Preparation method of efavirenz intermediate

Abstract

The invention discloses a preparation method of an efavirenz intermediate, relating to synthesis of an anti-virus medicine, namely an efavirenz key intermediate by adopting a green solvent, namely 2-methyltetrahydrofuran as a Grignard reaction solvent, and belonging to the technical field of organic synthesis. The preparation method comprises the following steps of: taking the 2-methyltetrahydrofuran as a solvent, enabling metal magnesium to react with ethyl bromide to obtain ethyl magnesium bromide, then dripping cyclopropylacetylene to generate cyclopropyne ethyl magnesium bromide, and finally performing addition reaction with 2-trifluoroacetyl p-chloroaniline to obtain 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1, 1, 1-trifluoro-3-butyn-2-ol. According to the method, the 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1, 1, 1-trifluoro-3-butyn-2-ol can be prepared with high selectivity and high yield, the product purity is more than 99.8%, and the yield can achieve 95.2-97.1%. Compared with traditional technologies, the preparation method disclosed by the invention has the following advantages: as the green solvent, namely the 2-methyltetrahydrofuran is adopted in Grignard reaction, the yield is high, the selectivity is good, the product is easy to separate, the reaction conditions are easy to control, the using quantity of the solvent is small, and the solvent is easy to recover, so that the preparation method is in line with a green chemical idea and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to the synthesis of a key intermediate of antiviral drug efavirenz by using green solvent 2-methyltetrahydrofuran as a Grignard reaction solvent. Background technique [0002] Efavirenz (Efavirenz) is an anti-HIV non-nucleoside reverse transcriptase inhibitor developed by Merck, the chemical name is: (-)-6-chloro-4-cyclopropylethynyl- 4-trifluoromethyl-2H-3,1-benzoxazin-2-one, English name: (-)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4- (trifluoromethyl )-2H-3,1-benzo-xaxin-2-one, the structural formula is as follows: [0003] [0004] Efavirenz is a chiral drug with a left-handed enantiomer chemical structure, and its synthesis mainly adopts the method of racemate resolution and asymmetric synthesis. The method of asymmetric synthesis of efavirenz is still in the stage of laboratory research, and the production method commonly used at present ...

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Problems solved by technology

[0006] The Grignard addition reaction product 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol is the product of efavirenz An important intermediate, the standard reaction process of this method generally adopts diethyl ether or tetrahydrofuran as a solvent, which has the following disadvantages: (1) When the solvent used is diethyl ether, diethyl ether is poor in safety and extremely volatile, flammable, explosive, difficult to store, and difficult to apply It is suitable for industrial production; when tetrahydrofuran is used as the solvent, the miscibility between tetrahydrofuran and water is high, the boiling point (65-66°C) is low, and the toxicity is high (rat oral LD50: 1650mg / kg), and it is easy to absorb water again after water removal; (2 ) When using ether or tetrahydrofuran as a solvent, the reaction yield is low, such as the yield reported in patent US5519021 is 73-74%;] (3) When using ether or tetrahydrofuran as a solvent, the reaction selectivity is not high, and there are a large number of by-products (4) when adopting ether or tetrahydrofuran as a solvent, a large amount of solvent needs to be supplemented during the reaction to dissolve ethylmagnesium bromide and dilute the reaction solution; (5) when adopting ether or tetrahydrofuran as a solvent, The post-processing operation is complicated, and after the reaction, it is necessary to add a large amount of additional organic solvent to extract the product

Solvent recovery and purification issues need further study when preparing products in large quantities

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