Novel route for preparing dolutegravir key intermediate 2,4-difluorobenzylamine

Abstract

The invention discloses a production route which is concise and green in route, low in cost and easy to industrialize to prepare 2,4-difluorobenzylamine. The route comprises the following four steps:a) by taking m-difluorobenzene as an initial raw material, under catalysis of lewis acid, carrying out a Foucault alkylation reaction with ethylene oxide so as to prepare an intermediate 2,4-difluorobenzene ethanol; b) carrying out a second step of reactions on the product of the step a) without separation or purification, and oxidizing the 2,4-difluorobenzene ethanol to generate 2,4-difluorobenzene phenylacetic acid; c) enabling the product 2,4-difluorobenzene phenylacetic acid of the step b) with sulfoxide chloride and an ammonia gas to react so as to prepare 2,4-difluorophenylacetamide; d)under induction of bromine, enabling the product 2,4-difluorophenylacetamide of the step c) to react with a sodium hypochlorite solution, and carrying out Hofmann degradation, thereby obtaining a target product 2,4-difluorobenzylamine. The preparation method disclosed by the invention is simple and easy in raw material obtaining, concise in route, green and environmentally friendly, low in cost and easy in industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of medicines and pesticide chemicals, and the specific content is a new synthesis route of 2,4-difluorobenzylamine, a key intermediate of dolutegravir. Background technique [0002] 2,4-Difluorobenzylamine is a very important chemical intermediate, and its most important use is to prepare the anti-AIDS drug dolutegravir. Dolutegravir is a new type of integrase inhibitor developed by GlaxoSmithKline and approved for marketing in the United States in 2013. Due to its advantages of high efficiency and low toxicity, the market sales have risen rapidly in recent years, and the momentum is unanimously optimistic. Among the several known synthetic routes of dolutegravir, 2,4-difluorobenzylamine is a key intermediate that cannot be bypassed. Therefore, it is very meaningful to develop an efficient, green and low-cost preparation process for 2,4-difluorobenzylamine. [0003] At present, the production industry ...

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Problems solved by technology

[0009] This method has relatively mild reaction conditions and high yield, but there are serious environmental protection problems. After chloromethylation and final hydrolysis, a large amount of waste acid and high-ammonia nitrogen and high-salt wastewater will remain.

[0010] In addition, the most reported route is the method of reducing 2,4-difluorobenzonitrile, wherein there is a method of pressurized hydrogenation reduction under an ammonia atmosphere (US5068371, Chemistry-AEuropean Journal, 2013,19(14 ), 4437-4440), there is also a method for reducing 2,4-dibenzonitrile with borane-THF complex (J.Med.Chem., 2006,49,6197-6208) and with liAlH 4 It is a reducing agent method (WO2012076673), but these methods all have problems such as large safety hazards, harsh operating conditions, low yield, and high cost

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