A kind of synthetic method of efavirenz key intermediate

Abstract

The invention provides a synthetic method of a key intermediate of efavirenz, comprising the following steps: reacting p-chloroaniline and pivaloyl chloride to protect the amino group to obtain N-(4-chlorophenyl)-2,2-dimethylpropane Amide; the above product and trifluoroacetic anhydride are hydrolyzed under acidic conditions to obtain 4-chloro-2-trifluoroacetylaniline hydrochloride after Friedel-Crafts acylation reaction under the action of aluminum trichloride; then through alkalization Obtain 4-chloro-2-trifluoroacetylaniline, and in the catalytic system that ligand (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol forms with cyclopropyne Magnesium chloride reaction, the key intermediate of efavirenz was prepared through asymmetric autocatalytic reaction. The method for synthesizing the key intermediate of efavirenz provided by the present invention has cheap and easy-to-obtain raw materials, low toxicity of the reagents used, mild reaction conditions, no need for frequent amino protection and deprotection, simple route, and excellent reaction yields in each step , the total yield is high.

Description

technical field [0001] The invention belongs to the technical field of preparation of efavirenz, in particular to a method for synthesizing a key intermediate of efavirenz. Background technique [0002] Efavirenz, chemical name (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzo Oxazin-2-one. Efavirenz is the preferred first-line anti-HIV virus drug, which is a selective non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus-type 1 (HIV-1), and inhibits HIV-1 reverse transcription through non-competitive binding Enzymatic activity, acting on templates, primers, or nucleoside triphosphates, with a small fraction of competitive inhibition, thereby preventing viral transcription and replication. Efavirenz is indicated for the treatment of adults, adolescents and children with HIV-1 infection in combination with other antiviral drugs. [0003] (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol is ...

AI Technical Summary

Problems solved by technology

In this method, the organic ligand is expensive and used in a large amount; the dangerous reagent n-butyllithium is used, and the asymmetric synthesis reaction needs to be carried out at low temperature (-50°C), the reaction conditions are harsh, and frequent amino protection and deprotection are required. , cumbersome operation, not suitable for industrial production

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