Biological preparation method of (R)-3-amino-4-(2,4,5-trifluorophenyl) tert-butyl butyrate

Abstract

The invention discloses a biological preparation method of (R)-3-amino-4-(2,4,5-trifluorophenyl) tert-butyl butyrate. According to the method, a 3-carbonyl-4-(2,4,5-trifluorophenyl) tert-butyl butyrate is used as a substrate; under the existence of transaminase, amino donors, auxiliary factors and cosolvents, a reaction is taken to produce a target product of (R)-3-amino-4-(2,4,5-trifluorophenyl) tert-butyl butyrate. The reaction is performed in a water phase buffer solution with the pH being 6.0 to 10.0. The transaminase is used for converting the 3-carbonyl-4-(2,4,5-trifluorophenyl) tert-butyl butyrate into the (R)-3-amino-4-(2,4,5-trifluorophenyl) tert-butyl butyrate for the first time. Compared with the prior art, the process has the advantages that the substrate stability is good; the enzymatic conversion rate is high; the operation is simple and convenient; the subsequent product does not have protein residue; a better green and economical performance is realized; the optical activity of the product is high.

Description

technical field [0001] The invention relates to the technical fields of biopharmaceuticals and green chemistry, in particular to a biological preparation method of (R)-3-amino-4-(2,4,5-trifluorophenyl) tert-butyl butyrate. Background technique [0002] Chiral drug 3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazine-7(8H)- Base)-4-(2,4,5-trifluorophenyl)butan-1-one is the drug Sitagliptin (trade name JANUVIA) ​​of Merck Company for the treatment of diabetes. Its chiral amino group can be provided by the chiral building block (R)-3-carbonyl-4-(2,4,5-trifluorophenyl)butyric acid tert-butyl ester (2), therefore, compound 2 can be used as the Important chiral precursor of gliptin. [0003] The use of transaminases to produce chiral amines has the characteristics of low cost, high efficiency and environmental protection. Patent US 20120329108 and others reported the substrate 3-carbonyl-1-(3-(trifluoromethyl)-5,6-dihydro-[1, Transamination reaction of 2,4]t...

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Problems solved by technology

[0003] The use of transaminases to produce chiral amines has the characteristics of low cost, high efficiency and environmental protection. Patent US 20120329108 and others reported the substrate 3-carbonyl-1-(3-(trifluoromethyl)-5,6-dihydro-[1, Transamination reaction of 2,4]triazol[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one, patent CN 201210555608.1 reported the transamination reaction of 3-carbonyl-4-(2,4,5-trifluorophenyl) methyl butyrate, but so far, no transaminase has been used to convert 3-carbonyl-4-( A report on the conversion of tert-butyl 2,4,5-trifluorophenyl)butyrate (1) to tert-butyl 3-amino-4-(2,4,5-trifluorophenyl)butyrate

[0004] The enzyme conversion process reported in the patent US 20120329108 is used in the last step of the synthesis of raw materials, and the separation cost is high due to the risk of residual protein

CN 201210555608 reported using methyl ester or ethyl ester as substrate, but its stability is poor

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