Method for biological catalysis preparation of (R)-2-hydroxyl-4-phenyl ethyl butyrate

Abstract

The invention relates to a method for preparing (R)-2-hydroxyl-4- phenylbutyric ethyl butyrate by adopting biological catalysis, which belongs to the technology field of the biocatalytic anisomerous reducing preparation medical chiral intermediate. The method comprises the following steps: utilizing produced bacteria Candida boidinii of high antimer selective carbonyl reductase screened etc.; fermenting and producing enzyme under the optimizing condition; taking 2-hydroxyl-4-phenylbutyric ethyl butyrate as a substrate in a single water phase system, a water / organic two-phase system or a water / resin two-phase system; adding grape sugar to wet thalli; and preparing (R)-2- hydroxyl-4- phenylbutyric ethyl butyrate. When the concentration of the substrate of 2-hydroxyl-4-phenylbutyric ethyl butyrate is 1 to 50g / L, (R)-2- hydroxyl-4- phenylbutyric ethyl butyrate is subjected to transformation for 1h to 48h, so as to ensure that the enantiomeric excess of the (R)-2- hydroxyl-4- phenylbutyric ethyl butyrate reaches 84.9 to 98.88 percent, the transformation rate of Moore reaches 72.0 to 84.6 percent, and coenzyme is not needed during the whole reaction process.

Description

technical field [0001] The invention relates to a biocatalytic method for preparing ethyl (R)-2-hydroxy-4-phenylbutyrate, and belongs to the technical field of biocatalytic asymmetric reduction preparation of medical chiral intermediates. Background technique [0002] Chiral (R)-2-hydroxy-4-phenylbutanoic acid ethyl ester (Benzenebutanoic acid, a-hydroxy-, ethylester, (aR)-), the molecular formula is C 12 h 16 o 3 , molecular weight 208.25, CAS number: 90315-82-5. (R)-2-Hydroxy-4-phenylbutyric acid ethyl ester is a key chiral intermediate in the synthesis of many angiotensin-converting enzyme inhibitors (ACEI) pril drugs. Due to the importance of ethyl (R)-2-hydroxy-4-phenylbutyrate in the synthesis of this class of drugs, many people have been attracted to conduct extensive research on its preparation, and a large number of preparation methods have been reported. [0003] At present, the production of ethyl (R)-2-hydroxy-4-phenylbutyrate can be carried out by chemical o...

AI Technical Summary

Problems solved by technology

[0010] Use whole cells of microorganisms to catalyze reactions such as using Rhodotorula minuta IFO 0920 and Candida holmii KPY 124020 to convert ethyl 2-carbonyl-4-phenylbutyrate in water / organic phase, ee value Reach 95% and 94%, shortcoming is that transformation rate is not high, the highest 58% (Shinobu Oda etc., Biosci.Biochem.62:1762-1767,1998); Symmetric catalytic conversion of 2-carbonyl-4-phenylbutyric acid ethyl ester to obtain product enantiomeric value of 82.25%, yield rate of 75.82% (Chemical Research and Application, 2006, 18 (4): 426-430; Food and Biology Journal of Technology, 2006, 25(2): 66-69)

[0011] Judging from the reports and studies on the biocatalytic synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate at present, there is a lack of microbial enzyme sources with high enantioselectivity and high yield. Therefore, microorganisms need to be screened , find a stable, more economical strain with higher catalytic efficiency, and select appropriate reaction conditions to maximize enantioselectivity and specific yield