R-3-hydroxybutyrate methyl ester biosynthesis preparation method

Abstract

The invention discloses a biosynthesis preparation method of a chiral pharmaceutical intermediate R-3- hydroxybutyrate methyl ester. The method comprises the following steps: constructing multiple enzymes, such as pha, phb and phc required by synthesizing (R)-3- hydroxybutyrate methyl ester in the gene of E.Coli; stably converting starch and other renewable resources into the (R)-3- hydroxybutyrate methyl ester with high efficiency; and simultaneously obtaining the (R)-3- hydroxybutyrate methyl ester with the help of auxiliary substrate ethanol. The preparation method can greatly reduce the production cost so as to break through the technical bottleneck of high industrialization cost and low chiral purity of the (R)-3- hydroxybutyrate methyl ester.

Description

technical field [0001] The invention relates to a chiral pharmaceutical intermediate, in particular to a biosynthetic preparation method of the chiral pharmaceutical intermediate R-3-hydroxybutyrate methyl ester. Background technique [0002] Methyl 3-hydroxybutyrate is a very important chiral pharmaceutical intermediate for the synthesis of many chiral drugs. The molecule of methyl 3-hydroxybutyrate contains a multifunctional group, and its chiral single enantiomer (R) Both methyl-3-hydroxybutyrate and methyl (S)-3-hydroxybutyrate are very promising and important chiral building blocks. For example, (S)-3-hydroxybutyric acid methyl ester is the chiral source of natural products such as lavandulol, Sclerotinia, galenicin, carbamycin and griseovirmycin, and (R)-3- Methyl 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. [0...

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Problems solved by technology

[0007] (2) Directly use alcohol dehydrogenase to catalyze methyl 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 an alcohol dehydrogenase system, 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 methyl acetoacetate to prepare (R)-3-hydroxyl For methyl butyrate strains (such as Rhodotorula, etc.), the conversion rate is generally low (less than 50%)

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