Method for preparing (S)-2-(3,4-difluorophenyl)ethylene oxide

A technology of difluorophenyl and oxirane is applied in the field of preparing chiral compound-2-oxirane, which can solve the problems of long reaction period, complicated post-processing and high cost, and achieves low cost and post-processing process. Simple, short reaction steps

Pending Publication Date: 2019-07-02
LESHAN VOCATIONAL & TECHN COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] As far as the above route is concerned, whether it is chemical synthesis, biocatalysis and chemical method combination or chemical resolution method, the target product is obtained through two or more steps, the overall reaction cycle is long, the post-treatment is complicated, and the efficiency is low. low, high cost

Method used

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  • Method for preparing (S)-2-(3,4-difluorophenyl)ethylene oxide
  • Method for preparing (S)-2-(3,4-difluorophenyl)ethylene oxide
  • Method for preparing (S)-2-(3,4-difluorophenyl)ethylene oxide

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Experimental program
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Effect test

Embodiment 1

[0044] Add N-methylmorpholine nitrogen oxide (16.2g, 2.3equiv., 138mmol), catalyst 1 (1.76g, 0.04equiv., 2.4mmol), 80mL of dichloromethane and 30mL of ethanol into a 250mL three-neck round bottom flask, Add 3,4-difluorostyrene (8.4g, 1.0equiv., 60.0mmol), stir at room temperature for 15 minutes, then cool to -45°C, start to slowly add 45mL of 85% m-chloroperoxybenzoic acid dissolved in ethanol dropwise (19.5g, 1.6equiv., 96.0mmol), the dropwise addition was completed in about half an hour, kept stirring for 4 hours, adjusted the pH to about 9 with 1.0mol / L sodium hydroxide solution, added 100mL dichloromethane and 15mL water for extraction , the organic layer was dried with anhydrous sodium sulfate for 3 hours, and the solvent was recovered under reduced pressure to obtain an orange viscous substance, which was obtained by column chromatography (eluent: petroleum ether / ethyl acetate=20 / 1) to obtain a yellow oily substance (S) -2-(3,4-difluorophenyl)oxirane 7.8g, yield 83%, e.e...

Embodiment 2

[0047]Add N-methylmorpholine nitrogen oxide (16.2g, 2.3equiv., 138mmol), catalyst 1 (1.76g, 0.04equiv., 2.4mmol), 80mL of dichloromethane and 30mL of ethanol into a 250mL three-neck round bottom flask, Add 3,4-difluorostyrene (8.4g, 1.0equiv., 60.0mmol), stir at room temperature for 15 minutes, then cool to -65°C, start to slowly add 45mL of 85% m-chloroperoxybenzoic acid dissolved in ethanol dropwise (19.5g, 1.6equiv., 96.0mmol), the dropwise addition was completed in about half an hour, kept stirring for 4 hours, adjusted the pH to about 9 with 1.0mol / L sodium hydroxide solution, added 100mL dichloromethane and 15mL water for extraction , the organic layer was dried with anhydrous sodium sulfate for 3 hours, and the solvent was reclaimed under reduced pressure to obtain an orange viscous substance, and a yellow oily substance ((S )-2-(3,4-difluorophenyl)oxirane) 7.1 g, yield 76%, e.e. value 91%.

Embodiment 3

[0049] Add N-methylmorpholine nitrogen oxide (16.2g, 2.3equiv., 138mmol), catalyst 3 (1.52g, 0.04equiv., 2.4mmol), 80mL of dichloromethane and 30mL of ethanol into a 250mL three-neck round bottom flask, Add 3,4-difluorostyrene (8.4g, 1.0equiv., 60.0mmol), stir at room temperature for 15 minutes, then cool to -45°C, start to slowly add 45mL of 85% m-chloroperoxybenzoic acid dissolved in ethanol dropwise (19.5g, 1.6equiv., 96.0mmol), the dropwise addition was completed in about half an hour, kept stirring for 4 hours, adjusted the pH to about 9 with 1.0mol / L sodium hydroxide solution, added 100mL dichloromethane and 15mL water for extraction , the organic layer was dried with anhydrous sodium sulfate for 3 hours, and the solvent was reclaimed under reduced pressure to obtain an orange viscous substance, and a yellow oily substance ((S )-2-(3,4-difluorophenyl)oxirane) 7.6 g, yield 81%, e.e. value 75%.

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Abstract

The invention relates to a method for preparing (S)-2-(3,4-difluorophenyl)ethylene oxide. The invention relates to the technical field of pharmaceutical and chemical synthesis, and discloses a methodfor producing the (S)-2-(3,4-difluorophenyl)ethylene oxide in one step through an asymmetric epoxidation reaction with a chiral Salen-manganese complex as a catalyst and 3,4-difluorostyrene as a substrate, wherein the ee value of the obtained target product is greater than 91%. The process has the advantages of short reaction steps, simple post-treatment process, low cost, mild conditions and highoptical purity of the obtained product.

Description

technical field [0001] The invention relates to the field of pharmaceutical and chemical synthesis, in particular to a method for preparing a chiral compound (S)-2-(3,4-difluorophenyl)oxirane. The chiral compound is an intermediate synthesized from the drug ticagrelor. Background technique [0002] Ticagrelor is a selective small molecule anticoagulant drug developed by AstraZeneca. The medicine takes effect quickly after oral administration, and can effectively improve the symptoms of patients with acute coronary heart disease. It reversibly acts on the purine 2 receptor (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells, so it is especially suitable for patients who need anticoagulant therapy before surgery. [0003] Patent CN103508899 summarizes several synthetic routes of ticagrelor in detail, among which the route reported in WO2008018822 is more commonly used, and the key step of this route is the synthesis of (S)-2-(3,4-difluorophenyl)epoxy Ethane (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D301/14C07D303/08
CPCC07D301/14C07D303/08
Inventor 岳李荣李喜安胡冬燕韩广田南泽东任华忠宋成英廖秀英封家福徐娇黄泓轲李静华张源魏荷琳杨迪笑王辉俊张红张知贵
Owner LESHAN VOCATIONAL & TECHN COLLEGE
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