Method for preparing chiral 3R, 5S-dihydroxyl compound by nonaqueous phase

Abstract

A process for preparing ethyl (3R, 5S)-dihydroxy-6-benzyloxy hexanoate via stereoselective microbial reduction is provided, which includes that ethyl 3,5-diketo-6-benzyloxy hexanoate is used as a substrate and a diketoreductase is used as biocatalyst. Specifically, the process includes these following steps: (1) the substrate, diketoreductase and cofactor regeneration system mediated by formate dehydrogenase are added to the reaction liquid and conducted to shake and react for at least one hour, and the reaction liquid is the mixture of organic solvent and buffer solution; (2) the product of step (1) is separated and purified to obtain the single enantiomer of (3R, 5S)-dihydroxy compound.

Description

technical field [0001] The invention belongs to the field of asymmetric preparation of chiral pharmaceutical intermediates by biocatalysis, and specifically relates to a biocatalyst using 3,5-dicarbonyl-6-benzyloxy-ethyl hexanoate as a substrate and dicarbonyl reductase as a biocatalyst , Reductive preparation of ethyl 3R,5S-dihydroxy-6-benzyloxy-hexanoate in a single optical purity. Background technique [0002] The two chiral centers in the structure of 3R, 5S-dicarbonyl-6-benzyloxy-ethyl hexanoate and the inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase statins The three-dimensional configuration of the chiral side chain is the same, so it is a key chiral intermediate for the synthesis of statins. [0003] At present, the preparation of such compounds is mainly accomplished by chemical synthesis, but there are following problems: chiral catalysts are needed, and the production cost is high; the total yield is lower than 50%; the optical purity of the product is di...

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Problems solved by technology

[0003] At present, the preparation of this type of compound is mainly completed by chemical synthesis, but there are the following problems: chiral catalyst is needed, and the production cost is high; the total yield is lower than 50% ; The optical purity of the product is difficult to meet the requirements; a large number of organic reagents are used, causing serious environmental pollution

[0006](2) Deoxyribose-5-phosphate aldolase (DERA) can use acetaldehyde and chloroacetaldehyde as substrates to simultaneously Introduction of two chiral centers gives 3R, 5S-dihydroxyl product (ee>99.9, de=96.6%) (see: J.Am.Chem.Soc.1994, 116:8422-8423; J.Proc.Natl.Acad .Sci.USA 2004,101:5788-5793), but the shortcoming of this method is that the enzyme dosage is bigger, the substrate inhibition is very strong and the initial reaction raw material is flammable and explosive reagent, so it is difficult to be used in industrial production

[0007] (3) Guo et al. (See: Tetrahedron: Asymmetry 2006, 17: 1589-1602) used Acinetobacter species SC13874 to reduce 3R, 5S-dicarbonyl-6-benzyloxy 3R,5S-dihydroxy-6-benzyloxy-ethylhexanoate was prepared from 3R,5S-dihydroxy-6-benzyloxy-ethylhexanoate, but the diastereomeric excess value of 63.3% hindered the application of this method

[0008] (4) Nitrilase can also be used in the preparation of 3R, 5S-dihydroxy compounds, but the synthesis of substrates is difficult and the separation of products is difficult (Org. Process. Res. Dev. 2006, 10: 661-665)

[0009](5) The publication number is CN 101429514A Chinese Invention Patent Application Publication Discloses a method for preparing 3R, 5S-dihydroxyl compounds using dicarbonyl reductase , is one of the most successful biocatalytic methods, the dicarbonyl reductase can catalyze the reduction of 3R, 5S-dicarbonyl-6-benzyloxy-ethyl hexanoate to 3R, 5S-dihydroxy-6-benzyloxy- Ethyl hexanoate, the de and ee values ​​of the product are all higher than 99.5%, and the substrate conversion rate is as high as 99.9%, but the disadvantage of this method is that the substrate concentration of the reaction is low (10g / L)

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