Method for preparing sofosbuvir

A technology for sofosbuvir and a compound, which is applied in the field of drug synthesis and achieves the effects of less by-product content, simple operation and reduced production cost

Inactive Publication Date: 2017-10-17
JIANGSU LONG HEALTHCARE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The present invention provides an improved preparation method of Sofosbuvir. In order to solve the objective and practical problems in the preparation of Sofosbuvir in the prior art, the reaction of this step is studied in depth, thereby reducing the cost of industrial production

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  • Method for preparing sofosbuvir
  • Method for preparing sofosbuvir
  • Method for preparing sofosbuvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add 15.0 g of compound 2, 180 g of tetrahydrofuran, and 831 mg of water into the reaction flask, and cool down to -5°C. 71.2 mL of a 1.7M tert-butylmagnesium chloride solution was added, and a solution of 33.9 g of compound 3 in tetrahydrofuran (150 g) was added dropwise. Then react at 5°C, stop the reaction when HPLC detects that the content of sofosbuvir no longer increases. At this time, the HPLC data related to compound 2 in the reaction solution:

[0034] Compound 2(%)

[0035] Add 2mol.L to the reaction solution -1 60g of dilute hydrochloric acid quenched the reaction, extracted with 300g ethyl acetate, and separated the water phase; the organic phase was washed three times with 23g of 8% sodium carbonate solution, combined with the aqueous sodium carbonate phase, added 75g of ethyl acetate for extraction, combined with the organic phase, 45g Brine was washed and evaporated to dryness under reduced pressure. 150g of dichloromethane was added, and the c...

Embodiment 2

[0037] Add 10.0 g of compound 2, 100 g of tetrahydrofuran, and 761 mg of water into the reaction flask, and cool down to -5°C. 47.8 mL of a 1.7 M tert-butylmagnesium chloride solution was added, and a solution of 22.6 g of compound 3 in tetrahydrofuran (100 g) was added dropwise. Then react at 5°C, stop the reaction when HPLC detects that the content of sofosbuvir no longer increases. At this time, the HPLC data related to compound 2 in the reaction solution:

[0038] Compound 2(%)

[0039] Add 2mol.L to the reaction solution -1 40g of dilute hydrochloric acid quenched the reaction, extracted with 200g ethyl acetate, and separated the water phase; the organic phase was washed three times with 15g of 8% sodium carbonate solution, combined with the aqueous sodium carbonate phase, added 50g of ethyl acetate for extraction, combined with the organic phase, 30g Brine was washed and evaporated to dryness under reduced pressure. 100g of dichloromethane was added, and the ...

Embodiment 3

[0041] Preparation of Sofosbuvir with different equivalents of water:

[0042] Add 10 g of compound 2, 100 g of tetrahydrofuran, and corresponding equivalents of water into the reaction flask respectively. Cool down to -5°C, add 2.1 equivalents of tert-butylmagnesium chloride solution, then dropwise add 22.6g of compound 3 in tetrahydrofuran (100g) solution, react at 5°C, and stop the reaction when HPLC detects that the content of sofosbuvir no longer increases.

[0043]

[0044]

[0045] According to the experimental results, it can be known that when the end of the reaction is reached, the composition of compound 2, sofosbuvir, and compound 4 in the reaction solution changes with the equivalent number of water added. When using tert-butylmagnesium chloride without adding water, the reaction not only cannot be complete, but also has poor selectivity, and there are more excessively acylated by-products 4, which is consistent with literature reports. With the addition of...

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Abstract

The invention discloses a method for preparing sofosbuvir and belongs to the technical field of medicine synthesis. The method comprises the following steps: putting tertiary butyl magnesium halide into a tetrahydrofuran solution of a compound 2 with certain amount of water, further putting a compound 3, and performing reaction, thereby obtaining sofosbuvir. As a certain amount of water is added in a reaction system, the conversion rate of reaction is remarkably increased, the content of main byproducts is reduced, then the preparation cost of the sofosbuvir is lowered, and remarkable social and economic benefits are achieved.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to an improved preparation method of sofosbuvir. technical background [0002] Viral hepatitis C is caused by the hepatitis C virus (HCV), and infection with the hepatitis C virus (HCV) is a serious health problem. Sofosbuvir is an important drug developed by Gilead for the treatment of hepatitis C virus. Its structural formula is as follows: [0003] [0004] The reported synthesis methods mainly include: [0005] 1. In J.Med.Chem., 2010, 53(19), 7202–7218, the synthetic route is as follows: [0006] [0007] The specific method is: react compound 2 and compound 5 in tetrahydrofuran solution in the presence of N-methylimidazole to generate sofosbuvir and an equivalent amount of by-product compound 6 (sofosbuvir isomer). The pure product sofosbuvir was then isolated by preparative HPLC with a final yield of 15.2%. Obviously, this method is not suitable f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/02
Inventor 付明伟葛敏李令超丁杰
Owner JIANGSU LONG HEALTHCARE
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