CN106608864B - Preparation method of sofosbuvir intermediate - Google Patents

Abstract

其中，所述亲核氟取代反应选用的氟取代试剂选自HF/Pyridine、Bu₄NH₂F₃、Et₃N.3HF、Me₃N.2HF、SiF₄、DAST等亲核试剂，较优为HF/Pyridine。本发明的索非布韦中间体6的新制备方法，通过对反应条件的优化及选择，产物收率以及纯度都较现有文献报道有大幅度提高，反应条件温且后处理简单，降低了成本，工艺稳定，适合工业化生产。The invention provides a preparation method of sofosbuvir intermediate 6: compound 1 is obtained by nucleophilic fluorine substitution reaction in an aprotic solvent at an appropriate temperature; the reaction formula is as follows:

Wherein, the fluorine substitution reagent selected for the nucleophilic fluorine substitution reaction is selected from nucleophiles such as HF/Pyridine, Bu ₄ NH ₂ F ₃ , Et ₃ N.3HF, Me ₃ N.2HF, SiF ₄ , DAST and the like, preferably For HF/Pyridine. The new preparation method of the sofosbuvir intermediate 6 of the present invention, through the optimization and selection of the reaction conditions, the product yield and purity are greatly improved compared with the existing literature reports, the reaction conditions are mild and the post-processing is simple, reducing the Cost, stable process, suitable for industrial production.

Description

The preparation method of sofosbuvir intermediate

technical field

The invention belongs to the field of chemical drug synthesis, and in particular relates to a preparation process of a new-generation anti-hepatitis C drug sofosbuvir intermediate 6.

Background technique

Sofosbuvir is the world's first oral anti-hepatitis C drug developed by Gilead Sciences. Sofosbuvir acts on the NS5B polymerase site, a nucleotide analog of viral RNA replication, to terminate HCV replication and is a novel HCV polymerase inhibitor. The US FDA approved its listing on December 6, 2013, with the trade name Sovaldi ^TM , which is clinically used for the treatment of HCV infection and HCV/HIV-1 co-infection. On January 16, 2014, the drug was approved by the European Medicines Agency (EMEA) for marketing in EU countries. The molecular formula of sofosbuvir is C22H29FN3O9P, CAS registration number: 1190307-88-0 The structural formula is as follows:

Sofosbuvir is safe and effective in the treatment of multiple types (HCV types 1, 2, 3, and 4) of hepatitis C; clinical trials have confirmed that for hepatitis C types 1 and 4, the drug combined with peginterferon and ribavirin has an overall Sustained virological response rate (SVR) is as high as 90%; for hepatitis C, the SVR of the drug combined with ribavirin is 89%-95%; for hepatitis C, the SVR of the drug combined with ribavirin is 61% -63%.

Intermediate 6, chemical name (2R,3R)-2-methyl-3-hydroxy-2-fluoro-3-((R)-2,2-dimethyl-1,3-dioxolane- 4-yl) ethyl propionate is an important intermediate in the synthesis of sofosbuvir.

Intermediate 6 obtains sofosbuvir through the following route, and 6 is hydrolyzed in ethanol with hydrochloric acid and lactonized to generate (2R)-3,5-dihydroxy-2-deoxy-2-C-methyl-2-fluoro-D- Ribo-γ-lactone (11), 11 is protected by hydroxyl of benzoyl chloride (BzCl) to give (2R)-3,5-di-O-benzoyl-2-deoxy-2-C-methyl-2 -Fluoro-D-ribono-gamma-lactone (12). 12 was reduced by lithium tri-tert-butoxyaluminum hydride (Li(O-tBu) ₃ AlH) to give (2R)-2-deoxy-2-C-methyl-2-fluoro-3,5-di-O-benzene Formyl-α/β-D-ribofuranose (13) ^[3] , 13 reacts with acetic anhydride under the action of 4-dimethylaminopyridine (DMAP) to generate (2R)-2-deoxy-2-C-methyl -2-Fluoro-1-O-acetyl-3,5-di-O-benzoyl-α/β-D-ribofuranose (14), 14 with N-benzoyl-O-trimethylsilyl Nucleophilic substitution of cytosine (16) to generate (2R)-3',5'-ON ⁴ -tribenzoyl-2'-deoxy-2'-fluoro-2'-C-methylcytidine (17) . 17 was treated with 70% acetic acid to give (2R)-3',5'-O-dibenzoyl-2'-deoxy-2'-fluoro-2'-C-methyluridine (18), 18 was treated with ammonia Deprotection in methanol solution generates (2'R)-2'-deoxy-2'-fluoro-2'-C-methyluridine (19), 19 and compound N-[(S)-2,3,4, 5,6Phenoxyphenoxyphosphoryl]-L-alanine isopropyl ester (20) undergoes affinity substitution to obtain sofosbuvir. As shown in route one:

About the synthesis of intermediate 6, bibliographical report mainly involves following method and technique:

1), the synthetic route that U.S. Patent US20080145901 provides: 2-fluoropropionate ethyl ester (compound 7) forms carbanion under the effect of diisopropylamine and methyl lithium, addition (R)-(+)-2,2- Intermediate 6 is obtained on the aldehyde group of dimethyl-1,3-dioxolane-4-carbaldehyde (compound 4); after-treatment to obtain an oily product with a yield of 43.4%; see route 2:

This method needs to be carried out at an ultra-low temperature of -75°C, and the yield is low, so it cannot be applied to industrial large-scale production.

2), the synthetic route provided by CN 102933570, (2S,3R)2-methyl-2,3-dihydroxy-3-((R)-2,2-dimethyl-1,3-dioxolane -4-yl)-propionic acid ethyl ester (8) was reacted with sulfonyl fluoride (SO ₂ F ₂ ) in the presence of organic base and fluoride ion source (Et ₄ NF·3HF) to give 6 in a comprehensive yield of 66% ; see route three:

This method uses a large amount of reagents, specifically, triethylamine is 6 to 7 equivalents of compound 8, fluoride ion source (Et ₄ NF·3HF) is 2 equivalents, and sulfonyl fluoride (SO ₂ F ₂ ) is 8 equivalents ; And the recovery of these reagents is difficult, so the reaction cost is increased, which is not conducive to industrial production.

The problem to be solved by the present invention is to overcome the deficiencies of the prior art, break through technical barriers, and provide an improved preparation process of intermediate 6, which has mild reaction conditions, simple and convenient operation, cheap and easy-to-obtain reagents, high yield, suitable for Industrial production.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a sofosbuvir intermediate (2R,3R)-2-methyl-3-hydroxy-2-fluoro-3-((R)-2,2-dimethyl-1 , 3-dioxolan-4-yl) ethyl propionate (referred to as intermediate or compound 6) preparation method including 2-methyl-3-((R)-2,2-dimethyl- 1,3-Dioxolane-4-yl)-2-epoxypropionic acid ethyl ester (referred to as compound 1) is obtained by nucleophilic fluorine substitution reaction in an aprotic solvent at appropriate temperature; the reaction formula is as follows:

The fluorine substitution reagent selected for the nucleophilic fluorine substitution reaction is selected from nucleophiles such as HF/Pyridine, Bu ₄ NH ₂ F ₃ , Et ₃ N.3HF, Me ₃ N.2HF, SiF ₄ , and DAST.

In a preferred embodiment of the above-mentioned preparation method of sofosbuvir intermediate 6, the fluorine substitution reagent is preferably HF/Pyridine.

In a preferred embodiment of the above-mentioned preparation method of sofosbuvir intermediate 6, the amount of the fluorine substitution reagent is 1.1-5.0 equivalents of compound 1, preferably 1.1-1.5 equivalents.

The preparation method of above-mentioned sofosbuvir intermediate 6, in a preferred embodiment, the aprotic solvent used in the reaction is selected from dichloromethane, chloroform, dichloroethane, benzene, toluene, ethylbenzene, xylene or Chlorobenzene; preferably dichloromethane.

In a preferred embodiment of the above-mentioned preparation method of sofosbuvir intermediate 6, the reaction temperature is appropriately 0-70°C; preferably 15-35°C.

On the other hand, the present invention also provides compound 1 and a preparation method thereof.

As for compound 1, it can be prepared by the following two methods:

Method (1): 2-methyl-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-propenoic acid ethyl ester (or called reaction bottom Compound 3) is epoxidized with an epoxidizing agent in an aprotic solvent at an appropriate temperature to obtain compound 1. The reaction formula is as follows;

In the reaction of the above method (1), the reaction substrate 3 can be prepared from the document The Journal of Organic Chemistry, 2009, 74(17): 6819-6824.

In the reaction of the above-mentioned method (1), in a preferred embodiment, the epoxidizing reagent is selected from peroxyacid reagents, such as: H ₂ O ₂ , peroxyacetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid (mCPBA) ) etc., preferably m-chloroperoxybenzoic acid (mCPBA).

In the reaction of the above-mentioned method (1), in a preferred embodiment, the aprotic solvent used in the reaction is selected from methylene chloride, chloroform, ethylene dichloride, benzene, toluene, ethylbenzene, xylene or chlorobenzene; preferably for dichloromethane.

In the reaction of the above method (1), in a preferred embodiment, the appropriate temperature used for the reaction is 10-90°C; preferably 35-45°C.

Method (2): Compound 4 and ethyl 2-bromopropionate (5) are obtained by Darzens reaction in the presence of a base in an aprotic solvent at an appropriate temperature, and the reaction formula is as follows:

In the reaction of the above method (2), the compounds 4 and 5 used were all obtained by purchasing.

In the reaction of the above method (2), in a preferred embodiment, the base is selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, and sodium amide, preferably sodium ethoxide.

In the reaction of the above method (2), in a preferred embodiment, when the base is selected from sodium ethoxide, the amount of sodium ethoxide is 1 to 5 equivalents of compound 4, preferably 1.1 to 1.5 equivalents.

In the reaction of the above method (2), in a preferred embodiment, the molar ratio of compound 4 to compound 5 is 1:1-1:10, preferably 1:1-1.2.

In the reaction of the above-mentioned method (2), in a preferred embodiment, the aprotic solvent used in the reaction is selected from methylene chloride, chloroform, ethylene dichloride, benzene, toluene, ethylbenzene, xylene or chlorobenzene; preferably for dichloromethane.

In the reaction of the above method (2), in a preferred embodiment, the appropriate temperature used for the reaction is -10 to 50°C; preferably, 0 to 25°C.

In the above preparation method, the monitoring of the reaction process can be carried out according to conventional technical methods and means in the art, such as thin layer chromatography TLC, column chromatography HPLC, GC and other chromatographic methods.

The advantages of the present invention are: (1) The yield of the intermediate 6 prepared by the present invention is higher than the preparation routes of the patents US20080145901 and CN102933570, and the operation is simple. (2) The conditions for preparing the intermediate 6 in the present invention are mild, compared with the low temperature of -75°C in the patent US20080145901, the present invention saves energy and is more suitable for industrial production. (3) The reagents used in the present invention are cheap and easy to obtain. When it is HF/Pyridine, the dosage is 1.1 to 1.5 equivalents of the substrate. Compared with the patent CN 102933570, the dosage of reagents is saved, which is in line with the economy of green chemical atoms and reduces the cost. Reduce the three waste pollution.

To sum up, the present invention proposes a new preparation method of sofosbuvir intermediate 6. Through the optimization and selection of reaction conditions, the product yield and purity are greatly improved compared with existing literature reports, and the reaction conditions are mild and mild. The post-processing is simple, the cost is reduced, the process is stable, and it is suitable for industrial production.

The present invention is further illustrated by the following examples; it should be pointed out that for those skilled in the art, without departing from the concept of the present invention, several improvements and modifications can also be made, and these improvements and modifications should also be regarded as the present invention. within the scope of protection of the invention.

Detailed ways

The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description. The reagents and starting materials used in the present invention are commercially available or prepared according to known literature methods. Specifically, compounds 4 and 5 were purchased industrial-grade reagents and were used directly without treatment. Other reagents were purchased from Sinopharm and used directly without treatment.

Comparative example: Synthesis of reference F.Ammadi, M.M.Chaabouni, H.Amri & A.Baklouti, Synthesis of α-Cyano-β-fluoro-α-hydroxyesters, Synthetic Communications, 1993, 23:17, 2389-2395, with HF pair The propylene oxide compound undergoes ring opening to obtain the corresponding fluorohydroxy compound. The comparative yield was 61%.

Example 1, preparation of compound 6

At room temperature, a solution of compound 1 (2.30 g, 10.0 mmol) in dichloromethane (10 ml) was added dropwise to a solution containing 70% HF/Py (w/w%) (10 ml) in dichloromethane (10 ml), and continued The reaction was stirred for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), the organic layer was washed with 5% sodium bicarbonate solution (15ml), washed with water (15ml) and dried over anhydrous sodium sulfate. Filter with suction, evaporate the solvent under reduced pressure, and recrystallize from methyl tert-butyl ether-n-hexane system to obtain 2.26 g of compound 6 as a white solid (yield 90.1%) with a purity of 99.3% (gas phase system: Agilent 6890N).

Example 2, the preparation of compound 6

A solution of compound 1 (2.30 g, 10.0 mmol) in dichloromethane (10 ml) was added dropwise to a solution containing 70% HF/Py (w/w%) (10 ml) in dichloromethane (10 ml) at 0 °C, The reaction was continued to stir for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), the organic layer was washed with 5% sodium bicarbonate solution (15ml), washed with water (15ml) and dried over anhydrous sodium sulfate. Filter with suction, evaporate the solvent under reduced pressure, and recrystallize from methyl tert-butyl ether-n-hexane system to obtain 1.64 g of compound 6 as a white solid (yield 65.4%) with a purity of 99.3% (gas phase system: Agilent 6890N).

Example 3, preparation of compound 6

A solution of compound 1 (2.30 g, 10.0 mmol) in dichloromethane (10 ml) was added dropwise to a solution containing 70% HF/Py (w/w%) (10 ml) in dichloromethane (10 ml) at 15 °C, The reaction was continued to stir for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), the organic layer was washed with 5% sodium bicarbonate solution (15ml), washed with water (15ml) and dried over anhydrous sodium sulfate. Filter with suction, evaporate the solvent under reduced pressure, and recrystallize from methyl tert-butyl ether-n-hexane system to obtain 2.22 g of compound 6 as a white solid (yield 88.6%) with a purity of 99.3% (gas phase system: Agilent 6890N).

Example 4, preparation of compound 6

At 35°C, a solution containing compound 1 (2.30 g, 10.0 mmol) in dichloromethane (10 ml) was added dropwise to a solution containing 70% HF/Py (w/w%) (10 ml) in dichloromethane (10 ml), The reaction was continued to stir for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), the organic layer was washed with 5% sodium bicarbonate solution (15ml), washed with water (15ml) and dried over anhydrous sodium sulfate. Filter with suction, evaporate the solvent under reduced pressure, and recrystallize from methyl tert-butyl ether-n-hexane system to obtain 2.14 g of compound 6 as a white solid (yield 85.3%) with a purity of 99.3% (gas phase system: Agilent 6890N).

Example 4, preparation of compound 6

Under reflux, a solution of compound 1 (2.30 g, 10.0 mmol) in dichloromethane (10 ml) was added dropwise to a solution containing 70% HF/Py (w/w%) (10 ml) in dichloromethane (10 ml), The reaction was continued to stir for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), the organic layer was washed with 5% sodium bicarbonate solution (15ml), washed with water (15ml) and dried over anhydrous sodium sulfate. Filter with suction, evaporate the solvent under reduced pressure, and recrystallize from methyl tert-butyl ether-n-hexane system to obtain 1.82 g of compound 6 as a white solid (yield 72.5%) with a purity of 99.3% (gas phase system: Agilent 6890N).

Example 5, the preparation of compound 6

At 70°C, a solution of compound 1 (2.30 g, 10.0 mmol) in toluene (10 ml) was added dropwise to a solution containing 70% HF/Py (w/w%) (10 ml) in toluene (10 ml), and the reaction was continued to stir 2 Hour. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), the organic layer was washed with 5% sodium bicarbonate solution (15ml), washed with water (15ml) and dried over anhydrous sodium sulfate. Filtration with suction, evaporated the solvent under reduced pressure, and recrystallized from methyl tert-butyl ether-n-hexane system to obtain 1.13 g of compound 6 (yield 45.2%) as a white solid with a purity of 99.3% (gas phase system: Agilent 6890N).

Example 6. Preparation of compound 1

Dissolve compound 3 (1.07g, 5.0mmol) in dichloromethane (10ml), add 75% m-chloroperoxybenzoic acid (mCPBA) (1.17g, 5.1mmol), heat under reflux at 45°C for 24h, and detect the reaction in gas phase Complete, the reaction solution was washed with saturated sodium hydrogen sulfite (5 ml), the m-chlorobenzoic acid was removed with a 5% aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. 1.0 g of compound 1 (yield 87.0%) as a colorless oily substance from which the solvent was evaporated under reduced pressure.

Compound 3 is according to literature Wang P, Chun B-K, Rachakonda S, et al. An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase [J]. The Journal of Organic Chemistry, 2009, 74 (17): 6819 -6824. Prepared. The gas phase system was an Agilent 6890N. Other reagents were purchased from Sinopharm Group and used directly without treatment.

Example 7. Preparation of compound 1

Dissolve compound 3 (1.07g, 5.0mmol) in dichloromethane (10ml), add 75% m-chloroperoxybenzoic acid (mCPBA) (1.17g, 5.1mmol), react at 25°C for 48h, and the gas phase detection reaction is basically complete , the reaction solution was washed with saturated sodium hydrogen sulfite (5ml), the m-chlorobenzoic acid was removed with a 5% aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. 0.75 g of compound 1 (yield 65.2%) as a colorless oily substance from which the solvent was evaporated under reduced pressure.

Example 8, preparation of compound 1

Compound 3 (1.07g, 5.0mmol) was dissolved in toluene (10ml), 75% m-chloroperoxybenzoic acid (mCPBA) (1.17g, 5.1mmol) was added, and the reaction was carried out at 90°C for 24h. Wash with saturated sodium hydrogen sulfite (5 ml), remove m-chlorobenzoic acid with 5% aqueous sodium hydrogen carbonate solution, and dry the organic layer over anhydrous sodium sulfate. 0.39 g of compound 1 (yield 34.2%) as a colorless oily substance from which the solvent was evaporated under reduced pressure.

Example 9: Preparation of Compound 1

At -10°C, to dichloromethane (20 ml) in which compound 4 (1.30 g, 10 mmol) and compound 5 (1.81 g, 10 mmol) were dissolved was slowly added dropwise sodium ethoxide (0.81 g, 12 mmol) in dichloromethane (5ml) solution, dripped in 15min, kept the temperature at -10°C for 6h, the reaction solution was concentrated to dryness under reduced pressure, extracted with methyl tert-butyl ether, and the ether solvent was evaporated under reduced pressure to obtain 0.82g of a colorless oily compound 1 (35.6% yield).

Example 10: Preparation of Compound 1

At 0°C, to dichloromethane (20 ml) in which compound 4 (1.30 g, 10 mmol) and compound 5 (1.81 g, 10 mmol) were dissolved was slowly added dropwise sodium ethoxide (0.81 g, 12 mmol) in dichloromethane ( 5ml) solution, dripped in 15min, kept the temperature of 0 ℃ and reacted for 6h, the reaction solution was concentrated to dryness under reduced pressure, extracted with methyl tert-butyl ether, and the ether solvent was evaporated under reduced pressure to obtain 0.93g of compound 1 (colorless oily substance). yield 40.5%).

Example 11: Preparation of Compound 1

At 0°C, to dichloromethane (20 ml) in which compound 4 (1.30 g, 10 mmol) and compound 5 (1.81 g, 10 mmol) were dissolved was slowly added dropwise sodium ethoxide (0.81 g, 12 mmol) in dichloromethane ( 5ml) solution, dripped in 15min, kept the temperature at 15°C and reacted for 6h, the reaction solution was concentrated to dryness under reduced pressure, extracted with methyl tert-butyl ether, and the ether solvent was evaporated under reduced pressure to obtain compound 1 (1.26g) as a colorless oil. yield 54.7%).

Example 12: Preparation of Compound 1

At 0°C, to dichloromethane (20 ml) in which compound 4 (1.30 g, 10 mmol) and compound 5 (1.81 g, 10 mmol) were dissolved was slowly added dropwise sodium ethoxide (0.81 g, 12 mmol) in dichloromethane ( 5ml) solution, dripped in 15min, kept the temperature at 45°C for reflux reaction for 6h, the reaction solution was concentrated to dryness under reduced pressure, extracted with methyl tert-butyl ether, and the ether solvent was evaporated under reduced pressure to obtain 0.70g of compound 1 as a colorless oil. (Yield 30.2%).

Claims (20)

1. The preparation method of the sofosbuvir intermediate 6 with low cost and greatly improved yield and purity comprises the following steps: the compound 1 is obtained by nucleophilic fluorine substitution reaction in an aprotic solvent at a proper temperature; the reaction formula is as follows:

wherein, the fluorine substitution reagent selected for the nucleophilic fluorine substitution reaction is HF/Pyridine, and the aprotic solvent used for the reaction is dichloromethane.

2. The method according to claim 1, wherein the fluorine-substituting reagent is used in an amount of 1.1 to 5.0 equivalents based on the compound 1.

3. The method according to claim 2, wherein the fluorine-substituting reagent is used in an amount of 1.1 to 1.5 equivalents based on the compound 1.

4. The method according to claim 1, wherein the reaction temperature is suitably 0 to 70 ℃.

5. The method according to claim 4, wherein the reaction temperature is 15 to 35 ℃.

6. Compound 1 in the preparation process as claimed in claim 1.

7. The process according to claim 1, wherein Compound 1 is prepared by: carrying out epoxidation on a reaction substrate 3 and an epoxidation reagent in an aprotic solvent at a proper temperature to obtain a compound 1, wherein the reaction formula is as follows;

characterized in that the epoxidizing agent is selected from H₂O₂Peracetic acid, perbenzoic acid, m-chloroperoxybenzoic acid (mCPBA).

8. The method of claim 7, wherein the epoxidizing agent is m-chloroperoxybenzoic acid (mCPBA).

9. The process according to claim 7, wherein the aprotic solvent used in the reaction is methylene chloride.

10. The process according to claim 7, wherein the reaction is carried out at a suitable temperature of 10 to 90 ℃.

11. The method according to claim 10, wherein the reaction is carried out at a suitable temperature of 35 to 45 ℃.

12. The process according to claim 1, wherein Compound 1 is prepared by: compound 4 is reacted with ethyl 2-bromopropionate 5 in the presence of a base in an aprotic solvent at an appropriate temperature by Darzens to give 1, of the formula:

characterized in that the base is selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide and sodium amide.

13. The process according to claim 12, wherein the base is sodium ethoxide.

14. The method according to claim 12, wherein the base is used in an amount of 1 to 5 equivalents based on the compound 4.

15. The method according to claim 14, wherein the base is used in an amount of 1.1 to 1.5 equivalents based on the compound 4.

16. The method according to claim 12, wherein the molar ratio of compound 4 to compound 5 is 1:1 to 1: 10.

17. The method according to claim 16, wherein the molar ratio of compound 4 to compound 5 is 1:1 to 1.2.

18. The process according to claim 12, wherein the aprotic solvent used in the reaction is methylene chloride.

19. The method according to claim 12, wherein the reaction is carried out at a temperature of from-10 to 50 ℃.

20. The method according to claim 19, wherein the reaction is carried out at a suitable temperature of 0 to 25 ℃.