Method for preparing (R)-2-chlorin-1-(3-chlorphenyl) ethanol by microorganism catalysis

Abstract

The invention provides a method for preparing (R)-2-Chloro-1-(3-chlorophenyl) ethanol through catalysis of microorganisms. The method utilizes producing strains, Vibrio fluvialis, Aureobacterium terregens, Alcaligenes faecalis, Bacillusthuringiensis, Trichosporon cutaneum, Candidaboidinii and so on of known carbonyl reductase with high enantioselectivity, to be fermented into enzyme under optimization conditions; in a single aqueous phase system or an aqueous / organic solvent biphasic system, 2-Chloro-1-(3-chlorophenyl) ethyl ketone is taken as a substrate, and glucose and macroporous resin are added; when the concentration of the substrate, 2-Chloro-1-(3-chlorophenyl) ethyl ketone, is between 50 and 140mmol / L (namely between 9.5 and 26.5 g / L), the transformation is performed for 48h, and the product (R)-2-Chloro-1-(3-chlorophenyl) ethanol is obtained after transformation conditions are optimized; the e.e value of the optical purity reaches 99.6 percent, the molar conversion rate reaches more than 99 percent, and coenzyme does not need to be added during the whole reaction process. The content of the (R)-2-Chloro-1-(3-chlorophenyl) ethanol prepared by the method reaches 99.2 percent, and the optical purity reaches 99.8 percent (e. e.).

Description

technical field [0001] The invention relates to a method for preparing (R)-2-chloro-1-(3-chlorophenyl)ethanol by microorganism catalysis, and belongs to the technical field of biocatalytic asymmetric reduction preparation of halogenated aryl chiral alcohols, which are pharmaceutical and chemical intermediates. Background technique [0002] Chiral drugs and their chiral intermediates are receiving more and more attention. For example, Fluoxetine, the first choice for antidepressants, was originally a racemic antidepressant. In 1997, its sales reached 2.7 billion US dollars. Later, it was found that its S-fluoxetine was 3 times more effective than R-fluoxetine (Ou Zhimin et al.: Journal of Wuxi University of Light Industry 2003, 22(1): 43-48), and the product was soon replaced by S-fluoxetine Instead, its important chiral intermediate is the chiral aryl alcohol 3-chloro-1-phenylpropanol. Another example is the anti-asthma drug formoterol, which is a long-acting β2 receptor ag...

AI Technical Summary

Problems solved by technology

[0012] It has been reported that (1R)-2-chloro-(halophenyl)ethanol was synthesized by asymmetric catalytic reduction of (1R)-2-chloro-(halophenyl)ethanone (Marc Devocelle, et.al. : Tetrahedron Letters 40, 4551-4554, 1999; Ohkuma.T, et.al.: Organic Letters, 9(2), 255-257, 2007), describe the use of rhodium (Rh) catalysts, which are expensive , high price, relatively harsh reaction conditions, complex catalyst recovery, large-scale industrial production is easy to cause pollution

Chinese patent CN1063422C (Kodama Haoxuan, etc.: 1996) discloses the product obtained by reacting racemic 2-halogenated-1-(substituted phenyl)ethanol and phthalic anhydride, and then adopts an optically active organic base as a decomposing compound Separate the ingredients to obtain an optically active intermediate, and finally hydrolyze or alcoholyze to obtain an optically active compound 2-halogenated-1-(substituted phenyl)ethanol. This method needs to start with a racemic raw material and undergo a three-step reaction to obtain the product , the yield is low, and at the same time in the resolution process, alkaloids with higher prices, multiple solvents and reagents are needed, which increases the production cost, and 50% of the useless enantiomers and some by-products are difficult to handle, resulting in environmental pollution

Chinese patent CN1228448C (Wang Yongmei et al., 2005) describes the preparation of (R)-2-halogenated-1-(substituted phenyl)ethanol using biocatalytic reduction, but as can be seen from the examples of this patent, this patent Using commercially available yeast as a biocatalyst, due to its complex enzyme system, the optical purity of the transformation product is not high, and the yield is low

And none of the above patents involves the compound (R)-2-chloro-1-(3-chlorophenyl)ethanol

There is no research report on the production of aryl chiral alcohol (R)-2-chloro-1-(3-chlorophenyl)ethanol by carbonyl reductase catalyzed by other species of microorganisms except yeast

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