Method for preparing L-homophenylalanine

Abstract

The invention discloses a process method for preparing single optical pure L-homophenylalanine by using L-homophenylalanine dehydrogenase as a biological catalyst. The method particularly comprises the following steps of: adding a substrate, ammonium formate, the L-homophenylalanine dehydrogenase and a formate dehydrogenase mediated coenzyme recycling and regenerating system into reaction liquid; after reacting under an oscillating or stirring condition, filtering from the reaction system to directly obtain an L-homophenylalanine product; and circulating the filtrate for the next reaction, wherein the reaction temperature is between 15 and 40 DEG C. The L-homophenylalanine is prepared by coordinating the L-homophenylalanine dehydrogenase with the coenzyme recycling and regenerating system and by adopting a simple filtering circulation process, wherein the substrate concentration reaches 560 mM; the NAD+ concentration of the required coenzyme is low; the coenzyme can be recycled and reused for many times, so that the cost of the coenzyme can be ignored; the yield excesses 95 percent; and important application value is achieved.

Description

technical field [0001] The invention belongs to the field of preparation of chiral pharmaceutical intermediates, and relates to a method for the asymmetric preparation of chiral pharmaceutical intermediates by biocatalysis, in particular to a method using 2-oxo-4-phenylbutyric acid and its esters as substrates , using homophenylalanine dehydrogenase as a biocatalyst to realize a process for the efficient preparation of L-homophenylalanine with single optical purity. Background technique [0002] L-homophenylalanine, namely (S)-2-amino-4-phenylbutyric acid, molecular formula C 10 h 13 NO 2 , the molecular weight is 179.22, and the CAS number is 943-73-7. L-homophenylalanine is a non-natural chiral α-amino acid, and this type of amino acid and its ester are important raw materials for preparing angiotensin (ACE) inhibitor drugs. It is the common intermediate of about 20 new antihypertensive drugs in the world. Captopril (Captopril), Temocapril, Cilazapril (Silazapril), et...

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Problems solved by technology

The former utilizes a chiral resolution reagent to resolve the racemate, but the maximum yield generally does not exceed 50% (see: Chem.Pharm.Bull.1989, 37:280-283); the asymmetric synthesis method utilizes a chiral catalyst Catalysis directly obtains enantiomers, but there are many shortcomings: complex reaction process, harsh reaction conditions (-60 ° C), high production costs, and serious environmental pollution (see: J.Am.Chem.Soc.1988, 110: 1547 -1557)

Another more general method is the method that amino acid aminotransferase catalyzes the corresponding keto acid transamination, such as the Chinese invention patent with the patent number 200710021346.X and the use of Lo et al. Aspartate aminotransferase and U.S. Patent No. 6,146,859 use tryptophan aminotransferase to successfully synthesi

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