Synthesis process of a key intermediate of sofosbuvir

Abstract

The present invention discloses a synthetic process for a key intermediate of sofosbuvir, which includes dissolving compound I in a solvent, adding a reducing agent for reduction to obtain compound II; chlorinating the obtained compound II in the previous step to obtain a chlorinated product, compound III; reacting compound III with compound IV under the action of a catalyst to obtain the target key intermediate compound V, separating out the isomeric compound V', converting the α-type compound V' into the β-type compound V, and combining compound V. The beneficial effects of the present invention are as follows: The use of DIBAL-H catalyst reduces the generation of by-products in the reduction reaction, improves the reaction yield, increases the atom economy, and then through configuration transformation, converts the isomeric products into the required intermediates, increases the yield of the final sofosbuvir product, improves the atomic utilization efficiency of the reaction, effectively increases the conversion rate of nucleosides, and the process has simple operation, which is beneficial to improving the yield of industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates, and particularly to a synthesis process of a key intermediate of sofosbuvir. Background Art

[0002] Sofosbuvir (also translated as sofosbuvir, English name Sofosbuvir, trade name Sovaldi, alias GS-7977, PSI-7977) is a new drug developed by Gilead Sciences 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 to combine with interferon. Clinical trials have confirmed that for hepatitis C genotypes 1 and 4, the overall sustained virological response rate (SVR) of this drug combined with peginterferon and ribavirin is as high as 90%; for hepatitis C genotype 2, the SVR of this drug combined with ribavirin is 89%-95%; for hepatitis C genotype 3, the SVR of this drug combined with ribavirin is 61%-63%. This drug was approved by the US Food and Drug Administration for listing in the United States in December 2013 and by the European Medicines Agency for listing in EU countries in January 2014. Sofosbuvir is a new action target and a new action mechanism, and it is the world's first NS5B polymerase inhibitor for the treatment of hepatitis C. Currently, there is no drug with the same action mechanism on the market. At the same time, it is also the first drug that can safely and effectively treat certain genotypes of hepatitis C without the need to combine with interferon.

[0003] 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:

[0004]

[0005] Currently, there have been multiple patents and literatures reporting the chemical synthesis of sofosbuvir and its intermediates. The synthetic routes used in industrial production are the routes reported in patents US20130324709, WO2013045419, WO2010135569, WO2013178571, and literatures J. Org. Chem. 2009, 74, 6819 - 6824, J. Med. Chem. 2010, 53, 7202 - 7218, etc. The common feature of these reports is that starting from compound I, namely 3,5 - dibenzoyl - 2 - deoxy - 2 - fluoro - 2 - methyl - D - ribonic acid - γ - lactone (Compound Ⅰ), the key intermediate (2'R)-N - benzoyl - 2'-deoxy - 2'-fluoro - 2'-methylcytidine 3',5'-dibenzoate (Compound Ⅴ) is synthesized through a reduction reaction and subsequent reactions. The chemical structure of Compound Ⅵ is as follows:

[0006]

[0007] Compound Ⅴ is hydrolyzed and deprotected to obtain Compound Ⅵ (2'R)-2'-deoxy - 2'-fluoro - 2'-C - methyluridine, which then reacts with a phosphate side chain (Compound Ⅶ) to obtain sofosbuvir (Compound Ⅷ). The overall reaction equation for the preparation of sofosbuvir is as follows:

[0008]

[0009] When industrially preparing sofosbuvir, starting from the nucleoside compound (Compound Ⅰ), in the first step, the reduction reaction is usually carried out by reducing Compound Ⅰ with the reducing agent Red - Al. Due to the strong reducing ability of Red - Al, the intermediate I will be further reduced to obtain by - products, reducing the product yield and the product being more complex. The post - treatment is relatively complicated, increasing the process cost. The current reaction equation is as follows:

[0010]

[0011] Patent CN107245064 reported a method of using borohydride to replace Red - Al for reduction. However, when using borohydride for reduction, the by - product content is as high as 47%. Although this patent gives a method for recovering the by - product, the by - product is oxidized in the presence of a catalyst to obtain the reaction substrate, and then reduced according to the same reaction to obtain a mixture of the product and the by - product. The recovery process is complex and increases the difficulty of product purification, which is not conducive to industrial production applications. Patent CN105906673 publicly reported a method of using lithium aluminum hydride (LiAlH4) as a reducing agent. Using modified lithium aluminum hydride instead of modified Red - Al has made great improvements in the dosage of the reducing agent and operation safety, but the yield has decreased significantly.

[0012] In addition, due to the issue of stereoselectivity, the obtained hemiacetal (Compound II) is chlorinated with sulfonyl chloride to obtain Compound III as the chlorinated product. Under the action of a Lewis acid, it reacts with TMS-protected N-Bz cytosine to obtain glycosylation products with α-configuration and β-configuration (β / α ≈ 3.5 - 4 / 1). After separating and purifying the glycosylation product with β-configuration, since the α-configuration is not the desired product, for the existing treatment methods of this isomeric impurity, one is to directly treat it as solid waste, the second is to recover part of Compound IV by alkaline hydrolysis. This results in a low overall yield, high cost, and high three wastes of Compound V, leading to a further reduction in the yield. The reaction equation is as follows:

[0013] After separating and purifying the desired glycosylation product with β-configuration, the β-configuration product is treated with AcOH / MeOH to obtain the intermediate 2-deoxy-2-fluoro-2-methylcytidine (Compound VI). Finally, the hydroxymethyl group of 2-deoxy-2-fluoro-2-methylcytidine and the chiral phosphonate fragment are condensed, and the product is recrystallized to complete the preparation of sofosbuvir.

[0014] Obviously, starting from the starting material Compound I, through reduction and chlorination, the chlorinated product reacts with TMS-protected N-Bz cytosine under the action of a Lewis acid to obtain glycosylation products with α-configuration and β-configuration (Compound V). The influencing factors for the yield of the β-type glycoside lie in the yield of the hemiacetal obtained by reducing Compound I and the stereoselectivity of the α and β configurations.

[0015] The present invention aims to provide a new synthesis process for the key intermediate (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine of sofosbuvir. By using a suitable reducing agent, while increasing the reduction yield of the lactone compound I, converting the α-configuration compound V' into the β-configuration compound V during the reaction transformation process, thereby increasing the total yield of the β-configuration product, so as to ultimately increase the yield of the glycosylation product with β-configuration. At the same time, reduce the generation of by-products, and finally increase the conversion rate of the key intermediate (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate of sofosbuvir, thereby increasing the total yield of sofosbuvir and improving the atom economy of the reaction. The reaction equation is as follows:

[0016] Summary of the Invention

[0017] Aiming at the problems in the current industrial synthesis of the key intermediate compound (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine of sofosbuvir, such as easy over-reduction during lactone reduction and poor overall reaction stereoselectivity, resulting in more by-products and reduced yield, the present invention adopts the following technical solutions:

[0018] A synthetic process for a key intermediate of sofosbuvir, comprising the following steps,

[0019] In the first step, dissolve compound I in a solvent, add a reducing agent for reduction to obtain compound II;

[0020] In the second step, chlorinate the obtained compound II in the previous step to obtain a chlorinated product, compound III;

[0021] In the third step, react compound III with compound IV under the action of a catalyst to obtain the target key intermediate compound V;

[0022] In the fourth step, separate the isomeric compound V' mixed in compound V, add a conversion reagent to the obtained α-type compound V' to convert compound V' from the α-type compound to the β-type compound V, and combine compound V.

[0023] 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).

[0024] 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 h, preferably at -78 °C for 2 h.

[0025] Furthermore, for the fourth step reaction, the catalyst for the configuration conversion reaction is boron trifluoride diethyl ether, and the reaction solvent is nitromethane.

[0026] Furthermore, the chlorinating agent used in the second step chlorination reaction is usually selected from sulfonyl chloride, thionyl chloride, or phosphorus oxychloride, preferably sulfonyl chloride.

[0027] Furthermore, the catalyst used in the third step reaction is tin tetrachloride, and the catalyst dosage is 3 to 4 eq.

[0028] Furthermore, the reaction conditions for the third step reaction are 70 to 90 °C and a reaction pressure of 2 to 3 bar for 10 to 20 h.

[0029] Furthermore, the solvent used in the third step reaction is chlorobenzene.

[0030] Furthermore, the reaction temperature for the fourth step isomerization conversion reaction is -5 to 0 °C, preferably 0 °C.

[0031] Furthermore, the molar ratio of compound III, compound IV, and the catalyst in the third step reaction is 1:1.5:3 to 4.

[0032] The beneficial effects of the present invention are as follows: 1. By using DIBAL-H catalyst, the generation of by-products in the reduction reaction is reduced, the reaction yield is increased, and the atom economy is enhanced. 2. Through configuration conversion, the isomeric products are converted into the required intermediates, the generation of waste is reduced, the yield of the final sofosbuvir product is increased, the atom utilization efficiency of the reaction is improved, the conversion rate of nucleosides is effectively increased, the operation is simple and conducive to improving the yield of industrial production, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a schematic diagram of the chemical structural formula of sofosbuvir;

[0034] Figure 2 It is a schematic diagram of the chemical structure of the key intermediate synthesized in the present invention;

[0035] Figure 3 It is a schematic diagram of the reaction equation for synthesizing sofosbuvir;

[0036] Figure 4 It is a schematic diagram of the reaction equation for the reduction reaction of Compound I;

[0037] Figure 5 It is a schematic diagram of the reaction equation for synthesizing intermediate Compound V;

[0038] Figure 6 It is a schematic diagram of the reaction flow equation of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0039] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention and the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0040] Example 1

[0041] In the first step, the reduction reaction: First, 18.6 g (0.05 mol) of Compound I was added to 500 ml of dichloromethane, and argon was introduced for protection. Then, 0.075 mol of diisobutylaluminum hydride / n-hexane solution was slowly added at -78 °C, and the reaction temperature was controlled for 2 h. After the reaction was completed, 100 ml of methanol was added to the reactants. Stir for 0.5 h, concentrate, first add dilute hydrochloric acid to make it neutral, then add 400 ml of ethyl acetate and 250 ml of water, separate the layers, and the organic layer was dried with anhydrous magnesium sulfate and concentrated to obtain 18.4 g of Compound II with a yield of 98.3%.

[0042] Step 2: Chlorination reaction. Take a 500 ml reaction flask, add 37.4 g of intermediate compound II, add 0.4 g of catalytic amount of tetrabutylammonium bromide, control the temperature below 0 °C, add 150 ml of sulfonyl chloride, react at 40 °C for 4 - 5 h. After the reaction is completed, cool the reaction solution to 0 °C, slowly add water, control the temperature not exceeding 15 °C, and after adding, raise the temperature to room temperature and stir for 1 hour. Let it stand for liquid separation. The organic phase is washed with 15% citric acid solution and then with 6.5% KOH solution, dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate is recovered under reduced pressure to obtain a white solid. Recrystallize with methyl tert-butyl ether to obtain 38.0 g of white solid, with a yield of 96.8%.

[0043] Step 3: Reaction for synthesizing nucleoside compound. Take a 2500 ml three-necked reaction flask, equip it with 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-benzoyl cytosine to the system. Under nitrogen protection, cool the system to below 10 °C in an ice bath, slowly add 78.15 g of stannic chloride, and after the addition is complete, keep the reaction at the same temperature for 1 h. Then, slowly raise the temperature of the reaction system to 80 °C, keep the pressure at 2 - 3 bar, and continue the reaction for 10 h. After the reaction is completed, cool the reaction system to room temperature, then cool it to -5 °C 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 in the filtrate under reduced pressure to obtain a yellow solid. Recrystallize with ethanol to obtain 52.94 g of white solid, with a yield of 92.3%.

[0044] Step 4: Further purification of the product. Separate the isomeric compound V' contained in the compound V obtained in the first step to obtain 12.5 g of isomeric compound V' with a yield of 21.8%. Dissolve 5.74 g of isomeric compound V' in 100 ml of nitromethane, keep the temperature at -5 - 0 °C, slowly add 0.01 mol of boron trifluoride diethyl etherate, and react for 0.5 - 1 h under the condition of 0 °C. After the reaction is completed, add sodium acetate to neutralize the acidity of the solution to neutral, evaporate to recover the solvent and diethyl ether, dissolve the residual solid in 100 ml of dichloromethane, wash 2 - 3 times with water, combine the organic phases, dry over anhydrous magnesium sulfate, and concentrate to obtain 5.53 g of compound V, with a yield of 96.3% and a purity of 99.9%. Combine it with the original compound V solution, and purify by crystallization to obtain the target product, 48.30 g of compound V in total, with an overall yield of 84.2%.

[0045] Example 2

[0046] Step 1: Reduction reaction. First, add 18.6 g (0.05 mol) of Compound I to 500 ml of dichloromethane. Protect the reaction by introducing argon gas. Slowly add 0.075 mol of lithium tri-sec-butylborohydride / n-hexane solution at -78 °C. Control the reaction temperature and react for 2 h. After the reaction is completed, add 100 ml of methanol to the reactants. Stir for 0.5 h and concentrate. First, adjust the pH to neutral with dilute hydrochloric acid, then add 400 ml of ethyl acetate and 250 ml of water. Separate the layers. Dry the organic layer with anhydrous magnesium sulfate and concentrate to obtain 17.4 g of Compound II with a yield of 93.0%.

[0047] Example 3

[0048] Step 1: Reduction reaction. First, add 18.6 g (0.05 mol) of Compound I to 500 ml of dichloromethane. Protect the reaction by introducing argon gas. Slowly add 0.075 mol of lithium tri-tert-butoxyaluminum hydride / n-hexane solution at -78 °C. Control the reaction temperature and react for 2 h. Add 100 ml of methanol to the reactants. Stir for 0.5 h and concentrate. First, adjust the pH to neutral with dilute hydrochloric acid, then add 400 ml of ethyl acetate and 250 ml of water. Separate the layers. Dry the organic layer with anhydrous magnesium sulfate and concentrate to obtain 17.24 g of Compound II with a yield of 92.1%.

[0049] Example 4

[0050] Step 2: Chlorination reaction. Combine the products of Step 1 and Step 2. Take a 500 ml reaction flask, add 37.4 g of intermediate Compound II, add 0.5 g of catalytic amount of tetrabutylammonium bromide. Control the temperature below 0 °C and add 150 ml of thionyl chloride. React at 40 °C for 4 - 5 h. After the reaction is completed, cool the reaction solution to 0 °C and slowly add water, controlling the temperature not to exceed 15 °C. After adding, raise the temperature to room temperature and stir for 1 h. Let it stand and separate the layers. Wash the organic phase with 15% citric acid solution and then with 6.5% KOH solution. Dry with anhydrous sodium sulfate, filter. Recover the solvent under reduced pressure from the filtrate to obtain a white solid. Recrystallize with methyl tert-butyl ether to obtain 35.4 g of white solid with a yield of 90.3%.

[0051] Example 5

[0052] The third-step reaction, the reaction for synthesizing a nucleoside compound. Take a 2500-milliliter three-necked reaction flask, equip it with a constant-pressure dropping funnel and a nitrogen protection device. Add 39.2 grams of intermediate compound III, 1000 milliliters of chlorobenzene, and 43.1 grams of N-benzoyl cytosine to the system. Under nitrogen protection, cool the system in an ice bath to below 10 °C, slowly add dropwise 78.15 g of tin tetrachloride. After the addition is complete, keep the reaction at a constant temperature for 1 h. Then, slowly raise the temperature of the reaction system to 70 °C, maintain the pressure at 2 - 3 bar, and continue the reaction for 10 h. After the reaction is completed, cool the reaction system to room temperature, then cool it to -5 °C in an ice-salt bath. Add 500 milliliters of a saturated sodium bicarbonate solution, stir for 30 minutes, extract twice with 400 milliliters of ethyl acetate, wash once with water, dry with anhydrous sodium sulfate, filter, and recover the solvent under reduced pressure from the filtrate to obtain a yellow solid. Recrystallize with ethanol to obtain 51.22 g of a white solid, with a yield of 89.3%.

[0053] Example 6

[0054] The third-step reaction, the reaction for synthesizing a nucleoside compound. Take a 2500-milliliter three-necked reaction flask, equip it with a constant-pressure dropping funnel and a nitrogen protection device. Add 39.2 grams of intermediate compound III, 1000 milliliters of chlorobenzene, and 43.1 grams of N-benzoyl cytosine to the system. Under nitrogen protection, cool the system in an ice bath to below 10 °C, slowly add dropwise 78.15 g of tin tetrachloride. After the addition is complete, keep the reaction at a constant temperature for 1 h. Then, slowly raise the temperature of the reaction system to 90 °C, maintain the pressure at 2 - 3 bar, and continue the reaction for 10 h. After the reaction is completed, cool the reaction system to room temperature, then cool it to -5 °C in an ice-salt bath. Add 500 milliliters of a saturated sodium bicarbonate solution, stir for 30 minutes, extract twice with 400 milliliters of ethyl acetate, wash once with water, dry with anhydrous sodium sulfate, filter, and recover the solvent under reduced pressure from the filtrate to obtain a yellow solid. Recrystallize with ethanol to obtain 52.54 g of a white solid, with a yield of 91.6%.

[0055] Example 7

[0056] The third-step reaction, the third-step reaction, the reaction for synthesizing a nucleoside compound. Take a 2500-milliliter three-necked reaction flask, equip it with a constant-pressure dropping funnel and a nitrogen protection device. Add 39.2 grams of intermediate compound III, 1000 milliliters of chlorobenzene, and 43.1 grams of N-benzoyl cytosine to the system. Under nitrogen protection, cool the system in an ice bath to below 10 °C, slowly add dropwise 78.15 g of tin tetrachloride. After the addition is complete, keep the reaction at a constant temperature for 1 h. Then, slowly raise the temperature of the reaction system to 80 °C, maintain the pressure at 2 - 3 bar, and continue the reaction for 20 h. After the reaction is completed, cool the reaction system to room temperature, then cool it to -5 °C in an ice-salt bath. Add 500 milliliters of a saturated sodium bicarbonate solution, stir for 30 minutes, extract twice with 400 milliliters of ethyl acetate, wash once with water, dry with anhydrous sodium sulfate, filter, and recover the solvent under reduced pressure from the filtrate to obtain a yellow solid. Recrystallize with ethanol to obtain 53.23 g of a white solid, with a yield of 92.8%.

[0057] Example 8

[0058] For the third-step reaction, the nucleoside compound synthesis reaction, take a 2500 mL three-necked reaction flask, equipped with 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-benzoyl cytosine to the system. Under nitrogen protection, cool the system to below 10 °C in an ice bath, slowly add dropwise 104.2 g of tin tetrachloride. After the addition is complete, keep the reaction at a constant temperature for 1 h, then slowly raise the temperature of the reaction system to 80 °C, maintain the pressure at 2 - 3 bar, and continue the reaction for 10 h. After the reaction is completed, cool the reaction system to room temperature, then cool it to -5 °C 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 with anhydrous sodium sulfate, filter, and recover the solvent under reduced pressure from the filtrate to obtain a yellow solid. Recrystallize with ethanol to obtain 53.57 g of a white solid, with a yield of 93.4%.

[0059] Example 9

[0060] In the fourth step, dissolve 5.74 g of isomer compound V' in 100 mL of nitromethane, keep the temperature at -5 to 0 °C, slowly add dropwise 0.01 mol of boron trifluoride diethyl etherate, and keep the reaction at -5 °C for 0.5 - 1 h. After the reaction is completed, add sodium acetate to neutralize the acidity of the solution to neutrality, evaporate to recover the solvent and diethyl ether. Dissolve the residual solid in 100 mL of dichloromethane, wash 2 - 3 times with water, combine the organic phases, dry with anhydrous magnesium sulfate, and concentrate to obtain 5.53 g of compound V, with a yield of 96.3% and a purity of 99.9%. Combine it into the original solution of compound V, and purify by crystallization to obtain the target product, a total of 47.20 g of compound V, with an overall yield of 82.3%.

[0061] Examples of the Comparative Document (CN104478976A)

[0062] Example 1

[0063] (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine-3',5'-dibenzoate Preparation - At a temperature of -25 to -15 °C, under nitrogen protection, 100 g of Red-Al (70% content) was added dropwise to a mixture of 35 g of toluene and 35 g of trifluoroethanol. After the addition was complete, the temperature was raised to room temperature and stirred for 1 hour for later use. - At a temperature of -20 to -15 °C, under nitrogen protection, 74.4 g (0.2 mol) of 3,5-dibenzooyl-2-deoxy-2-fluoro-2-methyl-D-ribose-γ-lactone (Compound III) and 150 g of toluene were added to the reaction flask. The modified Red-Al solution (148 g) prepared in the previous step was slowly added dropwise, and it took about 3 hours to complete the addition. After the addition was complete, it was kept warm for 30 minutes. When the starting material spot disappeared by TLC tracking, a toluene solution of Compound IV was obtained. - For the reaction solution from the previous step, at a temperature of -20 to -15 °C, 2.9 g (0.04 mol) of N,N-dimethylformamide (DMF) was added, and 83.3 g (0.7 mol) of thionyl chloride was slowly added dropwise. After the addition was complete, the temperature was naturally raised to 20 to 25 °C for the chlorination reaction. When the spot of Compound IV disappeared by TLC tracking, sulfur dioxide and hydrogen chloride generated were removed under reduced pressure, and then toluene was evaporated to dryness under reduced pressure below 50 °C. The remaining material was added with 250 g of toluene, stirred and dispersed, and the organic layer was separated. The organic layer was evaporated to dryness under reduced pressure to obtain the chlorinated product. It was dissolved in 300 g of dichloromethane to 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. The dichloromethane solution of the above chlorinated product was added, and then 104 g (0.4 mol) of tin tetrachloride was added. 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 for further treatment. - In the reaction flask, 160 g of acetic acid + 12 g of water were added, and the temperature was controlled at 20 - 25 °C. The condensation material from the previous step was added dropwise to the acid water and stirred for 1 hour, then filtered. The filtrate was added to a solution of 400 g of acetic acid + 380 g of water, stirred at 30 °C for 30 minutes, and then separated into layers. It was washed 3 times with a solution of 120 g of acetic acid + 135 g of water and washed 2 times with water, decolorized with activated carbon, filtered, 800 g of methanol was added to the filtrate, dichloromethane was recovered until the internal temperature reached 52 °C, cooled to 20 °C and stirred for 3 hours, and left overnight to obtain 68.5 g of the product. Yield: 60.0%. HPLC purity: 99.2%, diastereoisomers: 0.11%.Melting point: 239.5 - 240.6 °C, 1H-NMR (CDCl3, 500 MHz): 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), ESI-MS: 572 (M+1), Elemental analysis (C31H26FN3O7, %)(found / calculated): C 65.14 / 65.02, H 4.59 / 4.66, N 7.35 / 7.22.

[0064] Examples of Comparative Document (CN109422789 A)

[0065] Example 2

[0066] Add 100 g (0.36 mol, 1.3 eq) of RED-AL solution and 200 ml of toluene to a reaction flask. Cool the mixture to -15 °C with stirring, and slowly add trifluoroethanol (32.6 g), controlling the temperature below -10 °C. After warming to room temperature, the modified RED-AL solution is obtained and reserved for use. Add 100 g (0.269 mol, 1.0 eq) of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxomethyltetrahydrofuran-2-yl)methyl benzoate and 750 ml of dichloromethane to another reaction flask. Cool the mixture to -15 °C with stirring, and slowly dropwise add the above-mentioned modified RED-AL solution, controlling the temperature below -10 °C. After the reduction is completed, add a catalytic amount of tetrabutylammonium bromide (1 g), and then add 118.6 g (0.879 mol, 3.3 eq) of chlorosulfonic acid, controlling the temperature below 0 °C. After the addition is complete, warm the reaction solution to 40 °C and stir for 4 - 5 hours. Then cool the reaction solution to 0 °C, slowly add water, controlling the temperature not exceeding 15 °C. After the addition is complete, warm to room temperature and stir for 1 hour. Let it stand for liquid separation. The organic phase is washed with 15% citric acid solution and then with 6.5% KOH solution. The organic phase is concentrated under reduced pressure and then 500 ml of chlorobenzene is added to prepare a chlorobenzene solution of ((2R,3R,4R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate for use. Add 88.5 g (0.41 mol, 1.5 eq) of N-benzoyl cytosine, 0.7 g of ammonium sulfate, 66 g (0.41 mol, 1.5 eq) of hexamethyldisilazane and 500 ml of chlorobenzene to a 1 L reaction flask. Stir and heat to reflux (about 135 °C) until the solution becomes clear. Concentrate to dryness under reduced pressure, then add the above-mentioned chlorobenzene solution of ((2R,3R,4R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate and 282 g (1.08 mol, 4.0 eq) of tin tetrachloride, and heat to 85 °C until the reaction is complete. After the reaction solution cools to room temperature, add 100 ml of dichloromethane to dilute the reaction solution, and add the reaction solution to a suspension of dichloromethane containing 470 g of sodium bicarbonate. Slowly add water (840 ml) (note that gas overflows). Stir for 2 hours, then filter. The filter cake is repeatedly washed by slurrying with dichloromethane. After the filtrate is concentrated to remove the organic solvent, cool to -5 °C and stir for crystallization for 2 hours. Filter, wash the solid with isopropanol, and dry in vacuo at 70 °C to obtain 1-(2-deoxy-2-fluoro-2-methyl-3-5-O-dibenzoyl-β-ribofuranosyl)-N-4-benzoyl cytosine, 88 g, with an overall yield of 57.3%.

[0067] In summary, the overall 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 relatively high, the atom economy is good, the reaction selectivity is good, the amount of waste generated is small, and the pollution is low, making it suitable for industrial production.

[0068] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and without departing from the spirit or basic characteristics of the present invention, the present invention can be implemented in other specific forms. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the present invention. Any reference signs in the claims should not be construed as limiting the claimed invention.

[0069] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment only contains an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A synthetic process for a key intermediate of sofosbuvir, characterized in that it comprises the following steps: In the first step, compound I is dissolved in a solvent, and a reducing agent is added for reduction to obtain compound II; In the second step, the compound II obtained in the previous step is chlorinated to obtain a chlorinated product, compound III; In the third step, compound III reacts with compound IV under the action of a catalyst to obtain the target key intermediate compound V; In the fourth step, the isomer compound V' mixed in compound V is separated out, and a conversion reagent is added to the obtained α-form compound V' to convert compound V' from the α-form compound to the β-form compound V, and compound V is combined; The catalyst used in the first step reaction is diisobutylaluminum hydride DIBAl-H; The solvent used in the first step reaction is dichloromethane DCM, and the reaction is carried out at -78°C for 2 h; For the fourth step reaction, the catalyst for the configuration conversion reaction is boron trifluoride diethyl ether, and the reaction solvent is nitromethane; The chlorinating agent used in the second step chlorination reaction is sulfonyl chloride; The catalyst used in the third step reaction is tin tetrachloride, and the dosage of the catalyst is 3 - 4 eq; The reaction conditions for the third step reaction are 70 - 90°C and a pressure of 2 - 3 bar for 10 - 20 h; The solvent used in the third step reaction is chlorobenzene; The reaction temperature for the fourth step isomerization conversion reaction is -5 - 0°C; In the third step reaction, the molar ratio of compound III to compound IV and the catalyst is 1:1.5:3 - 4.

Images