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Tenofovir alafenamide series impurities and synthesis method thereof

A technology of tenofovir alafenamide and synthetic method, applied in the field of drug impurity synthesis

Inactive Publication Date: 2019-09-20
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And in the preparation process of tenofovir alafenamide, more impurities are generated, even new impurities appear, and for new impurities, a synthetic route is developed, and a high-purity reference substance is prepared, for tenofovir alafenamide Detection of phenolamine impurities is clearly necessary

Method used

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  • Tenofovir alafenamide series impurities and synthesis method thereof
  • Tenofovir alafenamide series impurities and synthesis method thereof
  • Tenofovir alafenamide series impurities and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0052] Preparation of Compound C:

[0053] Tenofovir monophenyl ester (compound I) 10.0g (27.55mmol, 1.0eq), acetonitrile 80g and thionyl chloride 6.6g (55.1mmol, 2.0eq) were added to the bottle, the temperature was raised to 80°C, and the reaction was stirred for 3.5 h, the reaction solution was concentrated to dryness, 40 g of dichloromethane was added to the system to dissolve, and 3.3 g of L-alanyl-L-alanine isopropyl ester (compound H) (16.53 In the solution of mmol, 0.6eq) and 10g dichloromethane, triethylamine is added dropwise at the same time to keep the pH at 6-8. The dichloromethane phase was washed three times with saturated sodium bicarbonate and sodium chloride respectively, the dichloromethane phase was concentrated, and isopropyl ether was added to precipitate a white solid, which was filtered and dried to obtain 2.14 g of a sample, which was compound C.

[0054] 1H NMR (400MHz, D2O): δ8.20-8.10(3H), 7.35-7.24(2H), 7.21(1H), 7.17-7.11(2H), 6.9(1H), 5.3(1H), 4....

Embodiment 1-2

[0056] Preparation of Compound C:

[0057]Add tenofovir monophenyl ester (compound I) 10.0g (27.55mmol, 1.0eq), acetonitrile 80g and thionyl chloride 3.3g (27.55mmol, 1.0eq) into the bottle, heat up to 50°C, and stir for 2h , Concentrate the reaction solution to dryness, add 40g of dichloromethane to the system to dissolve, and add 1.1g of L-alanyl-L-alanine isopropyl ester (compound H) (5.51 mmol, 0.2eq) and 10g dichloromethane solution, dripping triethylamine simultaneously keeps the pH to be 6-8, stirs and reacts for 2 hours after dripping, adds dichloromethane 200g and water 100g extracting liquid separation in the system, The dichloromethane phase was washed three times with saturated sodium bicarbonate and sodium chloride respectively, the dichloromethane phase was concentrated, and purified by column chromatography to obtain 0.31 g of a sample, which was Compound C.

[0058] 1H NMR (400MHz, D2O): δ8.20-8.10(3H), 7.35-7.24(2H), 7.21(1H), 7.17-7.11(2H), 6.9(1H), 5.3(1H),...

Embodiment 1-3

[0062] Preparation of Compound C:

[0063] Add tenofovir monophenyl ester (Compound I) 10.0g (27.55mmol, 1.0eq), acetonitrile 80g and thionyl chloride 13.2g (110.2mmol, 4.0eq) into the bottle, raise the temperature to 70°C, and stir for 6h , the reaction solution was concentrated to dryness, 40 g of dichloromethane was added to the system to dissolve, and 5.5 g (27.55 mmol, 27.55 mmol, 1.0eq) and 10g of dichloromethane solution, drop triethylamine at the same time to keep the pH at 6-8, stir and react for 3 hours after dropping, add 200g of dichloromethane and 100g of water to the system for extraction and separation, DCM phase Wash with saturated sodium bicarbonate and sodium chloride three times respectively, concentrate the dichloromethane phase, and purify by column chromatography to obtain 2.32 g of the sample, which is compound C.

[0064] 1H NMR (400MHz, D2O): δ8.20-8.10(3H), 7.35-7.24(2H), 7.21(1H), 7.17-7.11(2H), 6.9(1H), 5.3(1H), 4.8(1H) , 4.30-4.25, 4.25-4.12 (2H)...

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Abstract

The present invention provides tenofovir alafenamide series impurities and a synthesis method thereof. The series impurities are found in the process of synthesizing tenofovir alafluamine by the inventor of the invention, and are new impurities not reported in the prior art, so the synthesis method of the series impurities is provided, the studies of the tenofovir alafenamide impurities are benefited, and great convenience can be brought for the development of analytical methods and the quality studies of medicines.

Description

technical field [0001] The invention belongs to the field of drug impurity synthesis, in particular to the synthesis of tenofovir alafenamide impurities. [0002] Background technique: [0003] Tenofovir alafenamide fumarate (TAF), a new drug developed by Gilead Sciences for the treatment of chronic hepatitis B virus (HBV) infection with compensated liver disease, is named VEMLIDY , was approved for marketing by the US FDA on November 10, 2016, and was approved for marketing by the Ministry of Health, Labor and Welfare of Japan on December 19 of the same year, and was approved by the European Medicines Agency for marketing on January 9, 2017. Fospratenofovir tablets have not yet been imported and marketed in China, and Gilead has not yet submitted an application for new drug registration and marketing in China. [0004] During the preparation process of tenofovir alafenamide, many impurities are generated. Better control of the limit of impurities is necessary for the resear...

Claims

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Application Information

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IPC IPC(8): C07F9/6561G01N30/02G01N30/06
CPCC07B2200/07C07F9/65616G01N30/02G01N30/06
Inventor 唐云何帅杰亢世金张善军黄浩喜苏忠海
Owner CHENGDU BRILLIANT PHARMA CO LTD
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