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

Abstract

(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.

The Impact of Recent Developments in Technologies which Enable the Increased Use of Biocatalysts

“…The biphasic mixture of product and starting material was separated, and the organic material recirculated to increase the conversion. The asymmetric reduction of the chloroethyl precursor 27 was also reported, in this case using a ketoreductase from a metagenomic library . The process for the synthesis of alcohol 28 was optimized to give up to 500 g/L substrate concentration.…”

Whole‐cell biocatalysis platform for gram‐scale oxidative dearomatization of phenols

“…Examples of WC biocatalytic processes. (a) Select scaffolds accessed through WC biocatalytic reactions (Baker Dockrey et al., ; Guo et al., ; Hadi et al., ; Kaluzna et al., ; Matsuyama et al., ; Milker et al., ; Xie & Tang, ). (b) WC biocatalysis utilizing a multi‐enzyme cascade to generate chiral benzylic amines (Both et al., ) [Colour figure can be viewed at wileyonlinelibrary.com]…”

“…On an industrial scale, several processes have been designed to employ WC biocatalysts. Notably, WC biocatalysis has been utilized for the generation of valuable chemical feedstocks such as enantio‐enriched alcohols, (Matsuyama, Yamamoto, & Kobayashi, ) performance material monomers, (Kaluzna et al., ) and pharmaceutically relevant intermediates, (Guo et al., ) as well as the late‐stage functionalization of active pharmaceutical ingredients during route development (Figure a; Guo et al., ; Milker, Fink, Rudroff, & Mihovilovic, ; Xie & Tang, ). Recently, researchers at GlaxoSmithKline demonstrated that a WC biocatalysis platform is also useful for discovery of new synthetic routes on the gram‐scale, developing several biocatalytic routes to chiral 1,3‐substituted cyclohexanones, such as 2 (Hadi et al., ).…”

“…On an industrial scale, several processes have been designed to employ WC biocatalysts. Notably, WC biocatalysis has been utilized for the generation of valuable chemical feedstocks such as enantio-enriched alcohols, (Matsuyama, Yamamoto, & Kobayashi, 2002) performance material monomers, (Kaluzna et al, 2016) and pharmaceutically relevant intermediates, (Guo et al, 2017) as well as the late-stage functionalization of active pharmaceutical ingredients during route development ( Figure 1a; Guo et al, 2017;Milker, Fink, Rudroff, & Mihovilovic, 2017;Xie & Tang, 2007).…”

“…Despite advances in synthetic oxidative dearomatization methodology, these F I G U R E 1 Examples of WC biocatalytic processes. (a) Select scaffolds accessed through WC biocatalytic reactions (Baker Dockrey et al, 2018;Guo et al, 2017;Hadi et al, 2018;Kaluzna et al, 2016;Matsuyama et al, 2002;Milker et al, 2017;Xie & Tang, 2007). (b) WC biocatalysis utilizing a multi-enzyme cascade to generate chiral benzylic amines (Both et al, 2016) [Colour figure can be viewed at wileyonlinelibrary.com] reactions often exhibit substrate-controlled site-selectivity, low levels of stereoselectivity, and can require stoichiometric chiral reagents.…”