Preparation of (R) -4-phenyl-2-hydroxybutyrate

Abstract

The invention relates to a preparation method of (R)-4-phenyl-2-hydroxy-butanoic acid, comprising the following steps: bromohydrin reaction is carried out on 4- phenyl-1- butylenes for obtaining 4-phenyl-1-bromine-2-butanol and then 4-phenyl-1, 2-epoxy butane is obtained by cyclization under alkalescence condition; epoxy hydrolytic ferment ECU1040 is utilized for splitting the 4- phenyl-1, 2-epoxy butane to obtain the (R)-4-phenyl, -2-butanediol; finally, the (R)-4-phenyl, -2-butanediol is oxidized by the concentrated nitric acid for obtaining the target product of (R)-4-phenyl-2-hydroxy-butanoic acid. The method is simple and practical, the operation is simple and convenient, the raw material source is wide, the cost is low, and the yield is high; the product optical purity can reach more than 99 percent e.e; therefore, the method has good industrialization prospect.

Description

technical field [0001] The invention belongs to the field of preparation of synthetic angiotensin-converting enzyme inhibitor (ACEI) intermediates, in particular to a preparation method of (R)-4-phenyl-2-hydroxybutyric acid. Background technique [0002] (R)-4-Phenyl-2-hydroxybutyrate ethyl ester is an important intermediate in the synthesis of angiotensin-converting enzyme inhibitors (ACEI) drugs for the treatment of hypertension and congestive heart failure (CHF). Especially for Enalapril, Benazepril, Delapril, Quinapril, Lisinapril, Cilazapril ), Ramipril, Moexipril, Imidapril, Spirapril, Indolapril, Alacepril, etc. Synthesis of ACE inhibitors (ACEI). [0003] In 1992, the Japanese patent (JP04200391) reported that the racemic 4-phenyl-2-hydroxybutyric acid could be resolved by lipase to obtain (R)-4-phenyl-2-hydroxybutyric acid and (S)-4-benzene Base-2-hydroxybutyric acid ethyl ester, yield 19%, optical purity 97% e.e. In 1995, Chadha, A. et al. reported in Tetrahedr...

AI Technical Summary

Problems solved by technology

But the method is difficult to repeat

In 2000, Bachvall, J-E et al. reported in Org.Lett.2000, 2(8), page 1037 the dynamic resolution of α-hydroxy acid esters with chiral nail complexes, but this method is not suitable for 4-phenyl -Resolution of 2-hydroxybutyric acid, the optical purity is only 18% e.e

But D-malic acid is expensive

[0005] However, so far, the synthetic technology route that is simple and general, convenient to operate, low in cost and high in selectivity is convenient for industrial production of (R)-4-phenyl-2-hydroxybutyric acid, and further research is required.

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