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Method for asymmetric synthesis of anti-Aids drug, namely efavirenz key intermediate

An efavirenz and anti-AIDS technology, which is applied in the field of synthesis of the key propargyl alcohol intermediate of efavirenz, can solve the problems of complex operation, expensive ligands, danger, etc., achieve mild process conditions, increase ee value, The effect of short process flow

Inactive Publication Date: 2020-02-04
湖北随州双星生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method involves the protection and deprotection of the amino group and the corresponding separation and purification work, the operation is complicated, and the chiral auxiliary agent is expensive and difficult to obtain, which increases the difficulty and cost of industrial production
[0016] In summary, the above method for synthesizing the key intermediate of efavirenz uses dangerous Grignard reagents or organolithium reagents, which increases the difficulty of the synthesis process. The synthesis process is cumbersome and inconvenient to operate, and the ligands used are expensive, which increases the industrial production cost

Method used

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  • Method for asymmetric synthesis of anti-Aids drug, namely efavirenz key intermediate
  • Method for asymmetric synthesis of anti-Aids drug, namely efavirenz key intermediate
  • Method for asymmetric synthesis of anti-Aids drug, namely efavirenz key intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Under the protection of nitrogen, add 5mL of toluene, 0.0245g of barium fluoride, 0.045g of organic ligand quinidine, and 0.149mL of cyclopropyne into the round-bottomed flask respectively. Stir evenly at a temperature of 25°C, and slowly add dimethyl zinc dropwise. Solution 2.1mL, after the dropwise addition, stir at constant temperature for 3 hours, add tetraisopropyl titanate 0.41mL, continue stirring for 2 hours, then cool down to -35°C, add 5-chloro-2-aminotrifluorobenzophenone in one go 0.157 g, which was stirred at -35°C for 72 hours. TLC detects that the reaction is complete, add 20 mL of toluene to the reaction solution, then slowly add it to 20 mL of dilute hydrochloric acid to quench, then add 2 g of activated carbon and stir for 0.5 hours, then filter, separate the organic phase and the aqueous phase, and wash the organic phase with 100 mL of saturated saline , dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40°C. After purifi...

Embodiment 2

[0035] Under the protection of nitrogen, add 5mL of toluene, 0.025g of barium fluoride, 0.045g of organic ligand quinidine, and 0.16mL of cyclopropyne into the round-bottomed flask respectively. Stir at a temperature of 25°C and add dimethyl zinc slowly. Solution 2.2mL, after the dropwise addition, stir at constant temperature for 3 hours, add tetraisopropyl titanate 0.42mL, continue stirring for 2 hours, then cool down to -30°C, add 5-chloro-2-aminotrifluorobenzophenone in one go 0.161 g, kept at -30°C and stirred for 72 hours. TLC detects that the reaction is complete, add 20 mL of toluene to the reaction solution, then slowly add 20 mL of dilute hydrochloric acid to quench it, then add 2.5 g of activated carbon and stir for 0.5 hours, then filter, separate the organic phase and the aqueous phase, and use 100 mL of saturated saline for the organic phase Wash, dry over anhydrous sodium sulfate, and distill under reduced pressure at 43°C to obtain 0.163 g of white powder after...

Embodiment 3

[0037] Under the protection of nitrogen, add 6mL of toluene, 0.027g of barium fluoride, 0.046g of organic ligand quinidine, and 0.18mL of cyclopropyne into the round-bottomed flask, stir well at 24°C, and slowly add dimethyl zinc dropwise. Solution 2.4mL, after the dropwise addition, stir at constant temperature for 3.5 hours, add tetraisopropyl titanate 0.43mL, continue stirring for 2 hours, then cool down to -30°C, add 0.17g of 5-chloro-2-aminotrifluorobenzophenone at one time, Stirring was maintained at -30°C for 48 hours. TLC detects that the reaction is complete, add 20 mL of toluene to the reaction solution, then slowly add 20 mL of dilute hydrochloric acid to quench it, add 2.3 g of activated carbon and stir for 0.5 hours, then filter, separate the organic phase and the aqueous phase, and use 100 mL of saturated saline for the organic phase Washed, dried over anhydrous sodium sulfate, and distilled under reduced pressure at 40°C to obtain 0.166g of white powder after pu...

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Abstract

The invention discloses a method for asymmetric synthesis of an anti-Aids drug, namely an efavirenz key intermediate. The method comprises the following steps that in an organic solvent, fluoride, anorganic ligand (9S)-6'-methoxy-deoxidized cinchonine-9-ol and cyclopropyl acetylene are evenly stirred, an organic zinc solution is slowly added at the temperature of 15-25 DEG C, after constant-temperature stirring is conducted for 3-5 hours, tetraisopropyl titanate is added, stirring is continued to be conducted for 2-3 hours, then the temperature is decreased to minus 20 DEG C to 0 DEG C, 5-chloro-2-amino-trifluorobenzophenone is added, a mixture is stirred at the temperature of minus 20 DEG C to 0 DEG C for 5-12 hours, after a reaction is completed, a proton source is added for a quenchingreaction, then a certain amount of activated carbon is added, a mixture is stirred for 0.5 hour and filtered, an organic phase and a water phase are separated in an extraction mode, the organic phaseis washed, dried and subjected to vacuum concentration, and after purification, the efavirenz key intermediate is obtained. The technological process is short, the technological condition is mild, operation is easy, environmental protection is achieved, the cost is low, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to a method for synthesizing a key propargyl alcohol intermediate of efavirenz. Background technique [0002] Efavirenz is a chiral drug, its chemical name is: S-(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-2H-3,1-benzoxa Oxin-2-one, its structure is as follows: [0003] [0004] Efavirenz was approved by the US FDA in 1998 and is a selective non-nucleoside reverse transcriptase inhibitor for human immunodeficiency virus-1 (HIV-1). World Health Organization (WHO) guidelines list it as a component of treatment-naïve first-line antiretroviral (ARV) therapy. The most common NNRTI for first-line treatment, efavirenz (EFV), can be used as a first-line treatment option against HIV infection when used in combination with two NRTIs. [0005] (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol is a key intermediate in the synthesis of ef...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/70B01J31/26
CPCC07B53/00C07C213/00B01J27/138B01J31/26B01J31/2217C07B2200/07C07C2601/02B01J2531/46B01J35/19C07C215/70
Inventor 吴广文李灿廖先传周毅博张方方
Owner 湖北随州双星生物科技有限公司
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