Preparation method of 2 '-deoxy-2', 2 '-difluoro-beta-nucleocytidine and intermediate and salt thereof

Abstract

The invention provides a preparation method of 2 '-deoxy-2', 2 '-difluoro-beta-ribofuranose or a pharmaceutically acceptable salt thereof, which comprises the following steps: by taking D-arabinose as a raw material, carrying out hydroxyl protection, oxidation, fluorination, deprotection and acetylation to obtain an intermediate 1, 3, 5-triacetyl-2'-deoxy-2 ', 2'-difluoro-D-ribofuranose, and carrying out hydrolysis on the intermediate 1, 3, 5-triacetyl-2 '-deoxy-2', 2 '-difluoro-D-ribofuranose to obtain 2'-deoxy-2 ', 2'-difluoro-beta-ribofuranose. The method for preparing the 2 '-deoxy-2', 2 '-difluoro-beta-nucleocytidine or the pharmaceutically acceptable salt of the 2'-deoxy-2 ', 2'-difluoro-beta-nucleocytidine has the advantages of few steps and high yield, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis and relates to a preparation method of 2'-deoxy-2',2'-difluoro-β-nucleocytidine and its hydrochloride, and an intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose. Background Art

[0002] 2'-Deoxy-2',2'-difluoro-β-nucleocytidine hydrochloride (i.e., gemcitabine hydrochloride) is a cell cycle-specific antimetabolite drug that has a good effect on the treatment of viral diseases and cancer. It mainly acts on tumor cells in the DNA synthesis phase, i.e., S phase cells. Under certain conditions, it can prevent the progression from the G1 phase to the S phase. It has obvious cytotoxic activity against various cultured human and mouse tumors, and has good anti-cancer activity against a variety of tumors at non-lethal doses. As a prodrug, gemcitabine is a good substrate for deoxythymidine kinase phosphorylation in cells, and is converted into active products dFdCDP and dFdCTP under the action of the enzyme. It is mainly used clinically for the treatment of locally advanced or metastatic non-small cell lung cancer, pancreatic cancer, bladder cancer, breast cancer and other solid tumors. Its structural formula is as follows:

[0003]

[0004] Many methods for synthesizing 2'-deoxy-2', 2'-difluoro-β-nucleocytidine have been reported in the literature, among which the method of using D-glyceraldehyde and difluoroacetic acid as raw materials to form the main carbon chain through the Reformasty reaction is the most common (see non-patent literature 1, 2). 2'-deoxy-2', 2'-difluoro-β-nucleocytidine is a chiral compound. In the synthesis process of this method using D-glyceraldehyde as a raw material, the Reformasty reaction is involved, and the Reformasty reaction is a non-stereoselective reaction. Therefore, it is necessary to go through processes such as solvent crystallization to split isomers. The controllability of the reaction intermediate process is poor and the yield is low. CN03110317A reported the use of 1,6-anhydro-β-D-glucose as a raw material to obtain an intermediate through a stereoselective reaction, and then through nucleosidation and cyclization to obtain 2'-deoxy-2', 2'-difluoro-β-nucleocytidine. Although the method reported in CN03110317A avoids the Reformasty reaction in the synthesis of 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-furanose, the steps are complicated and the yield is low. In the nucleosidation reaction, N'-cis-(2-cyanovinyl)-N,N-bistrimethylsilylamine is used as a raw material, which has poor stereoselectivity, brings difficulties to separation and purification, and is not conducive to large-scale production.

[0005] Non-patent document 1: Hertel, Lw et al., Journal of Organic Synthesis (J.Org.Chem) 1958, 53, 2406

[0006] Non-patent document 2: Chou, TS et al., Synthesis, 1992, 565 Summary of the invention

[0007] The purpose of the present invention is to provide a method for preparing 2'-deoxy-2',2'-difluoro-β-nucleocytidine and its hydrochloride and its intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose using D-arabinose as a raw material. By using this method, the chiral compound 2'-deoxy-2',2'-difluoro-β-nucleocytidine and its hydrochloride and its intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose can be conveniently obtained through stereoselective reaction during the synthesis process. The preparation method of the present invention has simple steps, high yield, and is convenient for large-scale production.

[0008] Specifically, the present invention includes the following technical solutions.

[0009] A method for preparing an intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose is characterized in that D-arabinose is used as a raw material and is prepared through hydroxyl protection, oxidation, fluorination, deprotection and acetylation.

[0010] The preparation method of the intermediate of the present invention comprises the following steps:

[0011] 1) Protecting the hydroxyl group of D-arabinose to obtain 3,4-isopropylideneoxy-D-arabinopyranose methyl glycoside;

[0012] 2) oxidizing 3,4-isopropoxy-D-arabinopyranose methyl glycoside to obtain 2-oxo-3,4-isopropoxy-D-ribopyranose methyl glycoside;

[0013] 3) fluorinating 2-oxo-3,4-isopropylidene-D-ribopyranose methyl glycoside to obtain 2',2'-difluoro-3,4-isopropylidene-D-ribopyranose methyl glycoside;

[0014] 4) 2',2'-difluoro-3,4-isopropoxy-D-pyranose methyl glycoside is deprotected by hydrolysis to obtain 2'-deoxy-2',2'-difluoro-D-ribose;

[0015] 5) 2'-deoxy-2',2'-difluoro-D-ribose is acetylated to give 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose.

[0016] In the preparation method of the intermediate of the present invention, preferably, the hydroxyl protection includes formylation and isopropoxylation.

[0017] In the preparation method of the intermediate of the present invention, it is preferred that the hydroxyl protection step uses an acidic substance as a catalyst, and the acidic substance is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, a strong acidic cationic resin, formic acid, acetic acid, and trifluoroacetic acid.

[0018] In the preparation method of the intermediate of the present invention, it is preferred that the hydroxyl protection uses one or more water-binding agents selected from the following group: anhydrous calcium chloride, anhydrous zinc chloride, anhydrous magnesium sulfate, 4A molecular sieve, montmorillonite, trimethyl orthoformate, and triethyl orthoformate.

[0019] In the preparation method of the intermediate of the present invention, it is preferred that the hydroxyl protection is carried out in an anhydrous aprotic solvent selected from the following group or itself as a solvent: dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane, 1,1-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, ethyl acetate, propyl acetate, anisole, 1,2-dimethoxyethane, diglycerol ether, ethyl ether, n-butyl ether, isopropyl ether, dioxane, acetonitrile, tetrahydrofuran.

[0020] In the method for preparing the intermediate of the present invention, it is preferred that the amount of the acidic substance is 0.01 to 5 mol% of D-arabinose.

[0021] In the preparation method of the intermediate of the present invention, preferably, in the hydroxyl-protected formylation reaction in step 1), the molar ratio of D-arabinose to methanol is between 1:2 and 20, and / or

[0022] The reaction temperature is 10 to 65°C, and / or

[0023] The reaction time is 1 to 24 hours.

[0024] In the preparation method of the intermediate of the present invention, preferably, in the isopropoxylation reaction of the hydroxyl protection in step 1), the molar ratio of D-arabinose to acetone is between 1:2 and 15, and / or

[0025] The reaction temperature is between -5 and 40°C, and / or

[0026] The reaction time is 0.5 to 24 hours.

[0027] In the preparation method of the intermediate of the present invention, it is preferred that in the oxidation reaction, the oxidant is selected from CrO 3 , K 2 CrO 7 、PPC、NDC、KMnO 4 、NaClO、Ca(ClO) 2 , dimethyl sulfoxide-dicyclohexylcarbodiimide, dimethyl sulfoxide-SOC12, dimethyl sulfoxide-CF 3One or more of COOH, dimethyl sulfoxide-toluenesulfonyl chloride, 4-dimethylaminopyridine oxide or Dess-Martin reagent.

[0028] In the preparation method of the intermediate of the present invention, it is preferred that in the fluorination reaction, the fluorinating agent is selected from one or more of DFI, MST, (diethylamino) sulfur trifluoride, and N,N-dimethylpropylene urea-hydrogen fluoride complex.

[0029] In the method for preparing the intermediate of the present invention, it is preferred that the deprotection reaction is carried out under a strong acid, wherein the strong acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid.

[0030] In the method for preparing the intermediate of the present invention, it is preferred that the acetylation reaction is to form 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose using acetyl chloride or acetic anhydride.

[0031] In the preparation method of the intermediate of the present invention, one or more acid-binding agents selected from the following are used: trimethylamine, triethylamine, N,N-dimethylaniline, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine.

[0032] Furthermore, the present invention also provides a method for preparing the target product 2'-deoxy-2',2'-difluoro-β-nucleocytidine from the intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose by a common nucleoside preparation method.

[0033] The method for preparing 2'-deoxy-2',2'-difluoro-β-nucleocytidine can be as follows: silylation of cytosine; condensation of the intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose and the silylated cytosine; and removal of the acetyl group to obtain 2'-deoxy-2',2'-difluoro-β-nucleocytidine.

[0034] Furthermore, the present invention also provides a method for preparing 2'-deoxy-2',2'-difluoro-β-nucleocytidine into a pharmaceutically acceptable salt, comprising: salting 2'-deoxy-2',2'-difluoro-β-nucleocytidine, wherein the pharmaceutically acceptable salt is preferably hydrochloride.

[0035] The present invention uses D-arabinose as a raw material, and obtains an intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose through hydroxyl protection, oxidation, fluorination, deprotection, and acetylation, and then obtains 2'-deoxy-2',2'-difluoro-β-nucleocytidine hydrochloride by a commonly recognized method for preparing nucleosides. The synthetic steps of the provided method are as follows:

[0036] DETAILED DESCRIPTION

[0037] The present invention is described by the following specific examples for a better understanding of the present invention, but the scope of the present invention is not limited by these examples.

[0038] In the examples of the present invention, unless otherwise specified, all instruments, raw materials, chemical reagents, etc. are commercially available products well known to those skilled in the art; in the examples of the present invention, unless otherwise specified, the technical means used are conventional means well known to those skilled in the art. The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (such as TLC, HPLC, LCMS or NMR), and the reaction endpoint is generally taken as the disappearance of the reaction substrate.

[0039] The experimental methods in the embodiments of the specification that do not specify specific conditions are generally carried out according to conventional conditions in the art or according to conditions recommended by the manufacturer. In the present invention, unless otherwise specified, "above", "below", and "within" mean including the number. When "comprising" and "including" are used to describe the embodiments herein, other similar embodiments described as "consisting of" and / or "consisting essentially of" are also provided. When "consisting essentially of" is used to describe the embodiments herein, other similar embodiments described as "consisting of" are also provided. The term "and / or" used in phrases such as "A and / or B" herein is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0040] As used herein, "pharmaceutically acceptable" refers to products or compounds approved by the national drug regulatory authorities or listed in the Chinese Pharmacopoeia or other recognized pharmacopoeias for use in animals including humans.

[0041] As used herein, "pharmaceutically acceptable salts" are pharmaceutically acceptable organic or inorganic acid or base salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds of the present invention may be, for example, acid addition salts of compounds of the present invention carrying nitrogen atoms in the chain or ring, for example, acid addition salts of sufficiently basic compounds of the present invention, for example, acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid or nitric acid, or acid addition salts formed with organic acids, for example, benzenesulfonic acid, toluenesulfonic acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphor Cerebral acid, cinnamic acid, cyclopentanoic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0042] Example 1

[0043] Synthesis of 3,4-O-isopropylidene-D-arabinoside Methyl

[0044] In a 250mL round-bottom flask, add 10.0g D-arabinose, 5g 732 type strong acid cationic resin and 180mL anhydrous methanol, heat and stir until all dissolved, continue to reflux for 24 hours, filter out the resin, and then concentrate under reduced pressure to 60mL to precipitate 7.4g D-arabinoside methyl precipitate as a white solid, mp = 168 ~ 170 ° C, yield 63.2%.

[0045] 7.4 g (0.045 mol) of the white solid D-arabinose methyl glycoside prepared above, 8.0 mL (0.045 mol) of fresh triethyl orthoformate and 90 mL of anhydrous acetone, and 5 g of 732 type strong acid cationic resin were stirred at room temperature for 5 hours, and then detected by TLC (G254 silica gel plate, developing solvent acetone: petroleum ether = 2:3) until D-arabinose methyl glycoside disappeared. The resin was filtered off and concentrated to dryness on a rotary evaporator to obtain 9.1 g of a light yellow viscous liquid (3,4-O-isopropylidene-D-arabinose methyl glycoside), with a yield of 98.8%. δH: 1.4 and 1.5 (6H, s, s, CH(CH 3 ) 2 ), 3.5(3H, s, OCH 3 ), 3.6~4.4(5H,m,H 5’B ,5’e ,H 4’ ,H 3’ ,H 2’ ),4.65(1H,H 1’ )ppm. m / z: 205(M+1), 204(M), 189(M-CH 3 ).

[0046] Example 2

[0047] Synthesis of 2-Oxo-3,4-O-isopropylidene-D-ribopyranosyl Methylglycoside

[0048] In a 500mL round-bottom flask, add 9.1g (0.0445mol) 3,4-O-isopropylidene-D-arabinose methyl glycoside and 250mL toluene. Heat to reflux, add 61.6g (0.0445mol) NDC (nicotinic acid-dichromate) within 10 minutes under vigorous stirring, and then add 30mL pyridine. The reaction solution changes from orange to brown. Continue to reflux for 8 hours, filter out insoluble matter while hot, and wash the filter cake with toluene (100mL×3 times), combine the filtrate, and concentrate to dryness on a rotary evaporator. The concentrate is chromatographed on a 200-mesh silica gel column to obtain 6.9g 2-oxo-3,4-O-isopropylidene-D-pyranose methyl glycoside, 72.6%. δH: 1.4 and 1.5 (6H, s, s, CH(CH 3 ) 2 ), 3.5(3H, s, OCH 3 ), 4.0~4.8(5H,m,H 5’B , 5’e ,H 4’ ,H 3’ ,H 1’ )ppm. m / z: 201(M+1), 187(M-CH 3 ).

[0049] Example 3

[0050] Synthesis of 2-deoxy-2,2-difluoro-3,4-O-isopropylidene-D-arabinoside Methyl

[0051] In a 500 mL round-bottom flask, add 6.9 g (0.034 mol) of 2-oxo-3,4-O-isopropyl-D-pyranose methyl glycoside and 350 mL of anhydrous benzene, stir to dissolve, and 2Under the protection of air flow, 10mL (0.086mol) DAST (tetramethylgermane diaminodithiocarboxylate) was added dropwise, and the reaction was stirred at room temperature for 24 hours. TLC was used to detect until the raw material disappeared (G254 silica gel plate, developing solvent acetone: petroleum ether = 2:3). The reaction solution was washed with 20% sodium bicarbonate solution until neutral, and the organic layer was dried with anhydrous sodium sulfate overnight, and then concentrated to dryness to obtain 6.9g of crude product. The crude product was chromatographed on a 200-mesh silica gel column to obtain 6.0g of 2-deoxy-2,2-difluoro-3,4-O-isopropyl-D-pyranose methyl glycoside, with a yield of 78.6%. δH: 1.3 and 1.5 (6H, s, s, CH(CH 3 ) 2 ), 3.6(3H, m, OCH 3 ), 4.2(2H, m, H 5 ,),4.9(2H,m,H 4 ,H 1 ),5.2(1H,d,H 1’ )ppm. m / z: 209 (M-CH 3 ).

[0052] Example 4

[0053] Synthesis of 2-deoxy-2,2-difluoro-D-ribose

[0054] In a 500mL round-bottom flask, 6.0g (about 0.0267mol) of 2-deoxy-2,2-difluoro-3,4-O-isopropylidene-D-pyranose methyl glycoside obtained from the above reaction was dissolved in 20ml of dioxane, 200ml of 1N HCl was added, and the mixture was heated under reflux for 5-10 hours. After TLC detection, after complete hydrolysis, 0.5g of activated carbon was added after cooling to 40°C, stirring to room temperature, filtering, and adjusting the pH of the reaction mixture to 6-7 with 4NNaOH solution. The mixture was extracted with 30ml of dichloromethane for 3 times, and the organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed to obtain a syrupy compound, which was purified by TLC to obtain 4.4g of 2-deoxy-2,2-difluoro-D-ribose α / β mixture. α-Compound: HNMR (300Hz,CDCl3) 5.50PPm (m,1H,H 1 ),5.53ppm(m,1H,H 3 ),4.79ppm(m,1H,H 4 ),4.70~4.61ppm(m,2H,H 5 ); β-compound: 5.76ppm(m,1H,H 1 ),5.41ppm(m,1H,H 3 ),4.47ppm(m,1H,H 4 ),4.65ppm(m,2H,H5 )MS:171(M + ), fluorine content: theoretical value: 22.34%, measured value: 22.30%.

[0055] Example 5

[0056] Synthesis of the intermediate 1,3,5-triacetyl-2-deoxy-2,2-difluoro-D-ribofuranose

[0057] In a 250 ml round-bottom flask, 4.4 g (about 0.0259 mol) of 2-deoxy-2,2-difluoro-D-ribose was dissolved in 45 ml of anhydrous dichloromethane, 15 ml of triethylamine and 1 g of DMAP were added, and 7 g of acetyl chloride and 10 ml of anhydrous dichloromethane solution were slowly added at room temperature. The mixture was stirred overnight at room temperature and saturated with NaHCO 3 , water, and saturated brine until neutral, dried over anhydrous sodium sulfate, and filtered to obtain an anhydrous dichloromethane solution containing 7.0 g of syrup compound, namely 1,3,5-triacetyl-2-deoxy-2,2-difluoro-D-furanose, which was directly used in the next reaction.

[0058] Example 6

[0059] Synthesis of 2'-deoxy-2',2'-difluoro-β-nucleocytidine

[0060] In a 250ml round-bottom flask, 3.2g (0.0288mol) cytosine was dissolved in 50ml hexamethyldisilazane (HMDS), 0.5ml trimethylsilyl chloride (TMSCl) and 0.1g ammonium sulfate were added, nitrogen was passed through the reflux until the solution was clear, the hexamethyldisilazane was evaporated under reduced pressure, 50ml anhydrous dichloromethane was added, stirred to dissolve, and the anhydrous dichloromethane solution of 1,3,5-triacetyl-2-deoxy-2,2-difluoro-D-furanose synthesized above was added, the temperature was cooled to -10℃ by nitrogen passing through the flask, and 9.2ml anhydrous SnCl was added dropwise. 4 Mix the solution with 10 ml of anhydrous dichloromethane, add all the solution, heat to 0 °C, stir for 20 hours, then stir at room temperature for 3 to 4 hours, and pour in 200 ml of saturated NaHCO 3 The solution was filtered to remove the insoluble matter, the layers were separated, the organic phase was dried with anhydrous magnesium sulfate, filtered, the solvent was evaporated, the residue was dissolved with 100 ml of isopropanol, the temperature was cooled to -0°C with stirring, 60 ml of 2N NaOH solution was added dropwise, and stirring was continued for 0.5 hours. After the reaction was completed by TLC detection, 4N HCl was used to adjust the pH to 6-7, and 100 ml × 3 dichloromethane extractions were performed. The organic layer was washed with 1N HCl and saturated NaCl solution respectively, the solvent was evaporated, and the compound 2'-deoxy-2',2'-difluoro-β-nucleocytidine was crystallized with a mixed solvent of ethyl acetate-petroleum ether, 7.4 grams. [α] D(c=1.0,MeOH)+69.85; [α] 365 +410.41 Elemental Analysis: C 9 H 11 F 2 N 3 O 4 :Theoretical value: C,41.07,H,4.21,F,14.44,N,15.97 Actual value: C,41.10,H,4.26,F,14,51,N,15.58,IR(KBr):v=3486,3340,1656,1621,1033cm -1 .

[0061] Example 7

[0062] Synthesis of 2'-deoxy-2',2'-difluoro-β-nucleocytidine hydrochloride

[0063] In a 500ml round-bottom flask, add 7.4g of 2'-deoxy-2',2'-difluoro-β-nucleocytidine and 350ml of anhydrous ethanol, stir until the compound is completely dissolved, cool to below 10°C, slowly add 6ml of 5N HCl, then cool to -5°C, maintain this temperature, filter, rinse with cold anhydrous ethanol, and dry in vacuum to obtain 6.4g of 2'-deoxy-2',2'-difluoro-β-nucleocytidine hydrochloride. Optical rotation: [α] D (c=1.0,D 2 O) +47.56°; [α] 365 +255.7°Elemental analysis: C 9 H 12 CIF 2 N 3 O 4 : Theoretical value: C, 36.07; H, 4.04; CI, 11.83; F, 12.68; N, 14.02; Actual value C, 36.10; H, 4.08; CI, 11.88, F, 12.65; N, 13.86. IR (KBr): v = 3490, 3345, 1660, 1623, 1036 cm -1,13 CNMR(D 2 O)δ=61.01(C-5'),70.12(C-3'),52.16(C-4'),85.50(C-1'),97.40(C-5),124.03(C-2,),145.16(C-6),150.56(C-2),164.23(C-4).

[0064] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and substitutions that can be thought of by those skilled in the art are included in the present invention, and the protection scope is defined by the attached claims.

Claims

1. A method for preparing 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose, characterized in that: It is prepared from D-arabinose through hydroxyl protection, oxidation, fluorination, deprotection and acetylation.

2. The method according to claim 1, comprising the steps of: 1) Protecting the hydroxyl group of D-arabinose to obtain 3,4-isopropylideneoxy-D-arabinopyranose methyl glycoside; 2) oxidizing 3,4-isopropoxy-D-arabinopyranose methyl glycoside to obtain 2-oxo-3,4-isopropoxy-D-ribopyranose methyl glycoside; 3) fluorinating 2-oxo-3,4-isopropylidene-D-ribopyranose methyl glycoside to obtain 2',2'-difluoro-3,4-isopropylidene-D-ribopyranose methyl glycoside; 4) 2',2'-difluoro-3,4-isopropoxy-D-pyranose methyl glycoside is deprotected by hydrolysis to obtain 2'-deoxy-2',2'-difluoro-D-ribose; 5) 2'-deoxy-2',2'-difluoro-D-ribose is acetylated to give 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose.

3. The method according to claim 1 or 2, wherein the hydroxyl protection comprises formylation and isopropylidene oxylation.

4. The method according to claim 1 or 2, wherein the hydroxyl protection step uses an acidic substance as a catalyst, and the acidic substance is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, a strong acidic cationic resin, formic acid, acetic acid, and trifluoroacetic acid.

5. The method according to claim 1 or 2, characterized in that: The hydroxyl protection uses one or more water-binding agents selected from the group consisting of anhydrous calcium chloride, anhydrous zinc chloride, anhydrous magnesium sulfate, 4A molecular sieve, montmorillonite, trimethyl orthoformate, and triethyl orthoformate.

6. The method according to claim 1 or 2, wherein the hydroxyl protection is carried out in an anhydrous aprotic solvent selected from the group consisting of dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane, 1,1-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, ethyl acetate, propyl acetate, anisole, 1,2-dimethoxyethane, diglycol, ethyl ether, n-butyl ether, isopropyl ether, dioxane, acetonitrile, and tetrahydrofuran.

7. The method according to claim 4, wherein the amount of the acidic substance is 0.01 to 5 mol% of D-arabinose.

8. The method according to claim 3, wherein in the hydroxyl-protected formylation reaction of step 1), the molar ratio of D-arabinose to methanol is between 1:2 and 20, and / or The reaction temperature is 10 to 65°C, and / or The reaction time is 1 to 24 hours.

9. The method according to claim 3, wherein in the isopropoxylation reaction of the hydroxyl protection in step 1), the molar ratio of D-arabinose to acetone is between 1:2 and 15, and / or The reaction temperature is -5 to 40°C, and / or The reaction time is 0.5 to 24 hours.

10. The method according to claim 1 or 2, wherein in the oxidation reaction, the oxidant is selected from one or more of CrO3, K2CrO7, PPC, NDC, KMnO4, NaClO, Ca(ClO)2, dimethyl sulfoxide-dicyclohexylcarbodiimide, dimethyl sulfoxide-SOC12, dimethyl sulfoxide-CF3COOH, dimethyl sulfoxide-p-toluenesulfonyl chloride, 4-dimethylaminopyridine oxide or Des-Martin reagent; and / or In the fluorination reaction, the fluorinating agent is selected from one or more of DFI, MST, (diethylamino) sulfur trifluoride, and N,N-dimethylpropylene urea-hydrogen fluoride complex.

11. The method according to claim 1 or 2, wherein the deprotection reaction is carried out under a strong acid selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid.

12. The method according to claim 1 or 2, wherein the acetylation reaction is to form 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose using acetyl chloride or acetic anhydride.

13. The method according to claim 12, wherein: One or more acid-binding agents selected from the group consisting of trimethylamine, triethylamine, N,N-dimethylaniline, pyridine, 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine are used.

14. A method for preparing 2'-deoxy-2',2'-difluoro-β-nucleocytidine or a pharmaceutically acceptable salt thereof from an intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose, characterized in that: The intermediate is prepared by the method according to any one of claims 1 to 13.

15. The method for preparing 2'-deoxy-2',2'-difluoro-β-nucleocytidine or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: Also includes: Silanization of cytosine; condensing the intermediate 1,3,5-triacetyl-2'-deoxy-2',2'-difluoro-D-ribofuranose and the silylated cytosine; Removing the acetyl group to obtain 2'-deoxy-2',2'-difluoro-β-nucleocytidine; and / or Salt.

Images