CN115894576A - A kind of synthetic technique of sofosbuvir key intermediate - Google Patents

Abstract

The invention discloses a synthesis process of a key intermediate of sofosbuvir, which comprises dissolving compound I in a solvent, adding a reducing agent for reduction to obtain compound II; chlorinating compound II obtained in the previous step to obtain a chlorinated product compound III; The compound III and the compound IV are reacted under the action of the catalyst to obtain the target key intermediate compound V, the isomer compound V' is separated, the α-type compound V' is converted into the β-type compound V, and the compound V is combined. The beneficial effects of the present invention are: the generation of the by-product of the reduction reaction is reduced by the DIBAL-H catalyst, the reaction yield is improved, the atom economy is increased, and then the isomeric product is converted into the required intermediate by configuration conversion The body increases the yield of the final sofosbuvir product, improves the atomic utilization efficiency of the reaction, and effectively increases the conversion rate of nucleosides, and the process is simple to operate, which is conducive to improving the yield of industrial production.

Description

A synthesis process of a key intermediate of sofosbuvir

Technical Field

The present invention relates to the technical field related to pharmaceutical intermediates, and in particular to a synthesis process of a key intermediate of sofosbuvir.

Background Art

Sofosbuvir (also translated as Sofosbuvir, English name Sovaldi, alias GS-7977, PSI-7977) is a new drug developed by Gilead for the treatment of chronic hepatitis C. This drug is the first drug that can safely and effectively treat certain types of hepatitis C without the need for combined interferon. Clinical trials have confirmed that for hepatitis C types 1 and 4, the overall sustained virological response rate (SVR) of this drug combined with pegylated interferon and ribavirin is as high as 90%; for hepatitis C type 2, the SVR of this drug combined with ribavirin is 89%-95%; for hepatitis C type 3, the SVR of this drug combined with ribavirin is 61%-63%. The drug was approved for marketing in the United States by the U.S. Food and Drug Administration in December 2013, and was approved for marketing in EU countries by the European Medicines Agency in January 2014. Sofosbuvir has a new target and new mechanism of action. It is the world's first NS5B polymerization inhibitor for the treatment of hepatitis C. Currently, there is no drug with the same mechanism of action on the market. It is also the first drug that can safely and effectively treat certain genotypes of hepatitis C without the need for combined interferon.

The chemical name of sofosbuvir is (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphorylated phenoxy)amino)propionic acid isopropyl ester, and its structural formula is as follows:

At present, there are many patents and literature reports on the chemical synthesis of sofosbuvir and its intermediates. The synthesis routes used in industrial production are the routes reported in patents US20130324709, WO2013045419, WO2010135569, WO2013178571, and literature J.Org.Chem.2009,74,6819-6824, J.Med.Chem.2010,53,7202-7218, etc. The common point of these reports is that compound I, i.e., 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribonucleic acid-lactone (compound I), is used as the starting material to synthesize the key intermediate (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate (compound V) through reduction reaction and subsequent reaction. The chemical structure of compound VI is as follows:

Compound V is hydrolyzed and deprotected to obtain compound VI (2'R)-2'-deoxy-2'-fluoro-2'-C-methyluridine, which is then reacted with the phosphate side chain (compound VII) to obtain sofosbuvir (compound VIII). The overall reaction equation for preparing sofosbuvir is as follows:

When sofosbuvir is prepared industrially, when a nucleoside compound (Compound I) is used as a starting material, the first step is usually to reduce Compound I by a reduction reaction under the action of a reducing agent, red aluminum. Since red aluminum has a strong reducing ability, the intermediate I will be further reduced to obtain a by-product, which reduces the product yield and makes the product more complex. The post-processing is more complicated, and the process cost is increased. The current reaction equation is as follows:

Patent CN107245064 reports a method of reducing by replacing red aluminum with borohydride, but the reduction with borohydride results in a byproduct of up to 47%. Although the patent provides a method for recovering byproducts, the byproducts are oxidized in the presence of a catalyst to obtain a reaction substrate, and then reduced by the same reaction to obtain a mixture of products and byproducts, the recovery process is complicated and the difficulty of purifying the product is increased, which is not conducive to industrial production and application. Patent CN105906673 publicly reports a method of using lithium aluminum tetrahydride (LiAlH4) as a reducing agent, using modified lithium aluminum tetrahydride instead of modified red aluminum, which has great improvements in reducing agent dosage and operational safety, but the yield is significantly reduced.

In addition, due to the stereoselectivity problem, the hemiacetal (compound II) obtained by reduction is subjected to chlorination with sulfonyl chloride to obtain the chlorinated product compound III, which is reacted with TMS-protected N-Bz cytosine under the action of Lewis acid to obtain α-configuration and β-configuration glycosylation products (β/α≈3.5-4/1). The β-configuration glycosylation product is separated and purified. Since the α-configuration is not the desired product, the existing treatment methods for the isomeric impurities are: first, directly treating it as solid waste, and second, alkaline hydrolysis to recover part of compound IV, which results in a low comprehensive yield of compound V, high cost, high three wastes, and further reduced yield. The reaction equation is as follows:

After isolating and purifying the desired β-configuration glycosylation product, the β-configuration product is treated with AcOH/MeOH to obtain the intermediate 2-deoxy-2-fluoro-2-methylcytidine (compound VI). Finally, the hydroxymethyl and chiral phosphine ester fragments of 2-deoxy-2-fluoro-2-methylcytidine are condensed, and the product is recrystallized to complete the preparation of sofosbuvir.

Obviously, the starting material compound I is reduced and chlorinated, and the chlorinated product reacts with TMS-protected N-Bz cytosine under the action of Lewis acid to obtain α-configuration and β-configuration glycosylation products (compound V). The factors affecting the yield of β-glycoside lie in the yield of hemiacetal obtained by the reduction of compound I and the stereoselectivity of α and β configurations.

The present invention aims to provide a novel synthesis process of a key intermediate of sofosbuvir (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine. By using a suitable reducing agent, the reduction yield of a lactone compound I is increased, and at the same time, an α-configuration compound V' is converted into a β-configuration compound V during the reaction conversion process, thereby increasing the total yield of the β-configuration product, so as to achieve the purpose of ultimately increasing the yield of the β-configuration glycosylation product. At the same time, the generation of by-products is reduced, and ultimately the conversion rate of the key intermediate of sofosbuvir (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate is increased, thereby increasing the total yield of sofosbuvir and improving the atom economy of the reaction. The reaction equation is as follows:

Summary of the invention

In view of the problems that the lactone reduction is prone to over-reduction and the overall reaction stereoselectivity is poor, resulting in more by-products and reduced yield in the current industrial synthesis of the key intermediate compound (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine of sofosbuvir, the present invention adopts the following technical solutions:

A synthesis process of a key intermediate of sofosbuvir comprises the following steps:

The first step is to dissolve compound I in a solvent and add a reducing agent to reduce the compound II;

The second step is to chlorinate the compound II obtained in the previous step to obtain the chlorinated product compound III;

The third step is to react compound III with compound IV under the action of a catalyst to obtain the target key intermediate compound V;

The fourth step is to separate the isomer compound ' mixed in compound V, add a conversion reagent to the obtained α-type compound V' to convert compound II' from an α-type compound to a β-type compound V, and combine compound V.

Furthermore, the catalyst used in the first step reaction is one of diisobutylaluminum hydride (DIBAl-H), lithium tri-sec-butylborohydride (L-selectride) and lithium tri-tert-butoxyaluminum hydride, preferably diisobutylaluminum hydride (DIBAl-H).

Furthermore, the solvent used in the first step reaction is dichloromethane (DMC), and the reaction is carried out at -75 to -80°C for 2 to 2.5 hours, preferably at -78°C for 2 hours.

Furthermore, in the fourth step reaction, the catalyst used for the configuration conversion reaction is boron trifluoride etherate, and the reaction solvent is nitromethane.

Furthermore, the chlorinating agent used in the second step chlorination reaction is usually selected from sulfuryl chloride, thionyl chloride or phosphorus oxychloride, preferably sulfuryl chloride.

Furthermore, the catalyst used in the third step reaction is tin tetrachloride, and the amount of the catalyst used is 3 to 4 eq.

Furthermore, the reaction conditions of the third step reaction are 70-90° C. and 2-3 bar pressure for 10-20 hours.

Furthermore, the solvent used in the third step reaction is chlorobenzene.

Furthermore, the reaction temperature of the fourth step isomerization conversion reaction is -5 to 0°C, preferably 0°C.

Furthermore, in the third step reaction, the molar ratio of compound III to compound IV and the catalyst is 1:1.5:3-4.

The beneficial effects of the present invention are as follows: 1. The generation of byproducts of the reduction reaction is reduced by the DIBAL-H catalyst, the reaction yield is improved, and the atom economy is increased. 2. The isomeric product is converted into the desired intermediate through configuration conversion, the generation of waste is reduced, the yield of the final sofosbuvir product is increased, the atomic utilization efficiency of the reaction is improved, the conversion rate of the nucleoside is effectively increased, the operation is simple and it is conducive to improving the yield of industrial production, and it is suitable for industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic diagram of the chemical structure of sofosbuvir;

FIG2 is a schematic diagram of the chemical structure of a key intermediate synthesized in the present invention;

Figure 3 is a schematic diagram of the reaction equation for synthesizing Sofosbuvir;

Figure 4 is a schematic diagram of the reduction reaction equation of compound I;

FIG5 is a schematic diagram of the reaction equation for synthesizing intermediate compound V;

FIG. 6 is a schematic diagram of the reaction flow equation of the present invention.

DETAILED DESCRIPTION

The following will be combined with the embodiments of the present invention and the accompanying drawings to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Example 1

The first step is reduction reaction. First, add 18.6g (0.05mol) of compound I to 500ml of dichloromethane, pass argon gas for protection, slowly add 0.075mol of diisobutylaluminum hydride/n-hexane solution at -78°C, control the reaction temperature and react for 2h. After the reaction is completed, add 100ml of methanol to the reactant. Stir for 0.5h, concentrate, first add dilute hydrochloric acid to neutralize, then add 400ml of ethyl acetate and 250ml of water, separate the liquids, dry the organic layer with anhydrous magnesium sulfate, and concentrate to obtain 18.4g of compound II with a yield of 98.3%.

The second step is chlorination reaction. Take a 500ml reaction bottle, add 37.4g of intermediate compound II, add 0.4g of catalytic amount of tetrabutylammonium bromide, control the temperature below 0℃, add 150ml of sulfonyl chloride, react at 40℃ for 4-5h, after the reaction is completed, cool the reaction solution to 0℃, slowly add water, control the temperature not to exceed 15℃, and heat to room temperature and stir for 1 hour after adding. Let stand and separate, wash the organic phase with 15% citric acid solution and then with 6.5% KOH solution, dry with anhydrous sodium sulfate, filter, and recover the solvent in the filtrate under reduced pressure to obtain a white solid. Methyl tert-butyl ether is recrystallized to obtain 38.0g of white solid with a yield of 96.8%.

The third step reaction is the synthesis of nucleoside compounds. Take a 2500 ml three-necked reaction bottle, install a constant pressure dropping funnel and a nitrogen protection device, add 39.2 g of intermediate compound III, 1000 ml of chlorobenzene, and 43.1 g of N-benzoylcytosine to the system, and under nitrogen protection, cool the system to below 10°C in an ice bath, slowly drop 78.15 g of tin tetrachloride, and after the addition is complete, keep the reaction warm for 1 hour, then slowly heat the reaction system to 80°C, keep the pressure at 2-3 bar, and continue the reaction for 10 hours. After the reaction is completed, cool the reaction system to room temperature, cool to -5° in an ice-salt bath, add 500 ml of saturated sodium bicarbonate solution, stir for 30 minutes, extract twice with 400 ml of ethyl acetate, wash once with water, dry over anhydrous sodium sulfate, filter, and recover the solvent from the filtrate under reduced pressure to obtain a yellow solid, which is recrystallized from ethanol to obtain 52.94 g of a white solid with a yield of 92.3%.

In the fourth step, the product is further purified, and the isomer compound V' contained in the compound V obtained in the first step is separated to obtain 12.5g of isomer compound V' with a yield of 21.8%. 5.74g of isomer compound V' was dissolved in 100ml of nitromethane, the temperature was maintained at -5 to 0°C, 0.01mol of boron trifluoride ether was slowly added dropwise, and the reaction was maintained at 0°C for 0.5 to 1h. After the reaction was completed, sodium acetate was added to neutralize the solution to make it acidic to neutral, and the solvent and ether were recovered by evaporation. The residual solid was dissolved in 100ml of dichloromethane, washed with water 2-3 times, and the organic phases were combined, dried with anhydrous magnesium sulfate, and concentrated to obtain 5.53g of compound II. The yield was 96.3%, the purity was 99.9%, and it was combined into the original product compound V solution, crystallized and purified to obtain the target product, a total of 48.30g of compound V, and a total yield of 84.2%.

Example 2

The first step is reduction reaction. First, add 18.6g (0.05mol) of compound I to 500ml of dichloromethane, pass argon gas for protection, slowly add 0.075mol of lithium tri-sec-butyl borohydride/n-hexane solution at -78°C, control the reaction temperature and react for 2h. After the reaction is completed, add 100ml of methanol to the reactant. Stir for 0.5h and concentrate. First add dilute hydrochloric acid to neutralize, then add 400ml of ethyl acetate and 250ml of water, separate the liquids, dry the organic layer with anhydrous magnesium sulfate, and concentrate to obtain 17.4g of compound II with a yield of 93.0%.

Example 3

The first step is reduction reaction. First, add 18.6g (0.05mol) of compound I to 500ml of dichloromethane, pass argon gas to protect, slowly add 0.075mol of lithium tri-tert-butoxyaluminum hydride/n-hexane solution at -78°C, control the reaction temperature and react for 2h, add 100ml of methanol to the reactant. Stir for 0.5h and concentrate. First add dilute hydrochloric acid to neutralize, then add 400ml of ethyl acetate and 250ml of water, separate the liquids, dry the organic layer with anhydrous magnesium sulfate, and concentrate to obtain 17.24g of compound II, with a yield of 92.1%.

Example 4

The second step is chlorination reaction. Combine the products of the first and second steps, take a 500ml reaction bottle, add 37.4g of intermediate compound II, add 0.5g of catalytic tetrabutylammonium bromide, control the temperature below 0℃, add 150ml of thionyl chloride, react at 40℃ for 4-5h, after the reaction is completed, cool the reaction solution to 0℃, slowly add water, control the temperature not to exceed 15℃, and heat to room temperature and stir for 1 hour after adding. Let stand and separate, wash the organic phase with 15% citric acid solution and then with 6.5% KOH solution, dry with anhydrous sodium sulfate, filter, and recover the solvent in the filtrate under reduced pressure to obtain a white solid. Recrystallize methyl tert-butyl ether to obtain 35.4g of white solid with a yield of 90.3%.

Example 5

The third step is the reaction of synthesizing nucleoside compounds. Take a 2500 ml three-necked reaction bottle, install a constant pressure dropping funnel and a nitrogen protection device, add 39.2 g of intermediate compound III, 1000 ml of chlorobenzene, and 43.1 g of N-benzoylcytosine to the system. Under nitrogen protection, the system is cooled to below 10°C in an ice bath, and 78.15 g of tin tetrachloride is slowly added dropwise. After the addition is completed, the reaction is kept warm for 1 hour, and then the reaction system is slowly heated to 70°C, the pressure is maintained at 2-3 bar, and the reaction is continued for 10 hours. After the reaction is completed, the reaction system is cooled to room temperature, cooled to -5° in an ice-salt bath, 500 ml of saturated sodium bicarbonate solution is added, stirred for 30 minutes, extracted twice with 400 ml of ethyl acetate, washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is decompressed to recover the solvent to obtain a yellow solid, which is recrystallized from ethanol to obtain 51.22 g of a white solid with a yield of 89.3%.

Example 6

The third step is the reaction of synthesizing nucleoside compounds. Take a 2500 ml three-necked reaction bottle, install a constant pressure dropping funnel and a nitrogen protection device, add 39.2 g of intermediate compound III, 1000 ml of chlorobenzene, and 43.1 g of N-benzoylcytosine to the system. Under nitrogen protection, the system is cooled to below 10°C in an ice bath, and 78.15 g of tin tetrachloride is slowly added dropwise. After the addition is completed, the reaction is kept warm for 1 hour, and then the reaction system is slowly heated to 90°C, the pressure is maintained at 2-3 bar, and the reaction is continued for 10 hours. After the reaction is completed, the reaction system is cooled to room temperature, cooled to -5° in an ice-salt bath, 500 ml of saturated sodium bicarbonate solution is added, stirred for 30 minutes, extracted twice with 400 ml of ethyl acetate, washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is decompressed to recover the solvent to obtain a yellow solid, which is recrystallized from ethanol to obtain 52.54 g of a white solid with a yield of 91.6%.

Example 7

The third step reaction, the third step reaction, the synthesis of nucleoside compound reaction, take a 2500 ml three-necked reaction bottle, install a constant pressure dropping funnel, a nitrogen protection device, add 39.2 grams of intermediate compound III, 1000 ml of chlorobenzene, 43.1 grams of N-benzoylcytosine to the system, under nitrogen protection, the system is ice-cooled to below 10°C, 78.15 g of tin tetrachloride is slowly added dropwise, after the addition is complete, the reaction is kept warm for 1 hour, then the reaction system is slowly heated to 80°C, the pressure is maintained at 2-3 bar, and the reaction is continued for 20 hours. After the reaction is completed, the reaction system is cooled to room temperature, cooled to -5° under an ice-salt bath, 500 ml of saturated sodium bicarbonate solution is added, stirred for 30 minutes, extracted twice with 400 ml of ethyl acetate, washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is decompressed to recover the solvent to obtain a yellow solid, which is recrystallized from ethanol to obtain 53.23 g of a white solid with a yield of 92.8%.

Example 8

The third step is the reaction of synthesizing nucleoside compounds. Take a 2500 ml three-necked reaction bottle, install a constant pressure dropping funnel and a nitrogen protection device, add 39.2 g of intermediate compound III, 1000 ml of chlorobenzene, and 43.1 g of N-benzoylcytosine to the system, and under nitrogen protection, cool the system to below 10°C in an ice bath, slowly drop 104.2 g of tin tetrachloride, and after the addition is complete, keep the reaction warm for 1 hour, then slowly heat the reaction system to 80°C, keep the pressure at 2-3 bar, and continue the reaction for 10 hours. After the reaction is completed, the reaction system is cooled to room temperature, cooled to -5° in an ice-salt bath, and 500 ml of saturated sodium bicarbonate solution is added. Stir for 30 minutes, extract twice with 400 ml of ethyl acetate, wash once with water, dry over anhydrous sodium sulfate, filter, and recover the solvent from the filtrate under reduced pressure to obtain a yellow solid, which is recrystallized from ethanol to obtain 53.57 g of a white solid with a yield of 93.4%.

Example 9

The fourth step is to dissolve 5.74 g of isomer compound V' in 100 ml of nitromethane, maintain the temperature at -5 to 0°C, slowly drop 0.01 mol of boron trifluoride etherate, and react at -5°C for 0.5 to 1 h. After the reaction is completed, sodium acetate is added to neutralize the solution to make it acidic to neutral, evaporate and recover the solvent and ether, add 100 ml of dichloromethane to dissolve the residual solid, wash with water 2-3 times, combine the organic phases, dry with anhydrous magnesium sulfate, and concentrate to obtain 5.53 g of compound II. The yield is 96.3% and the purity is 99.9%. It is combined into the original product compound V solution, crystallized and purified to obtain the target product, a total of 47.20 g of compound V, and a total yield of 82.3%.

Comparative Document (CN104478976A) Example

Example 1

Preparation of (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine-3',5'-dibenzoate At -25 to -15°C, under nitrogen protection, 100 g of red aluminum (70% content) was dripped into a mixture of 35 g of toluene and 35 g of trifluoroethanol, and the mixture was heated to room temperature and stirred for 1 hour for standby use. At -20 to -15°C, under nitrogen protection, 74.4 g (0.2 mol) of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribose-γ-lactone (Compound III) and 150 g of toluene were added to a reaction bottle, and 148 g of the modified red aluminum solution in the previous step was slowly dripped into the reaction bottle, and the mixture was dripped in about 3 hours. After the dripping was completed, the mixture was kept warm for 30 minutes. The raw material point disappeared after TLC tracking, and a toluene solution of Compound IV was obtained. Add 2.9 g (0.04 mol) of N,N-dimethylformamide (DMF) to the reaction solution at -20 to -15°C, slowly add 83.3 g (0.7 mol) of thionyl chloride, and after the addition is complete, naturally raise the temperature to 20 to 25°C for chlorination reaction. TLC tracks the disappearance of compound IV, remove the generated sulfur dioxide and hydrogen chloride under reduced pressure, and then evaporate to dry toluene under reduced pressure below 50°C. Add 250 g of toluene to the remaining material, stir and disperse, and separate the organic layer. Evaporate the organic layer under reduced pressure to obtain the chlorinated product. Add 300 g of dichloromethane to dissolve, and obtain a solution of the chlorinated product (compound V). In an autoclave, 86.1 g of N-benzoyl-O-(trimethylsilyl)cytosine (Compound V) was dissolved in 200 g of dichloromethane, and the above-mentioned chlorinated dichloromethane solution was added. Then, 104 g (0.4 mol) of tin tetrachloride was added, and the reaction was carried out at 75-80°C for about 20 hours until the chlorinated product basically disappeared. The reaction solution was cooled to room temperature and was left for disposal. In the reaction bottle, 160 g of acetic acid + 12 g of water were added, and the temperature was controlled at 20-25°C. The condensation material in the previous step was dripped into the acid water, stirred for 1 hour, and filtered. The filtrate was added to a solution of 400 g acetic acid + 380 g water, stirred at 30°C for 30 minutes, separated into layers, washed 3 times with a solution of 120 g acetic acid + 135 g water, washed 2 times with water, decolorized with activated carbon, filtered, 800 g methanol was added to the filtrate, dichloromethane was recovered to an internal temperature of 52°C, cooled to 20°C, stirred for 3 hours, and overnight, to obtain 68.5 g of the product, with a yield of 60.0%. HPLC purity: 99.2%, diastereoisomer: 0.11%. Melting point: 239.5～240.6℃, hydrogen spectrum (1H-NMR) (CDCl3, 500MHz): 1.48 (d, 3H), 4.62 (dd, 1H), 4.72 (d, 1H), 4.88 (d, 1H), 5.56 (br dd, 1H), 6.51 (br d, 1H), 7.46-7.56 (m, 7H), 7.61-7.70 (m, 3H), 7.88 (m, 2H), 8.06-8.10 (m, 5H), 8.70 (s, 1H), mass spectrum (ESI-MS): 572 (M+1), elemental analysis (C31H26FN3O7, %) (measured value/calculated value): C 65.14/65.02, H 4.59/4.66, N 7.35/7.22.

Comparative Document (CN109422789 A) Example

Example 2

Add RED-AL (red aluminum) solution 100g (0.36mol, 1.3eq) and toluene (200ml) to the reaction bottle, stir and cool to -15℃, slowly add trifluoroethanol (32.6g), control the temperature below -10℃, and warm to room temperature to obtain the improved RED-AL solution for use. Add ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxomethyltetrahydrofuran-2-yl)methyl benzoate 100g (0.269mol, 1.0eq) and dichloromethane 750ml to another reaction bottle, stir and cool to -15℃, slowly add the above improved RED-AL solution dropwise, control the temperature below -10℃. After the reduction is completed, add a catalytic amount of tetrabutylammonium bromide (1g), then add chlorosulfonic acid 118.6g (0.879mol, 3.3eq), and control the temperature below 0℃. After the addition, the reaction solution was heated to 40°C, stirred for 4-5 hours, and then cooled to 0°C. Water was slowly added, and the temperature was controlled not to exceed 15°C. After the addition, the temperature was raised to room temperature and stirred for 1 hour. The liquid was separated by standing, and the organic phase was washed with 15% citric acid solution and then with 6.5% KOH solution. After the organic phase was concentrated under reduced pressure, 500ml of chlorobenzene was added to prepare a chlorobenzene solution of ((2R, 3R, 4R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl benzoate for use. 88.5g (0.41mol, 1.5eq) of N-benzoylcytosine, 0.7g of ammonium sulfate, 66g (0.41mol, 1.5eq) of hexamethyldisilazane and 500ml of chlorobenzene were added to a 1L reaction bottle, and stirred and heated to reflux (about 135°C) until the solution was clear. After concentrating to dryness under reduced pressure, add the above-mentioned chlorobenzene solution of ((2R,3R,4R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate and 282g (1.08mol, 4.0eq) of tin tetrachloride, and heat to 85°C until the reaction is complete. After the reaction solution cools to room temperature, 100ml of dichloromethane is added to dilute the reaction solution, and the reaction solution is added to a suspension of dichloromethane containing 470g of sodium bicarbonate, and water (840ml) is slowly added (note that there is gas overflow). After stirring for 2 hours, the mixture was filtered, and the filter cake was repeatedly washed with dichloromethane. After the filtrate was concentrated to remove the organic solvent, the mixture was cooled to -5°C and stirred for crystallization for 2 hours. The mixture was filtered, and the solid was washed with isopropanol and dried in vacuo at 70°C to obtain 1-(2-deoxy-2-fluoro-2-methyl-3-5-O-dibenzoyl-β-furanosyl)-N-4-benzoylcytosine, 88 g, with a total yield of 57.3%.

In summary, the total yield of the present invention is between 75% and 80%, which is much higher than the yield obtained by the technical solution provided in the comparative document. The nucleoside conversion rate is high, the atom economy is good, the reaction selectivity is good, less waste is generated, and the pollution is low, which is suitable for industrial production.

It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and range of equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims (10)

1. A synthesis process of a key intermediate of sofosbuvir, characterized in that it comprises the following steps: The first step is to dissolve compound I in a solvent and add a reducing agent to reduce the compound II; The second step is to chlorinate the compound II obtained in the previous step to obtain the chlorinated product compound III; The third step is to react compound III with compound IV under the action of a catalyst to obtain the target key intermediate compound V; The fourth step is to separate the isomer compound ' mixed in compound V, add a conversion reagent to the obtained α-type compound V' to convert compound II' from an α-type compound to a β-type compound V, and combine compound V. 2. The synthesis process of a key intermediate of sofosbuvir according to claim 1, characterized in that the catalyst used in the first step reaction is diisobutylaluminum hydride (DIBAl-H). 3. A synthesis process for a key intermediate of sofosbuvir according to claim 1, characterized in that: the solvent used in the first step reaction is dichloromethane (DMC), and the reaction is reacted at -78 ° C for 2h. 4. A synthesis process for a key intermediate of sofosbuvir according to claim 1, characterized in that: in the fourth step reaction, the catalyst used for the configuration conversion reaction is boron trifluoride etherate, and the reaction solvent is nitromethane. 5. A synthesis process for a key intermediate of sofosbuvir according to claim 1, characterized in that: the chlorinating agent used in the second step chlorination reaction is sulfonyl chloride. 6. A synthesis process for a key intermediate of sofosbuvir according to claim 1, characterized in that: the catalyst used in the third step reaction is tin tetrachloride, and the amount of the catalyst is 3 to 4 eq. 7. A synthesis process for a key intermediate of sofosbuvir according to claim 1, characterized in that: the reaction conditions of the third step reaction are 70-90° C. and 2-3 bar pressure for 10-20 hours. 8. A synthesis process for a key intermediate of Sofosbuvir according to claim 1, characterized in that: the solvent used in the third step reaction is chlorobenzene. 9. The synthesis process of a key intermediate of sofosbuvir according to claim 1, characterized in that the reaction temperature of the fourth step isomerization conversion reaction is -5 to 0°C, preferably 0°C. 10. The synthesis process of a key intermediate of sofosbuvir according to claim 1, characterized in that the molar ratio of compound III to compound IV and the catalyst in the third step reaction is 1:1.5:3-4.

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