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Synthetic method of efavirenz key intermediate

A technology of efavirenz and synthetic method, which is applied in the field of preparation of efavirenz, can solve the problems of high price and dosage of organic ligands, unsuitability for industrial production, harsh reaction conditions, etc., and achieves simple routes and excellent reaction yields , the effect of high total yield

Active Publication Date: 2018-12-07
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

Method used

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  • Synthetic method of efavirenz key intermediate
  • 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 an efavirenz key intermediate. The synthetic method comprises the following steps: carrying out reaction on parachloroaniline and pivaloyl chloride to protect amino to obtain N-(4-chlorphenyl)-2,2-dimethyl propanamide; carrying out Friedel-Crafts acylation reaction on the product and Friedel-Crafts acylation under action of aluminum trichloride to hydrolyze to obtain 4-chloro-2-trifluoroacetyl aniline hydrochloride in an acidic condition; and then carrying out alkalization to obtain 4-chloro-2-trifluoroacetyl aniline, carrying out reaction with cyclopropyl acetylene magnesium chloride in a catalytic system formed by a ligand (1R, 2S)-1-phenyl-2-(1-pyrrolidyl)-1-propyl alcohol, and carrying out an asymmetrical self-catalytic reaction to obtain the efavirenz key intermediate. The synthetic method of the efavirenz key intermediate, provided by the invention, is cheap and easily available in raw material, low in toxicity of reagent and mild in reaction condition, amino protection and deprotection are not carried out frequently, the line is concise, the yields of reaction of each step are excellent, and 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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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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