WO2016112746A1

WO2016112746A1 - Method for preparing ribofuranose phosphate derivatives

Info

Publication number: WO2016112746A1
Application number: PCT/CN2015/095524
Authority: WO
Inventors: 李泽标; 丁海明; 严军; 戴宇; 顾文超; 张兆国
Original assignee: 南通常佑药业科技有限公司
Priority date: 2015-01-16
Filing date: 2015-11-25
Publication date: 2016-07-21
Also published as: CN104610404B; CN104610404A

Abstract

Disclosed in the present invention is a method for preparing ribofuranose phosphate derivatives, and the preparation steps thereof comprises: coupling starting materials of isopropyl L-alanine hydrochloride, phenol dichlorophosphate and substituted phenol under the action of alkali; reducing carbonyl into alcoholic hydroxyl by means of treating (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro pentonic acid GAMMA-lactone 3,5-dibenzoate with a strong reducing agent in the solvent of dichloromethane or ethers; reacting the intermediate of formula 2-1 with p-toluene sulfonyl chloride under the action of alkali to obtain p-toluene sulfonate; coupling the intermediate of formula 2-2 with a benzoyl cytosine derivative under the action of a condensation agent; converting cytosine of the intermediate of formula 2-3 into uracil under the action of an organic acid; removing benzoyl acting as protecting group from the intermediate of formula 2-4 under the action of an alkaline reagent; and coupling the intermediate of formula 2-5 with formula 1 under the action of a Grignard reagent to obtain Sofosbuvir.

Description

Preparation method of furan ribose phosphate derivative

Technical field

The invention relates to a preparation method of a furan ribose phosphate derivative, and belongs to the field of medicinal chemical synthesis.

Background technique

Hepatitis C virus (referred to as hepatitis C, hepatitis C) is a viral hepatitis caused by hepatitis C virus (HCV) infection. According to the World Health Organization, the global hepatitis C infection rate is about 3%, about 180 million people are infected with HCV, and about 35,000 new cases of hepatitis C are reported each year. Hepatitis C is globally prevalent and can cause chronic inflammation, necrosis and fibrosis in the liver. 1% to 5% of 100 patients can develop cirrhosis or even hepatocellular carcinoma (HCC) and die.

Currently, there are six genotypes of HCV virus. The standard treatment regimen is peginterferon (Peg-IFN) plus ribavirin (RBV). The total cure rate is less than 50%. It is necessary to adhere to a sufficient dose for more than one year. Peg-IFN, which is injected once a week, has many disadvantages such as adverse reactions, drug interactions, and poor patient compliance, and its clinical use is limited. Therefore, direct antiviral drugs (DAAs) that increase cure rates, shorten treatment time, and use total oral administration without Peg-IFN to treat hepatitis C continue to emerge. Sofosbuvir is a prodrug of a fluorine-containing nucleotide analogue and has a strong inhibitory effect on hepatitis C virus (HCV) NS5B polymerase. It can be used as a component in the treatment of chronic hepatitis C (CHC) antiviral combination therapy. One, for HCV genotype 2 (GT2), HCV genotype 3 (GT3) infection, sofosbuvir only needs to be combined with RBV, becoming the world's first all-oral treatment without the use of interferon (IFN). Infected patients with HCV genotypes 1 and 4 must be associated with RBV and Peg-IFN is used in combination.

Sofosbuvir is a ribofuran phosphate derivative, the English name is Sofosbuvir, the Chinese name is N-[(S)-2-(S)-(2R,3R,4R,5R)-5-(2,4-two Oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramido Isopropyl propionate, the structural formula is

At present, most of the preparation methods of sofosbuvir have the following disadvantages: the yield of the side chain fragment of the main chain is low, the product is not easy to be purified, and the quality of the subsequent reaction is affected; the process route is long and the operation is cumbersome; the solvent of the material used is large and difficult to recycle; The yield of the finished product of sofosbuvir is low, the content of isomer is too large, and the purity is not easy to control.

To this end, a new technical solution is urgently needed to solve the above technical problems.

Summary of the invention

It is an object of the present invention to provide a novel process for the preparation of a ribofuranosyl phosphate derivative.

The technical solution adopted by the invention is:

A preparation method of a furan ribose phosphate derivative, wherein the preparation steps include:

a, preparation of intermediate formula 1:

Using L-alanine isopropyl ester hydrochloride, phenol dichlorophosphate and substituted phenol as starting materials, the docking reaction is carried out under the action of a base;

b. Preparation of intermediate formula 2-1:

(2R)-2-deoxy-2-fluoro-2-methyl-D-erythropentanoic acid GAMMA-lactone 3,5-dibenzoate in strong solvent in dichloromethane or ether solvent Acting to reduce the carbonyl group to an alcoholic hydroxyl group;

c. Preparation of intermediate formula 2-2:

Intermediate 2-1 is reacted with p-toluenesulfonyl chloride under the action of a base to obtain p-toluenesulfonate;

d, preparation of intermediate formula 2-3:

The intermediate formula 2-2 and the benzoylcytosine derivative are subjected to a docking reaction under the action of a condensing agent;

e, Preparation of intermediate formula 2-4:

Intermediate formula 2-3 converts cytosine to uracil under the action of an organic acid;

f, preparation of intermediate formula 2-5:

Intermediate formula 2-4 is deprotected by benzoyl group under the action of an alkali reagent;

g, preparation of Sofosbuvir:

The intermediate formula 2-5 is docked with the formula 1 under the action of a format reagent to obtain Sofosbuvir.

Further, in step a, the substituted phenol is one of 4-chlorophenol, 4-bromophenol, 4-nitrophenol or perfluorophenol; the base is in DIPEA, triethylamine or piperidine One; the reaction temperature is -78 to 0 ° C; the reaction solvent is dichloromethane, tetrahydrofuran, toluene or diethyl ether.

Further, in step a, the crude intermediate formula 1 obtained after the docking reaction is subjected to a purification step to obtain a fine product, and the solvent used in the purification step is one or more of methyl tert-butyl ether, n-hexane, ethyl acetate or isopropyl ether. Kind of mixture.

Further, in step b, the strong reducing agent is lithium tri-tert-butoxyaluminum hydride, RED-AL toluene solution or DIBAL-H solution; the reaction temperature is -30 to 30 ° C; the ether solvent is Tetrahydrofuran or diethyl ether.

Further, in the step c, the base is triethylamine, DIPEA or DMAP; the reaction temperature is -10 to 30 ° C; and the reaction solvent is dichloromethane, toluene or isopropyl ether.

Further, in step d, hexamethyldisilazane or N,O-bis(trimethylsilyl)acetamide is added as a hydroxy protecting agent; the condensing agent is tin tetrachloride or trifluoromethanesulfonic acid Trimethylsilyl ester; the reaction temperature is -10 to 100 ° C; the reaction solvent is dichloromethane or acetonitrile.

Further, in the step e, the organic acid is glacial acetic acid or glacial acetic acid; and the reaction temperature is 30 to 120 °C.

Further, in the step f, the alkali reagent is sodium methoxide or ammonia methanol; the reaction temperature is 0 to 30 ° C; the reaction solvent is methanol;

Further, in the step g, the format reagent is t-butyl magnesium chloride; the reaction temperature is -50 to 30 ° C; and the reaction solvent is tetrahydrofuran, toluene, DMF or DMSO.

The invention has the advantages of starting from the easily available (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro-olithionic acid GAMMA-lactone 3,5-dibenzoate The raw materials are synthesized in six steps, and the route is short; the purity of each intermediate is easy to control, which is beneficial to control the impurity content; the yield of the raw materials and the intermediate formula 1 is high, and the excessive loss of materials is avoided; The operation is simple, the solvent can be recycled and used, and the pollution is small; the prepared sofosbuvir has high purity, the impurities are easy to control, and the process is suitable for industrial production.

DRAWINGS

Figure 1 is a process road diagram of the present invention.

detailed description

Example 1:

Preparation of intermediate formula 1:

Add 200 mL of dichloromethane, 50 g of L-alanine isopropyl ester hydrochloride and 38.3 g of DIPEA to the reaction flask, stir, cool to -78 ° C, react for 30 min, then add phenol dichlorophosphate in dichloromethane. Solution (63 g / 120 mL); after completion of the dropwise addition, the reaction was stirred for 30 min, and then the temperature was raised to -10 ° C for 3 hours. 55.4 g of perfluorophenol and 35.2 g of DIPEA were dissolved in 200 mL of dichloromethane, and added dropwise to the above reaction solution; after completion, the reaction was stirred, and the reaction was monitored by TLC; the reaction was completed, suction filtered, and the filter cake was washed with 50 mL of dichloromethane. The organic phase was combined, concentrated under reduced pressure, and then purified and purified with EtOAc EtOAc EtOAc EtOAc EtOAc. . The crude product was purified by ethyl acetate and n-hexane to yield 65.6. Yield: 48%.

Preparation of intermediate formula 2-1:

In the reaction flask, under anhydrous and anaerobic conditions, add 45g of (2R)-2-deoxy-2-fluoro-2-methyl-D-erythroic acid GAMMA-lactone 3,5-dibenzoic acid The ester and 150 mL of tetrahydrofuran were stirred and dissolved, and the temperature was lowered to -20 ° C. A solution of lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (46 g / 150 mL) was added dropwise, the reaction was stirred for 30 min, then the temperature was raised to 0 ° C, and the reaction was confirmed by TLC; After quenching with saturated ammonium chloride solution, the tetrahydrofuran was evaporated under reduced pressure, and ethyl acetate (300 mL) was added, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL×2) The organic phase was washed with a sodium solution, dried over anhydrous sodium sulfate, filtered, and then evaporated. The product is not purified Then proceed to the next step.

Preparation of intermediate formula 2-2:

Intermediate 2-1, 200 mL of dichloromethane and 24.6 g of triethylamine were added to the reaction flask, and the mixture was stirred uniformly; the temperature was lowered to 0 to 5 ° C, 23.8 g of p-toluenesulfonyl chloride was added, and the reaction was stirred for 1 hour, and then the temperature was raised to room temperature. After the reaction was completed, the reaction mixture was washed with water (100 mL×2), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by 3-4 times of isopropyl alcohol to give 56.8 g of Intermediate Compound 2-2.

Preparation of intermediate formula 2-3:

Add 32g of hexamethyldisilazane, 100mL of chlorobenzene, 2g of ammonium sulfate, and 21.5g of benzoylcytosine to the reaction flask, stir, heat to reflux reaction, monitor the reaction by TLC; complete the reaction, concentrate under reduced pressure, add 300 mL of dichloromethane was stirred and dissolved, then 55 g of intermediate formula 2-2 was added, stirred, 78.1 g of tin tetrachloride was added, and the temperature was raised to reflux. The reaction was monitored by TLC: the reaction was completed, cooled to room temperature, and 32 g of sodium hydrogencarbonate and 60 g of silicon were added. The mixture was stirred with celite, filtered, and filtered, and then filtered with methylene chloride (200mL×3). The organic phase was combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate 2-3 crude. The crude product was purified with 4 times isopropyl alcohol to afford 47.8 g of white solid.

Preparation of intermediate formula 2-4:

In the reaction flask, 300 g of glacial acetic acid, 100 g of water, and 45 g of intermediate formula 2-3 were added, stirred and dissolved, and heated to reflux, about 90-105 ° C; TLC detection reaction, the reaction was completed, the temperature was lowered to room temperature, 300 g of water was added; After 30 min, suction filtration, the cake was washed with saturated sodium bicarbonate and dried to give 32.7 g of white solid.

Preparation of intermediate formula 2-5:

In the reaction flask, add 30g of intermediate formula 2-4, 300mL methanol, stir to dissolve, add 3.5g sodium methoxide, stir, then warm up to reflux reaction, monitor the reaction by TLC; reaction is completed, cool to room temperature, add citric acid and water quench After the reaction was stirred, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The crude product was purified with 120 mL of isopropyl alcohol to afford 12. Yield: 78%.

Preparation of Sofosbuvir:

In the reaction flask, under anhydrous and anaerobic conditions, add 12g of intermediate formula 2-5, 120mL tetrahydrofuran, stir, cool to -30 ° C, add 53.2g 1.7M t-butyl magnesium chloride dropwise; drop, stir reaction for 1 hour Then, the temperature was raised to -10 ° C, and a solution of 21.3 g of N-[(S)-(4,-bromophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester in 100 mL of tetrahydrofuran was added dropwise; The reaction was carried out at -10 ° C for 1 hour, then warmed to room temperature and the reaction was monitored by TLC. After completion of the reaction, the temperature was lowered to 0 ° C, and the reaction was quenched with concentrated hydrochloric acid/water (50 mL / 300 mL). The mixture was evaporated to dryness. The combined organic layers were dried with EtOAc EtOAc. The crude oil was purified with 5 times dichloromethane to yield 13.5 g of white solid.

Example 2:

Preparation of intermediate formula 1:

Add 200 mL of dichloromethane, 50 g of L-alanine isopropyl ester hydrochloride and 30 g of triethylamine to the reaction flask, stir, cool to -78 ° C, react for 30 min, then add phenol dichlorophosphorus dropwise. A solution of the acid ester in dichloromethane (63 g / 1200 mL); after the dropwise addition, the reaction was stirred for 30 min, then warmed to -10 ° C for 3 hours. 42.7 g of 4-nitrophenol and 30.6 g of triethylamine were dissolved in 200 mL of dichloromethane, and added dropwise to the above reaction solution; after completion, the reaction was stirred, and the reaction was monitored by TLC; after completion of the reaction, suction filtration, filter cake with 50 mL The organic phase was combined and concentrated under reduced pressure. EtOAc (EtOAc m. The crude product was purified by ethyl acetate and n-hexane to yield 52.3 g. Yield: 43%.

Preparation of intermediate formula 2-1:

Under anhydrous and anaerobic conditions, 17.4 g of trifluoroethanol and 60 mL of toluene were added to the reaction flask under nitrogen atmosphere, stirred, and cooled to -20 ° C. 52.8 g of RED-AL toluene solution was added dropwise with stirring; After an hour, warm to room temperature and store for later use.

Add 45g of (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro-pentanoic acid GAMMA-lactone 3,5-dibenzoate, 200mL of dichloromethane, and stir. Dissolve, cool down to -15 ~ -20 ° C, add the prepared RED-AL solution; drop, -15 ~ -20 ° C reaction, TLC monitoring reaction; reaction is completed, adding citric acid aqueous solution for quenching, heating The mixture was allowed to stand at room temperature, and the mixture was separated and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated -1 product, directly proceed to the next reaction.

Preparation of intermediate formula 2-2:

Intermediate 2-1, 200 mL of toluene and 31.6 g of DIPEA were added to the reaction flask, and the mixture was stirred uniformly; the temperature was lowered to 0 to 5 ° C, 23.1 g of p-toluenesulfonyl chloride was added, the reaction was stirred for 1 h, and the reaction was further heated to room temperature, and the reaction was monitored by TLC; The reaction is completed, and the reaction solution is water (100 mL). ×2) Washing, drying over anhydrous sodium sulfate, and evaporation to dryness at 40 ° C or less to give a crude solid. The crude product was purified by 3-4 times of isopropyl alcohol to give 58.4 g of Intermediate Compound 2-2.

Preparation of intermediate formula 2-3:

21.5 g of benzoylcytosine, 20.5 g of N,O-bis(trimethylsilyl)acetamide and 100 mL of acetonitrile were added to the reaction flask, stirred, and the temperature was raised to reflux. The reaction was monitored by TLC; the reaction was completed and cooled to room temperature. Then, adding 55g of intermediate formula 2-2, stirring, adding 78.5g of tin tetrachloride, heating to reflux reaction, monitoring reaction by TLC: reaction is completed, cooled to room temperature, adding 32g of sodium hydrogencarbonate and 60g of diatomaceous earth, stirring, pumping Filtration and filtration of the cake were followed by acetonitrile (200 mL×3). The organic phase was combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness The crude product was purified with 4 times isopropyl alcohol to yield 48.9 g of a white solid product.

Preparation of intermediate formula 2-4:

In the reaction flask, 300 g of glacial acetic acid, 100 g of water, and 45 g of intermediate formula 2-3 were added, stirred and dissolved, and heated to reflux, about 90-105 ° C; TLC detection reaction, the reaction was completed, the temperature was lowered to room temperature, 300 g of water was added; After 30 min, suction filtration, the filter cake was washed with saturated sodium bicarbonate and dried to give 32.6 g of white solid.

Preparation of intermediate formula 2-5:

In the reaction flask, add 30g of intermediate formula 2-4, 300mL methanol, stir to dissolve, add 3g sodium methoxide, stir, then warm to reflux reaction, monitor the reaction by TLC; reaction is completed, cool to room temperature, add citric acid and water to quench The reaction mixture was stirred and evaporated to dryness. Crude with 120mL isopropanol The system yielded 12.8 g of a white solid product. Yield: 78%.

Preparation of Sofosbuvir:

In the reaction flask, under anhydrous and anaerobic conditions, add 12g of intermediate formula 2-5, 120mL tetrahydrofuran, stir, cool to -30 ° C, add 53.6g 1.7M t-butyl magnesium chloride dropwise; drop, stir reaction for 1 hour Then, the temperature was raised to -10 ° C, and a solution of 19.6 g of N-[(S)-(4,-nitrophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester in 120 mL of tetrahydrofuran was added dropwise; After completion, the reaction was carried out at -10 ° C for 1 hour, then the temperature was raised to room temperature, and the reaction was monitored by TLC. After the reaction is completed, the temperature is lowered to 0 ° C, and the reaction is quenched by adding concentrated hydrochloric acid/water (50 mL/300 mL); tetrahydrofuran is distilled off under reduced pressure, then 200 mL of methyl t-butyl ether is added, and the mixture is stirred, and the aqueous layer is taken with methyl The butyl ether (50 mL × 3) was evaporated. EtOAc m. The crude oil was purified with 5 times dichloromethane to yield 14.8 g of white solid.

Example 3:

Preparation of intermediate formula 1:

Add 200 mL of toluene, 50 g of L-alanine isopropyl ester hydrochloride and 26.4 g of piperidine to the reaction flask, stir, cool to -78 ° C, react for 30 min, then add phenol dichlorophosphate in toluene solution (63 g) /120 mL); After completion of the dropwise addition, the reaction was stirred for 30 min, and then the temperature was raised to -10 ° C for 3 hours. 46.5 g of 4-bromophenol and 25 g of piperidine were dissolved in 100 mL of toluene, and added dropwise to the above reaction solution; after completion of the dropwise addition, the reaction was stirred, and the reaction was monitored by TLC; the reaction was completed, suction filtered, and the filter cake was washed with 50 mL of toluene and organic. The phase was concentrated under reduced pressure, and then dissolved with 500 mL of methyl tert-butyl ether. The mixture was filtered and filtered, and the filter cake was washed with 50 mL of methyl tert-butyl ether. The organic phase was concentrated under reduced pressure to give 119.6 g of crude white. The crude product was purified by ethyl acetate and n-hexane to afford 60.5 g. Yield: 46%.

Preparation of intermediate formula 2-1:

In the reaction flask, under anhydrous and anaerobic conditions, add 45g of (2R)-2-deoxy-2-fluoro-2-methyl-D-erythroic acid GAMMA-lactone 3,5-dibenzoic acid Ester and 150mL tetrahydrofuran, stir and dissolve, reduce to -20 ° C, add 180mL 1M DIBAL-H solution, stir the reaction for 30min, then warm to 0 ° C reaction, TLC detection reaction; reaction is completed, add saturated ammonium chloride solution for quenching Then, tetrahydrofuran was distilled off under reduced pressure, and ethyl acetate (300 mL) was added, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL×2), and the organic phase was combined, and the organic phase was washed with saturated sodium chloride solution Drying over sodium sulfate, suction filtration and concentration under reduced pressure afforded Intermediate 2-1 product. The product was taken to the next step without purification.

Preparation of intermediate formula 2-2:

Add intermediate formula 2-1, 200mL isopropyl ether and 29g DMAP to the reaction flask, stir evenly; cool down to 0 ~ 5 ° C, add 23g p-toluenesulfonyl chloride, stir the reaction for 1h, then warm to room temperature reaction, TLC monitoring reaction After completion of the reaction, the reaction mixture was washed with water (100 mL×2), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by 3-4 times of isopropyl alcohol to give 57.3 g of Intermediate Compound 2-2.

Preparation of intermediate formula 2-3:

Add 32g of hexamethyldisilazane, 100mL of chlorobenzene, 2g of ammonium sulfate, and 21.5g of benzoylcytosine to the reaction flask, stir, heat to reflux reaction, monitor the reaction by TLC; complete the reaction, concentrate under reduced pressure, add Dissolve and dissolve in 300 mL of acetonitrile, cool to 0-5 ° C, then add 55 g of intermediate formula 2-2, stir, add 66.4 g of trimethylsilyl trifluoromethanesulfonate, Stirring, heating to 65 ° C reaction, TLC monitoring reaction: the reaction was completed, a saturated sodium bicarbonate solution was added, extracted with ethyl acetate (200 mL × 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentrated to dryness under reduced pressure afforded 62.9 g of Intermediate Intermediate 2-3. The crude product was purified with 4 times isopropyl alcohol to afford 46.8 g of white solid.

Preparation of intermediate formula 2-4:

In the reaction flask, 300 g of glacial acetic acid, 100 g of water, and 45 g of intermediate formula 2-3 were added, stirred and dissolved, and heated to reflux, about 90-105 ° C; TLC detection reaction, the reaction was completed, the temperature was lowered to room temperature, 300 g of water was added; After 30 min, suction filtration, the filter cake was washed with saturated sodium bicarbonate and dried to give 32.3 g of white solid.

Preparation of intermediate formula 2-5:

In the reaction flask, add 90g ammonia methanol, cool down to about 5 °C, add 30g of intermediate formula 2-4; slowly warm to room temperature after the completion of the reaction, TLC monitoring reaction; after the reaction is completed, the solvent is distilled off under reduced pressure, 150mL of acetic acid is added The ester was beaten and suction filtered to give 21.7 g of a crude solid. Yield: 75%.

Preparation of Sofosbuvir:

In the reaction flask, under anhydrous and anaerobic conditions, add 12g of intermediate formula 2-5, 120mL of tetrahydrofuran, stir, cool to -30 ° C, add 53g of t-butyl magnesium chloride dropwise; drip, stir the reaction for 1 hour, then heat up To a temperature of -10 ° C, 20.9 g of N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester was added dropwise to 150 mL. Tetrahydrofuran solution; after completion, the reaction was carried out at -10 ° C for 1 hour, then the temperature was raised to room temperature, and the reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to 0 ° C, and concentrated hydrochloric acid/water (50 mL/300 mL) was added dropwise to quench the reaction; tetrahydrofuran was distilled off under reduced pressure, then 200 mL of diethyl ether was added, and the mixture was stirred and water. The layers were extracted with EtOAc (EtOAc)EtOAc. The crude oil was purified with 5 times dichloromethane to yield 15.5 g of white solid.

Claims

A method for preparing a furan ribose phosphate derivative, characterized in that the preparation step comprises:

a, preparation of intermediate formula 1:

Using L-alanine isopropyl ester hydrochloride, phenol dichlorophosphate and substituted phenol as starting materials, the docking reaction is carried out under the action of a base;

b. Preparation of intermediate formula 2-1:

(2R)-2-deoxy-2-fluoro-2-methyl-D-erythropentanoic acid GAMMA-lactone 3,5-dibenzoate in strong solvent in dichloromethane or ether solvent Acting to reduce the carbonyl group to an alcoholic hydroxyl group;

c. Preparation of intermediate formula 2-2:

Intermediate 2-1 is reacted with p-toluenesulfonyl chloride under the action of a base to obtain p-toluenesulfonate;

d, preparation of intermediate formula 2-3:

The intermediate formula 2-2 and the benzoylcytosine derivative are subjected to a docking reaction under the action of a condensing agent;

e, Preparation of intermediate formula 2-4:

Intermediate formula 2-3 converts cytosine to uracil under the action of an organic acid;

f, preparation of intermediate formula 2-5:

Intermediate formula 2-4 is deprotected by benzoyl group under the action of an alkali reagent;

g, preparation of Sofosbuvir:

The intermediate formula 2-5 is docked with the formula 1 under the action of a format reagent to obtain Sofosbuvir.
The method for preparing a furan ribose phosphate derivative according to claim 1, wherein in the step a, the substituted phenol is 4-chlorophenol, 4-bromophenol, 4-nitrophenol or perfluoro One of phenol; the base is one of DIPEA, triethylamine or piperidine; the reaction temperature is -78 to 0 ° C; and the reaction solvent is dichloromethane, tetrahydrofuran, toluene or diethyl ether.
The method for preparing a furan ribose phosphate derivative according to claim 1 or 2, wherein in the step a, the crude intermediate compound obtained after the docking reaction is subjected to a purification step to obtain a fine product, and the solvent used in the purification step is a A mixture of one or more of t-butyl ether, n-hexane, ethyl acetate or isopropyl ether.
The method for preparing a furan ribose phosphate derivative according to claim 1, wherein in the step b, the strong reducing agent is lithium tri-tert-butoxyaluminum hydride, RED-AL toluene solution or DIBAL- H solution; the reaction temperature is -30 to 30 ° C; the ether solvent is tetrahydrofuran or diethyl ether.
The method for preparing a furan ribose phosphate derivative according to claim 1, wherein in the step c, the base is triethylamine, DIPEA or DMAP; the reaction temperature is -10 to 30 ° C; The reaction solvent is dichloromethane, toluene or isopropyl ether.
The method for preparing a ribofuranosyl phosphate derivative according to claim 1, wherein in the step d, hexamethyldisilazane or N,O-bis(trimethylsilyl)acetamide is added. It is a hydroxy protecting agent; the condensing agent is tin tetrachloride or trimethylsilyl trifluoromethanesulfonate; the reaction temperature is -10 to 100 ° C; and the reaction solvent is dichloromethane or acetonitrile.
The preparation method of a furan ribose phosphate derivative according to claim 1 The method is characterized in that in the step e, the organic acid is glacial acetic acid or glacial acetic acid; and the reaction temperature is 30 to 120 °C.
The method for preparing a furan ribose phosphate derivative according to claim 1, wherein in the step f, the alkali reagent is sodium methoxide or ammonia methanol; the reaction temperature is 0 to 30 ° C; The reaction solvent is methanol;
The method for preparing a furan ribose phosphate derivative according to claim 1, wherein in the step g, the format reagent is t-butyl magnesium chloride; the reaction temperature is -50 to 30 ° C; The reaction solvent is tetrahydrofuran, toluene, DMF or DMSO.