Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound

A technology for cyclopropylacetylene and compounds, applied in the field of preparation of -2-amino-5-chloro-α-cyclopropylacetylene-α-trifluoromethylbenzyl alcohol, which can solve burns, high cost, high price, etc. problem, to achieve the effect of cost reduction

Inactive Publication Date: 2010-07-28
SHANGHAI ACEBRIGHT PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The alkaline reagents used in these two methods are butyllithium or diethylzinc, both of which are hazardous chemicals. They will have a strong exothermic chemical reaction with any form of water or even humid air, and even catch fire and contact the human body. Contact can also cause burns, so it is more difficult to operate in industry
And two kinds of reagent prices are all more expensive, cause the cost of synthetic (S)-2-amino-5-chloro-α-cyclopropylacetylene-α-trifluoromethyl benzyl alcohol to be relatively high at present

Method used

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  • Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound
  • Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound
  • Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of cyclopropynemagnesium chloride:

[0039] After the reaction bottle was fully replaced with argon, 4.64ml of cyclopropyne was added, cooled to 0°C, and 28.6ml of n-butylmagnesium chloride was slowly added dropwise, and the internal temperature was controlled at 15°C. After the dropwise addition, continue to stir at 0°C for 2 hours to obtain cyclopropyne magnesium chloride.

Embodiment 2

[0041] After the reaction flask was fully replaced with argon, 90ml of dry methyl tert-butyl ether and NaH (6.0g) were added, cooled to 10°C, trifluoroethanol (3.1ml) was added dropwise, and the internal temperature was controlled at 25°C. Cool to 20°C after dropwise addition, add (1R,2S)-N-pyrrolidinylnorephedrine (13.5g), stir at 25°C for 1 hour, add zinc chloride (9.0g), stir at 25°C 1 hour. 28.6 ml of tetrahydrofuran solution of cyclopropyne magnesium chloride (1.8 M) obtained in Example 1 was added dropwise, and the inner temperature was kept at 25°C. The addition was completed in about 5 minutes, and was added after washing with 1 ml of tetrahydrofuran. After the addition was complete, stir at 25°C for 1 hour. Then cool to -20°C and add 5-chloro-2-aminotrifluorobenzophenone (10.0g), react at this temperature for 1 hour, raise the temperature to -10°C for 3 hours, then slowly raise the temperature to 0°C for 3 hours, Finally, the temperature was naturally raised to roo...

Embodiment 3

[0043] After the reaction bottle was fully replaced with argon, 100ml of dry toluene and NaH (6.0g) were added, cooled to 10°C, trichloroethanol (5.3ml) was added dropwise, and the internal temperature was controlled at 25°C. Cool to 20°C after dropwise addition, add (1R,2S)-N-pyrrolidinylnorephedrine (13.5g), stir at 25°C for 1 hour, add zinc chloride (10.0g), stir at 25°C 1 hour. 28.6 ml of tetrahydrofuran solution of cyclopropyne magnesium chloride (1.8 M) obtained in Example 1 was added dropwise, and the inner temperature was kept at 25°C. The addition was completed in about 5 minutes, and was added after washing with 1 ml of tetrahydrofuran. After the addition was complete, stir at 25°C for 1 hour. Then cool to -20°C and add 5-chloro-2-aminotrifluorobenzophenone (10.0g), react at this temperature for 2 hours, heat up to -5°C for 3 hours, then slowly heat up to 5°C for 3 hours, Finally, the temperature was naturally raised to room temperature for 4 hours. After the rea...

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Abstract

The invention discloses a method for preparing a chiral cylopropyl acetenyl tertiary alcohol compound.The steps of the method are as follows: (a) cylopropyl ethylnen or other derivatives react with a chiral induction reagent, a chirality auxiliary reagent and zinc halide in an organic solvent under the action of an alkaline reagent so as to obtain a zinc complex; (b) addition reaction is carried out between the obtained zinc complex and 5-chlorin-2-amino trifluoro-benzophenone; (c) (S)-2-amino-5-chlorin-alpha-cylopropyl ethylnen-alpha-benzyl alcohol trifluoride is collected from reaction liquid. Compared with butyl lithium and diethylzinc, the alkaline reagent adopted in the invention is safer; in addition, the cheap zinc halide is used as a ligand, which greatly reduces the cost. Therefore, the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a process for the preparation of (S)-2-amino-5-chloro-α-cyclopropylacetylene-α-trifluoromethylbenzyl alcohol. Background technique [0002] The chemical name of Efavirenz is (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-oxazepine Naphthalene-2-one, the structural formula is as follows: [0003] [0004] Efavirenz was approved by the U.S. FDA in 1998 for anti-human immunodeficiency virus (HIV) infection, and is the preferred drug for non-nucleoside reverse transcriptase inhibitors (NNRTIs) recommended by the current international AIDS treatment guidelines. Efavirenz combined with two nucleoside reverse transcriptase inhibitors (NRTI) drugs can be used as the first-line treatment for anti-HIV infection. [0005] (S)-2-Amino-5-chloro-α-cyclopropylacetylene-α-trifluoromethylbenzyl alcohol is a key intermediate for the synthesis of efavirenz, and there are mainly two synthetic methods curren...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/68C07C213/00C07C213/10C07B53/00
Inventor 李金亮赵楠
Owner SHANGHAI ACEBRIGHT PHARMA GRP
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