueous solution three times. The solvent was distilled away under reduced pressure, so as to obtain a light yellow oily product containing (3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-ol.

(1050) The light yellow oily product was directly used in the subsequent reaction.

(1051) .sup.1H-NMR (CDCl.sub.3) value:

(1052) 7.74-7.22 (20H, m), 5.43-5.28 (1H, m), 4.96 (0.5H, d, J=48.2 Hz), 4.86 (0.5H, ddd, J=51.5, 5.9, 4.0 Hz), 4.60-4.53 (1H, m), 3.93 (0.5H, t, J=7.9 Hz), 3.48-3.32 (2H, m), 3.26 (0.5H, dd, J=9.2, 5.3 Hz), 1.08 (4.5H, s), 1.07 (4.5H, s), 0.92 (4.5H, s), 0.91 (4.5H, s)

(1053) ##STR00254##

(1054) 0.1 mg of dimethylaminopyridine and 0.1 mL of acetic anhydride were added to a solution of the light yellow oily product obtained in Example 31 (7) in 1.0 mL of tetrahydrofuran. The obtained mixture was stirred at room temperature for 1 hour, and it was then left at room temperature overnight. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 9/1), so as to obtain 67 mg of (3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl=acetate in the form of a colorless oily product.

(1055) .sup.1H-NMR (CDCl.sub.3) value:

(1056) 7.60-7.48 (8H, m), 7.44-7.23 (12H, m), 6.02 (0.5H, dd, J=4.6, 1.3 Hz), 5.96 (0.5H, dd, J=16.2, 3.0 Hz), 5.06 (0.5H, ddd, J=48.9, 5.0, 3.0 Hz), 4.99 (0.5H, ddd, J=50.9, 8.6, 4.6 Hz), 4.34-4.18 (1H, m), 3.84-3.77 (0.5H, m), 3.66-3.60 (1H, m), 3.41 (0.5H, td, J=7.6, 3.3 Hz), 3.31-3.18 (1H, m), 2.12 (1.5H, s), 1.89 (1.5H, s), 1.03 (4.5H, s), 0.99 (4.5H, s), 0.95 (9H, s)

(1057) ##STR00255##

(1058) 0.03 mL of a 30% hydrogen bromide/acetic acid solution was added to a solution of 59 mg of (3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl=acetate in 1.0 mL of methylene chloride, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, methylene chloride and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a 5% sodium hydrogen carbonate aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain a light brown oily product containing (3S,4S,5R)-2-bromo-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophene.

(1059) 24 mg of cytosine and 0.2 mL of N,O-bis(trimethylsilyl)acetamide were added to the obtained light brown oily product, and the obtained mixture was then stirred 80 C. for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1), so as to obtain 43 mg of ((3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl)cytosine in the form of a colorless oily product.

(1060) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 15/85.

(1061) .sup.1H-NMR (CDCl.sub.3+D.sub.2O) value:

(1062) 8.12 (0.15H, d, J=7.3 Hz), 7.69-7.25 (20.85H, m), 6.89 (0.85H, dd, J=23.1, 4.0 Hz), 6.26 (0.15H, dd, J=16.2, 2.3 Hz), 5.71 (0.15H, d, J=7.3 Hz), 5.55 (0.85H, d, J=7.3 Hz), 5.02 (0.15H, dt, J=48.2, 2.6 Hz), 4.85 (0.85H, dt, J=51.1, 3.3 Hz), 4.42 (0.85H, d, J=7.3 Hz), 4.30 (0.15H, dt, J=11.7, 3.0 Hz), 3.88 (0.15H, t, J=6.6 Hz), 3.65-3.48 (2.7H, m), 3.34 (0.15H, t, J=9.2 Hz), 1.07 (7.65H, s), 0.99 (1.35H, s), 0.91 (9H, s)

(1063) ##STR00256##

(1064) 0.24 mL of 1 mol/L tetrabutyl ammonium fluoride/tetrahydrofuran solution was added to a solution of 43 mg of ((3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl)cytosine in 1.0 mL of tetrahydrofuran. The obtained mixture was stirred at room temperature for 2 hours, and was then left overnight. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 2/1), so as to obtain 14 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a white solid.

(1065) As a result of the measurement of H-NMR, the / ratio was found to be 16/84.

(1066) .sup.1H-NMR (DMSO-d.sub.6) value:

(1067) 8.01-7.96 (1H, m), 7.30-7.22 (2H, br), 6.46 (0.84H, dd, J=14.5, 5.3 Hz), 6.15 (0.16H, dd, J=17.2, 5.9 Hz), 5.93 (0.16H, d, J=5.3 Hz), 5.87 (0.84H, d, J=4.0 Hz), 5.80-5.76 (1H, m), 5.25 (0.84H, t, J=5.3 Hz), 5.17-4.82 (1.16H, m), 4.29-4.20 (0.84H, m), 4.15-4.06 (0.16H, m), 3.80-3.55 (2H, m), 3.25-3.16 (1H, m)

Example 32

(1068) ##STR00257##

(1069) 2.9 mL of 30% hydrogen bromide/acetic acid was added dropwise to a suspension of 5.0 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in 1.3 mL of acetic acid at room temperature, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, 20 mL of toluene and 20 mL of water were added to the reaction mixture, and the obtained mixture was then stirred for 5 minutes. Thereafter, the water layer was removed. The obtained organic layer was washed with 20 mL of a 10% sodium hydrogen carbonate aqueous solution, and the solvent was then distilled away under reduced pressure. 10 mL of acetonitrile and 10 mL of a 10% sodium hydrogen carbonate aqueous solution were added to the obtained oily product, and the obtained mixture was then stirred at room temperature for 1 hour and was then left overnight. Thereafter, 20 mL of toluene and 10 mL of water were added to the reaction mixture, and the obtained mixture was then stirred for 5 minutes. After that, the water layer was removed, and the solvent was then distilled away under reduced pressure, so as to obtain a colorless oily product containing 2,3,5-tri-O-benzoyl-D-ribofuranose.

(1070) The colorless oily product was directly used in the subsequent reaction.

(1071) ##STR00258##

(1072) 1.3 g of O-methylhydroxylamine hydrochloride and 5.0 mL of methanol were added to the colorless oily product obtained in Example 32 (1), and thereafter, 1.8 mL of triethylamine was added dropwise to the mixture under cooling on ice. The obtained mixture was stirred at room temperature for 3 hours. Thereafter, 10 mL of toluene and 10 mL of a 10% sodium chloride aqueous solution were added to the reaction mixture. The water layer was removed, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/1), so as to obtain 2.7 g of (2R,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl=tribenzoate in the form of a colorless oily product.

(1073) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 4:1.

(1074) .sup.1H-NMR (CDCl.sub.3) value:

(1075) 8.05-8.01 (4H, m), 7.99-7.94 (2H, m), 7.62-7.35 (9.8H, m), 6.92 (0.2H, d, J=5.9 Hz), 6.57 (0.2H, dd, J=5.9, 2.6 Hz), 6.16 (0.8H, dd, J=6.6, 3.3 Hz), 5.87 (0.2H, dd, J=8.9, 3.00 Hz), 5.81 (0.8H, dd, J=7.9, 3.3 Hz), 4.68-4.62 (1H, m), 4.46-4.31 (2H, m), 4.03 (0.6H, s), 3.92 (2.4H, s), 3.24 (0.2H, brs), 3.06 (0.8H, brs)

(1076) ##STR00259##

(1077) A mixture of 2.7 g of (2R,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl=tribenzoate, 5 mL of acetonitrile, 0.5 mL of N-methylimidazole and 1.7 g of 2,4,5-trichlorobenzenesulfonyl chloride was stirred at room temperature for 8 hours, and it was then left at room temperature for 3 days. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1), so as to obtain 3.0 g of (2R,3R,4S)-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentane-1,3,4-triyl=tribenzoate in the form of a colorless oily product.

(1078) .sup.1H-NMR (CDCl.sub.3) value:

(1079) 8.08-7.96 (5H, m), 7.91-7.88 (2H, m), 7.64-7.33 (10.75H, m), 6.91 (0.25H, d, J=5.9 Hz), 6.55 (0.25H, t, J=5.3 Hz), 6.06-5.95 (1.75H, m), 5.55-5.49 (0.75H, m), 5.48-5.42 (0.25H, m), 4.91-4.84 (1H, m), 4.69-4.62 (1H, m), 3.97 (0.75H, s), 3.85 (2.25H, s)

(1080) ##STR00260##

(1081) 1.8 g of anhydrous lithium bromide and 4.0 mL of 1,3-dimethyl-2-imidazolidinone were added to a solution of 3.0 g of the (2R,3R,4S)-5-(methoxyimino)-2-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentane-1,3,4-triyl=tribenzoate in 4.0 mL of tetrahydrofuran, and the obtained mixture was then stirred at 50 C. for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 4/1), so as to obtain 1.5 g of (2S,3S,4S)-2-bromo-5-(methoxyimino)pentane-1,3,4-triyl=tribenzoate in the form of a colorless oily product.

(1082) .sup.1H-NMR (CDCl.sub.3) value:

(1083) 8.12-7.93 (6H, m), 7.65-7.36 (9.87H, m), 6.82 (0.13H, d, J=5.9 Hz), 6.53 (0.13H, t, J=6.6 Hz), 6.14-6.06 (0.13 mH, m), 6.04-5.95 (1.74H, m), 4.84-4.54 (3H, m), 3.80 (0.39H, s), 3.70 (2.61H, s)

(1084) ##STR00261##

(1085) 2.8 mL of a 50% glyoxylic acid aqueous solution was added to a solution of 1.5 g of the (2S,3S,4S)-2-bromo-5-(methoxyimino)pentane-1,3,4-triyl=tribenzoate in 5.0 mL of acetonitrile, and the obtained mixture was then stirred at 70 C. for 16 hours. Thereafter, the reaction mixture was cooled to room temperature, ethyl acetate and water were then added to the mixture, and the water layer was then removed. The organic layer was successively washed with a 10% sodium hydrogen carbonate aqueous solution and water, and the solvent was then distilled away under reduced pressure to obtain 1.4 g of an oily product.

(1086) The obtained oily product was a mixture of (2S,3S,4S)-2-bromo-5-oxopentane-1,3,4-triyl=tribenzoate and a water adduct thereof.

(1087) .sup.1H-NMR (CDCl.sub.3) value:

(1088) 9.73 (1H, d, J=9.2 Hz), 8.13-7.98 (6H, m), 7.66-7.39 (9H, m), 6.03 (1H, dd, J=7.3, 3.3 Hz), 5.68 (1H, d, J=7.3 Hz), 4.85-1.74 (2H, m), 6.03 (1H, dd, J=10.6, 6.6 Hz)

(1089) ##STR00262##

(1090) 1.2 g of a 15%-18% sodium hydrogen sulfide aqueous solution was added to a solution of 1.4 g of the oily product obtained in Example 32 (5) in 4.0 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 30 minutes. Thereafter, 15 mL of ethyl acetate and 15 mL of a 10% sodium chloride aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with 15 mL of a 10% sodium chloride aqueous solution twice to obtain an ethyl acetate solution of 2,3,5-tri-O-benzoyl-4-thio-D-ribofuranose.

(1091) The ethyl acetate solution was directly used in the subsequent reaction.

(1092) .sup.1H-NMR (CDCl.sub.3) value:

(1093) 8.12-7.88 (6H, m), 7.63-7.29 (9H, m), 6.03 (1H, dd, J=7.9, 3.3 Hz), 5.88 (1H, dd, J=4.0.2.0 Hz), 5.50 (1H, dd, J=4.6, 2.0 Hz), 4.74 (1H, dd, J=11.6, 6.3 Hz), 4.61 (1H, dd, J=11.9, 5.9 Hz), 4.23 (1H, td, J=7.3, 5.5 Hz), 2.64 (1H, d, J=4.6 Hz)

(1094) ##STR00263##

(1095) 1.6 mg of dimethylaminopyridine and 0.28 mL of acetic anhydride were added to the ethyl acetate solution obtained in Example 32 (6), and the obtained mixture was then stirred at room temperature for 1 hour and was then left at room temperature for 3 days. Thereafter, water was added to the reaction mixture. The water layer was removed, and the organic layer was then washed with water. After that, the solvent was distilled away under reduced pressure. The obtained residue was recrystallized from methanol, so as to obtain 402 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio--D-ribofuranose in the form of a white solid.

(1096) .sup.1H-NMR (CDCl.sub.3) value:

(1097) 8.08-8.02 (2H, m), 7.98-7.95 (2H, m), 7.91-7.88 (2H, m), 7.64-7.58 (1H, m), 7.55-7.44 (4H, m), 7.36-7.29 (4H, m), 6.06 (1H, d, J=2.0 Hz), 5.99 (1H, dd, J=4.0, 2.0 Hz), 5.91 (1H, dd, J=8.6, 4.0 Hz), 4.73 (1H, dd, J=11.2, 5.9 Hz), 4.53 (1H, dd, J=11.2, 5.9 Hz), 4.25 (1H, dt, J=8.6, 5.9 Hz), 2.12 (3H, s)

(1098) ##STR00264##

(1099) 0.44 mL of N,O-bis(trimethylsilyl)acetamide was added to a suspension of 208 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio--D-ribofuranose and 67 mg of cytosine in 2.0 mL of acetonitrile, and the obtained mixture was then stirred at 60 C. for 1 hour. Thereafter, 0.22 mL of trimethylsilyl trifluoromethanesulfonate was added to the reaction mixture, and the obtained mixture was then stirred at 80 C. for 4 hours. Thereafter, ethyl acetate was added to the reaction mixture, and the thus obtained mixture was then washed with a saturated sodium hydrogen carbonate aqueous solution. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 4/1), so as to obtain 70 mg of 1-(2,3,5-tri-O-benzoyl-4-thio--D-ribofuranosyl)cytosine in the form of a white solid.

(1100) .sup.1H-NMR (CDCl.sub.3) value:

(1101) 8.14-7.95 (6H, m), 7.89 (1H, d, J=7.3 Hz), 7.63-7.36 (9H, m), 6.90 (1H, d, J=5.9 Hz), 5.94-5.89 (2H, m), 5.59 (1H, d, J=7.9 Hz), 4.79 (1H, dd, J=11.9, 5.9 Hz), 4.66 (1H, dd, J=11.6, 5.0 Hz), 4.10-4.0 (1H, m)

(1102) ##STR00265##

(1103) 0.1 mL of a 28% sodium methoxide/methanol solution was added to a suspension of 70 mg of 1-(2,3,5-tri-O-benzoyl-4-thio--D-ribofuranosyl)cytosine in 2.0 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour and was then left overnight. Thereafter, 0.2 mL of acetic acid was added to the reaction mixture, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 2/1), so as to obtain 18 mg of 1-(4-thio-(3-D-ribofuranosyl)cytosine in the form of a white solid.

(1104) .sup.1H-NMR (DMSO-d.sub.6) value:

(1105) 7.97 (1H, d, J=7.3 Hz), 7.14 (2H, brd), 5.94 (1H, d, J=6.6 Hz), 5.76 (1H, d, J=7.3 Hz), 5.42 (1H, brs), 5.29 (1H, brs), 5.14 (1H, brs), 4.08-3.98 (2H, m), 3.69-3.51 (2H, m), 3.20 (1H, dd, J=9.2, 5.9 Hz)

Example 33

(1106) ##STR00266##

(1107) 22 mL of a 20% sodium hydroxide aqueous solution and 617 mg of tetrabutylammonium chloride were added to a solution of 6.58 g of 2-deoxy-1-O-methyl-D-ribofuranoside in 44 mL of toluene, and thereafter, 10.8 mL of benzoyl chloride was added to the mixture at a temperature of 10 C. to 25 C. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 70/30), so as to obtain 11.8 g of 2-deoxy-3,5-O-dibenzoyl-1-O-methyl-D-ribofuranoside in the form of a colorless oily product.

(1108) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 1:1.

(1109) RT (min): 1.73, 1.76.

(1110) .sup.1H-NMR (CDCl.sub.3) value:

(1111) 8.13-7.99 (4H, m), 7.63-7.51 (2H, m), 7.49-7.38 (4H, m), 5.67-5.59 (0.5H, m), 5.49-5.40 (0.5H, m), 5.24 (0.5H, dd, J=5.6, 2.3 Hz), 5.20 (0.5H, d, J=4.6 Hz), 4.70-4.45 (3H, m), 3.43 (1.5H, s), 3.37 (1.5H, s), 2.64-2.50 (1H, m), 2.36 (0.5H, td, J=9.6, 4.6 Hz), 2.21 (0.5H, dd, J=14.5, 1.3 Hz)

(1112) ##STR00267##

(1113) 32.4 mL of 1 mol/L hydrochloric acid was added to a solution of 6.49 g of 2-deoxy-3,5-O-dibenzoyl-1-O-methyl-D-ribofuranoside in 32.4 mL of acetic acid, and the obtained mixture was then stirred at 55 C. for 2.58 hours. Thereafter, 20 mL of acetic acid and 20 mL of 1 mol/L hydrochloric acid were added to the reaction mixture, and the thus obtained mixture was then stirred at the same temperature as described above for 2.58 hours. Thereafter, toluene and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with water and a saturated sodium hydrogen carbonate aqueous solution and was then dried over anhydrous magnesium sulfate, so as to obtain 6.23 g of 2-deoxy-3,5-O-dibenzoyl-D-ribofuranoside in the form of a colorless oily product.

(1114) As a result of the measurement of .sup.1H-NMR, the anomeric ratio was found to be 6:4.

(1115) RT (min): 1.41, 1.44.

(1116) .sup.1H-NMR (CDCl.sub.3) value:

(1117) 8.11-7.99 (4H, m), 7.63-7.51 (2H, m), 7.51-7.37 (4H, m), 5.80-5.69 (1H, m), 5.67-5.60 (0.4H, m), 5.54-5.48 (0.6H, m), 4.76-4.47 (3H, m), 3.11-3.03 (0.4H, m), 2.86 (0.6H, t, J=5.3 Hz), 2.62-2.48 (1H, m), 2.45-2.25 (1H, m)

(1118) ##STR00268##

(1119) 1.98 g of O-methylhydroxylammonium chloride, 3.78 mL of triethylamine and 3 mL of a 5%-10% hydrochloric acid/methanol solution were added to a solution of 6.23 g of 2-deoxy-3,5-O-dibenzoyl-D-ribofuranoside in 62 mL of methanol, and the obtained mixture was then stirred at room temperature for 11.7 hours. Thereafter, the solvent was distilled away under reduced pressure, and ethyl acetate and water were then added to the obtained residue. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 6.65 g of (2R,3S)-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl dibenzoate in the form of a light yellow oily product.

(1120) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 64:36.

(1121) RT (min): 1.50.

(1122) .sup.1H-NMR (CDCl.sub.3) value:

(1123) 8.04 (4H, d, J=7.9 Hz), 7.62-7.54 (2H, m), 7.51-7.30 (4.64H, m), 6.85 (0.36H, t, J=5.9 Hz), 5.47-5.37 (1H, m), 4.61 (1H, d, J=3.3 Hz), 4.57 (1H, d, J=3.3 Hz), 4.44 (0.64H, dd, J=5.9, 2.6 Hz), 4.40 (0.36H, dd, J=5.9, 2.6 Hz), 4.29-4.17 (1H, m), 3.87 (1.08, s), 3.78 (1.92H, s), 3.07-2.85 (1H, m), 2.82 (1H, t, J=5.9 Hz)

(1124) ##STR00269##

(1125) 5.51 g of 2,4,5-trichlorobenzenesulfonyl chloride and 2.14 mL of 1-methylimidazole were added to a solution of 6.65 g of (2R,3S)-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl dibenzoate in 67 mL of acetonitrile at room temperature, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. 20 mL of ethyl acetate and 30 mL of hexane were added to the obtained residue, and a solid was then removed by filtration. After that, the solvent was distilled away under reduced pressure, so as to obtain 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate in the form of a colorless oily product.

(1126) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 54:46.

(1127) RT (min): 2.06.

(1128) .sup.1H-NMR (CDCl.sub.3) value:

(1129) 8.00-8.00 (1H, each s), 7.93 (4H, t, J=7.6 Hz), 7.64-7.54 (2H, m), 7.50-7.39 (5H, m), 7.34 (0.54H, d, J=4.0 Hz), 6.80 (0.46H, t, J=5.6 Hz), 5.56-5.49 (1H, m), 5.42-5.30 (1H, m), 4.63 (1H, brs), 4.61 (1H, s), 3.86 (1.38H, s), 3.77 (0.62H, s), 2.99-2.91 (1H, m), 2.90-2.83 (0.46H, m), 2.82-2.71 (0.54H, m)

(1130) ##STR00270##

(1131) 1.52 g of lithium bromide was added to a solution of 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate in 17.9 mL of tetrahydrofuran and 16.1 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 50 C. for 3 hours. Thereafter, ethyl acetate and a 25% lithium bromide aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a 13% lithium bromide aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate 100/0 to 75/25), so as to obtain 4.84 g of (2R,3S)-2-bromo-5-(methoxyimino)pentane-1,3-diyl dibenzoate in the form of a colorless oily product.

(1132) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 55:45.

(1133) RT (min): 1.87.

(1134) .sup.1H-NMR (CDCl.sub.3) value:

(1135) 8.11-8.01 (4H, m), 7.64-7.54 (2H, m), 7.51-7.37 (4.55H, m), 6.78 (0.45H, t, J=5.3 Hz), 5.73-5.60 (1H, m), 4.77-4.67 (1H, m), 4.64-4.43 (2H, m), 3.86 (1.35H, s), 3.75 (1.65H, s), 3.09-2.87 (1H, m), 2.84 (1H, t, J=6.3)

(1136) ##STR00271##

(1137) 7.1 mL of a 35% formaldehyde aqueous solution, 4.3 mL of water and 1.4 mL of concentrated hydrochloric acid were added to a solution of 3.54 g of (2R,3S)-2-bromo-5-(methoxyimino)pentane-1,3-diyl dibenzoate in 35 mL of acetone at room temperature, and the obtained mixture was then stirred at 30 C. for 1.5 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 3.75 g of a colorless oily product.

(1138) The obtained colorless oily product was a mixture of (2R,3S)-2-bromo-5-oxopentane-1,3-diyl dibenzoate and a water adduct thereof.

(1139) RT (min): 1.71, 1.81.

(1140) ##STR00272##

(1141) A solution of 720 mg of sodium monohydrogen sulfide n-hydrate in 5 mL of 1-methylpyrrolidone was added to a solution of 3.75 g of the colorless oily product obtained in Example 33 (6) in 33 mL of 1-methylpyrrolidone under cooling on ice, and the obtained mixture was then stirred at the same temperature as described above for 1.42 hours. Thereafter, 249 mg of a sodium monohydrogen sulfide n-hydrate was added to the reaction mixture, and the thus obtained mixture was then stirred at the same temperature as described above for 0.58 hours. Thereafter, ethyl acetate and a saline were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain a 1-methylpyrrolidone solution of 2-deoxy-3,5-O-dibenzoyl-4-thio-D-ribofuranoside.

(1142) RT (min): 1.56.

(1143) m/z (ESI-positive): 341.1 [M+HH2O].sup.+

(1144) ##STR00273##

(1145) 29.2 mL of tetrahydrofuran, 0.916 mL of acetic anhydride and 10 mg of 4-dimethylaminopyridine were added to the 1-methylpyrrolidone solution of 2-deoxy-3,5-O-dibenzoyl-4-thio-D-ribofuranoside obtained in Example 33 (7), and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25). 4 mL of methanol was added to the obtained solid, and the solid was then collected by filtration, so as to obtain 0.942 g of 1-O-acetyl-2-deoxy-3,5-O-dibenzoyl-4-thio--D-ribofuranoside in the form of a white solid.

(1146) RT (min): 1.77.

(1147) .sup.1H-NMR (DMSO-d.sub.6) value:

(1148) 7.96 (4H, dt, J=7.9, 1.3 Hz), 7.71-7.61 (2H, m), 7.56-7.44 (4H, m), 6.11 (1H, dd, J=5.9, 3.3 Hz), 5.77-5.69 (1H, m), 4.55-4.40 (2H, m), 3.99 (1H, qd, J=5.9, 1.3 Hz), 2.76-2.54 (2H, m), 2.01 (3H, s)

(1149) ##STR00274##

(1150) 0.700 mL of N,O-bistrimethylsilyl acetamide was added to a solution of 111 mg of cytosine and 200 mg of 1-O-acetyl-2-deoxy-3,5-O-dibenzoyl-4-thio--D-ribofuranoside in 2 mL of acetonitrile at room temperature, and the obtained mixture was then stirred in a nitrogen atmosphere at 60 C. for 70 minutes. Thereafter, 0.361 mL of trimethylsilyl trifluoromethanesulfonate was added to the reaction mixture, and the thus obtained mixture was then stirred at the same temperature as described above for 2.5 hours, and then at 80 C. for 2 hours. Thereafter, dichloromethane and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 to 40/60), and then by HPLC, so as to obtain 1-(2-deoxy-3,5-bis-O-benzoyl-4-thio-D-ribofuranosyl)cytosine in the form of a brown oily product.

(1151) As a result of the measurement of .sup.1H-NMR, the / ratio was found to be 5347.

(1152) The obtained brown oily product was separated by high performance liquid chromatography, so as to obtain 13.6 mg of 1-(2-deoxy-3,5-bis-O-benzoyl-4-thio--D-ribofuranosyl)cytosine.

(1153) Conditions for high performance liquid chromatography

(1154) Column: Sunfire prep C18 OBD 10 m, 19 mm150 mm (Waters)

(1155) Mobile phase: 0.1% formic acidwater/0.1% formic acidacetonitrile (volume ratio: 70/30 to 55/45)

(1156) Flow rate: 17 mL/min

(1157) Detection: UV (254 nm)

(1158) Temperature: room temperature

(1159) Retention time: form: 7.34 min; form: 8.50 min

(1160) form

(1161) RT (min): 1.25.

(1162) .sup.1H-NMR (CDCl.sub.3) value:

(1163) 8.09-8.02 (4H, m), 7.95 (1H, d, J=7.3 Hz), 7.63-7.54 (2H, m), 7.45 (4H, d, J=7.9 Hz), 6.71 (1H, t, J=7.3 Hz), 5.80 (1H, d, J=7.3 Hz), 5.75 (1H, q, J=3.7 Hz), 4.59 (2H, d, 6.6 Hz), 4.00 (1H, td, 6.6, 3.3 Hz), 2.99-2.13 (2H, brs), 2.82 (1H, dq, 13.9, 3.5 Hz), 2.44-2.33 (1H, m)

(1164) form

(1165) RT (min): 1.19.

(1166) .sup.1H-NMR (CDCl.sub.3) value:

(1167) 8.22 (1H, d, J=7.3 Hz), 8.08 (2H, dd, J=7.9, 1.3 Hz), 7.85 (2H, dd, J=7.9, 1.3 Hz), 7.62-7.52 (2H, m), 7.50-7.36 (4H, m), 6.45 (1H, dd, J=7.3, 2.0 Hz), 5.80 (1H, d, J=7.3 Hz), 5.73-5.67 (1H, m), 4.56-4.38 (2H, m), 4.24 (1H, dt, J=6.9, 2.0 Hz), 2.95-2.82 (1H, m), 2.66 (1H, dt, J=15.2, 2.6 Hz)

(1168) ##STR00275##

(1169) 1 mL of a 7 mol/L ammonia/methanol solution was added to a solution of 9.6 mg of 1-(2-deoxy-3,5-bis-O-benzoyl-4-thio--D-ribofuranosyl)cytosine in 1 mL of methanol, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/methanol=95/5 to 30/70), so as to obtain 4.7 mg of 1-(2-deoxy-4-thio--D-ribofuranosyl)cytosine in the form of a white solid.

(1170) RT (min): 0.27.

(1171) .sup.1H-NMR (DMSO-d.sub.6) value:

(1172) 7.931H, d, J=7.3 Hz), 7.19 (1H, brs), 7.12 (1H, brs), 6.35 (1H, dd, J=8.6, 6.6 Hz), 5.78 (1H, d, J=7.3 Hz), 5.23 (1H, d, J=3.3 Hz), 5.12 (1H, t, J=5.3 Hz), 4.36-4.29 (1H, m), 3.64-3.22 (3H, m), 2.28-2.01 (2H, m), 1.83 (1H, s)

Example 34

(1173) ##STR00276##

(1174) 0.2 mL of 30% hydrogen bromide/acetic acid was added dropwise to a solution of 238 mg of 1-O-methyl-2,3,5-tri-O-benzoyl-L-lyxose in 1.0 mL of acetic acid at room temperature, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, methylene chloride and water were added to the reaction mixture, and the thus obtained mixture was then stirred for 5 minutes. Thereafter, the water layer was removed. The obtained organic layer was washed with a 10% sodium hydrogen carbonate aqueous solution, and the solvent was then distilled away under reduced pressure, to obtain a brown oily product.

(1175) Separately, 0.2 mL of 30% hydrogen bromide/acetic acid was added dropwise to a solution of 238 mg of 1-O-methyl-2,3,5-tri-O-benzoyl-L-lyxose in 1.0 mL of methylene chloride at room temperature, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, methylene chloride and water were added to the reaction mixture, and the thus obtained mixture was then stirred for 5 minutes. After that, the water layer was removed. The obtained organic layer was washed with a 10% sodium hydrogen carbonate aqueous solution, and the solvent was then distilled away under reduced pressure. 2.0 mL of acetone and 2.0 mL of water were added to the obtained oily product, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure, so as to obtain a brown oily product.

(1176) Brown oily products obtained in the above-described two operations were combined with each other, and the thus combined product was then purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1), so as to obtain 462 mg of a colorless oily product containing 2,3,5-tri-O-benzoyl-L-lyxose.

(1177) ##STR00277##

(1178) 125 mg of O-methylhydroxylamine hydrochloride and 1.0 mL of methanol were added to 462 mg of a mixture comprising 2,3,5-tri-O-benzoyl-L-lyxose, and thereafter, 0.18 mL of triethylamine was added dropwise to the mixture under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1), so as to obtain 201 mg of (2S,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl=tribenzoate in the form of a colorless oily product.

(1179) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 4:1.

(1180) .sup.1H-NMR (CDCl.sub.3) value:

(1181) 8.08-7.98 (6H, m), 7.62-7.32 (9.8H, m), 6.91 (0.2H, d, J=5.9 Hz), 6.56 (0.2H, t, J=6.3 Hz), 6.06 (0.8H, t, J=6.9 Hz), 5.83-5.76 (1H, m), 4.58-4.44 (2H, m), 4.39-4.35 (1H, m), 3.88 (0.6H, s), 3.74 (2.4H, s)

(1182) ##STR00278##

(1183) 2.0 mL of ethyl acetate and 0.08 mL of triethylamine were added to 201 mg of (2S,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl=tribenzoate, and thereafter, 0.04 mL of methanesulfonyl chloride was added dropwise to the mixture under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour, and was then left at room temperature overnight. Thereafter, 0.2 mL of triethylamine and 0.1 mL of methanesulfonyl chloride were added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1), so as to obtain 197 mg of (2S,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl=tribenzoate in the form of a colorless oily product.

(1184) .sup.1H-NMR (CDCl.sub.3) value:

(1185) 8.10-8.00 (6H, m), 7.62-7.41 (9.8H, m), 6.87 (0.2H, d, J=5.9 Hz), 6.47 (0.2H, dd, J=5.9, 4.6 Hz), 6.07-6.03 (1H, m), 5.95 (0.8H, t, J=6.3 Hz), 5.47 (0.8H, dt, J=7.5, 3.3 Hz), 5.39 (0.2H, td, J=6.3, 3.3 Hz), 4.85-4.75 (1H, m), 4.69-4.60 (1H, m), 4.39-4.35 (1H, m), 3.91 (0.6H, s), 3.77 (2.4H, s), 3.05 (2.4H, s), 3.01 (0.6H, s)

(1186) ##STR00279##

(1187) 0.35 mL of a 50% glyoxylic acid aqueous solution was added to a solution of 197 mg of (2S,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl=tribenzoate in 1.0 mL of acetonitrile. The obtained mixture was stirred at 70 C. for 9 hours, and was then left at room temperature overnight. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1), so as to obtain 130 mg of (2S,3S,4R)-2-((methylsulfonyl)oxy)-5-oxopentane-1,3,4-triyl=tribenzoate in the form of a colorless oily product.

(1188) .sup.1H-NMR (CDCl.sub.3) value:

(1189) 9.73 (1H, s), 8.11-8.04 (6H, m), 7.66-7.42 (9H, m), 6.09 (1H, t, J=5.3 Hz), 5.68 (1H, d, J=5.9 Hz), 5.61-5.56 (1H, m), 4.81 (1H, dd, J=12.6, 4.0 Hz), 4.66 (1H, dd, J=12.6, 6.6 Hz), 3.05 (3H, s)

(1190) ##STR00280##

(1191) 0.11 mL of a 15%-18% sodium hydrogen sulfide aqueous solution was added to a solution of 130 mg of (2S,3S,4R)-2-((methylsulfonyl)oxy)-5-oxopentane-1,3,4-triyl=tribenzoate in 0.5 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, 10 mL of ethyl acetate was added to the reaction mixture, and the thus obtained mixture was then washed with a 10% sodium chloride aqueous solution three times, so as to obtain an ethyl acetate solution of 2,3,5-tri-O-benzoyl-4-thio-D-ribofuranose.

(1192) 0.1 mg of dimethylaminopyridine and 0.025 mL of acetic anhydride were added to the obtained ethyl acetate solution. The obtained mixture was stirred at room temperature for 1 hour, and was then left at room temperature for 4 days. Thereafter, the reaction mixture was washed with water, and the solvent was then distilled away under reduced pressure. The obtained residue was recrystallized from 10 mL of methanol, so as to obtain 28 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio--D-ribofuranose in the form of a white solid.

(1193) 1H-NMR (CDCl.sub.3) value:

(1194) 8.06-8.02 (2H, m), 7.98-7.95 (2H, m), 7.91-7.88 (2H, m), 7.64-7.58 (1H, m), 7.55-7.44 (4H, m), 7.36-7.29 (4H, m), 6.06 (1H, d, J=10.3 Hz), 5.99 (1H, dd, J=3.6, 1.7 Hz), 5.91 (1H, dd, J=8.6, 4.0 Hz), 4.74 (1H, dd, J=11.2, 5.9 Hz), 4.53 (1H, dd, J=11.2, 5.9 Hz), 4.25 (1H, dt, J=8.6, 5.9 Hz), 2.12 (3H, s)

Example 35

(1195) ##STR00281##

(1196) 13.5 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 3.8 g of 5-methyl-3-phenoxyoxolane-2-one in 40 mL of toluene at 78 C., and the obtained mixture was then stirred for 15 minutes. Thereafter, 1 mL of methanol was added to the reaction mixture, and thereafter, 50 mL of a 20% potassium sodium tartrate aqueous solution was added to the mixture at room temperature. The thus obtained mixture was stirred for 1 hour, and the water layer was then removed. The water layer was extracted with 100 mL of ethyl acetate, and the combined organic layer was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 3.9 g of 5-methyl-3-phenoxyoxolan-2-ol in the form of a colorless oily product.

(1197) .sup.1H-NMR (CDCl.sub.3) value:

(1198) 6.85-7.30 (5H, m), 5.40-5.55 (1H, m), 4.70-4.80 (1H, m), 4.45-4.55 (1H, m), 3.15-3.40 (2H, m), 1.65-2.60 (2H, m), 1.35-1.40 (3H, m)

(1199) ##STR00282##

(1200) 20 mL of methanol and 1.8 g of O-methylhydroxylamine hydrochloride were added to 3.6 g of 5-methyl-3-phenoxyoxolan-2-ol that was a colorless oily product, and thereafter, 2.79 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 5.5 hours. Thereafter, methanol was distilled away under reduced pressure, 100 mL of ethyl acetate and 100 mL of water were then added to the residue, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain 3.65 g of 5-(methoxyimino)-4-phenoxypentan-2-ol in the form of a colorless oily product.

(1201) .sup.1H-NMR (CDCl.sub.3) value:

(1202) 6.65-7.40 (6H, m), 4.90-5.60 (1H, m), 4.00-4.20 (1H, m), 3.70-4.00 (3H, m), 1.50-2.50 (3H, m), 1.20-1.30 (3H, m)

(1203) ##STR00283##

(1204) 3.3 mL of triethylamine was added to a solution of 3.6 g of 5-(methoxyimino)-4-phenoxypentan-2-ol in 36 mL of tetrahydrofuran, and thereafter, 1.2 mL of methanesulfonyl chloride was added to the mixture at a temperature of 0 C. to 10 C. The obtained mixture was stirred at 15 C. or lower for 1 hour. Thereafter, 200 mL of ethyl acetate and 200 mL of water were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), so as to obtain 4.4 g of 5-(methoxyimino)-4-phenoxypentan-2-yl methanesulfonate in the form of a light yellow oily product.

(1205) .sup.1H-NMR (CDCl.sub.3) value:

(1206) 6.60-7.40 (6H, m), 4.90-5.40 (2H, m), 3.80-4.00 (3H, m), 2.70-3.10 (3H, m), 1.90-2.40 (2H, m), 1.45-1.55 (3H, m)

(1207) ##STR00284##

(1208) 15 mL of 2 mol/L hydrochloric acid was added to a mixture of 2.0 g of 5-(methoxyimino)-4-phenoxypentan-2-yl methanesulfonate, 4.8 mL of a 36% formalin aqueous solution and 60 mL of acetone, and the obtained mixture was then stirred at room temperature for 4 hours. Thereafter, the solvent was distilled away under reduced pressure, and 30 mL of ethyl acetate and 30 mL of water were then added to the residue. After that, the water layer was removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), so as to obtain 0.66 g of a mixture of colorless oily 5-oxo-4-phenoxypentan-2-yl methanesulfonate and a water adduct thereof.

(1209) .sup.1H-NMR (CDCl.sub.3) value:

(1210) 9.71-9.76 (1H, m), 7.26-7.33 (2H, m), 7.01-7.04 (1H, m), 6.88-6.92 (2H, m), 5.05-5.15 (1H, m), 4.67-4.77 (1H, m), 3.00 (1.4H, s), 2.83 (1.6H, s), 2.0-2.4 (2H, m), 1.48-1.55 (3H, m)

(1211) ##STR00285##

(1212) 0.53 g of a sodium hydrogen sulfide x-hydrate (Wako Pure Chemical Industries, Ltd.) was added to a solution of 0.62 g of 5-oxo-4-phenoxypentan-2-yl methanesulfonate in 6 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, 30 mL of ethyl acetate and 30 mL of water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with 30 mL of water, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), so as to obtain 0.34 g of 5-methyl-3-phenoxythiolan-2-ol in the form of a colorless oily product.

(1213) .sup.1H-NMR (CDCl.sub.3) value:

(1214) 7.25-7.35 (2H, m), 6.90-7.00 (3H, m), 5.40-5.55 (1H, m), 4.90 (1H, m), 3.75-3.90 (1H, m), 2.40-2.70 (1H, m), 1.90-2.20 (2H, m), 1.42-1.46 (3H, m)

Example 36

(1215) ##STR00286##

(1216) 1.83 g of a 15% sodium hydrogen sulfide aqueous solution was added to a solution of 400 mg of 2-chloromethyl-4,6-dibenzyloxybenzaldehyde in 4.5 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at 15 C. for 1 hour. Thereafter, 40 mL of ethyl acetate and 20 mL of a 10% sodium chloride aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution, and 30 mL of hexane was then added thereto. A solid was collected by filtration, so as to obtain 206 mg of 5,7-bis(benzyloxy)-1,3-dihydrobenzothiophen-1-ol in the form of a white solid.

(1217) .sup.1H-NMR (CDCl.sub.3) value:

(1218) 7.30-7.45 (10H, m), 6.68 (1H, dd, J=2.1, 6.9 Hz), 6.48 (1H, d, J=8.4 Hz), 6.47 (1H, d, J=8.4 Hz), 5.14 (H, d, J=12.3 Hz), 5.09 (1H, d, J=12.3 Hz), 5.03 (2H, s), 4.49 (1H, dd, J=2.1, 14.7 Hz), 4.02 (1H, d, J=14.7 Hz), 2.45 (1H, d=6.9 Hz)

Example 37

(1219) ##STR00287##

(1220) 2.1 mL of trifluoromethanesulfonic acid was added to a solution of 13.8 g of 5-(hydroxymethyl)oxolane-2-one and 19.0 g of 2,4,6-tris(benzyloxy)-1,3,5-triazine in 150 mL of dioxane at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 5 hours. Thereafter, the reaction mixture was added to a mixture of 400 mL of ethyl acetate and 300 mL of a saturated sodium hydrogen carbonate aqueous solution. The organic layer was fractionated, and it was successively washed with 300 mL of water and 300 mL of a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=2/3 to 1/1), so as to obtain 22.4 g of 5-((benzyloxy)methyl)oxolane-2-one in the form of a colorless oily product.

(1221) .sup.1H-NMR (CDCl.sub.3) value:

(1222) 7.33-7.28 (5H, m), 4.68-4.61 (1H, m), 4.572 (1H, s), 4.566 (1H, s), 3.68 (1H, dd, J=10.8, 4.5 Hz), 3.58 (1H, dd, J=10.8, 4.2 Hz), 2.57-2.42 (2H, m), 2.35-2.06 (2H, m)

(1223) ##STR00288##

(1224) 2.3 g of sodium tetrahydroborate was added to a solution of 9.9 g of 5-((benzyloxy)methyl)oxolane-2-one in 12 mL of ethanol and 48 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5 C. to 10 C., and thereafter, a solution of 7.0 g of calcium chloride in 25 mL of ethanol was then added dropwise to the mixture over 20 minutes. Thereafter, 25 mL of tetrahydrofuran was added to the reaction mixture, and the obtained mixture was then stirred at room temperature for 200 minutes. Thereafter, 200 mL of ethyl acetate was added to the reaction mixture, and 1 mol/L hydrochloric acid was then added dropwise to the mixture. The organic layer was fractionated. The obtained organic layer was washed with 100 mL of a saturated sodium hydrogen carbonate aqueous solution, and then with 100 mL of a saturated sodium chloride aqueous solution twice, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 9.4 g of 5-(benzyloxy)pentane-1,4-diol in the form of a colorless oily product.

(1225) .sup.1H-NMR (CDCl.sub.3) value:

(1226) 7.35-7.31 (5H, m), 4.55 (2H, s), 3.89-3.81 (1H, m), 3.71-3.58 (2H, m), 3.49 (1H, dd, J=9.3, 3.3 Hz), 3.36 (1H, dd, J=9.3, 7.8 Hz), 2.92 (1H, brs), 2.55 (1H, brs), 1.67-1.41 (4H, m)

(1227) ##STR00289##

(1228) 0.96 g of sodium hydride (60 wt % in oil) was added to a solution of 5.0 g of 5-(benzyloxy)pentane-1,4-diol in 50 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 5.3 mL of triisopropylsilyl chloride was added dropwise to the reaction mixture at a temperature of 5 C. to 10 C. The reaction mixture was stirred at room temperature for 1 hour, and it was then added to a mixture of 100 mL of ethyl acetate and 100 mL of water. The organic layer was fractionated. The obtained organic layer was successively washed with 100 mL of a saturated sodium hydrogen carbonate aqueous solution, 100 mL of water and 100 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/5 to 1/5), so as to obtain 5.4 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-ol in the form of a colorless oily product.

(1229) .sup.1H-NMR (CDCl.sub.3) value:

(1230) 7.35-7.26 (5H, m), 4.56 (2H, s), 3.85-3.79 (1H, m), 3.72 (2H, t, J=5.9 Hz), 3.49 (1H, dd, J=9.3, 3.9 Hz), 3.38 (1H, dd, J=9.3, 7.2 Hz), 2.86 (1H, d, J=3.3 Hz), 1.76-1.45 (4H, m), 1.15-1.00 (21H, m)

(1231) ##STR00290##

(1232) 0.35 mL of methanesulfonyl chloride was added dropwise to a solution of 1.5 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-ol and 0.7 mL of triethylamine in 15 mL of ethyl acetate at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction mixture was added to a mixture of 100 mL of ethyl acetate and 50 mL of 1 mol/L hydrochloric acid. The organic layer was fractionated. The obtained organic layer was successively washed with 50 mL of a saturated sodium hydrogen carbonate aqueous solution, 50 mL of water and 50 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.8 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-yl methanesulfonate in the form of a colorless oily product.

(1233) .sup.1H-NMR (CDCl.sub.3) value:

(1234) 7.36-7.26 (5H, m), 4.92-4.83 (1H, m), 4.58 (1H, d, J=17.6 Hz), 4.54 (1H, d, J=17.6 Hz), 3.77-3.58 (4H, m), 3.02 (3H, s), 1.90-1.52 (4H, m), 1.15-1.00 (21H, m)

(1235) ##STR00291##

(1236) 0.33 g of p-toluenesulfonic acid was added to a solution of 1.53 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-yl methanesulfonate in 20 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction mixture was added to a mixture of 50 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution. The organic layer was fractionated, and it was successively washed with 10 mL of water and 30 mL of a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=2/3 to 3/2), so as to obtain 0.8 g of 1-benzyloxy-5-hydroxypentan-2-yl methanesulfonate in the form of a colorless oily product.

(1237) .sup.1H-NMR (CDCl.sub.3) value:

(1238) 7.36-7.26 (5H, m), 4.93-4.84 (1H, m), 4.58 (1H, d, J=12.0 Hz), 4.53 (1H, d, J=12.0 Hz), 3.74-3.57 (4H, m), 3.02 (3H, s), 1.84-1.64 (4H, m)

(1239) ##STR00292##

(1240) 440 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin Periodinane) was added to a solution of 200 mg of 1-benzyloxy-5-hydroxypentan-2-yl methanesulfonate in 2 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 100 mg of Dess-Martin Periodinane was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction mixture was added to a mixture of 50 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution, and the obtained mixture was then filtrated with Celite. The organic layer was fractionated. The obtained organic layer was washed with 30 mL of a sodium thiosulfate aqueous solution twice, and then with 30 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/2 to 1/1), so as to obtain 141 mg of 1-benzyloxy-5-oxopentan-2-yl methanesulfonate in the form of a colorless oily product.

(1241) .sup.1H-NMR (CDCl.sub.3) value:

(1242) 9.79 (1H, s), 7.36-7.26 (5H, m), 4.89-4.80 (1H, m), 4.57 (1H, d, J=13.5 Hz), 4.52 (1H, d, J=13.5 Hz), 3.67-3.57 (2H, m), 3.01 (3H, s), 2.79-2.61 (2H, m), 2.10-1.83 (2H, m)

(1243) ##STR00293##

(1244) 58 mg of a sodium hydrogen sulfide n-hydrate was added to a solution of 103 mg of 1-benzyloxy-5-oxopentan-2-yl methanesulfonate in 3 mL of N,N-dimethylformamide at room temperature, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, the reaction mixture was added to a mixture of 30 mL of ethyl acetate and 20 mL of a saturated sodium hydrogen carbonate aqueous solution. The organic layer was fractionated, and it was washed with 20 mL of a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/3 to 1/2), so as to obtain 49 mg of 5-((benzyloxy)methyl)thiolan-2-ol in the form of a colorless oily product.

(1245) As a result of the measurement of .sup.1H-NMR, the cis/trans ratio was found to be 50:50.

(1246) Moreover, 3, 30, 60, 90 and 120 minutes after initiation of the reaction, approximately 20 mg of the reaction mixture was precisely weighed with a precision balance, and the remaining amount of the 1-benzyloxy-5-oxopentan-2-yl methanesulfonate used as a raw material was measured by HPLC. As a result, it was found that the remaining amount of the substance was 53% three minutes after initiation of the reaction, and that the substance was completely consumed from 30 minutes after initiation of the reaction.

(1247) .sup.1H-NMR (CDCl.sub.3) value:

(1248) 7.38-7.26 (5H, m), 5.55-5.45 (1H, m), 4.59 (1H, s), 4.56 (0.5H, d, J=12.0 Hz), 4.45 (0.5H, d, J=12.0 Hz), 3.85-3.57 (2H, m), 3.42-3.31 (1H, m), 2.72 (0.5H, d, J=6.90 Hz), 2.29-1.87 (4.5H, m)

Example 38

(1249) ##STR00294##

(1250) 3.35 g of O-methylhydroxylamine hydrochloride was added to a mixture of 8.02 g of 2,3,5-tris(O-benzyl)-D-arabinofuranose, 48 mL of acetonitrile and 24 mL of water, and thereafter, 3.45 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 4 hours. Thereafter, 80 mL of ethyl acetate and 50 mL of a 8% sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and the water layer was then extracted with ethyl acetate twice. The organic layer was combined with the extract, and the obtained mixture was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 8.48 g of (2R,3R,4R)-1,3,4-tris(benzyloxy)-5-(methoxyimino)pentan-2-ol in the form of a colorless oily product.

(1251) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 78:22.

(1252) .sup.1H-NMR (CDCl.sub.3) value:

(1253) 2.60 (0.22H, d, J=1.5 Hz), 2.68 (0.78H, d, J=1.5 Hz), 3.56-3.60 (2.22H, m), 3.67 (0.78H, dd, J=7.1, 3.6 Hz), 3.79 (0.22H, dd, J=7.5, 3.0 Hz), 3.85 (0.66H, s), 3.86 (2.34H, s), 3.97-4.04 (1H, m), 4.27 (00.78H, dd, J=7.8, 3.9 Hz), 4.38-4.65 (6H, m), 4.93 (0.22H, dd, J=6.0, 3.0 Hz), 6.90 (0.22H, d, J=6.3 Hz), 7.23-7.35 (15H, m), 7.43 (0.78H, dd, J=8.1, 0.6 Hz)

(1254) ##STR00295##

(1255) 1.54 mL of triethylamine and 0.89 mL of N-methylimidazole were added to a solution of 3.33 g of (2R,3R,4R)-2,3,5-tris(benzyloxy)-4-hydroxypentanal=O-methyloxime in 33 mL of acetonitrile, and thereafter, 0.86 mL of methanesulfonyl chloride was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, 40 mL of water and 80 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was successively washed with a mixed solution of 20 mL of 1 mol/L hydrochloric acid and 20 mL of a 10% sodium chloride aqueous solution, and with a mixed solution of 20 mL of a 5% sodium hydrogen carbonate aqueous solution and 20 mL of a 10% sodium chloride aqueous solution, and it was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography, so as to obtain 3.16 g of (2R,3S,4R)-1,3,4-tris(benzyloxy)-5-(methoxyimino)pentan-2-yl=methanesulfonate in the form of a colorless oily product.

(1256) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 75:25.

(1257) .sup.1H-NMR (CDCl.sub.3) value:

(1258) 2.93 (2.25H, s), 2.95 (0.75H, s), 3.80 (1H, dd, J=11.4, 6.9 Hz), 3.85 (0.75H, s), 3.86 (2.25H, s), 3.90 (1H, dd, J=11.4.2.1 Hz), 3.98 (0.75H, t, J=4.5 Hz), 4.16 (0.75H, ddd, J=7.7, 4.5, 0.6 Hz), 4.41-4.62 (4.25H, m), 4.67 (2H, dd, J=20.4, 11.1 Hz), 4.80 (0.25H, dd, J=7.5, 4.5 Hz), 4.99 (1H, m), 6.81 (0.25H, d, J=6.3 Hz), 7.24-7.37 (15.75H, m)

(1259) ##STR00296##

(1260) 10 mL of 2 mol/L hydrochloric acid and 3.10 mL of a 35% formaldehyde aqueous solution were added to a solution of 2.06 g of (2R,3S,4R)-1,3,4-tris(benzyloxy)-5-(methoxyimino)pentan-2-yl=methanesulfonate in 40 mL of acetone in a nitrogen atmosphere, and the obtained mixture was then stirred at room temperature for 5 hours. Thereafter, 40 mL of a 10% sodium chloride aqueous solution and 40 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was washed with a mixed solution of 20 mL of a 5% sodium hydrogen carbonate aqueous solution and 20 mL of a 10% sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 1.50 g of (2R,3S,4S)-1,3,4-tris(benzyloxy)-5-oxopentan-2-yl=methanesulfonate in the form of a colorless oily product.

(1261) .sup.1H-NMR (CDCl.sub.3) value:

(1262) 2.97 (1H, s), 3.76 (1H, dd, J=11.4, 6.6 Hz), 3.89 (1H, dd, J=11.4, 3.0 Hz), 4.04 (1H, dd, J=3.3, 0.9 Hz), 4.18 (1H, dd, J=5.3, 3.3 Hz), 4.47-4.60 (4H, m), 4.67 (2H, dd, J=22.2, 11.4 Hz), 5.97 (1H, m), 7.20-7.25 (2H, m), 7.27-7.36 (13H, m)

(1263) ##STR00297##

(1264) 0.06 g of a sodium hydrogen sulfide x-hydrate was added to a solution of 0.10 g of (2R,3S,4S)-1,3,4-tris(benzyloxy)-5-oxopentan-2-yl=methanesulfonate in 2 mL of N,N-dimethylformamide, and the obtained mixture was then stirred at room temperature for 12 hours. Thereafter, 2 mL of water and 5 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was washed with 5 mL of a 10% sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 0.02 g of (3S,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)thiolan-2-ol in the form of a colorless oily product.

(1265) .sup.1H-NMR (CDCl.sub.3) value:

(1266) 3.69 (1H, d, J=12.6 Hz), 3.77-3.82 (3H, m), 4.19 (2H, m), 4.51-4.67 (6H, m), 5.26 (1H, d, J=12.6 Hz), 7.22-7.37 (15H, m)

Example 39

(1267) ##STR00298##

(1268) 10 mL of ethyl acetate and 0.19 mL of methanesulfonyl chloride were added to 0.99 g of (2R,3R,4S)-2-hydroxy-5-(methoxyimino)pentane-1,3,4-triyl=tribenzoate, and thereafter, 0.39 mL of triethylamine was added dropwise to the mixture under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, 0.19 mL of triethylamine and 0.39 mL of methanesulfonyl chloride were added to the reaction mixture. The thus obtained mixture was stirred at room temperature for 2 hours, and was then left at room temperature for 2 days. Thereafter, ethyl acetate and water were added to the reaction mixture, the organic layer was then fractionated, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1), so as to obtain 1.02 g of (2R,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl=tribenzoate in the form of a colorless oily product.

(1269) .sup.1H-NMR (CDCl.sub.3) value:

(1270) 8.11-8.00 (6H, m), 7.64-7.41 (9.75H, m), 6.92 (0.25H, d, J=5.9 Hz), 6.55 (0.25H, dd, J=5.3, 4.0 Hz), 6.11 (0.25H, dd, J=5.9, 4.0 Hz), 6.08-6.02 (1.5H, m), 5.53-5.46 (1H, m), 5.01-4.91 (1H, m), 4.59-4.47 (1H, m), 3.97 (0.75H, s), 3.88 (2.25H, s), 3.17 (2.25H, s), 3.13 (0.75H, s)

(1271) ##STR00299##

(1272) 1.8 mL of a 50% glyoxylic acid aqueous solution was added to a solution of 1.02 g of (2R,3S,4S)-5-(methoxyimino)-2-((methylsulfonyl)oxy)pentane-1,3,4-triyl=tribenzoate in 3.0 mL of acetonitrile, and the obtained mixture was then stirred at 80 C. for 4 hours. Thereafter, the reaction mixture was cooled to room temperature, ethyl acetate and water were then added to the mixture, and the water layer was then removed. The organic layer was successively washed with a 10% sodium hydrogen carbonate aqueous solution and water, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1), so as to obtain 317 mg of a colorless oily product.

(1273) The obtained oily product was a mixture of (2R,3S,4R)-2-((methylsulfonyl)oxy)-5-oxopentane-1,3,4-triyl=tribenzoate and a water adduct thereof.

(1274) .sup.1H-NMR (CDCl.sub.3) value:

(1275) 9.74 (1H, s), 8.20-7.96 (6H, m), 7.66-7.42 (9H, m), 6.12 (1H, dd, J=7.9, 2.6 Hz), 5.87 (1H, d, J=2.6 Hz), 5.64-5.58 (1H, m), 4.96 (1H, dd, J=13.2, 2.6 Hz), 4.49 (1H, dd, J=13.2, 5.3 Hz), 3.13 (3H, s)

(1276) ##STR00300##

(1277) 0.27 mL of a 15%-18% sodium hydrogen sulfide aqueous solution was added to a solution of 317 mg of the colorless oily product obtained in Example 39 (2) in 1.5 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, 10 mL of ethyl acetate was added to the reaction mixture, and the thus obtained mixture was washed with 10 mL of a 10% sodium chloride aqueous solution three times, to obtain an ethyl acetate solution of 2,3,5-tri-O-benzoyl-4-thio-L-lyxose.

(1278) 0.4 mg of 4-dimethylaminopyridine and 0.061 mL of acetic anhydride were added to the obtained ethyl acetate solution. The obtained mixture was stirred at room temperature for 1 hour, and was then left at room temperature overnight. Thereafter, the reaction mixture was washed with water, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1), so as to obtain 107 mg of 1-O-acetyl-2,3,5-tri-O-benzoyl-4-thio-L-lyxose in the form of a colorless oily product.

(1279) The obtained compound was a single anomer.

(1280) .sup.1H-NMR (CDCl.sub.3) value:

(1281) 8.05-8.01 (2H, m), 7.96-7.92 (2H, m), 7.90-7.87 (2H, m), 7.64-7.31 (9H, m), 6.20 (1H, d, J=4.0 Hz), 6.09 (1H, dd, J=5.9, 4.0 Hz), 5.94 (1H, t, J=3.6 Hz), 4.77 (1H, dd, J=11.2, 7.3 Hz), 4.61 (1H, dd, J=11.2, 7.3 Hz), 4.37 (1H, q, J=6.8 Hz), 2.15 (3H, s)

Example 40

(1282) ##STR00301##

(1283) 720 mL of acetyl chloride was added dropwise to 1200 mL of a methanol solution of 12.0 kg of (2R,3R,4S)-3,4,5-trihydroxy-2-hydroxymethyloxolane at a temperature of 15 C. or lower over 30 minutes, and the obtained mixture was then stirred at a temperature of 20 C. to 30 C. for 1 hour. Thereafter, 2100 mL of a 28% sodium methoxide/methanol solution and 1000 mL of toluene were added to the reaction mixture, and methanol was then distilled away under reduced pressure, to obtain 4500 mL of a toluene solution of (2R,3R,4S)-3,4-dihydroxy-2-hydroxymethyl-5-methoxyoxolane.

(1284) 2400 mL of a 50% sodium hydroxide aqueous solution, 6000 mL of toluene and 72.0 g of tetrabutylammonium chloride were added to 4500 mL of the obtained toluene solution at a temperature of 30 C. or lower, and thereafter, 3290 mL of 4-methylbenzoyl chloride was added dropwise to the mixture at a temperature of 15 C. or lower over 1 hour. The thus obtained mixture was stirred at 30 C. for 3 hours. Thereafter, the water layer was removed, and the organic layer was successively washed with 3000 mL of water and 3000 mL of a 10% sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 3.94 kg of ((2R,3S,4S)-3,4-di((4-methylphenyl)carbonyloxy)-5-methoxyoxiran-2-yl)methyl=4-methylbenzoate in the form of a white solid.

(1285) .sup.1H-NMR (CDCl.sub.3) value:

(1286) 2.33-2.45 (9H, m), 3.49 (3H, s), 4.53-4.57 (1H, m), 4.60-4.76 (1H, m), 4.82 (1H, dd, J=3.2, 12.0 Hz), 5.16 (1H, s), 5.44-5.48 (1H, m), 5.55 (1H, d, J=5.6 Hz), 7.08-7.26 (6H, m), 7.86-7.97 (6H, m)

(1287) ##STR00302##

(1288) 50 mL of a 30% hydrogen bromide/acetic acid solution was added to a mixed solution of 50.0 g of ((2R,3S,4S)-3,4-di((4-methylphenyl)carbonyloxy)-5-methoxyoxiran-2-yl)methyl=4-methylbenzoate in 50 mL of acetic acid and 25 mL of toluene at 25 C., and the obtained mixture was then stirred at the same temperature as described above for 2 hours. Thereafter, 100 mL of hexane was added to the reaction mixture, and a solid was then collected by filtration, so as to obtain 37.7 g of ((2R,3S,4S)-5-bromo-3,4-di((4-methylphenyl)carbonyloxy)oxiran-2-yl)methyl=4-methylbenzoate in the form of a white solid.

(1289) .sup.1H-NMR (CDCl.sub.3) value:

(1290) 2.44 (3H, s), 2.42 (3H, s), 2.37 (3H, s), 4.72-4.92 (3H, m), 5.59 (1H, d, J=4.4 Hz), 5.92 (1H, s), 6.19 (1H, s), 7.08-7.30 (6H, m), 7.82-8.03 (6H, m)

(1291) ##STR00303##

(1292) 71.0 g of sodium hydrogen carbonate was added to a mixed solution of 400 g of ((2R,3S,4S)-5-bromo-3,4-di((4-methylphenyl)carbonyloxy)oxiran-2-yl)methyl=4-methylbenzoate in 950 mL of toluene, 480 mL of water and 600 mL of acetonitrile at 25 C., and the obtained mixture was then stirred at 55 C. for 6 hours 30 minutes. Thereafter, 500 mL of a 10% sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the water layer was then removed. The organic layer was washed with 3 L of a 10% sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 361 g of ((2R,3S,4S)-3,4-di((4-methylphenyl)carbonyloxy)-5-hydroxyoxiran-2-yl)methyl=4-methylbenzoate in the form of a white solid.

(1293) .sup.1H-NMR (CDCl.sub.3) value:

(1294) 2.37-2.45 (9H, m), 4.73-4.92 (3H, m), 5.59 (1H, d, J=4.4 Hz), 5.92 (1H, s), 6.59 (1H, s), 7.04-7.26 (6H, m), 7.83-8.03 (6H, m)

(1295) ##STR00304##

(1296) 360 mL of pyridine, 180 g of p-toluenesulfonic acid dihydrate and 106 g of O-methylhydroxylamine hydrochloride were added to a solution of 361 g of ((2R,3S,4S)-3,4-di((4-methylphenyl)carbonyloxy)-5-hydroxyoxiran-2-yl)methyl=4-methylbenzoate in 1080 mL of methanol, and thereafter, 176 mL of triethylamine was added dropwise to the mixture at 25 C. The obtained mixture was stirred at the same temperature as described above for 8 hours. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with a 10% sodium chloride aqueous solution twice, hydrochloric acid twice, a sodium hydrogen carbonate aqueous solution once and a saturated sodium chloride aqueous solution once, and it was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 394 g of (2R,3R,4R)-1,3-di((4-methylphenyl)carbonyloxy)-2-hydroxy-5-(methoxyimino)pentan-4-yl=4-methylbenzoate in the form of a colorless oily product.

(1297) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 75:25.

(1298) .sup.1H-NMR (CDCl.sub.3) value:

(1299) 2.37-2.43 (9H, m), 3.40 (1H, d, J=8.4 Hz), 3.79 (2.25H, s), 4.11 (0.75H, s), 4.36-4.40 (1H, m), 4.53-4.59 (1H, m), 5.66 (0.75H, dd, J=3.2, 8.4 Hz), 5.84 (0.25H, dd, J=2.8, 8.4 Hz), 6.17 (0.75H, dd, J=3.2, 6.0 Hz) 6.57 (0.25H, dd, J=2.8, 5.2 Hz), 6.76 (0.25H, d, J=5.2 Hz), 7.06-7.29 (6H, m), 7.45 (0.75H, d, J=6.0 Hz), 7.89-8.03 (6H, m)

(1300) ##STR00305##

(1301) 195 g of (2,4,5-trichlorobenzene)sulfonyl chloride was added to a solution of 338 g of (2R,3R,4R)-1,3-di((4-methylphenyl)carbonyloxy)-2-hydroxy-5-(methoxyimino)pentan-4-yl=4-methylbenzoate in 1200 mL of acetonitrile at 25 C., and thereafter, 130 mL of N-methylimidazole was added dropwise to the mixture at a temperature of 0 C. to 10 C. over 40 minutes. The obtained mixture was stirred at 10 C. for 5 hours. Thereafter, 1500 mL of ethyl acetate and 1000 mL of water were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with a 10% sodium chloride aqueous solution twice, hydrochloric acid once, a sodium hydrogen carbonate aqueous solution once and a saturated sodium chloride aqueous solution once, and it was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain (2R,3R,4R)-1-(methoxyimino)-2,5-di((4-methylphenyl)carbonyoxy)-4-(((2,4,5-trichlorobenzene)sulfonyl)oxy)pentan-3-yl=4-methylbenzoate in the form of a colorless oily product.

(1302) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 75:25.

(1303) .sup.1H-NMR (CDCl.sub.3) value:

(1304) 2.37-2.49 (9H, m), 3.82 (2.25H, s), 3.96 (0.75H, s), 4.62-4.80 (2H, m), 5.35-5.51 (1H, m), 5.90-6.05 (1.75H, m), 6.30-6.38 (0.25H, m), 6.74-6.76 (0.25H, m), 7.15-7.35 (7H, m), 7.44-7.49 (0.75H, m), 7.75-7.99 (7H, m)

(1305) ##STR00306##

(1306) 110 g of lithium bromide was added to a mixed solution of (2R,3R,4R)-1-(methoxyimino)-2,5-di((4-methylphenyl)carbonyloxy)-4-(((2,4,5-trichloro benzene)sulfonyl)oxy)pentan-3-yl=4-methylbenzoate in 450 mL of tetrahydrofuran and 370 mL of 1,2-dimethylimidazole at a temperature of 10 C. or lower, and the obtained mixture was then stirred at 25 C. for 6 hours. Thereafter, 800 mL of ethyl acetate and 800 mL of water were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain (2S,3S,4R)-2-bromo-1,4-di((4-methylphenyl)carbonyloxy)-5-(methoxyimino)pentan-3-yl=4-methylbenzoate in the form of a colorless oily product.

(1307) .sup.1H-NMR was measured. As a result, the syn-anti ratio was found to be 79:21.

(1308) .sup.1H-NMR (CDCl.sub.3) value:

(1309) 2.34-2.41 (9H, m), 3.38 (2.37H, s), 3.88 (0.63H, s), 4.44-4.75 (3H, m), 6.04-6.11 (1.79H, m), 6.41-6.44 (0.21H, m), 6.75 (0.21H, d, J=5.6 Hz), 7.11-7.26 (6H, m), 7.53 (0.79H, d, J=5.2 Hz), 7.78-7.96 (6H, m)

(1310) ##STR00307##

(1311) 420 mL of a 50% glyoxylic acid aqueous solution was added to a solution of (2S,3S,4R)-2-bromo-1,4-di((4-methylphenyl)carbonyloxy)-5-(methoxyimino)pentan-3-yl=4-methylbenzoate in 900 mL of acetonitrile, and the obtained mixture was then stirred at 75 C. for 12 hours. Thereafter, the reaction mixture was cooled to room temperature, and 600 mL of ethyl acetate and 200 mL of water were then added to the mixture. After that, the water layer was removed. The organic layer was successively washed with a 10% sodium chloride aqueous solution and with a mixed solution of a sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and it was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure to obtain 337 g of a brown oily product.

(1312) The obtained oily product was a mixture of (2S,3S,4S)-2-bromo-1,4-di((4-methylphenyl)carbonyloxy)-5-oxopentan-3-yl 4-methylbenzoate and a water adduct thereof.

(1313) .sup.1H-NMR (CDCl.sub.3) value:

(1314) 2.34-2.45 (9H, m), 4.55-4.85 (3H, m), 5.78-5.80 (1H, m), 5.95-6.00 (1H, m), 7.18-7.26 (6H, m), 7.89-7.96 (6H, m), 9.72 (1H, s)

(1315) ##STR00308##

(1316) 584 mL of a 25% sodium hydrogen sulfide aqueous solution was added dropwise to a solution of 337 g of the oily product obtained in Example 40 (7) in 1000 mL of N,N-dimethylformamide at 10 C. over 30 minutes, and the obtained mixture was then stirred at 15 C. for 2 hours. Thereafter, 1000 mL of ethyl acetate and a saturated sodium chloride aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with a sodium hydrogen carbonate aqueous solution three times, and was then dried over anhydrous magnesium sulfate, so as to obtain an ethyl acetate solution of ((2R,3S,4S)-3,4-di((4-methylphenyl)carbonyloxy)-5-hydroxythiolan-2-yl)methyl=4-methylbenzoate.

(1317) 15.0 g of N,N-dimethyl-4-aminopyridine was added to the obtained ethyl acetate solution, and 180 mL of acetic anhydride was then added thereto dividedly over four times at 0 C. The obtained mixture was left at rest at room temperature for 16 hours. Thereafter, 400 mL of water was added to the reaction mixture, and the water layer was then removed. The organic layer was washed with a sodium hydrogen carbonate aqueous solution four times, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was recrystallized from methanol, so as to obtain 167 g of ((2R,3S,4S)-5-(acetyloxy)-3,4-di((4-methylphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate in the form of a white solid.

(1318) .sup.1H-NMR (DMSO-d.sub.6) value:

(1319) 1.99 (1.50H, s), 2.04 (1.50H, s), 2.31-2.45 (9H, m), 3.78-3.87 (1H, m), 4.46-4.53 (1H, m), 4.64-4.71 (1H, m), 5.66-5.73 (1H, m), 6.08-6.21 (1H, m), 6.31 (0.50H, d, J=4.4 Hz), 6.40 (0.50H, d, J=4.4 Hz), 6.96-7.28 (6H, m), 7.76-7.96 (6H, m)

(1320) ##STR00309##

(1321) 25 mL of triethylsilane was added to a solution of 25 g of ((2R,3S,4S)-5-(acetyloxy)-3,4-di((4-methylphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate in 75 mL of trifluoroacetic acid, and the obtained mixture was then stirred at room temperature for 8 hours 30 minutes. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then recrystallized from methanol, so as to obtain 167 g of ((2R,3S,4S)-5-(acetyloxy)-3,4-di((4-methylphenyl)carbonyloxy)thiolan-2-yl)methyl=4-methylbenzoate in the form of a white solid.

(1322) .sup.1H-NMR (DMSO-d.sub.6) value:

(1323) 2.31-2.45 (9H, m), 3.18 (1H, dd, J=5.6, 16.0 Hz), 3.52 (1H, d, J=4.8, 16.0 Hz), 3.92 (1H, ddd, J=4.8, 9.2, 10.8 Hz), 4.57 (1H, dd, J=9.2, 14.8 Hz), 4.67 (1H, dd, J=10.8, 14.8), 5.72-5.77 (1H, m), 5.85-5.88 (1H, m), 7.15-7.26 (6H, m), 7.88-7.96 (6H, m)

Example 41

(1324) ##STR00310##

(1325) 92 mL of a 1 mol/L methyl magnesium bromide/tetrahydrofuran solution and 23 mL of a 3 mol/L methyl magnesium bromide/diethyl ether solution were added dropwise to a solution of 23.2 g of (2S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxyoxolane-3-one in 100 mL of tetrahydrofuran at 40 C., and the obtained mixture was then stirred at the same temperature as described above for 30 minutes. Thereafter, the temperature of the reaction mixture was increased to 0 C. over 1 hour, and 500 mL of a saturated ammonium chloride aqueous solution and 500 mL of ethyl acetate were then added to the mixture. The organic layer was fractionated, and it was washed with 300 mL of a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography, so as to obtain 12.0 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol in the form of a colorless oily product.

(1326) .sup.1H-NMR (CDCl.sub.3) value:

(1327) 7.37-7.24 (10H, m), 4.80-4.48 (5H, m), 4.12 (1H, m), 3.53-3.42 (2H, m), 3.44 (3 Hs), 3.38 (1H, d, J=0.6 Hz), 3.34 (1H, d, J=4.2 Hz), 1.31 (3H, s).

(1328) ##STR00311##

(1329) 1.2 g of sodium hydride was added to an N,N-dimethylformamide solution of 7.2 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol, and thereafter, 5.1 g of benzyl bromide was added dropwise to the mixture at a temperature of 15 C. or lower. The obtained mixture was stirred at room temperature for 1.5 hours. Thereafter, 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with 200 mL of 1 mol/L hydrochloric acid and 200 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure, so as to obtain 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolane in the form of a colorless oily product.

(1330) .sup.1H-NMR (CDCl.sub.3) value:

(1331) 7.44-7.22 (15H, m), 4.82-4.46 (6H, m), 4.70 (1H, s), 4.27 (1H, q, J=3.9 Hz), 3.59-3.43 (3H, m), 3.46 (3H, s), 1.34 (3H, s).

(1332) ##STR00312##

(1333) 4.9 g of concentrated sulfuric acid was added dropwise to a solution of 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolane in 80 mL of acetic acid and 20 mL of water at room temperature, and the obtained mixture was then stirred at 70 C. for 3 hours. Thereafter, the reaction mixture was cooled to 30 C., and 200 mL of water and 200 mL of ethyl acetate were then added to the mixture. The organic layer was fractionated, and it was successively washed with 200 mL of 1 mol/L hydrochloric acid and 200 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 5.5 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol in the form of a colorless oily product.

(1334) .sup.1H-NMR (dmso-d.sub.6) value:

(1335) 7.38-7.24 (15H, m), 6.56 (0.64H, d, J=4.8 Hz), 5.84 (0.36H, d, J=6.9 Hz), 5.01 (0.64H, d, J=4.8 Hz), 4.99 (0.36H, d, J=6.9), 4.75-4.47 (6H, m), 4.17 (0.36H, m), 4.03 (0.64H, m), 3.79 (0.64H, d, J=7.5 Hz), 3.66 (0.36H, d, J=6.0 Hz), 3.61-3.49 (2H, m), 1.34 (1.92H, s), 1.33 (1.08H, s).

(1336) ##STR00313##

(1337) 0.69 g of O-methylhydroxylamine hydrochloride was added to a mixture of 2.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol and 10 mL of methanol, and thereafter, 0.56 g of triethylamine was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 6 hours. Thereafter, the solvent was distilled away under reduced pressure, and 20 mL of ethyl acetate and 20 mL of water were then added to the obtained residue. The organic layer was fractionated, and was then washed with water twice. The solvent was distilled away under reduced pressure, so as to obtain 2.0 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-4-((methoxyimino)methyl)pentan-2-ol in the form of a colorless oily product.

(1338) .sup.1H-NMR (CDCl.sub.3) value:

(1339) 7.42 (s (1H), 7.35-18 (15H, m), 4.64-4.39 (6H, m), 4.06 (1H, m), 3.87 (3H, s), 3.76-3.68 (4H, m), 1.58 (3H, s).

(1340) ##STR00314##

(1341) 0.66 g of triethylamine and 0.53 g of N-methylimidazole were added to a solution of 2.0 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-4-((methoxyimino)methyl)pentan-2-ol in 1.0 mL of acetonitrile, and thereafter, 0.75 g of methanesulfonyl chloride was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, 30 mL of water and 50 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was washed with 20 mL of 1 mol/L hydrochloric acid twice, and then, it was successively washed with 20 mL of a saturated sodium hydrogen carbonate aqueous solution and 20 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 1.7 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-5-(methoxyimino)-4-methylpentan-2-yl=methanesulfonate in the form of a colorless oily product.

(1342) .sup.1H-NMR (CDCl.sub.3) value:

(1343) 7.35 (1H, s), 7.34-7.22 (15H, m), 5.23 (1H, m), 4.81-3.39 (6H, m), 3.96 (1H, d, J=10.8 Hz), 3.89-3.79 (2H, m), 3.87 (3H, s), 2.96 (3H, s), 1.48 (3H, s).

(1344) ##STR00315##

(1345) 3.5 mL of 2 mol/L hydrochloric acid and 1.12 g of a 35% formaldehyde aqueous solution were added to a solution of 0.7 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-5-(methoxyimino)-4-methylpentan-2-yl=methanesulfonate in 14 mL of acetone in a nitrogen atmosphere, and the obtained mixture was then stirred at room temperature for 22 hours. Thereafter, 1.2 g of a 35% formaldehyde aqueous solution and 2 mL of acetone were added to the reaction mixture, and the thus obtained mixture was then stirred at 40 C. for 5 hours. Thereafter, 15 mL of water and 20 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with 20 mL of a saturated sodium hydrogen carbonate aqueous solution and 20 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 0.31 g of (2R,3R,4R)-1,3,4-tris(benzyloxy)-4-methyl-5-oxopentan-2-yl=methanesulfonate in the form of a colorless oily product.

(1346) .sup.1H-NMR (CDCl.sub.3) value:

(1347) 9.51 (1H, s), 7.38-7.24 (15H, m), 5.09 (1H, m), 4.77-4.43 (6H, m), 4.09 (1H, d, J=4.5 Hz), 3.96-3.77 (2H, m), 2.93 (3H, s), 10.43 (3H, s).

(1348) ##STR00316##

(1349) 0.035 g of a sodium hydrogen sulfide x-hydrate was added to an N,N-dimethylformamide solution of 0.12 g of (2R,3R,4R)-1,3,4-tris(benzyloxy)-4-methyl-5-oxopentan-2-yl=methanesulfonate, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, water and 5 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was then washed with 5 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 0.05 g of (3R,4S,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methylthiolan-2-ol in the form of a colorless oily product.

(1350) .sup.1H-NMR (CDCl.sub.3) value:

(1351) 7.37-7.22 (15H, m), 5.29 (1H, d, J=6.0 Hz), 4.75-4.37 (6H, m), 4.02 (1H, d, J=6.3 Hz), 3.94 (1H, dd, J=9.3, 4.8 Hz), 3.80 (1H, m), 3.70 (1H, dd, J=9.3, 8.1 Hz), 1.95 (1H, d, J=6.3 Hz), 1.48 (3H, s).

Example 42

(1352) ##STR00317##

(1353) 190 mg of (2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxyoxolan-3-yl=benzoate was dissolved in 4 mL of a mixed solvent of acetonitrile/water (3/1), and thereafter, 83.5 mg of O-methylhydroxylamine hydrochloride and 0.09 mL of triethylamine were added to the obtained solution. The thus obtained mixture was then stirred for 2 hours. Thereafter, 82 mg of pyridinium p-toluenesulfonate was added to the reaction mixture, and the thus obtained mixture was then stirred for 69 hours. Thereafter, a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the water layer was then removed. The water layer was extracted with ethyl acetate, and the organic layer was then combined with the extract. The thus obtained mixture was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to obtain a colorless oily product. 0.42 mL of triethylamine was added to a solution of this oily product in 3 mL of tetrahydrofuran, and 0.12 mL of methanesulfonyl chloride was then added to the mixture at 0 C. The obtained mixture was stirred for 30 minutes. Thereafter, a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the water layer was then removed. The water layer was extracted with ethyl acetate, and the organic layer was then combined with the extract. The thus obtained mixture was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 202 mg of (2R,3R,5E)-3-benzoyloxy-4,4-difluoro-2-(methylsulfonyloxy)-5-(methoxyimino)pentyl benzoate in the form of a colorless oily product.

(1354) .sup.1H-NMR (CDCl.sub.3) value:

(1355) 8.10-8.05 (4H, m), 7.67-7.40 (7H, m), 6.17 (1H, ddd, 12.9 Hz, 10.8 Hz, 3.0 Hz), 5.62 (1H, ddd, 8.4 Hz, 3.0 Hz, 2.7 Hz), 4.89 (1H, dd, 12.6 Hz, 2.7 Hz), 4.60 (1H, dd, 12.6 Hz, 8.4 Hz), 3.90 (3H, s), 3.06 (3H, s) ppm.

(1356) ##STR00318##

(1357) 1 mol/L hydrochloric acid and a 35% formaldehyde aqueous solution were added to a solution of 202 mg of (2R,3R,5E)-3-benzoyloxy-4,4-difluoro-2-(methylsulfonyloxy)-5-(methoxyimino)pentyl benzoate in 4 mL of acetone, and the obtained mixture was then stirred at room temperature for 72 hours. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate=2/3 to 1/4), so as to obtain 70.5 mg of (3R,4R)-5-benzoyloxy-2,2-difluoro-1,1-dihydroxy-4-(methylsulfonyloxy)pentan-3-yl=benzoate in the form of a colorless oily product.

(1358) .sup.1H-NMR (CDCl.sub.3) value:

(1359) 8.08-8.02 (4H, m), 7.64-7.36 (6H, m), 6.19 (1H, ddd, 12.9 Hz, 12.9 Hz, 2.7 Hz), 5.70 (1H, ddd, 8.7 Hz, 2.4 Hz, 2.4 Hz), 5.30 (1H, br), 4.93 (1H, br), 4.92 (1H, dd, 12.6 Hz, 2.4 Hz), 4.59 (1H, dd, 12.6 Hz, 8.7 Hz), 3.10 (1H, br), 3.08 (3H, s) ppm.

(1360) ##STR00319##

(1361) 17 mg of a sodium hydrogen sulfide n-hydrate was added to a solution of 70.5 mg of (3R,4R)-5-benzoyloxy-2,2-difluoro-1,1-dihydroxy-4-(methylsulfonyloxy)pentan-3-yl=benzoate in 1 mL of N,N-dimethylformamide, and the obtained mixture was then stirred at room temperature for 5 minutes. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 0/1), so as to obtain 26.5 mg of (2R,3R)-2-((benzoyloxy)methyl)-4,4-difluoro-5-hydroxythiolan-3-yl benzoate in the form of a colorless oily product.

(1362) .sup.1H-NMR (CDCl.sub.3) value:

(1363) 8.04 (2H, d, J=7.2 Hz), 7.90 (0.6H, d, J=7.2 Hz), 7.82 (1.4H, d, J=7.2 Hz), 7.27-7.65 (6H, m), 5.98 (1H, m), 5.36-5.54, (1H, m), 4.62 (0.6H, d, J=7.5 Hz), 4.55 (0.7H, dd, J=11.4, 8.1 Hz), 4.44 (0.7H, d, J=11.4, 6.1 Hz), 4.28 (0.7H, ddd, J=8.1 Hz, 6.1 Hz, 6.6 Hz), 2.80-3.15 (1H, br).

Example 43

(1364) ##STR00320##

(1365) 0.64 g of sodium tetrahydroborate was added to a solution of 1.2 g of 5-methyl-4-phenyloxolane-2-one in 2 mL of ethanol and 20 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5 C. to 10 C., and thereafter, a solution of 2.0 g of calcium chloride in 8 mL of ethanol was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 200 minutes. Thereafter, 30 mL of ethyl acetate was added to the reaction mixture, and thereafter, 20 mL of 3 mol/L hydrochloric acid was added dropwise to the mixture. The organic layer was fractionated, and it was washed with a saturated sodium hydrogen carbonate aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.05 g of 3-phenylpentane-1,4-diol in the form of a colorless oily product.

(1366) .sup.1H-NMR (CDCl.sub.3) value:

(1367) 7.35-7.15 (5H, m), 3.95 (1H, dqb, J=6.9 Hz, 6.3H), 3.70-3.61 (1H, m), 3.57-3.46 (1H, m), 2.69 (1H, ddd, J=8.3 Hz, 8.3 Hz, 5.1 Hz), 2.28-2.15 (1H, m), 2.00-1.80 (1H, m), 1.04 (3H, d, J=6.3 Hz).

(1368) ##STR00321##

(1369) 1.25 mL of triisopropylsilyl chloride was added dropwise to a solution of 1.0 g of 3-phenylpentane-1,4-diol and 0.45 g of imidazole in 20 mL of N,N-dimethylformamide in a nitrogen atmosphere at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 19 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19 to 1/10), so as to obtain 1.2 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-ol in the form of a colorless oily product.

(1370) .sup.1H-NMR (CDCl.sub.3) value:

(1371) 7.33-7.12 (5H, m), 4.00-3.89 (1H, m), 3.76-3.68 (1H, m), 3.63-3.53 (1H, m), 2.81-2.78 (1H, m), 2.75-2.67 (1H, m), 2.20-2.08 (1H, m), 1.99-1.88 (1, m), 1.15-1.00 (24H, m).

(1372) ##STR00322##

(1373) 0.46 mL of methanesulfonyl chloride was added dropwise to a solution of 1.0 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-ol and 1.67 mL of triethylamine in 10 mL of an ethyl acetate at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 5.5 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.2 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-yl methanesulfonate in the form of a yellow oily product.

(1374) .sup.1H-NMR (CDCl.sub.3) value:

(1375) 7.35-7.15 (5H, m), 4.90 (1H, dq, J=6.3 Hz, 6.8 Hz), 3.66-3.58 (1H, m), 3.46-3.35 (1H, m), 3.10-3.02 (1H, m), 2.85 (3H, s), 2.27-2.14 (1H, m), 1.94-1.81 (1H, m), 1.31 (3H, d, J=6.3 Hz), 1.09-0.95 (21H, m).

(1376) ##STR00323##

(1377) 0.24 g of p-toluenesulfonic acid monohydrate was added to a solution of 1.05 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-yl methanesulfonate in 15 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/4 to 1/1), so as to obtain 0.56 g of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate in the form of a colorless oily product.

(1378) .sup.1H-NMR (CDCl.sub.3) value:

(1379) 7.38-7.16 (5H, m), 4.92 (1H, dq, J=7.8 Hz, 6.3 Hz), 3.62-3.53 (1H, m), 3.44-3.34 (1H, m), 3.05-2.95 (1H, m), 2.92 (3H, s), 2.29-2.16 (1H, m), 1.99-1.85 (1H, m), 1.28 (3H, d, J=6.3 Hz).

(1380) ##STR00324##

(1381) 1.2 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin Periodinane) was added to a solution of 490 mg of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate in 5 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with a sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/10 to 1/1), so as to obtain 414 mg of 5-oxo-3-phenylpentan-2-yl methanesulfonate in the form of a colorless oily product.

(1382) .sup.1H-NMR (CDCl.sub.3) value:

(1383) 9.69 (1H, m), 7.38-7.18 (5H, m), 4.93-4.85 (1H, m), 3.50-3.43 (1H, m), 3.15-3.04 (1H, m), 2.93-2.80 (4H, m), 1.31 (3H, d, J=4.5 Hz).

(1384) ##STR00325##

(1385) 240 mg of a sodium hydrogen sulfide n-hydrate was added to a solution of 256 mg of 5-oxo-3-phenylpentan-2-yl methanesulfonate in 3 mL of N,N-dimethylformamide at room temperature, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution twice and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/19 to 1/9), so as to obtain 80 mg of 5-methyl-4-phenylthiolan-2-ol in the form of a colorless oily product.

(1386) .sup.1H-NMR (CDCl.sub.3) value:

(1387) 7.38-7.17 (5H, m), 5.82-5.72 (0.17H, m), 5.63-5.58 (0.83H, m), 3.99-3.90 (0.83H, m), 3.82-3.51 (0.83H, m), 3.66-3.47 (0.34H, m), 2.75-2.68 (0.17H, m), 2.56-2.31 (1.83H, m), 1.10 (0.51H, d, J=6.9 Hz), 0.84 (2.49H, d, J=6.9 Hz).

Example 44

(1388) ##STR00326##

(1389) 4.0 g of sodium tetrahydroborate was added to a solution of 12.2 g of (3aR,6R,6aR)-2,2,6-trimethyltetrahydro-2H-furo(3,4-d)(1,3)dioxol-4-ol in 10 mL of ethanol and 120 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5 C. to 10 C., and thereafter, a solution of 10.3 g of calcium chloride in 50 mL of ethanol was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 4 hours. Thereafter, 200 mL of ethyl acetate and 300 mL of water were added to the reaction mixture. The organic layer was fractionated, and the water layer was then extracted with 200 mL of ethyl acetate six times. The organic layer was combined with the extract, and the obtained mixture was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/4 to 1/1), so as to obtain 7.4 g of (1R)-1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethan-1-ol in the form of a colorless oily product.

(1390) .sup.1H-NMR (CDCl.sub.3) value:

(1391) 4.34-4.27 (1H, m), 4.03-3.71 (4H, m), 2.73-2.62 (2H, m), 1.41 (3H, s), 1.36 (3H, s), 1.33 (3H, d, J=6.0 Hz).

(1392) ##STR00327##

(1393) 4.46 mL of triisopropylsilyl chloride was added dropwise to a solution of 3.5 g of (1R)-1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethan-1-ol and 1.63 g of imidazole in 50 mL of N,N-dimethylformamide in a nitrogen atmosphere at a temperature of 5 C. to 10 C. and the obtained mixture was then stirred at room temperature for 23 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 7.1 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethan-1-ol in the form of a colorless oily product.

(1394) .sup.1H-NMR (CDCl.sub.3) value:

(1395) 4.29 (1H, ddd, J=3.6, 5.1, 10.2 Hz), 4.12 (1H, br), 4.02-3.94 (2H, m), 3.88 (1H, dd, J=10.2, 10.2 Hz), 3.67 (1H, dd, J=3.6, 10.2 Hz), 1.40-1.03 (30H, m).

(1396) ##STR00328##

(1397) 0.75 mL of methanesulfonyl chloride was added dropwise to a solution of 1.6 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethan-1-ol and 2.7 mL of triethylamine in 16 mL of ethyl acetate at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 10 minutes. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.98 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethyl methanesulfonate in the form of a colorless oily product.

(1398) .sup.1H-NMR (CDCl.sub.3) value:

(1399) 5.17 (1H, dq, J=3.3, 6.6 Hz), 4.35-4.27 (2H, m), 3.94-3.82 (2H, m), 3.02 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.47 (3H, s), 1.37 (3H, s), 1.17-1.03 (21H, m).

(1400) ##STR00329##

(1401) 5.8 mL of a 1 mol/L tetrabutyl ammonium fluoride/tetrahydrofuran solution was added to a solution of 1.98 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethyl methanesulfonate in 24 mL of tetrahydrofuran at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 20 minutes. Thereafter, a saturated ammonium chloride aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.8 g of (1R)-1-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate in the form of a colorless oily product.

(1402) The obtained oily product contained fluorotris(propan-2-yl)silane. However, the oily product was directly used in the subsequent reaction.

(1403) .sup.1H-NMR (CDCl.sub.3) value:

(1404) 4.96 (1H, dq, J=6.3, 6.3 Hz), 4.32 (1H, dt, J=4.5, 6.3 Hz), 4.17-4.11 (1H, m), 3.90-3.79 (2H, m), 3.75 (1H, br), 3.06 (3H, s), 1.53 (3H, d, J=6.3 Hz), 1.47 (3H, s), 1.38 (3H, s).

(1405) ##STR00330##

(1406) 3 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin Periodinane) was added to a solution of 1.8 g of (1R)-1-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate (which contained fluorotris(propan-2-yl)silane) and 1.16 mL of pyridine in 20 mL of dichloromethane at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate, a saturated sodium hydrogen carbonate aqueous solution and a sodium thiosulfate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with water and a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.7 g of (1R)-1-((4S,5R)-5-formyl-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate in the form of a yellow oily product.

(1407) The obtained oily product contained fluorotris(propan-2-yl)silane. However, the oily product was directly used in the subsequent reaction.

(1408) .sup.1H-NMR (CDCl.sub.3) value:

(1409) 9.69 (1H, d, J=3.0 Hz), 4.99 (1H, dq, J=5.1, 6.6 Hz), 4.50-4.39 (2H, m), 3.02 (3H, s), 1.60 (3H, s), 1.50 (3H, d, J=6.6 Hz), 1.42 (3H, s).

(1410) ##STR00331##

(1411) 0.38 g of a sodium hydrogen sulfide n-hydrate was added to a solution of 0.85 g of (1R)-1-((4S,5R)-5-formyl-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate (which contained fluorotris(propan-2-yl)silane) in 8 mL of N,N-dimethylformamide at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution twice and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/19 to 1/4), so as to obtain 0.11 g of (3aR,6S,6aS)-2,2,6-trimethyltetrahydro-2H-thieno(3,4-d)(1,3)dioxol-4-ol in the form of a white solid.

(1412) .sup.1H-NMR (CDCl.sub.3) value:

(1413) 5.21 (1H, s), 4.77-4.70 (2H, m), 3.82 (1H, dq, J=3.3, 6.9 Hz), 1.76 (1H, br), 1.49 (3H, s), 1.38 (3H, d, J=6.9 Hz), 1.33 (3H, s).

Example 45

(1414) ##STR00332##

(1415) 4.1 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 1.0 g of 5-phenyloxolane-2-one in 12 mL of toluene at 60 C., and the obtained mixture was then stirred for 30 minutes. Thereafter, 1 mL of methanol was added to the reaction mixture, and thereafter, 40 mL of a 20% potassium sodium tartrate aqueous solution was then added to the mixture at room temperature. The thus obtained mixture was stirred for 1 hour. Thereafter, the water layer was removed, and the solvent was then distilled away under reduced pressure, so as to obtain 0.98 g of 5-phenyloxolan-2-ol in the form of a colorless oily product.

(1416) As a result of the measurement of .sup.1H-NMR, it was found that the obtained oily product was a mixture of isomer A and isomer B, and that the ratio of A:B=56:54.

(1417) .sup.1H-NMR (CDCl.sub.3) value:

(1418) 7.46-7.23 (5H+5H, m, A+B), 5.77-5.75 (1H, m, A), 5.64-5.62 (1H, m, B), 5.25 (1H, t, J=6.9 Hz, A), 5.04-4.98 (1H, m, B), 2.98-2.92 (1H, m, B), 2.90-2.83 (1H, m, B), 2.59-2.42 (1H, m, A), 2.36-2.02 (1H+4H, m, A+B), 2.21-1.91 (1H, m, A), 1.86-1.75 (1H, m, A).

(1419) ##STR00333##

(1420) 12 mL of acetonitrile, 6 mL of water and 1.0 g of O-methylhydroxylamine hydrochloride were added to 0.98 g of the 5-phenyloxolan-2-ol, and thereafter, 1.08 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 0.5 hours. Thereafter, hexane, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 1.10 g of 4-(methoxyimino)-1-phenylbutan-1-ol in the form of a colorless oily product.

(1421) As a result of the measurement of .sup.1H-NMR, it was found that the obtained oily product was a mixture of isomer A and isomer B, and that the ratio of A:B=60:40.

(1422) .sup.1H-NMR (CDCl.sub.3) value:

(1423) 7.41 (1H, t, J=5.9 Hz, A), 7.38-7.25 (5H+5H, m, A+B), 6.68 (1H, t, J=5.7 Hz, A), 4.77-4.71 (1H, m, A), 4.70-4.64 (1H, m, B), 3.87 (3H, s, B), 3.81 (3H, s, A), 2.54-2.25 (2H+2H, m, A+B), 2.20 (1H, d, J=3.6 Hz, A), 2.17 (1H, d, J=3.6 Hz, B), 2.06-1.80 (2H+2H, m, A+B).

(1424) ##STR00334##

(1425) 0.24 mL of N-methylimidazole was added to a solution of 0.39 g of 4-(methoxyimino)-1-phenylbutan-1-ol in 4 mL of acetonitrile. Thereafter, 0.19 mL of methanesulfonyl chloride was added to the mixture at a temperature of 0 C. to 10 C., and the thus obtained mixture was then stirred at a temperature of 5 C. or lower for 1.5 hours. Thereafter, 0.24 mL of methanesulfonyl chloride was added to the reaction mixture, ethyl acetate and water were then added thereto, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained product was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 59/41), so as to obtain 0.07 g of (4-chloro-4-phenylbutylidene)(methoxy)amine in the form of a light yellow oily product.

(1426) As a result of the measurement of .sup.1H-NMR, it was found that the obtained oily product was a mixture of isomer A and isomer B, and that the ratio of A:B=58:42.

(1427) .sup.1H-NMR (CDCl.sub.3) value:

(1428) 7.41-7.30 (6H+5H, m, A+B), 6.63 (1H, t, J=5.4 Hz, B), 4.92 (1H, t, J=6.8 Hz, A), 4.84 (1H, dd, J=6.2, 8.0 Hz, B), 3.86 (3H, s, B), 3.82 (3H, s, A), 2.53-2.20 (4H+4H, m, A+B).

(1429) ##STR00335##

(1430) 0.1 mL of 2 mol/L hydrochloric acid was added to a mixture of 82 mg of (4-chloro-4-phenylbutylidene)(methoxy)amine, 0.32 mL of a 36% formalin aqueous solution and 4 mL of acetone, and the obtained mixture was then stirred at room temperature for 0.5 hours. Thereafter, hexane and water were added to the reaction mixture, and the water layer was then removed. The solvent was distilled away under reduced pressure, so as to obtain 61 mg of 4-chloro-4-phenylbutanal in the form of a colorless oily product.

(1431) .sup.1H-NMR (CDCl.sub.3) value:

(1432) 9.78 (1H, t, J=0.9 Hz), 7.41-7.28 (5H, m), 4.94 (1H, dd, J=6.6, 7.5 Hz), 2.66 (2H, t, J=6.9 Hz), 2.39 (2H, dd, J=6.6, 7.4 Hz), 3.86 (3H, s, B), 3.82 (3H, s, A), 2.53-2.20 (4H+4H, m, A+B).

(1433) ##STR00336##

(1434) 32 mg of anhydrous sodium hydrogen sulfide was added to a solution of 61 mg of 4-chloro-4-phenylbutanal in 1 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 60/40), so as to obtain 37 mg of 5-phenylthiolan-2-ol in the form of a colorless oily product.

(1435) As a result of the measurement of .sup.1H-NMR, it was found that the obtained oily product was a mixture of isomer A and isomer B, and that the ratio of A:B=68:32.

(1436) .sup.1H-NMR (CDCl.sub.3) value:

(1437) 7.45 (2H, brd, J=7.8 Hz, A), 7.39-7.20 (3H+5H, m, A+B), 5.80 (1H, m, B), 5.64 (1H, t, J=4.2 Hz, A), 4.80 (1H, dd, J=5.0, 7.1 Hz, B), 4.56 (1H, dd, J=6.1, 10.5 Hz, A), 2.65-2.00 (4H+4H, m, A+B).

Example 46

(1438) ##STR00337##

(1439) 80 mg of a sodium hydrogen sulfide x-hydrate was added to a solution of 295 mg of diethyl 2-bromo-2-(3-oxopropyl)malonate in 3 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 15 minutes, and then at room temperature for 15 minutes. Thereafter, 10 mL of ethyl acetate and 10 mL of water were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was successively washed with 10 mL of 1 mol/L hydrochloric acid, 10 mL of a saturated sodium hydrogen carbonate aqueous solution and 10 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=5/1), so as to obtain 29 mg of diethyl 5-hydroxydihydrothiophene-2,2(3H)-dicarboxylate in the form of a colorless oily product.

(1440) .sup.1H-NMR (CDCl.sub.3) value:

(1441) 1.23-1.31 (6H, m), 2.30 (2H, m), 2.58 (1H, m), 2.67 (1H, d, J=6.9 Hz), 2.77 (1H, m), 4.15-4.30 (4H, m), 5.62 (1H, dt, J=6.9 Hz, 3.3 Hz).

Example 47

(1442) ##STR00338##

(1443) A mixture of 10 g of 3-bromo-2-oxooxolane, 6.6 g of benzylamine, 21 g of potassium carbonate and 200 mL of acetonitrile was stirred at 70 C. for 1 hour 30 minutes. Thereafter, 7.9 mL of 4-methylbenzoyl chloride was added dropwise to the reaction mixture at a temperature of 5 C. to 10 C., and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 400 mL of ethyl acetate and 200 mL of water were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was successively washed with 100 mL of water and 100 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then dissolved in 100 mL of ethyl acetate under heating. After that, 100 mL of hexane was added dropwise to the reaction mixture at 50 C. A solid was collected by filtration, so as to obtain 11.2 g of N-benzyl-4-methyl-N-(2-oxooxolan-3-yl)benzamide.

(1444) .sup.1H-NMR (CDCl.sub.3) value:

(1445) 7.47-7.15 (9H, m), 4.85-4.50 (3H, m), 4.27-4.14 (1H, m), 4.06-3.89 (1H, m), 2.71-2.50 (1H, m), 2.34 (3H, s), 2.36-2.20 (1H, m)

(1446) ##STR00339##

(1447) 4.4 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 2.0 g of N-benzyl-4-methyl-N-(2-oxooxolan-3-yl)benzamide in 30 mL of toluene and 10 mL of methylene chloride at 60 C., and the obtained mixture was then stirred for 30 minutes. Thereafter, the reaction mixture was heated to 15 C., and 6.6 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to the mixture at 60 C. The obtained mixture was stirred for 25 minutes. Thereafter, 1 mL of methanol was added to the reaction mixture, and 80 mL of a 20% potassium sodium tartrate aqueous solution was then added thereto at room temperature. The water layer was removed, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40 to 35/65), so as to obtain 0.89 g of N-benzyl-N-(2-hydroxyoxolan-3-yl)benzamide in the form of a colorless oily product.

(1448) As a result of the measurement of .sup.1H-NMR, it was found that the obtained oily product was a mixture of isomer A and isomer B, and that the ratio of A:B=61:39.

(1449) .sup.1H-NMR (CDCl.sub.3) value:

(1450) 7.40-7.10 (9H+9H, m, A+B), 5.47 (1H, brs, A), 5.24 (1H, dd, J=5.1, 7.8 Hz, B), 4.90-4.48 (2H+2H, m, A+B), 4.25-3.50 (3H+3H, m, A+B), 2.35 (3H, s, A), 2.32 (3H, s, B), 2.22-1.92 (2H+2H, m, A+B).

(1451) ##STR00340##

(1452) 1.2 mL of acetonitrile, 0.6 mL of water and 0.1 g of O-methylhydroxylamine hydrochloride were added to 0.2 g of N-benzyl-N-(2-hydroxyoxolan-3-yl)benzamide, and the obtained mixture was then stirred at room temperature for 0.5 hours. The reaction mixture was then left at rest for 11 hours. Thereafter, hexane, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40 to 30/70), so as to obtain 99 mg of N-benzyl-N-(4-hydroxy-1-(methoxyimino)butan-2-yl)-4-methylbenzamide in the form of a colorless oily product.

(1453) As a result of the measurement of .sup.1H-NMR, it was found that the obtained oily product was a mixture of isomer A and isomer B, and that the ratio of A:B=80:20.

(1454) .sup.1H-NMR (CDCl.sub.3) value:

(1455) 7.38-7.15 (10H+10H, m, A+B), 5.14 (1H, q, J=7.2 Hz, B), 4.86 (1H, q, J=6.3 Hz, A), 4.70-4.50 (2H+2H, m, A+B), 3.85 (3H, s, B), 3.79 (3H, s, A), 3.58 (2H+2H, brs, A+B), 3.36 (3H, s, B), 3.35 (3H, s, A), 2.22-1.88 (2H+2H, m, A+B).

(1456) ##STR00341##

(1457) 0.083 mL of triethylamine was added to a solution of 99 mg of N-benzyl-N-(4-hydroxy-1-(methoxyimino)butan-2-yl)-4-methylbenzamide in 3 mL of tetrahydrofuran, and thereafter, 0.028 mL of methanesulfonyl chloride was added to the mixture at a temperature of 0 C. to 10 C. The obtained mixture was stirred at a temperature of 5 C. or lower for 105 minutes. Thereafter, 0.028 mL of methanesulfonyl chloride was added to the reaction mixture. After that, ethyl acetate and water were added to the mixture, and the water layer was then removed. The organic layer was successively washed with water and a saturated sodium chloride aqueous solution, and the solvent was then distilled away under reduced pressure, so as to obtain 3-(N-benzyl-1-(4-methylphenyl)formamide)-4-(methoxyimino)butyl methanesulfonate.

(1458) As a result of the measurement of .sup.1H-NMR, signals of methanesulfonate were observed at 2.90 ppm and 2.93 ppm.

(1459) ##STR00342##

(1460) 0.05 mL of 2 mol/L hydrochloric acid was added to a mixture of the obtained 3-(N-benzyl-1-(4-methylphenyl)formamide)-4-(methoxyimino)butyl methanesulfonate, 0.23 mL of a 36% formalin aqueous solution and 3 mL of acetone, and the obtained mixture was then stirred at room temperature for 75 minutes. Thereafter, hexane, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 3-(N-benzyl-1-(4-methylphenyl)formamide)-4-oxobutyl methanesulfonate.

(1461) As a result of the measurement of .sup.1H-NMR, a signal of aldehyde was observed at 9.42 ppm.

(1462) ##STR00343##

(1463) 29 mg of anhydrous sodium hydrogen sulfide was added to a solution of 3-(N-benzyl-1-(4-methylphenyl)formamide)-4-oxobutyl methanesulfonate in 3 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 50/50), so as to obtain 46 mg of N-benzyl-N-(2-hydroxythiolan-3-yl)-4-methylbenzamide in the form of a colorless oily product.

(1464) As a result of the measurement of .sup.1H-NMR, it was found that the obtained oily product was a mixture of isomer A and isomer B, and that the ratio of A:B=57:43.

(1465) .sup.1H-NMR (CDCl.sub.3) value:

(1466) 7.40-7.14 (9H+9H, m, A+B), 5.56 (1H, brs, B), 5.42 (1H, brs, A), 4.95-4.80 (1H, m, B), 4.80-4.54 (2H+2H, m, A+B), 4.16-4.07 (1H, m, A), 3.10-2.95 (1H+1H, m, A+B), 2.77-2.64 (1H, m, A), 2.36 (3H, s, B), 2.34 (3H, s, A), 2.28-2.04 (2H+2H, m, A+B).

Example 48

(1467) ##STR00344##

(1468) 16.4 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 4.3 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolane-2-one in 100 mL of tetrahydrofuran at 78 C., and the obtained mixture was then stirred for 7.5 hours. Thereafter, 15 mL of methanol was added to the reaction mixture, and 100 mL of a saturated potassium sodium tartrate aqueous solution was then added to the mixture at room temperature. The thus obtained mixture was stirred for 30 minutes, and the water layer was then removed. The water layer was extracted with 100 mL of ethyl acetate. The organic layer was combined with the extract, and the obtained mixture was then washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), so as to obtain 2.8 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolan-2-ol in the form of a colorless oily product.

(1469) .sup.1H-NMR (CDCl.sub.3) value:

(1470) 8.36-8.43 (1H, m), 7.47-7.57 (1H, m), 7.20-7.32 (1H, m), 6.99-7.09 (1H, m), 5.61 (0.18H, t, J=5.1 Hz), 5.43-5.55 (0.73H, m), 5.35 (0.28H, s), 5.16 (0.27H, d, J=2.1 Hz), 5.04 (0.39H, s), 4.86 (0.15H, d, J=5.7 Hz), 4.31-4.58 (1H, m), 4.01-4.28 (1H, m), 2.49-2.60 (0.40H, m), 2.37-2.47 (0.16H, m), 1.74-2.27 (1.02H, m), 1.49-1.62 (0.42H, m), 1.23-1.42 (3H, m)

(1471) ##STR00345##

(1472) 8.0 mL of methanol and 712 mg of O-methylhydroxylamine hydrochloride were added to 1.5 g of 5-methyl-3-(pyridin-2-ylsulfanyl)oxolan-2-ol, and thereafter, 1.1 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 2 hours. Thereafter, the solvent was distilled away under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were then added to the residue, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone=4/1), so as to obtain 1.74 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-ol in the form of a colorless oily product.

(1473) .sup.1H-NMR (CDCl.sub.3) value:

(1474) 8.37-8.45 (1H, m), 7.48-7.58 (1.76H, m), 7.14-7.30 (1H, m), 6.99-7.10 (1H, m), 6.76-6.82 (0.24H, m), 5.06-5.19 (0.88H, m), 4.69-4.79 (0.79H, m), 3.97-4.12 (1H, m), 3.82-3.87 (3H, m), 2.91-3.05 (0.33H, m), 1.76-2.22 (2H, m), 1.21-1.29 (3H, m)

(1475) ##STR00346##

(1476) 1.2 mL of triethylamine was added to a solution of 1.7 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-ol in 7.0 mL of tetrahydrofuran, and thereafter, 602 L of methanesulfonyl chloride was added to the mixture at a temperature of 0 C. to 10 C. The thus obtained mixture was stirred at a temperature of 15 C. or lower for 1.5 hours. Thereafter, 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 2.12 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in the form of a brown oily product.

(1477) .sup.1H-NMR (CDCl.sub.3) value:

(1478) 8.39-8.45 (1H, m), 7.47-7.57 (1.8H, m), 7.16-7.23 (1H, m), 7.00-7.07 (1H, m), 6.89 (0.2H, d, J=7.5 Hz), 4.95-5.16 (1H, m), 4.67-4.78 (1H, m), 3.79-3.91 (3H, m), 3.07 (0.87H, s), 3.01-3.04 (0.59H, m), 2.97 (1.54H, s), 2.39-2.51 (0.54H, m), 2.05-2.35 (1.46H, m), 10.48-1.55 (3H, m)

(1479) ##STR00347##

(1480) 14 mL of 2 mol/L hydrochloric acid was added to a mixture of 2.1 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate, 4.7 mL of a 36% formalin aqueous solution and 60 mL of acetone, and the obtained mixture was stirred at room temperature for 2 hours, and then at 50 C. for 3 hours. Thereafter, the solvent was distilled away under reduced pressure, 100 mL of ethyl acetate and 100 mL of water were then added to the residue, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone=3/1), so as to obtain 0.90 g of 5-oxo-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in the form of a colorless oily product.

(1481) ##STR00348##

(1482) 0.74 g of sodium hydrogen sulfide (Wako Pure Chemical Industries, Ltd.) was added to a solution of 0.60 mg of 5-oxo-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in 10 mL of N,N-dimethylformamide at a temperature of 0 C. to 10 C., and the obtained mixture was then stirred at the same temperature as described above for 1.5 hours. Thereafter, 30 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with 30 mL of water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=5/1), so as to obtain 120 mg of 5-methyl-3-(pyridin-2-ylsulfanyl)thiolan-2-ol in the form of a light yellow oily product.

(1483) .sup.1H-NMR (CDCl.sub.3) value:

(1484) 8.33-8.43 (1H, m), 7.48-7.58 (1H, m), 7.20-7.34 (1H, m), 6.99-7.09 (1H, m), 5.62-5.70 (0.37H, m), 5.50-5.59 (0.63H, m), 4.41-4.53 (0.36H, m), 4.22-4.30 (0.24H, m), 4.14-4.21 (0.20H, m), 3.85-3.94 (0.20H, m), 3.54-3.80 (1H, m), 2.45-2.68 (0.80H, m), 2.33-2.42 (0.31H, m), 2.22-2.30 (0.28H, m), 1.99-2.11 (0.42H, m), 1.77-1.88 (0.19H, m), 1.50 (0.97H, d, J=6.8 Hz), 1.44 (0.89H, d, J=6.4 Hz), 1.33-1.40 (1.14H, m)

INDUSTRIAL APPLICABILITY

(1485) The compound of the present invention is useful as an intermediate for producing a thionucleoside, and the production method of the present invention is useful as a method for producing a thionucleoside.