Method for preparing chiral medicinal intermediate R-3-hydroxy butyric acid ethyl ester by microbial fermentation

Abstract

The invention discloses a method for preparing chiral medicinal intermediate R-3-hydroxy butyric acid ethyl ester. By using the method, a regenerative carbon source such as starch and the like can be efficiently and stably converted into (R)-3-hydroxy butyric acid by constructing multiple enzymes such as pha, phb and phc required for synthesizing the (R)-3-hydroxy butyric acid ethyl ester into genes of E.Coli, and the (R)-3-hydroxy butyric acid ethyl ester can be obtained by means of an auxiliary substrate ethanol at the same time. The preparation method of the invention can greatly lower theproduction cost so as to break through the technical bottlenecks of high industrialized cost and low chiral purity of the (R)-3-hydroxy butyric acid ethyl ester.

Description

technical field [0001] The invention relates to a chiral pharmaceutical intermediate, in particular to a method for preparing the chiral pharmaceutical intermediate R-3-hydroxybutyrate ethyl ester by microbial fermentation. Background technique [0002] Ethyl 3-hydroxybutyrate is a very important chiral pharmaceutical intermediate for the synthesis of many chiral drugs. The molecule of ethyl 3-hydroxybutyrate contains a multifunctional group, and its chiral single enantiomer (R) Ethyl-3-hydroxybutyrate and ethyl (S)-3-hydroxybutyrate are very promising and important chiral building blocks. For example, ethyl (S)-3-hydroxybutyrate is the chiral source of natural products such as lavandulol, Sclerotinia, galenicin, carbamycin and griseovirmycin, and (R)-3- Ethyl hydroxybutyrate is an important chiral compound for the synthesis of imipenem, meropenem, panipenem, faropenem, ertapenem, doripenem, biapenem and other penem antibiotics and L-carnitine intermediate. [0003] At pr...

AI Technical Summary

Problems solved by technology

The chemical method can obtain higher yields, but the main disadvantage is that the stereoselectivity of the reaction is low, and the preparation of chiral catalysts is difficult

[0007] (2) Directly use alcohol dehydrogenase to catalyze ethyl acetoacetate. This method not only requires enzyme protein to participate in the reaction, but also needs to add expensive coenzyme factors, which is limited in practical application

For example, yeast cells contain alcohol dehydrogenase, which can realize the in situ regeneration of coenzymes without adding expensive coenzyme factors, but it is known that it can be used for the asymmetric reduction of ethyl acetoacetate to prepare (R)-3-hydroxyl For ethyl butyrate strains (such as Rhodotorula, etc.), the conversion rate is generally low (less than 50%)

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