Preparation method of ethyl 4-chloro-3-hydroxybutanoate

Abstract

The invention relates to a preparation method of ethyl 4-chloro-3-hydroxybutanoate.In a reaction kettle, ethyl acetate is added to purified water, so as to be used as a solvent, hydrophosphate is used as a solution pH buffering agent, ethyl 4-chloroacetoacetate is used as a reaction substrate, the reaction time is 6 to 10 h, the reaction temperature is 28 to 33 DEG C, and after reaction, the steps of filtration, extraction and concentration under reduced pressure are performed, so as to obtain a crude product of the ethyl 4-chloro-3-hydroxybutanoate; wherein biocatalysts include keto reductase, glucose dehydrogenase and NADPH (Nicotinamide Adenine Dinucleotide Phosphate), and a hydrogen donor is glucose; the molar concentration of the hydrophosphate is 0.04 mol / L to 0.08 mol / L, the mass-to-volume ratio concentration of the substrate of the ethyl 4-chloroacetoacetate is 8 g / mL to 15 g / mL, the used mass of the keto reductase and the glucose dehydrogenase is 3% to 8% of that of the ethyl 4-chloroacetoacetate, wherein the use ratio of the keto reductase to the glucose dehydrogenase is 2:3, and the mass of the NADPH is 0.1% to 0.3% of that of the ethyl 4-chloroacetoacetate. According to the preparation method, the operation steps and the reaction steps are simplified, and the yield of the ethyl 4-chloro-3-hydroxybutanoate can be increased.

Description

Technical field [0001] The invention relates to a method for preparing compounds, in particular to a method for preparing ethyl 4-chloro-3-hydroxybutyrate. Background technique [0002] Ethyl 4-chloro-3-hydroxybutyrate is a key chiral intermediate for the preparation of hydroxymethylglutaryl CoA (HMG-CoA) reductase inhibitors such as statins. Statins are currently the world’s best-selling cholesterol-lowering and lipid-lowering drugs. Therefore, ethyl 4-chloro-3-hydroxybutyrate, which is a key chiral intermediate of statins, has a high demand and a wide range of applications. range. [0003] At present, there are two methods for producing ethyl 4-chloro-3-carbonylbutyrate: [0004] The first is to synthesize 4-chloro-3-hydroxybutyronitrile (A3) by ring-opening sodium cyanide using epichlorohydrin, and then obtain ethyl 4-chloro-3-hydroxybutyrate by alcoholysis with ethanol and hydrogen chloride. The method is widely used today. Among them, the molar yield of A3 synthesized by epic...

AI Technical Summary

Problems solved by technology

The yield of ethyl 4-chloro-3-hydroxybutyrate synthesized by this method is about 82%, but what it obtains is racemate D-1, so it must be chemically resolved, and chemical resolution requires Some precious chemical reagents are used, and the yield is also low, less than 50%. The whole route leads to a yield of about 40%. On the whole, the efficiency of this method is even much lower than the first one.