Development of a Practical Enzymatic Process for Preparation of (S)-2-Chloro-1-(3,4-difluorophenyl)ethanol,Organic Process Research & Development

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Development of a Practical Enzymatic Process for Preparation of (S)-2-Chloro-1-(3,4-difluorophenyl)ethanol
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2017-09-01 00:00:00 , DOI: 10.1021/acs.oprd.7b00230
Xiang Guo ₁ , Jia-Wei Tang ₁ , Jiang-Tao Yang ₁ , Guo-Wei Ni ₁ , Fu-Li Zhang ₁ , Shao-Xin Chen ₁

Affiliation

(S)-2-Chloro-1-(3,4-difluorophenyl)ethanol (1) is a vital chiral intermediate for the synthesis of Ticagrelor—an effective treatment for acute coronary syndromes. A ketoreductase (KRED) KR-01 in our KRED library was screened to transform 2-chloro-1-(3,4-difluorophenyl)ethanone (2) into the chiral alcohol 1. During process optimization, the bioreduction procedure was performed at a substrate concentration of 500 g/L, giving a near 100% conversion with >99.9% ee. The product 1 was directly obtained by extraction and can be used for the synthesis of (1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid ethyl ester (3) with a yield of 98% and >99.9% de, greatly simplifying the original process operation and reducing the safety risk. This process is green and environmentally sound with high productivity of biocatalysis and a space–time yield of 145.8 mmol/L/h. It has an opportunity to be very useful in industrial applications. Additional studies have indicated that KR-01 can also be used to prepare (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethanol (4) with a substrate concentration of 500g/L.

中文翻译：

开发实用的酶法制备（S）-2-氯-1-（3,4-二氟苯基）乙醇

（小号）- 2-氯-1-（3,4-二氟苯基）乙醇（1）是用于替卡格雷-的有效治疗的合成用于急性冠脉综合征的重要手性中间体。筛选了我们的KRED库中的酮还原酶（KRED）KR-01，将2-氯-1-（3,4-二氟苯基）乙酮（2）转化为手性醇1。在工艺优化过程中，生物还原程序是在底物浓度为500 g / L的条件下进行的，转化率接近100％，ee≥99.9％。产物1是通过萃取直接获得的，可用于合成（1 R，2 R）-2-（3,4-二氟苯基）环丙烷甲酸乙酯（3）的收率达98％和> 99.9％de，大大简化了原始工艺操作并降低了安全风险。此过程绿色环保，具有高生物催化生产率，时空产率为145.8 mmol / L / h。它有机会在工业应用中非常有用。进一步的研究表明，KR-01也可用于制备底物浓度为500g / L的（R）-1-（3,5-双（三氟甲基）苯基）乙醇（4）。

更新日期：2017-09-04

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