Method for producing prostaglandin derivative

Abstract

The present invention relates to a novel production method of a novel prostaglandin derivative or a pharmaceutically acceptable salt thereof useful as a medicament, and an intermediate therefor. According to the present invention, a production method of a novel prostaglandin derivative or a pharmaceutically acceptable salt thereof including a conversion step from a compound represented by the following formula 3 to a compound represented by the formula 1 can be provided: ##STR00001##
wherein each symbol is as defined in the DESCRIPTION.

Claims

1. A compound represented by the formula 3: ##STR00045## wherein, in the formula 3, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms; R.sup.3 is a hydroxy-protecting group; a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration; and Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms.

2. A method for producing a compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, comprising protecting a hydroxy group of a compound represented by the formula 3, and converting same to a compound represented by the formula 1 by subsequently removing R.sup.3 and hydrolyzing a CO.sub.2Z group: ##STR00046## wherein, in the formula 1, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms or a substituted cycloalkyl group having 3 to 5 carbon atoms; R.sup.1 and R.sup.2 are each independently a hydroxy-protecting group; and a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration, ##STR00047## wherein, in the formula 3, R.sup.3 is a hydroxy-protecting group different from R.sup.1 and R.sup.2; Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms; and R and a methyl group bonded by a wavy line are as defined above.

3. A method for producing a compound represented by the formula 2 or a pharmaceutically acceptable salt thereof, comprising oxidizing a hydroxy group of the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof according to claim 2, and removing R.sup.1 and R.sup.2: ##STR00048## wherein, in the formula 2, R and a methyl group bonded by a wavy line are as defined in claim 2.

4. The production method according to claim 2, wherein the compound represented by the formula 3 is produced by reducing a carbonyl group of a compound represented by the formula 4 and then removing R.sup.4: ##STR00049## wherein, in the formula 4, R.sup.3, R, a methyl group bonded by a wavy line and Z are as defined in claim 2; and R.sup.4 is a hydroxy-protecting group different from R.sup.3.

5. The production method according to claim 4, wherein the compound represented by the formula 4 is obtained by oxidizing a hydroxy group of the compound represented by the formula 5 to convert same to the corresponding aldehyde, and reacting the compound with a compound represented by the formula 6: ##STR00050## wherein, in the formula 5, R.sup.3, R.sup.4, and Z are as defined in claim 4, ##STR00051## wherein, in the formula 6, R′ is an alkyl group having 1 to 4 carbon atoms, and R and a methyl group bonded by a wavy line are as defined in claim 4.

6. The production method according to claim 5, wherein a compound represented by the formula 5 is obtained by arylselenylating a compound represented by the formula 7 to convert same to a compound represented by the formula 8, protecting a hydroxy group, removing R.sup.5 to convert the compound to a compound represented by the formula 9, and oxidatively eliminating an arylselenyl group to introduce a double bond: ##STR00052## wherein, in the formula 7, R.sup.4 and Z are as defined in claim 5; and R.sup.5 is a hydroxy-protecting group different from R.sup.3 and R.sup.4, ##STR00053## wherein, in the formula 8, R.sup.4, R.sup.5 and Z are as defined above; and Ar is an aryl group or a substituted aryl group, ##STR00054## wherein, in the formula 9, R.sup.3 is as defined in claim 5; and R.sup.4, Ar and Z are as defined above.

7. A compound represented by the formula 4, ##STR00055## wherein, in the formula 4, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms; R.sup.3 is a hydroxy-protecting group; R.sup.4 is a hydroxy-protecting group different from R.sup.3; a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and α-configuration; and Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms.

8. A method for producing a compound represented by the formula 3, comprising reducing a carbonyl group of the compound represented by the formula 4, and removing R.sup.4: ##STR00056## wherein, in the formula 3, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms; R.sup.3 is a hydroxy-protecting group; a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration; and Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms, ##STR00057## wherein, in the formula 4, R.sup.3, R, a methyl group bonded by a wavy line, and Z are as defined above; and R.sup.4 is a hydroxy-protecting group different from R.sup.3.

9. A method for producing a compound represented by the formula 4, comprising oxidizing a hydroxy group of a compound represented by the formula 5 to convert the compound to the corresponding aldehyde, and reacting same with a compound represented by the formula 6 ##STR00058## wherein, in the formula 5, R.sup.3 is a hydroxy-protecting group; R.sup.4 is a hydroxy-protecting group different from R.sup.3; and Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms, ##STR00059## wherein, in the formula 6, R′ is an alkyl group having 1 to 4 carbon atoms, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms, and a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration, ##STR00060## wherein, in the formula 4, R.sup.3, R.sup.4, R, a methyl group bonded by a wavy line, and Z are as defined above.

10. A method for producing a compound represented by the formula 2 or a pharmaceutically acceptable salt thereof, comprising arylselenylating a compound represented by the formula 7 to convert same to a compound represented by the formula 8, protecting a hydroxy group of the compound represented by the formula 8, removing R.sup.5 to convert the compound to a compound represented by the formula 9, oxidatively eliminating an arylselenyl group of the compound represented by the formula 9 to introduce a double bond and convert the compound to a compound represented by the formula 5, oxidizing a hydroxy group of the compound represented by the formula 5 to convert same to the corresponding aldehyde, reacting same with a compound represented by the formula 6 to convert the compound to a compound represented by the formula 4, reducing a carbonyl group of the compound represented by the formula 4, removing R.sup.4 to convert the compound to a compound represented by the formula 3, protecting a hydroxy group of the compound represented by the formula 3, subsequently removing R.sup.3 and hydrolyzing a CO.sub.2Z group to convert the compound to a compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, and oxidizing a hydroxy group of the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, and removing R.sup.1 and R.sup.2 to convert the compound to a compound represented by the formula 2 or a pharmaceutically acceptable salt thereof, ##STR00061## wherein, in the formula 2, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms or a substituted cycloalkyl group having 3 to 5 carbon atoms; and a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration, ##STR00062## wherein, in the formula 7, Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms; R.sup.4 is a hydroxy-protecting group; and R.sup.5 is a hydroxy-protecting group different from R.sup.3 and R.sup.4, ##STR00063## wherein, in the formula 8, R.sup.4, R.sup.5 and Z are as defined above; and Ar is an aryl group or a substituted aryl group, ##STR00064## wherein, in the formula 9, R.sup.4, Ar and Z are as defined above; and R.sup.3 is a hydroxy-protecting group different from R.sup.4, ##STR00065## wherein, in the formula 5, R.sup.3, R.sup.4 and Z are as defined above, ##STR00066## wherein, in the formula 6, R′ is an alkyl group having 1 to 4 carbon atoms, and R and a methyl group bonded by a wavy line are as defined above, ##STR00067## wherein, in the formula 4, R, R.sup.3, R.sup.4, a methyl group bonded by a wavy line and Z are as defined above, ##STR00068## wherein, in the formula 3, R, R.sup.3, a methyl group bonded by a wavy line and Z are as defined above, ##STR00069## wherein, in the formula 1, R.sup.1 and R.sup.2 are each independently a hydroxy-protecting group; and R and a methyl group bonded by a wavy line, are as defined above.

11. The compound according to claim 1, wherein, in the formula 3, the methyl group bonded by a wavy line is as defined in claim 1, R is an ethyl group or a cyclopropyl group, R.sup.3 is an acetyl group, and Z is a methyl group.

12. The compound according to claim 7, wherein, in the formula 4, the methyl group bonded by a wavy line is as defined in claim 7, R is an ethyl group or a cyclopropyl group, R.sup.3 is an acetyl group, R.sup.4 is a 2-tetrahydropyranyl group, and Z is a methyl group.

13. The compound according to claim 2, wherein the methyl group bonded by a wavy line in the formula 1 is as defined in claim 2, R is an ethyl group or a cyclopropyl group, R.sup.1 and R.sup.2 are each a 2-tetrahydropyranyl group, the methyl group bonded by a wavy line in the formula 3 is as defined in claim 2, R is as defined in the formula 1, R.sup.3 is an acetyl group, and Z is a methyl group.

Description

EXAMPLE

(1) The present invention is explained in detail in the following by referring to Examples; however, the present invention is not limited thereto.

(2) % means mol % for yield and mass % for others unless particularly indicated. The room temperature refers to a temperature of 15-30° C. unless particularly indicated. The following .sup.1H-NMR values were measured at a resolution of 400 MHz.

Reference Example 1

(3) Production of methyl 7-((1R,2R,3R,5S)-5-hydroxy-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)heptanoate (Compound (7a))

(4) ##STR00036##

(5) To a suspension of 4-(carboxybutyl)triphenylphosphonium bromide (107 g) in THF (657 mL) was added 1 M potassium bis(trimethylsilyl)amide (KHMDS) (483 mL) and the mixture was stirred for 1 hr and cooled to −78° C. Then, a solution of (3aR,4S,5R,6aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)hexahydro-5-((tetrahydro-2H-pyran-2-yl)oxy)-2H-cyclopenta[b]furan-2-ol (30 g) in THF (377 mL) was added thereto and the mixture was stirred at the same temperature for 30 min. The mixture was heated to room temperature and stirred overnight to give a mixture. Water was added to the mixture and the mixture was extracted with tert-butylmethylether, acidified with disodium hydrogen citrate and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Acetone (1440 mL) was added thereto, N,N-diisopropylethylamine (iPr.sub.2EtN) (58.8 mL), methyl iodide (MeI) (22.1 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (68.6 mL) were added at 0° C., and the mixture was stirred at room temperature for 3.5 hr. Then, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a viscous oil (26.4 g). To the oil (26.4 g) was added ethyl acetate (1494 mL), and the mixture was stirred under a hydrogen atmosphere for 40 min using 5% Pd/C (9.9 g) as a catalyst. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate=3:1 (vol) to a mixed solution of hexane:ethyl acetate=1:3 (vol) to give compound (7a) (20.2 g).

(6) .sup.1H NMR (300 MHz, CDCl.sub.3) δ4.68 (m, 1H), 4.22-4.19 (m, 1H), 4.15-4.04 (m, 1H), 3.88-3.73 (m, 2H), 3.66 (s, 3H), 3.60-3.38 (m, 2H), 2.55-2.25 (m, 1H), 2.24 (t, J=7.5 Hz, 2H), 1.95-1.15 (m, 21H), 0.87(d, J=3.0 Hz, 9H), 0.03(d, J=3.0 Hz, 6H)

Reference Example 2

(7) Production of dimethyl (S)-(+)-(6-cyclopropyl-3-methyl-2-oxohex-5-yn-1-yl)phosphonate (Compound (6a))

(8) ##STR00037##

(9) THF (76.1 mL) was added to dimethyl methylphosphonate (13.3 g), and 2.65 M n-butyllithium (39.5 mL) was added dropwise thereto at −78° C. The reaction mixture was stirred at −78° C. for 1 hr, a solution of methyl (S)-5-cyclopropyl-2-methylpent-4-ynoate (7.50 g) in THF (32.6 mL) was added thereto, and the mixture was stirred at the same temperature for 4 hr to give a mixture. To the mixture was added an aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate =3:1 (vol) to hexane to give compound (6a) (7.10 g). yield 61%.

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) δ3.81 (s, 3H), 3.78 (s, 3H), 3.20 (ddd, J=14.4, 22.8, 28.4 Hz, 2H), 2.91 (q, J=6.8 Hz, 1H), 2.33 (dddd, J=2.0, 6.8, 16.8, 44.4 Hz, 2H), 1.18 (d, J=7.2 Hz, 3H), 1.18 (m, 1H), 0.71 (m, 2H), 0.60 (m, 2H).

Example 1

(11) Production of methyl 7-((1R,2R,3R,5S)-5-hydroxy-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)2-phenylselenoheptanoate (Compound (8a)) (Step 1)

(12) ##STR00038##

(13) 15.0 g of compound (7a) produced in Reference Example 1 was dissolved in 350 mL of THF, a solution (104 mL) of 1.12 M lithium diisopropylamide (LDA) in THF was added thereto at −78° C., and the mixture was stirred at the same temperature for 30 min. A solution of diphenyl diselenide (PhSeSePh) (24.8 g) in THF (53 mL) was added dropwise at −78° C., and the mixture was stirred at the same temperature for about 2 hr to give a mixture. The mixture was diluted with ethyl acetate, partitioned by adding saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (8a) as a crude product (19.9 g).

Example 2

(14) Production of methyl (2E)-7-((1R,2R,3R,5S)-5-acetoxy-2-hydroxymethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)2-phenylselenoheptanoate (Compound (9a)) (Step 2)

(15) ##STR00039##

(16) To the crude product (19.9 g) of compound (8a) obtained in Example 1 were added pyridine (33.3 mL), acetic anhydride (Ac.sub.2O) (33.3 mL), and 4-dimethylaminopyridine (387 mg) and the mixture was stirred at room temperature for 1 hr. Water was added thereto, and the mixture was extracted with a mixed solvent of hexane and ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, THF (176 mL) was added and the mixture was ice-cooled. 1 M tetrabutylammonium fluoride (TBAF) (63.5 mL) was added, and the mixture was stirred at room temperature for 3 hr to give a mixture. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate=3:1 (vol) to a mixed solution of hexane:ethyl acetate=1:3 (vol) to give compound (9a) (14.1 g) as an oil. The content of the geometrical isomer with a double bond moiety at the 2-position (Z form) and the content of the dihydro form having a single bond at the double bond moiety were not more than 0.1%.

Example 3

(17) Production of methyl (2E)-7-((1R,2R,3R,5S)-5-acetoxy-2-hydroxymethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-2-enoate (Compound (5a)) (Step 3)

(18) ##STR00040##

(19) To compound (9a) (14.1 g) obtained in Example 2 was added dichloromethane (211 mL) and the mixture was stirred. Pyridine (4.10 mL) and 30% aqueous hydrogen peroxide (10.4 mL) were added thereto and the mixture was stirred at 0° C. for 1 hr to give a reaction mixture. The reaction mixture was diluted with dichloromethane, distilled water was added, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate=3:1 (vol) to ethyl acetate, a mixed solution of ethyl acetate:methanol=20:1 (vol) to give compound (5a) (9.06 g).

(20) .sup.1H NMR (300 MHz, CDCl.sub.3) δ6.94 (dt, J=15.6, 6.9 Hz, 1H), 5.80 (d, J=15.6 Hz, 1H), 5.07 (m, 1H), 4.72 (m, 0.55H), 4.54 (m, 0.45H), 4.15-4.04 (m, 1H), 4.04-3.88 (m, 1H), 3.88-3.73 (m, 2H), 3.66 (s, 3H), 3.60-3.48 (m, 2H), 2.04 (t, J=7.5 Hz, 2H), 1.95-1.15 (m, 18H).

Example 4

(21) Production of methyl (2E)-7-((1R,2R,3R,5S)-5-acetoxy-2-((1E,4S)-7-cyclopropyl-4-methyl-3-oxohept-1-en-6-yn-1-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-2-enoate (Compound (4a)) (Step 4)

(22) ##STR00041##

(23) Compound (5a) (9.06 g) obtained in Example 3 was dissolved in ethyl acetate (146 mL), and the solution was cooled to −10° C. N,N-diisopropylethylamine (iPr.sub.2EtN) (23.8 mL) was added thereto, a solution of SO.sub.3-pyridine (SO.sub.3—Py) (10.9 g) in DMSO (27.2 mL) was added and the mixture was stirred at −10° C. for 30 min to give the first mixture. To the first mixture were poured ethyl acetate (226 mL) and 1N hydrochloric acid (90.6 mL), and the mixture was partitioned by adding water.

(24) The obtained first organic layer was concentrated under reduced pressure. To the composition obtained by concentration under reduced pressure was added hexane, and the mixture was successively washed with aqueous copper sulfate solution, saturated brine and water, and the thus-obtained second organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an aldehyde corresponding to compound (5a) (methyl 7-((1R,2R,3R,5S)-5-acetoxy-2-formyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)heptanoate) (8.6 g).

(25) Lithium chloride (1.10 g) was heated to 170° C., dried under reduced pressure, and acetonitrile (43.2 mL) was added thereto. A solution of compound (6a) (6.69 g) synthesized as in Reference Example 2 in acetonitrile (86.4 mL) and N,N-diisopropylethylamine (iPr.sub.2EtN) (3.76 mL) were added dropwise thereto and the mixture was stirred at 25° C. for 1 hr. A solution of the above-mentioned aldehyde (8.6 g) corresponding to compound (5a) in acetonitrile (86.4 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 15 hr to give the second mixture. To the second mixture were added ethyl acetate (103 mL) and saturated aqueous ammonium chloride solution (103 mL) and the mixture was partitioned by diluting with water. The aqueous layer was extracted with ethyl acetate. The obtained third organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate=86:14 (vol) to ethyl acetate to give compound (4a) (8.13 g) as a colorless oil. The yield in the reaction to obtain compound (4a) from compound (5a) was 61%.

(26) .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.92 (dt, J=15.6, 6.9 Hz, 1H), 56.80-6.68 (m, 1H), 56.32-6.24 (m, 1H), 5.79 (d, J=15.6 Hz, 1H), 5.12 (brt, J=5.7 Hz, 1H), 4.54 (dt, J=12.8, 3.0 Hz, 1H), 4.12-3.96 (m, 1H), 3.83-3.58 (m, 2H), 3.65 (s, 3H), 3.50-3.38 (m, 1H), 3.14-2.83 (m, 1H), 2.75-2.16 (m, 5H), 2.06 (s, 3H), 1.95-1.05 (m, 22H), 1.18 (d, J=7.2 Hz, 3H), 0.75-0.54 (m, 4H).

Example 5

(27) Production of methyl (2E)-7-((1R,2R,3R,5S)-5-acetoxy-2-((1E,3S,4S)-7-cyclopropyl-3-hydroxy-4-methylhept-1-en-6-yn-1-yl)-3-hydroxycyclopentyl)hept-2-enoate (Compound (3a)) (Step 5)

(28) ##STR00042##

(29) Compound (4a) (8.13 g) obtained in Example 4 was dissolved in toluene (58.4 mL), 1M toluene solution of R-(+)-2-methyloxazaborolidine (CBS) was added thereto, and the mixture was stirred under ice-cooling (−10° C. to 5° C.) for 30 min. Diethylaniline borane (DEANB) (2.79 mL) was added dropwise, and the mixture was stirred under ice-cooling (−10° C. to 5° C.) for 15 hr to give a mixture. The mixture was diluted with ethyl acetate, methanol (3.1 mL) was added, and the mixture was partitioned by adding 1N hydrochloric acid and water. The obtained aqueous layer was extracted with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (3a) as a crude product (6.53 g).

(30) The crude product (6.53 g) of the obtained compound (3a), acetonitrile (24.3 mL) and methanol (12.1 mL) were added thereto and dissolved, 0.1N hydrochloric acid (12.2 mL) was added and the mixture was stirred at 35° C. for 3 hr. 0.1N Aqueous sodium hydrogen carbonate solution (12.2 mL) and water were added thereto and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The composition obtained by concentrated under reduced pressure was purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate=67:33 (vol) to ethyl acetate to give compound (3a) (6.35 g) and a stereoisomer thereof (compound with reverse configuration of the 15-position hydroxy group) (0.70 g).

(31) .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.93 (dt, J=15.6, 6.9 Hz, 1H), 5.80 (d, J=15.6 Hz, 1H), 55.65-5.45 (m, 2H), 5.15 (brs, 1H), 4.14-3.85 (m, 2H), 3.73 (s, 3H), 2.60-2.30 (m, 1H), 2.28 (t, J=7.6 Hz, 2H), 2.30-2.13 (m, 2H), 2.04 (s, 3H), 1.85-1.10 (m, 12H), 0.96 (m, 3H), 0.72-0.58 (m, 4H).

Example 6

(32) Production of (2E)-7-((1R,2R,3R,5S)-2-((1E,3S,4S)-7-cyclopropyl-4-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)hept-1-en-6-yn-1-yl)-5-hydroxy-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-2-enoic acid (Compound (1a)) (Step 6)

(33) ##STR00043##

(34) Compound (3a) (5.22 g) obtained in Example 5 was dissolved in dichloromethane (75.7 mL), 3,4-dihydro-2H-pyran (DHP) (3.22 mL) and p-toluenesulfonic acid monohydrate (p-TsOH. H.sub.2O) (56.6 mg) were added thereto at 0° C., and the mixture was stirred at the same temperature for 30 min to give the first mixture. The first mixture was partitioned by adding dichloromethane (75.7 mL) and water (83.5 mL). The obtained aqueous layer was extracted with dichloromethane. The obtained organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (3a) in which a hydroxy group was protected by THP (hereinafter to be referred to as compound (3a′)) as a crude product (7.19 g).

(35) The above-mentioned crude product (7.19 g) of compound (3a′) was dissolved in THF (46.0 mL), lithium hydroxide monohydrate (4.91 g) was added thereto, and the mixture was heated to 40° C. and stirred for 15 hr to give the second mixture. The second mixture was diluted with ethyl acetate (46.0 mL), 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate=1:1 (vol) to a mixed solution of hexane:ethyl acetate=1:3 (vol) to give compound (1a) (5.21 g).

(36) .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.00-6.87 (m, 1H), 5.81 (d, J=14.8 Hz, 1H), 5.63-5.41, 5.30-5.18 (m, 2H), 4.82-4.60 (m, 2H), 4.13-3.75 (m, 6H), 3.53-3.39 (m, 2H), 2.59-1.00 (m, 28H), 0.92 (m, 3H), 0.74-0.63 (m, 2H), 0.60-0.52 (m, 2H).

Example 7

(37) Production of (2E)-7-((1R,2R,3R)-2-((1E,3S,4S)-7-cyclopropyl-3-hydroxy-4-methylhept-1-en-6-yn-1-yl)-3-hydroxy-5-oxocyclopentyl)hept-2-enoic acid (Compound (2a)) (Step 7)

(38) ##STR00044##

(39) Compound (1a) (5.21 g) obtained in Example 6 was dissolved in dichloromethane (52.2 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane; Dess-Martin reagent) (4.55 g) was added thereto, and the mixture was stirred at room temperature for 1 hr to give the first mixture. The first mixture was diluted with dichloromethane (52.3 mL), 1M aqueous sodium thiosulfuric acid solution was added, and the mixture was stirred for 2 hr and partitioned by adding water. The obtained aqueous layer was extracted with dichloromethane, and the obtained organic layers were combined and washed successively with water and brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a carbonyl form of compound (1a) as a crude product (4.69 g).

(40) The above-mentioned crude product (4.69 g) of the carbonyl form of compound (1a) was dissolved in acetonitrile (16.6 mL) and methanol (8.31 mL), 0.1N hydrochloric acid (8.31 mL) was added thereto, and the mixture was stirred at 35° C. for 3 hr to give the second mixture. To the second mixture were added 0.1N aqueous sodium hydrogen carbonate solution (8.31 mL) and water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The composition obtained by concentrated under reduced pressure was purified by silica gel column chromatography using a mobile phase in which a gradient was applied from a mixed solution of hexane:ethyl acetate=1:2 (vol) to ethyl acetate and to a mixed solution of ethyl acetate:methanol =20:1 (vol) to give compound (2a) (2.94 g).

(41) .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.98 (dt, J=15.6, 6.9 Hz, 1H), 5.81 (d, J=15.6 Hz, 1H), 5.66 (brs, 2H), 4.05-3.93 (m, 2H), 2.71 (dd, J=18.2, 7.4 Hz, 1H), 2.40-1.00 (m, 16H), 0.89 (d, J=6.8 Hz, 3H), 0.71-0.67 (m, 2H), 0.59-0.55 (m, 2H).

INDUSTRIAL APPLICABILITY

(42) The present invention can provide a method for producing a novel compound (2) or a pharmaceutically acceptable salt thereof, which is useful as a blood flow improving agent, in a good yield.

(43) Compound (3) and compound (4) according to the present invention are useful as synthetic intermediates for producing compound (2) or a pharmaceutically acceptable salt thereof.

(44) Furthermore, the production method of the present invention is useful as an industrial-scale synthetic method since the method can be carried out by convenient operations via compounds easy to handle.

(45) This application is based on a patent application No. 2017-210311 filed in Japan, the contents of which are incorporated in full herein.