CN110950919B

CN110950919B - Synthetic method of sofosbuvir

Info

Publication number: CN110950919B
Application number: CN201911240294.4A
Authority: CN
Inventors: 葛敏; 付明伟
Original assignee: Nanjing Zhengji Pharmaceutical Research Co ltd
Current assignee: Nanjing Zhengji Pharmaceutical Research Co ltd
Priority date: 2019-12-06
Filing date: 2019-12-06
Publication date: 2021-06-04
Anticipated expiration: 2039-12-06
Also published as: CN110950919A

Abstract

The invention discloses a synthesis method of sofosbuvir, which comprises the steps of adding a compound 1, a compound 2 and dichloromethane into a reaction bottle, cooling to 0 ℃, adding aluminum trichloride, adding a proper amount of pyridine, and reacting at the reaction temperature of 15-20 ℃ to generate the sofosbuvir. The invention has high reaction conversion rate and good regioselectivity and stereoselectivity, thereby reducing the synthesis cost of sofosbuvir and having remarkable social benefit and economic benefit.

Description

Synthetic method of sofosbuvir

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a synthetic method of sofosbuvir.

Background

Viral hepatitis c is caused by Hepatitis C Virus (HCV), infection of which is a serious health problem. Sofosbuvir is an important drug developed by Gilidde for the treatment of hepatitis C virus, and has the following structural formula:

the synthetic methods that have been reported are mainly:

1. in j.med.chem.,2010,53(19), 7202-:

the specific method comprises the following steps: the compound 1 and the compound 5 react in a tetrahydrofuran solution in the presence of N-methylimidazole to generate the sofosbuvir and an equivalent amount of a by-product compound 6 (sofosbuvir isomer). The pure sofosbuvir was then isolated by preparative HPLC with a final yield of 15.2%. It is clear that this process is not suitable for industrial scale production.

2. In j.org.chem.,2011,76(20), 8311-:

the specific method comprises the following steps: under anhydrous condition, reacting compound 1 with tert-butyl magnesium halide (preferably tert-butyl magnesium chloride) to generate active intermediate, dripping tetrahydrofuran solution of compound 2, and reacting at about 5 deg.C to generate target product. During the reaction, more byproduct compound 4 is generated, the final yield is 68%, and the purity is 99.7%. Compared with the former method, the method has great improvement, the purity meets the requirement of the raw material medicine, in the actual reaction, the conversion of the compound 1 is not complete, and a large amount of the compound 4 which is the main byproduct is generated, so that the conversion rate of the reaction is not high, the treatment and purification after the reaction are difficult, and a lot of cost is increased for the scale-up production.

3. The following synthesis method is described in CN 10639515:

the specific method comprises the following steps: the compound 1 and the compound 2 are reacted in tetrahydrofuran or ethyl acetate in the presence of Lewis acid (zinc chloride, magnesium chloride, aluminum chloride, ferric chloride, stannic chloride, boron trifluoride and the like, preferably magnesium chloride) and base (triethylamine, DBU, N, N-diisopropylethylamine and the like, preferably N, N-diisopropylethylamine) to obtain sofosbuvir. The yield is about 88 percent, and the purity is 98 percent. Obviously, the method has higher yield, but the purity of the method is far from the level of the raw material medicine. If the Sofosbuvir with the purity is purified into qualified bulk drugs, the yield is greatly reduced, and the manufacturing cost is greatly increased.

4. In org.lett; 2017,19,2218-2221. the following synthesis method is described:

the specific method comprises the following steps: and (3) reacting the compound 1 with the compound 2 in the presence of dimethyl aluminum chloride by using pyridine as a reaction solvent to obtain the sofosbuvir. Under the optimal process conditions, the yield is 84%, the compound 4 accounts for 1%, and the compound 6 accounts for about 0.2%. Obviously, the method has higher yield and less main impurities, but dimethylaluminum chloride is relatively expensive, and the presence of a large amount of pyridine makes the post-reaction treatment extremely complicated, thereby causing more three wastes. When purified to the level of the drug substance, the actual yield is greatly reduced and the manufacturing cost is increased by a lot.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide a synthesis method of sofosbuvir, which solves the problems of low raw material conversion rate and high content of various byproducts in the preparation of sofosbuvir in the prior art. The synthesis method of sofosbuvir has high reaction conversion rate and purity, thereby remarkably reducing the synthesis cost of sofosbuvir.

The technical scheme is as follows: the invention relates to a synthesis method of sofosbuvir, which comprises the following steps:

the method comprises the following steps:

adding the compound 1, the compound 2 and dichloromethane into a reaction bottle, cooling to 0 ℃, adding aluminum trichloride, adding a proper amount of pyridine, and reacting at the reaction temperature of 15-20 ℃ to generate the sofosbuvir.

Further, the mass of the dichloromethane was 7.5 times that of the compound 1.

Further, the molar ratio of the compound 1 to aluminum trichloride is 1: 0.1-1: 0.8.

Further, the molar ratio of the compound 1 to aluminum trichloride is 1: 0.3.

Further, the molar ratio of the compound 1 to pyridine is 1: 1-1: 8.

Further, the molar ratio of the compound 1 to pyridine is 1: 4.

The discovery of the synthetic method is very accidental. Since the solubility of compound 1 in dichloromethane is extremely low, while the solubility of compound 2 and the desired product sofosbuvir in dichloromethane is very high, the low solubility of compound 1 in dichloromethane for such essentially selective transesterification reactions theoretically results in the formation of more by-product compound 4, making the reaction less effective. Therefore, almost no one can consider carrying out the reaction using methylene chloride as a reaction solvent. However, the experimental results are quite different from the theoretical predictions, and the best experimental result is obtained by using dichloromethane as the solvent under certain conditions.

The invention has the beneficial effects that: the method has the characteristics of simple operation, low auxiliary material price, high conversion rate of main raw materials, low content of various byproducts and simple subsequent purification treatment, obviously reduces the production cost, is suitable for industrial production, and has obvious social benefit and economic benefit.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The invention is further described below with reference to examples:

example 1

Adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and 150g of dichloromethane into a reaction bottle, cooling to 0 ℃, adding 3.1g (0.0232mol) of aluminum trichloride, and dropwise adding 24.3g (0.307mol) of pyridine; then, the reaction is stopped at 20 ℃, and when the content of the sofosbuvir is not increased any more through HPLC detection, the HPLC data of the reaction liquid relative to the compound 1 are as follows:

compound 1 (%)	Compound 6 (%)	Sofosbuvir (%)	Compound 4 (%)
				1.33	0.46	97.78	0.43

Adding 120g of 10% diluted hydrochloric acid into the reaction solution to quench the reaction, extracting with 300g of ethyl acetate, recovering the solvent under reduced pressure, and purifying to obtain 39.68g of a pure sofosbuvir product, wherein the yield is as follows: 97.5 percent.

Example 2

Preparation of sofosbuvir from aluminum trichloride in different molar amounts

Respectively adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and 150g of dichloromethane into a reaction bottle, and cooling to 0 ℃; adding aluminum trichloride with different molar weights, and then dropwise adding 24.3g (0.307mol) of pyridine; the reaction was then stopped at 20 ℃ and worked up as in example 1 when the increase in sofosbuvir content was no longer detected by HPLC, at which time the HPLC data for compound 1 in the reaction mixture:

experiments show that the molar ratio of the aluminum trichloride to the compound 1 is 0.1-0.8, and good reaction results are obtained.

Example 3

Preparation of sofosbuvir from pyridine with different molar amounts

Respectively adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and 150g of dichloromethane into a reaction bottle, and cooling to 0 ℃; adding 3.1g (0.0232mol) of aluminum trichloride, and then dropwise adding pyridine with different molar weights; the reaction was then stopped at 20 ℃ and worked up as in example 1 when the increase in sofosbuvir content was no longer detected by HPLC, at which time the HPLC data for compound 1 in the reaction mixture:

it was found by experiment that the molar amount of base had a great influence on the reaction conversion, regioselectivity and stereoselectivity, and pyridine was optimal 4 times as much as 1 molar amount of compound.

Example 4

Preparing sofosbuvir by using different solvents:

respectively adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and 150g of different solvents into a reaction flask, and cooling to 0 ℃; 3.1g (0.0232mol) of aluminum trichloride is added, and 24.3g (0.307mol) of pyridine is added dropwise; the reaction was then stopped at 20 ℃ when the increase in sofosbuvir content was no longer detected by HPLC and worked up as in example 1. HPLC data and yields for compound 1 in the reaction liquid when the reaction was stopped:

from the experimental results, it was found that the compositions of compound 1, compound 6, sofosbuvir and compound 4 in the reaction solution at the end of the reaction varied with the kind of the solvent, and methylene chloride was most preferable as the reaction solvent in combination.

Example 5

Preparing sofosbuvir by using different bases:

respectively adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and 150g of dichloromethane into a reaction bottle, and cooling to 0 ℃; 3.1g (0.0232mol) of aluminum trichloride is added, and then different alkalis with equal molar quantity are added; the reaction was then stopped at 20 ℃ and worked up as in example 1 when the increase in sofosbuvir content was no longer detected by HPLC, at which time the HPLC data for compound 1 in the reaction mixture:

example 6

Preparation of sofosbuvir with different masses of dichloromethane:

respectively adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and dichloromethane solvents with different masses into a reaction bottle, and cooling to 0 ℃; 3.1g (0.0232mol) of aluminum trichloride is added, and 24.3g (0.307mol) of pyridine is added dropwise; the reaction was then stopped at 20 ℃ when the increase in sofosbuvir content was no longer detected by HPLC and worked up as in example 1. HPLC data and yields for compound 1 in the reaction liquid when the reaction was stopped:

it was found by experiment that the amount of dichloromethane had a great influence on the reaction conversion, regioselectivity and stereoselectivity, and that the mass of dichloromethane 7.5 times the mass of compound 1 was optimal.

Example 7

Adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and 150g of dichloromethane into a reaction bottle, cooling to 0 ℃, adding 3.1g (0.0232mol) of aluminum trichloride, and dropwise adding 24.3g (0.307mol) of pyridine; then, the reaction is stopped at 15 ℃, and when the content of the sofosbuvir is not increased any more by HPLC detection, the HPLC data of the reaction liquid relative to the compound 1 are as follows:

compound 1 (%)	Compound 6 (%)	Sofosbuvir (%)	Compound 4 (%)
				1.54	0.53	97.44	0.49

Adding 120g of 10% diluted hydrochloric acid into the reaction solution to quench the reaction, extracting with 300g of ethyl acetate, recovering the solvent under reduced pressure, and purifying to obtain 39.13g of pure sofosbuvir, wherein the yield is as follows: 96.2 percent.

Example 8

Adding 20.0g (0.0768mol) of the compound 1, 40.0g (0.0882mol) of the compound 2 and 150g of dichloromethane into a reaction bottle, cooling to 0 ℃, adding 3.1g (0.0232mol) of aluminum trichloride, and dropwise adding 24.3g (0.307mol) of pyridine; then the reaction was stopped at 18 ℃ when the increase in sofosbuvir content no longer occurred as measured by HPLC, at which time the HPLC data for compound 1 in the reaction solution:

compound 1 (%)	Compound 6 (%)	Sofosbuvir (%)	Compound 4 (%)
				1.39	0.48	97.68	0.45

Adding 120g of 10% diluted hydrochloric acid into the reaction solution to quench the reaction, extracting with 300g of ethyl acetate, recovering the solvent under reduced pressure, and purifying to obtain 39.49g of pure sofosbuvir, wherein the yield is as follows: 97.1 percent.

In conclusion, the synthesis method of sofosbuvir provided by the invention has the advantages of mild reaction conditions, convenience in reagent storage, safety in use, simplicity in post-treatment and the like, has good environmental benefits and economic benefits, and is suitable for large-scale production of raw material pharmaceutical factories.

While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and suitable modifications of the method and applications described herein may be made and used to implement and apply the techniques of the present invention within the context, spirit and scope of the invention. Certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

1. The synthesis method of sofosbuvir is characterized in that the synthesis route is as follows:

the method comprises the following steps:

adding the compound 1, the compound 2 and dichloromethane into a reaction bottle, cooling to 0 ℃, adding aluminum trichloride, adding a proper amount of pyridine, and reacting at the reaction temperature of 15-20 ℃ to generate sofosbuvir;

the mass of the dichloromethane is 7.5 times of that of the compound 1;

the molar ratio of the compound 1 to pyridine is 1: 4.

2. The method for synthesizing sofosbuvir according to claim 1, wherein: the molar ratio of the compound 1 to the aluminum trichloride is 1: 0.1-1: 0.8.

3. The method for synthesizing sofosbuvir according to claim 2, wherein: the molar ratio of the compound 1 to the aluminum trichloride is 1: 0.3.