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

A technology of difluorophenyl and ethylene oxide, which is applied in the field of one-step enzymatic preparation of ticagrelor intermediate-2-oxirane, can solve problems such as being unsuitable for industrialized generation and application, and achieve mild reaction conditions, Simple operation and high yield

Pending Publication Date: 2020-04-28
SYNCOZYMES SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, carbonyl reductase is used to catalytically reduce the substrate to (S)-2-chloro-1-(3,4-difluorophenyl)ethanol, and then the epoxidation is stirred in sodium hydroxide or potassium hydroxide solution. The target product is generated, and the crude product still needs to be purified by column chromatography after extraction with methyl tert-butyl ether, which is not suitable for industrial production applications

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0029] Example 1 Preparation of Ketoreductase

[0030] The genetically engineered bacteria (vector pET21a, host cell E.Coli BL21(DE3)) containing the coding gene of ketoreductase (SEQ ID No.1) was inoculated into 5mL LB test tube medium containing ampicillin for activation culture (37°C) Cultivate for 12h), transfer the activated culture to 400mL LB liquid medium containing ampicillin according to 1% inoculum, cultivate OD to 0.6-0.8 at 37°C, add IPTG (final concentration 0.1mM) and induce culture at 25°C for 16h. The cells were collected by centrifugation to obtain ketoreductase cells. After resuspending the cells in 40mL phosphate buffer (10mM, pH 7.5), the cells were sonicated for 15min in an ice water bath, and the supernatant was collected by centrifugation, pre-frozen at -20°C and then vacuum freeze-dried After 48h, crushed to obtain recombinant ketoreductase enzyme powder.

Embodiment 2

[0031] Example 2 Preparation of (S)-2-(3,4-difluorophenyl) ethylene oxide

[0032] Add methyl tert-butyl ether (500mL), 0.05M pH=9.0 phosphate buffer (300mL), isopropanol (100g) and the substrate 2-chloro-1-(3,4-di Fluorophenyl) ethyl ketone (200g), after stirring evenly, add ketoreductase enzyme powder (20g), coenzyme NADP (60mg) and D201 resin, and react with magnetic stirring at 25°C for 12h while TLC monitors the progress of the reaction. After the reaction, the filtrate was filtered, the filtrate was allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted twice with 100 mL*2 methyl tert-butyl ether, combined with the aforementioned organic phase, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure. 155.7 g of (S)-2-(3,4-difluorophenyl) ethylene oxide was obtained, and the ee value of the S type product was 99.99%. The infrared spectrum of the product is attached figure 1 , The product purity HPLC spectrum ...

Embodiment 3

[0033] Example 3 Preparation of (S)-2-(3,4-difluorophenyl) ethylene oxide

[0034] Add methyl tert-butyl ether (2.5L), 0.05M pH=10.0 phosphate buffer (2.5L), isopropanol (1kg) and the substrate 2-chloro-1-(3,4) to the reaction vessel -Difluorophenyl) ethyl ketone (2kg), after stirring evenly, add ketoreductase enzyme powder (500g), coenzyme NADP (600mg) and D201 resin, and magnetically stir the reaction at 25°C for 20h while TLC monitors the progress of the reaction. After the reaction, the filtrate was filtered, the filtrate was allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted twice with 100 mL*2 methyl tert-butyl ether, combined with the aforementioned organic phase, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure. 1.52 kg of (S)-2-(3,4-difluorophenyl) ethylene oxide was obtained, and the ee value of the S type product was 99.99%. The chiral purity HPLC spectrum of the product is attached Figure 4...

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Abstract

The invention discloses a method for preparing a ticagrelor intermediate (S)-2-(3,4-difluorophenyl) oxirane by one-step enzymatic reaction. Under an alkaline condition, 2-chloro-1-(3,4-difluorophenyl)ethanone is subjected to a reductive cyclization by using ketoreductase so as to obtain the (S)-2-(3,4-difluorophenyl) oxirane. The method adopts a liquid-liquid-solid three-phase reaction so as to obtain the target product in one step, is easy to operate and mild in reaction conditions, and is suitable for industrial production.

Description

Technical field: [0001] The invention belongs to the field of biopharmaceuticals, and specifically relates to a method for preparing ticagrelor intermediate (S)-2-(3,4-difluorophenyl)ethylene oxide by a one-step enzymatic method. Background technique: [0002] Ticagrelor, trade name Brilinta, chemical name (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl )Cyclopropyl]amino]-5-propylthiotriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentadiol, The structure is as formula I. Ticagrelor is a new type of drug for the treatment of acute coronary syndromes developed by AstraZeneca Pharmaceuticals. PLATO studies have shown that ticagrelor is significantly better than clopidogrel, so it has been listed in many domestic and foreign guidelines Recommended in the first line. [0003] [0004] Among them, (S)-2-(3,4-difluorophenyl)oxirane (Formula II) is one of the key intermediates for the preparation of ticagrelor. Because of its unique structure of chiral center, its The ...

Claims

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Application Information

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IPC IPC(8): C12P17/02
CPCC12P17/02
Inventor 王波竺伟包蕾杨坤于
Owner SYNCOZYMES SHANGHAI
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