A kind of synthetic method of efavirenz key intermediate

A synthetic method, the technology of efavirenz, applied in the field of preparation of efavirenz, can solve the problems of high price and dosage of organic ligands, unsuitable for industrial production, harsh reaction conditions, etc., and achieve simple route and excellent reaction yield , the effect of high total yield

Active Publication Date: 2021-10-22
JIANGSU SHAXING CHEM
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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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  • A kind of synthetic method of efavirenz key intermediate

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Embodiment Construction

[0017] A kind of synthetic method of efavirenz key intermediate, comprises the following steps:

[0018] S1: Add 25.50g of p-chloroaniline to a mixture of 70ml of methyl tert-butyl ether and 24ml of sodium hydroxide solution (10mol / L), cool down to 10°C, slowly add 25.60g of pivaloyl chloride dropwise, drop for 40min After completion, keep stirring at 10-15°C for 2 hours, then rise to room temperature and stir for 4 hours. Cooled to 0°C, white crystals precipitated, filtered with suction, washed the filter cake with water, and dried under reduced pressure at 55°C for 5 hours to obtain 41.27g of white solid N-(4-chlorophenyl)-2,2-dimethylpropanamide ;

[0019] S2: Add 60.10g of anhydrous aluminum trichloride to 300ml of dichloromethane, lower the temperature to -20°C, slowly add 44.10g of TFAA dropwise, control the temperature at -23~-20°C, and finish dropping in 1h. Insulation reaction 2h. Add 38.11 g of N-(4-chlorophenyl)-2,2-dimethylpropanamide in 3 batches at -25°C, comp...

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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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/68C07C213/00C07C233/15C07C231/02C07C225/22C07C221/00
CPCC07B2200/07C07C213/00C07C221/00C07C231/02C07C2601/02C07C233/15C07C225/22C07C215/68
Inventor 潘江平王宏胜刘海军刘西统
Owner JIANGSU SHAXING CHEM
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