Method for preparing a ß-nucleoside compound

Abstract

A method for preparing a -nucleoside compound, including the following steps: 1) performing a silylation reaction of a nitrogenous base or an analogue thereof in the presence of TMSOTf to give the nitrogenous base or the analogue thereof being protected by trimethylsilyl; 2) performing a direct glycosylation reaction of the reaction liquid, without being isolated, and a five- or six-membered ring saccharide or a derivative thereof closed by a hydroxyl protecting group to give a closed -nucleoside compound; and 3) performing a deprotection reaction to give the -nucleoside compound. The method uses a one-pot process to prepare the key intermediates of the -nucleoside compound, and the yield of materials in -configuration increases significantly. The method has the benefits of simple operations, being energy conservation and environment protection, and being suitable for industrial applications.

Claims

1. A method for preparing a -nucleoside compound, comprising the following steps: 1) performing a silylation reaction of a nitrogenous base or a nitrogenous base analogue in the presence of trimethylsilyl trifluoromethanesulfonate to give the nitrogenous base or the nitrogenous base analogue protection by trimethylsilyl; 2) performing a direct glycosylation reaction of the reaction liquid of step 1), without being isolated, and a five- or six-membered ring saccharide or a five- or six-membered ring saccharide derivative protected by a removable protecting group to give a protected -nucleoside compound; and 3) performing a deprotection reaction of the protected -nucleoside compound to give the -nucleoside compound.

2. The method of claim 1, wherein the nitrogenous base or the nitrogenous base analogue is selected from: ##STR00021## wherein R.sub.1 is selected from hydrogen, C.sub.1-6 alkyl or a substituted alkyl, and C.sub.3-8 cycloalkyl or a substituted cycloalkyl, X is selected from nitrogen, CH, and CR.sub.2, R.sub.2 and R.sub.3 are independently selected from hydrogen, C.sub.1-6 alkyl or a substituted alkyl, and halogen, R.sub.4 is selected from hydrogen, C.sub.1-6 alkyl or a substituted alkyl, halogen, amino, NHR.sub.1, and carbonyl, and a dotted line bond indicates the presence or absence of a double bond.

3. The method of claim 1, wherein the five-membered ring saccharide or the five-membered ring saccharide derivative being protected by a removable protecting group has the structure as shown in the following formula (I): ##STR00022## or, the six-membered ring saccharide or the six-membered ring saccharide derivative being protected by a removable protecting group has the structure as shown in the following formula (II): ##STR00023## in formula (I) and formula (II): L is a leaving group, R.sub.5 is a hydroxy protecting group, and R.sub.6a, R.sub.6b, R.sub.6c, R.sub.7a, R.sub.7b, R.sub.7c may independently be selected from hydrogen, halogen, C.sub.1-6 alkyl or a substituted alkyl, and OR.sub.5, R.sub.6a is OR.sub.5 when different from R.sub.7a, R.sub.6b is OR.sub.5 when different from R.sub.7b, and R.sub.6c is OR.sub.5 when different from R.sub.7c.

4. The method of claim 1, wherein the reaction of step 1) is carried out in an organic solvent together with an organic base, the organic solvent is selected from dichloromethane, toluene, acetonitrile, chloroform, diethyl ether, 1,2-dichloroethane, and tetrahydrofuran, and the organic base is selected from triethylamine, 1,8-diazadicycloundec-7-ene, pyridine, and 2,6-dimethylpyridine.

5. The method of claim 1, wherein in step 1), the mole ratio of nitrogenous base to trimethylsilyl trifluoromethanesulfonate is in a range of 1:1 to 1:5.

6. The method of claim 1, wherein the reaction temperature of step 1) is in a range of 20 C. to 20 C.

7. The method of claim 1, wherein the reaction temperature of step 2) is in a range of 20 C. to 25 C.

8. The method of claim 2, wherein R.sub.1 is selected from hydrogen, methyl, ethyl, propyl, and cyclopropyl.

9. The method of claim 2, wherein X is selected from nitrogen, CH, C(CH.sub.3), C(CH.sub.2CH.sub.3), C(F), C(Cl), C(Br), C(I), and C(CF.sub.3).

10. The method of claim 2, wherein R.sub.2 and R.sub.3 are independently selected from hydrogen, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, and halogen.

11. The method of claim 2, wherein R.sub.4 is selected from hydrogen, methyl, ethyl, propyl, hydroxymethyl, halogen, amino, and carbonyl.

12. A method for preparing a protected -nucleoside compound as shown in formula (V), ##STR00024## comprising the following steps: 1) performing a silylation reaction of the compound as shown in formula (VI) in the presence of trimethylsilyl trifluoromethanesulfonate to give the compound as shown in formula (VII); 2) performing a direct glycosylation reaction of the reaction liquid of step 1, without being isolated, and the compound of formula (VIII) to give a protected -nucleoside compound as shown in formula (V); the reaction route is as follows: ##STR00025## wherein X is selected from nitrogen, CH, and CR.sub.2, R.sub.2 is selected from hydrogen, C.sub.1-6 alkyl or a substituted alkyl, and halogen, L is a leaving group, R.sub.5 is a hydroxy protecting group, and R.sub.6 and R.sub.7 may independently be selected from hydrogen, halogen, and C.sub.1-6 alkyl or a substituted alkyl, or one of which is OR.sub.5.

13. A method for preparing a -nucleoside compound, comprising performing a deprotection reaction of the protected -nucleoside compound of claim 4 to give the -nucleoside compound.

14. The method of claim 13, wherein the -nucleoside compound is selected from decitabine, gemcitabine, azacitidine, trifluridine, and capecitabine.

15. The method of claim 12, wherein R.sub.2 is selected from hydrogen, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, and halogen.

16. The method of claim 12, wherein the reaction of step 1) is carried out in an organic solvent together with an organic base, the organic solvent is selected from dichloromethane, toluene, acetonitrile, chloroform, diethyl ether, 1,2-dichloroethane, and tetrahydrofuran, and the organic base is selected from triethylamine, 1,8-diazadicycloundec-7-ene, pyridine, and 2,6-dimethylpyridine.

17. The method of claim 12, wherein in step 1), the mole ratio of nitrogenous base to trimethylsilyl trifluoromethanesulfonate is in a range of 1:1 to 1:5.

18. The method of claim 12, wherein the reaction temperature of step 1) is in a range of 20 C. to 20 C.

19. The method of claim 12, wherein the reaction temperature of step 2) is in a range of 20 C. to 25 C.

Description

DETAILED DESCRIPTION

Terms and Definitions

(1) Glycosides: also known as glucosides, the compounds in which sugars or saccharide derivatives, such as aminosugar, uronic acid or the like, bound to another class of non-saccharide materials through the anomeric carbon atom of the sugar. Wherein the non-saccharide moiety is known as aglycone or genin, its linking bond is known as a glycosidic linkage.

(2) N-glycoside: the glycoside linked between the anomeric carbon of saccharide and the nitrogen atom of aglycone is known as N-glycoside. The 1 nucleoside and analogues or nucleoside compounds thereof are mainly N-glycoside compounds.

(3) Nucleoside: the glucoside formed by the condensation between nitrogenous bases and saccharide components is known as nucleoside, which includes purine and pyrimidine glucosides of nucleic acid, further includes other native and synthetic heterocyclic base ribosides, also the compounds with C1 on the sugars linked to the oxygen atom or carbon atom on the heterocyclic base. Compounds linked by the bases and pentose, i.e. compounds formed by the linkage between N-9 of purine or N-1 of pyrimidine and C-1 of ribose or deoxyribose through a 1-glucoside bond, include two classes, ribosenucleoside and deoxyribose nucleoside. Nucleosides constituting RNA are ribosenucleosides, mainly adenosine, guanosine, cytidine and uridine. Nucleosides constituting DNA are deoxyribose nucleosides, mainly deoxyadenosine, deoxyguanosine, deoxycytidine and deoxythymidine.

(4) Nitrogenous base: a class of alkaline organic compounds, which are derivatives of purine and pyrimidine. Purine or analogues thereof includes adenine, urine purine, xanthine, hypoxanthine and other purine derivatives; pyrimidine or analogues thereof includes cytosine, uracil, thymine, 5-methylcytosine, 5-hydroxymethylcytosine, dihydrouracil, and other pyrimidine derivatives. The nitrogenous bases or analogues thereof of the present invention comprise groups that may react with TMSOTf in a silylation reaction, for example amino, hydroxy or the like.

(5) Derivatives: A complex product derived from a simple compound in which the hydrogen atoms or atomic groups were substituted with other atoms or atomic groups.

(6) Five-membered ring saccharides: also known as furanose. Five-membered ring saccharides of the present invention are all the furanoses known in the art. Exemplary five-membered ring saccharides include, but not limited to, D-ribose (e.g., -D-ribofuranose), 2-deoxy-D-ribose (e.g., 2-deoxy -D-ribose), D-fructose (e.g., -D-fructofuranose, -D-fructofuranose), D-glucose (e.g., -D-glucofuranose), L-arabinose (e.g., -L-arabinofuranose), D-arabinose (e.g., -D-arabinofuranose), apiose (e.g., -D-apiose), glucuronic acid (e.g., -D-glucuronic acid) or the like.

(7) Six-membered ring saccharides: also known as pyranose. Six-membered ring saccharides of the present invention are all the pyranoses known in the art. Exemplary six-membered ring saccharides include, but not limited to, D-glucose (e.g., -D-pyranoglucose, -D-pyranoglucose), D-galactose (e.g., -D-galactopyranose), D-mannose (e.g., -D-mannopyranose), D-xylose (e.g., -D-xylopyranose), D-fructose (e.g., -D-fructopyranose), L-sorbose (e.g., -L-sorbofuranose) and L-galactose (e.g., -L-galactopyranose).

(8) Exemplary derivatives of five- or six-membered ring saccharide may be products deprived from saccharide molecules in which structures the groups, such as hydrogen atom, carbon atom or hydroxy, were substituted with other atoms or atomic groups. For example, the hydroxy in the molecular structure of saccharide was substituted with a hydrogen atom, halogen, alkyl or the like, the carbon atom in the molecular structure of saccharide was substituted with atoms such as oxygen, sulfur, or the like.

(9) Alkyl: alkyls in the present invention preferably refer to C1-C6 alkyls, for example methyl, ethyl, propyl, butyl, isopropyl, t-butyl, pentyl, hexyl or the like. Substituted alkyl: indicating that the hydrogens on the alkyl were substituted with one or more substituents, for example, the substituents may be hydroxy, halogen, alkyl, amino or the like.

(10) Removable protecting groups: with regard to saccharide molecules, the removable protecting groups in the present invention generally refer to hydroxy protecting groups, also may comprise protecting groups of other groups for saccharide derivatives. Hydroxy protecting groups may be hydroxy protecting groups commonly used in the art, including ester protecting groups (e.g., pivaloyl (t-BuCO, Piv), benzoyl (PhCO), chloracetyl (ClCH.sub.2CO) or the like), silyl ether protecting groups (e.g., trimethylsilyl (TMS), triethylsilyl (TES), t-butyl dimethylsilyl (TBS), triisopropylsilyl (TIPS), t-butyl dimethylsilyl (TBDPS) or the like), alkyl ether protecting groups (e.g., methyl ether (Me), benzyl ether (Bn), p-methoxy benzyl ether (PBM), 3,4-dimethoxy benzyl ether (DMB or DMPB), trityl ether, t-butyl ether and allyl ether or the like) and alkoxyalkyl ether protecting groups (e.g., methoxy methyl ether (MOM), methylthio methyl ether (MTM), methoxyethoxy methyl ether (MEM), benzyloxy methyl ether (BOM), trimethylsilyl ethoxy methyl ether (SEM) or the like). The preferable hydroxy protecting groups in the present invention may be: t-butyl dimethyl silyl (TBS), triisopropyl silyl (TIPS), p-chlorbenzoyl (4Cl-Bz), tetrahydrofuryl (THP), benzoyl (Bz) or the like.

(11) Leaving groups: In a nucleophilic substitution reaction, the reactant attacked by the nucleophilic reagent is the substrate, while the atom or atomic group with a pair of electrons broken out from the substrate molecule is known as a leaving group, usually indicated with L. The common leaving groups all may used in the present invention, for example halogen, OCOR, OTs, ONO.sub.2, OH or the like. The preferable leaving groups in the present invention may be: halogen, acetoxy (AcO), methylsulfonyloxy (OMs) or the like.

(12) The method of the present invention is generic to be used for preparing various -nucleoside compounds, including, but not limited to: Decitabine, Gemciyabine, Azacitidine, Trifluridine, Capecitabine, Fludarabine, Clofarabine, Cladribine, Cytarabine, Vidarabine, Troxacibine, Lamivudine, Zidovudine, Epavudine or the like.

(13) The features and benefits of the present methods will be illustrated in detail below through the preparation embodiments of decitabine, which were provided only for the purpose of exemplary illustration, without being used for confining the applicable scope of the present technical schemes and the protection scope of the present invention.

(14) Preparation route of decitabine in Embodiments 1-3 was shown as below:

(15) ##STR00016##

Embodiment 1 Preparation of Decitabine

1-(3,5-di-O-p-chlorobenzoyl-2-deoxy-(3-D-ribofuranose)-5-azacytosine (Intermediate D)

(16) To the reaction flask were added 5-azacytosine 20.0 g and dichloromethane 87.5 mL, into which was added triethylamine 62.1 mL with stirring at 15 C., and dropped trimethylsilyl trifluoromethanesulfonate 118.9 g, continued stirring for 30 min after the system was dissolved to clear. The reaction liquid, without being isolated, was directly added into 1-chloro-3,5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose 38.3 g, and stirred for about 3 h at 0 C. until the reaction liquid was clear. Triethylamine 37 mL was added to quench the reaction, into which was added dichloromethane and water 500 mL for each respectively, the organic phase was filtered, isolated and concentrated to dry, to the residue of which was added 500 mL water and stirred adequately, suction filtered, and the solid was dried for 6 h at 45 C. in vacuum, crushed, and continued drying for 3 h to give the intermediate D 42.8 g, with a yield of 95.1%. HPLC detection: -configuration 72.1%, -configuration 21.0%, total purities 6.9%, the maximum single purity 2.9%.

(17) Decitabine Crude

(18) To the reaction flask were added the above intermediate D 42.8 g, anhydrous methanol 1.3 L, sodium methoxide 2.8 g, stirred for 3 h at 25 C., into which was added 3.0 g glacial acetic acid to quench the reaction, filtered, the filtrate was stirred for 6 h at 0 C. for crystallization to give an off-white solid 8.1 g, with a field of 42.1%. HPLC detection: purity 98.7%, the maximum single purity 0.51%.

(19) Decitabine Refining

(20) To the reaction flask were added the above crude solid 8.1 g, anhydrous methanol 80 mL, which were heated to be clear, filtered while hot, the filtrate was cooled in air to crystallize naturally for 6 h, filtered, the solid was dried for 4 h in vacuum to give the finished decitabine 5.8 g, with a field of 71.6%. HPLC detection: purity 99.8%, the maximum single purity 0.05%.

Embodiment 2 Preparation of Decitabine

1-(3,5-di-O-p-chlorobenzoyl-2-deoxy--D-ribofuranose)-5-azacytosine (Intermediate D)

(21) To the reaction flask were added 5-azacytosine 88.5 g and dichloromethane 395 mL, into which was added triethylamine 274.4 mL with stirring at 10 C. Trimethylsilyl trifluoromethanesulfonate 526.3 g was dropped in and continued stirring for 30 min after the system was dissolved to clear. The reaction liquid, without being isolated, was directly added into 1-chloro-3,5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose 169.6 g, and stirred for about 6 h at 10 C. until the reaction liquid was clear. Triethylamine 164.6 mL was added to quench the reaction, into which was added dichloromethane and water 1500 mL for each respectively, the organic phase was filtered, and concentrated to dry, to the residue of which was added 1500 mL water and stirred adequately, suction filtered, and the solid was dried for 6 h at 45 C. in vacuum, crushed, and continued drying for 3 h to give the intermediate D 185.7 g, with a field of 93.2%. HPLC detection: -configuration 77.3%, -configuration 17.6%, the maximum single purity 2.1%.

(22) Decitabine Crude

(23) To the reaction flask were added the above intermediate D 185.7 g, anhydrous methanol 5.6 L, sodium methoxide 11.9 g, stirred for 3 h at 25 C., into which was added 13.2 g glacial acetic acid to quench the reaction, filtered, the filtrate was stirred for 6 h at 10 C. for crystallization to give an off-white solid 32.6 g, with a field of 38.9%. HPLC detection: purity 98.9%, the maximum single purity 0.63%.

(24) Decitabine Refining

(25) To the reaction flask were added the above crude solid 32.6 g, anhydrous methanol 3260 mL, which were heated to be clear, filtered while hot, the filtrate was cooled in air to crystallize naturally for 6 h, filtered, the solid was dried for 4 h in vacuum to give decitabine 22.7 g, with a field of 69.8%. HPLC detection: purity 99.8%, the maximum single purity 0.04%.

Embodiment 3 Preparation of Decitabine

1-(3,5-di-O-p-chlorobenzoyl-2-deoxy--D-ribofuranose)-5-azacytosine (Intermediate D)

(26) To the reaction flask were added 5-azacytosine 30.0 g and dichloromethane 87.5 mL, into which was added triethylamine 86.7 mL with stirring at 0 C. Trimethylsilyl trifluoromethanesulfonate 158.4 g was dropped in and continued stirring for 30 min after the system was dissolved to clear. The reaction liquid, without being isolated, was directly added into 1-chloro-3,5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose 38.3 g, and stirred for about 1.5 h at 5 C. until the reaction liquid was clear. Triethylamine 37 mL was added to quench the reaction, into which was added dichloromethane and water 500 mL for each respectively, the organic phase was filtered, and concentrated to dry, to the residue of which was added 500 mL water and stirred adequately, suction filtered, and the solid was dried for 6 h at 45 C. in vacuum, crushed, and continued drying for 3 h to give the intermediate D 43.5 g, with a field of 96.7%. HPLC detection: -configuration 80.8%, -configuration 12.2%, the maximum single purity 1.5%.

(27) Decitabine Crude

(28) To the reaction flask were added the above intermediate D 43.5 g, anhydrous methanol 1.4 L, sodium methoxide 2.9 g, stirred for 3 h at 25 C., into which was added 3.2 g glacial acetic acid to quench the reaction, filtered, the filtrate was stirred for 6 h at 0 C. for crystallization to give an off-white solid 8.9 g, with a field of 45.3%. HPLC detection: purity 99.2%, the maximum single purity 0.25%.

(29) Decitabine Refining

(30) To the reaction flask were added the above crude solid 8.9 g, anhydrous methanol 90 mL, which were heated to be clear, filtered while hot, the filtrate was cooled in air to crystallize naturally for 6 h, filtered, the solid was dried for 4 h in vacuum to give decitabine 6.7 g, with a field of 75.2%. HPLC detection: purity 99.9%, the maximum single purity 0.02%.

Control Embodiment 4 Preparation of Decitabine

(31) ##STR00017##

1-(3.5-di-O-p-chlorobenzoyl-2-deoxy--D-ribofuranose)-5-azacytosine (Intermediate D)

(32) To the reaction flask were added 5-azacytosine 80 g and hexamethyldisilazane 100 g, into which was added trimethylchlorosilane 50 g with stirring, after the reflux reaction with heating for 66.5 h, the excess amount of hexamethyldisilazane was evaporated off under reduced pressure, concentrated to dry and transferred into the reaction flask.

(33) Then, to the reaction flask were added 1-chloro-3,5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose 102 g, dichloromethane 960 mL, into which was dropped trimethylsilyl trifluoromethanesulfonate 109 g at 2030 C., and reacted for 13 h at 252 C. (the proportion of / configuration in the product was about 1:1), into which were added purified water 400 mL and dichloromethane 1080 mL, stirred, filtered, into the organic phase was dropped a 10% sodium bicarbonate solution to neutral, filtered, the organic phase was rinsed and then dried, filtered, the filtrate was concentrated to the volume of the total amount of the filtrate when the solid resolved was filtered off, continued to concentrate until the filtrate was dry, to the residue of which was added toluene, stirred for 25 min, and then filtered, washed, the filter cake was dried in air for 8 h at room temperature, and then dried in vacuum for 4 h at 405 C. to give a solid 24.9 g, with a yield of about 20.7%, HPLC detection: -configuration 70.5%, -configuration 20.8%, the total purities 8.7%, the maximum single purity 4.2%.

(34) Decitabine Crude

(35) To the reaction flask were added 1-(3,5-di-O-p-chlorobenzoyl-2-deoxy--D-ribofuranose)-5-azacytosine 24.9 g, anhydrous methanol 1479 g and sodium methoxide 1.6 g, reacted for about 4.5 h at 252 C., the reaction liquid was adjusted to pH 7.07.5 with a 10% solution of acetic acid in anhydrous methanol after the reaction was complete under the monitor of TLC, filtered, and the filtrate was concentrated (the water bath temperature of 402 C.) until there was solid being resolved (concentrated to approximately 5% the volume of the filtrate), left for 6 h at room temperature for crystallization, filtered, washed, and the filter cake was dried at 405 C. for 4 h in vacuum to give a solid 4.36 g, with a yield of 38.8%. HPLC detection: purity 98.2%, the maximum single purity 1.2%.

(36) Decitabine Refining

(37) To the reaction flask were added anhydrous methanol 400 mL, Decitabine crude 4.36 g, which were heated to be clear, filtered while hot, the filtrate was cooled to 1525 C. with stirring to crystallize for 12 h, filtered, the filter cake was washed with anhydrous methanol, dried at 40 C. for 4 h in vacuum to give decitabine 3.18 g, with a yield of 72.9%. HPLC detection: purity 99.7%, the maximum single purity 0.07%.

Embodiment 5 Preparation of Azacitidine Intermediate

(38) ##STR00018##

(39) To the reaction flask were added 5-azacytosine 20.0 g and dichloromethane 87.5 mL, into which was added triethylamine 62.1 mL with stirring. Trimethylsilyl trifluoromethanesulfonate 118.9 g was dropped in and continued stirring for 30 min after the system was dissolved to clear. 1,2,3-triacetoxy-5-deoxy-D-ribose 28.4 g was added, stirred for about 1.5 hours until the reaction liquid was clear. Triethylamine 37 mL was added to quench the reaction, into which was added dichloromethane and water 500 mL for each respectively, the organic phase was filtered, and concentrated to dry, to the residue of which was added 500 mL water and stirred adequately, suction filtered, and the solid was dried for 6 hours at 45 C. in vacuum, crushed, and continued drying for 3 hours to give the azacitidine intermediate, 30.7 g, with a yield of 93.0%. HPLC detection: -configuration 85.3%, -configuration 8.4%.

Embodiment 6 Preparation of Capecitabine Intermediate

(40) ##STR00019##

(41) To the reaction flask were added 5-fluorocytosine 23.0 g and dichloromethane 87.5 mL, into which was added triethylamine 62.1 mL with stirring. Trimethylsilyl trifluoromethanesulfonate 118.9 g was dropped in and continued stirring for 30 min after the system was dissolved to clear. 1,2,3,5-tetraacetyl-D-ribofuranose 23.2 g was added, stirred at 5C for about 1.5 hours until the reaction liquid was clear. Triethylamine 37 mL was added to quench the reaction, into which was added dichloromethane and water 500 mL for each respectively, the organic phase was filtered, and concentrated to dry, to the residue of which was added 500 mL water and stirred adequately, suction filtered, and the solid was dried for 6 hours at 45 C. in vacuum, crushed, and continued drying for 3 hours to give the capecitabine intermediate, 26.7 g, with a yield of 91.0%. HPLC detection: -configuration 72.3%, -configuration 20.4%.

Embodiment 7 Preparation of Trifluridine Intermediate

(42) ##STR00020##

(43) To the reaction flask were added 5-trifluoromethyluracil 32.1 g, dichloromethane 87.5 mL, into which was added triethylamine 62.1 mL with stirring. Trimethylsilyl trifluoromethanesulfonate 118.9 g was dropped in and continued stirring for 30 min after the system was dissolved to clear. 1-chloro-3,5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose 38.3 g was added, stirred at 0 C. for about 3 hours until the reaction liquid was clear. Triethylamine 37 mL was added to quench the reaction, into which was added dichloromethane and water 500 mL for each respectively, the organic phase was filtered, and concentrated to dry, to the residue of which was added 500 mL water and stirred adequately, suction filtered, and the solid was dried for 6 hours at 45 C. in vacuum, crushed, and continued drying for 3 hours to give the trifluridine intermediate, 46.0 g, with a yield of 90%. HPLC detection: -configuration 66.3%, -configuration 27.6%.