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Organism coupling preparation method of R(-)-4-cyan-3-hydroxybutyric acid ethyl ester

A technology of ethyl hydroxybutyrate and hydroxybutyronitrile is applied in the field of biological coupling preparation of fine chemicals, which can solve the problems of limited industrial application, complicated process and need for recrystallization treatment, and achieve obvious economic and environmental benefits. High purity and optical purity, realizing the effect of industrial production

Inactive Publication Date: 2010-12-15
LIANYUNGANG HONGYE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The product yield obtained by this method is 46%, and the ee value is more than 99%. However, in this method, the intermediate product 4-cyano-3-hydroxybutyric acid needs to be recrystallized, the process is complicated, and the nitrilase used is expensive. There is no industrial product for sale, resulting in the method not being able to realize industrial production
The chemical method uses chiral 3-hydroxy-γ-butyrolactone as a raw material, uses acetic anhydride or acetyl chloride as an acylating agent, and then cyanates after ring opening to obtain the target product. The yield of these methods is relatively high (52-59%) , but the raw material chiral 3-hydroxy-γ-butyrolactone is not easy to obtain, which limits its industrial application (Tetrahedron: Asymmetry (2005), 16, 2717-2721; WO2002096915; WO2004031131)

Method used

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  • Organism coupling preparation method of R(-)-4-cyan-3-hydroxybutyric acid ethyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1. The biocoupling preparation method of R(-)-4-cyano-3-hydroxybutyrate ethyl ester, its steps are as follows:

[0034] (1) Preparation of 4-chloro-3-hydroxybutyronitrile: Add epichlorohydrin to the buffer solution made of buffer dissolved in water, control the pH value of the reaction solution to 6, control the reaction temperature to 10°C, and drop Sulfuric acid solution and sodium cyanide solution, insulation reaction 2 hours after dropwise addition, organic solvent dichloromethane extracts and desolventizes to obtain product; The molar ratio of substance is: epichlorohydrin: sulfuric acid: sodium cyanide: buffering agent=1: 1.0:1.0:0.1; the buffer used is disodium hydrogen phosphate-sodium dihydrogen phosphate (1:1);

[0035] (2) Preparation of ethyl 4-chloro-3-hydroxybutyrate: add ethanol hydrochloride to 4-chloro-3-hydroxybutyronitrile, react at 20°C for 4 hours, then precipitate and filter, and the resulting filtrate is the product; The weight content o...

Embodiment 2

[0037] Example 2. The biocoupling preparation method of R(-)-4-cyano-3-hydroxybutyrate ethyl ester, its steps are as follows:

[0038] (1) Preparation of 4-chloro-3-hydroxybutyronitrile: Add epichlorohydrin to the buffer solution made by dissolving the buffer in water, control the pH value of the reaction solution to 10, control the reaction temperature to 50°C, and add dropwise Sulfuric acid solution and sodium cyanide solution, after dropwise addition, keep warm for 6 hours, and extract the product after extraction with organic solvent toluene; the molar ratio of substances is: epichlorohydrin: sulfuric acid: sodium cyanide: buffer = 1: 1.6: 1.6:0.5; the buffer used is boric acid-potassium chloride (1:1);

[0039] (2) Preparation of ethyl 4-chloro-3-hydroxybutyrate: add ethanol hydrochloride to 4-chloro-3-hydroxybutyronitrile, react at 80°C for 10 hours, then precipitate and filter, and the resulting filtrate is the product; The weight content of hydrochloric acid in ethan...

Embodiment 3

[0041] Example 3. The biocoupling preparation method of R(-)-4-cyano-3-hydroxybutyrate ethyl ester, its steps are as follows:

[0042] (1) Preparation of 4-chloro-3-hydroxybutyronitrile: Add epichlorohydrin to the buffer solution made of buffer dissolved in water, control the pH value of the reaction solution to 8.5, control the reaction temperature to 25°C, and drop Sulfuric acid solution and sodium cyanide solution, insulation reaction 5 hours after dropping, organic solvent ethyl acetate extracts and desolventizes to obtain product; The molar ratio of substance is: epichlorohydrin: sulfuric acid: sodium cyanide: buffering agent=1: 1.3: 1.3: 0.4; the buffer used is tris;

[0043] (2) Preparation of ethyl 4-chloro-3-hydroxybutyrate: add ethanol hydrochloride to 4-chloro-3-hydroxybutyronitrile, react at 60°C for 6 hours, then precipitate and filter, and the resulting filtrate is the product; The weight content of hydrochloric acid in ethanol hydrochloride is 30%; The weight ...

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Abstract

The invention relates to an organism coupling preparation method of R(-)-4-cyan-3-hydroxybutyric acid ethyl ester. The method comprises the following steps of: reacting epichlorohydrin as a raw material with sulfuric acid and sodium cyanide in a buffer solution to obtain 4-chlorine-3-hydroxy butyronitrile; then undergoing Pinner reaction by using the 4-chlorine-3-hydroxy butyronitrile and hydrochloric acid ethanol to generate 4-chlorine-3-hydroxybutyric acid ethyl butyrate; and finally acting the 4-chlorine-3-hydroxybutyric acid ethyl butyrate with sodium cyanide and sulfuric acid under the catalysis of halogenohydrin dehalogenation enzyme to obtain R(-)-4-cyan-3-hydroxybutyric acid ethyl ester. By using the lowly-cost and easily-obtained epichlorohydrin as the raw material and the manner of combining chemical synthesis and biological catalysis, the invention greatly reduces the production cost, has temperate reaction condition, simple process and high chemical and optical purity of the product, and has obvious economic and environmental benefits beneficial to industrial production by adopting halogenohydrin dehalogenation enzyme catalysis in industrial production.

Description

technical field [0001] The invention relates to a biocoupling preparation method of fine chemicals, in particular to a preparation method of R(-)-4-cyano-3-hydroxybutyric acid ethyl ester. Background technique [0002] R(-)-ethyl 4-cyano-3-hydroxybutyrate (R(-)-ethyl 4-cyano-3-hydroxybutyrate) is a very important chiral compound, which is a synthetic HMG-CoA reductase inhibitor Atorvastatin intermediates, HMG-CoA reductase inhibitors can control cholesterol biosynthesis. It is also an intermediate in the synthesis of L-Carnitine and (R)-4-amino-3-hydroxybutyric acid (GABOB). L-Carnitine is a vehicle for transporting long-chain fatty acids through the cell membrane into the mitochondria for energy generation. It is often used as a nutritional supplement for athletes, and it is also commonly used in nutritional products for infants and young children. (R)-4-amino-3-hydroxybutyric acid (GABOB) is a contractile agent of γ-aminobutyric acid, which can be used to control some ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/00
Inventor 付瑞新王明
Owner LIANYUNGANG HONGYE CHEM
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