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A process for preparing (R)-4-cyano-3-hydroxybutyric acid ester

A kind of hydroxybutyrate, the preparation process technology, applied in the field of optically pure 4-cyano-3-hydroxybutyrate products

Inactive Publication Date: 2002-02-27
LOTTE FINE CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Besides, this method is not suitable for producing various ester products

Method used

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  • A process for preparing (R)-4-cyano-3-hydroxybutyric acid ester

Examples

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example 1

[0021] The following examples are intended to illustrate the present invention and should not be considered as defining the scope of the present invention due to additional requirements. Example 1: Preparation of (S)-3-acetoxy-4-bromobutanoic acid

[0022] Add (S)-3-hydroxybutyrolactone (102 grams) and 30% hydrobromic acid (675 grams, 2.5 equivalents) to a two-liter three-necked flask equipped with a reflux condenser, a thermometer and a mechanical stirrer. . The mixture was stirred at 40°C for 3 hours. After cooling the reaction mixture, further dichloromethane (1000 mL) was added to the mixture. The reaction mixture was rinsed with aqueous sodium acetate. The organic layer was separated, dried over magnesium sulfate and concentrated to yield (S)-3-acetoxy-4-bromobutanoic acid (213 g, 95%).

example 2

[0023] 1H-NMR (D 2 O, ppm): δ21(S, 3H, CH 3 COO), 2.8-2.9 (dd, 2H, CH 2 COOH), 3.5-3.6 (dd, 2H, BrCH 2 CH), 5.3-5.4 (m, 1H, BrCH 2 CH) Example 2: Preparation of (S)-3,4-epoxybutyric acid sodium salt

[0024] A 5 liter flask was charged with (S)-3-acetoxy-4-bromobutanoic acid from Example 1. Slowly add 1NC normality sodium hydroxide aqueous solution and keep the temperature below zero. The reaction mixture was stirred at 0°C for 1 hour. The relatively pure sodium salt of (S)-3,4-epoxybutyric acid can be detected by NMR.

[0025] 1H-NMR (D 2 O, ppm): δ2.3-2.5 (m, 2H, CH 2 -CO 2 Na), 2.6-2.9(m, 2H), 3.2-3.3(m, 1H)

[0026] 13C-NMR (D 2 O, ppm): δ40.87 (-CH 2 -CO 2 Na), 48.24 (4-CH 2 ), 51.08 (3-CH), 179.41 (-CO 2 Na) Example 3: Preparation of (S)-3,4-epoxybutyric acid potassium salt

[0027] A 5 liter flask was charged with (S)-3-acetoxy-4-bromobutanoic acid from Example 1. Aqueous 1 N (normal strength) potassium hydroxide (3 L, 3 mol) was slowly added while main...

example 4

[0029] 13C-NMR (D 2 O): δ40.87(-CH 2 -CO 2 K), 48.24 (4-CH 2 ), 51.08 (3-CH), 179.41 (-CO 2 K) Example 4: Preparation of (S)-3,4-epoxybutyric acid calcium salt

[0030] A 2-liter three-neck flask equipped with a thermometer, a pH meter and a mechanical stirrer was charged with distilled water (1 liter), (S)-3-acetoxy-4-bromobutanoic acid (90 g, 0.4 mol) and Calcium hydroxide (45 g, 0.6 mol). The reaction mixture was stirred at 0-5°C for 2 hours to yield (S)-3-4-epoxybutyric acid calcium salt. More than 99% conversion was determined by NMR.

[0031] 1H-NMR (D 2 O, ppm): δ2.3-2.5 (m, 2H, CH 2 -CO 2 Ca), 2.5-2.8(m, 2H, 4-H), 3.2-3.3(m, 1H, 3-H) Example 5: Preparation of (S)-3,4-epoxybutanoic acid tetrabutylammonium salt

[0032] A 2-liter three-neck flask equipped with a thermometer, a pH meter and a mechanical stirrer was charged with distilled water (1 liter), (S)-3-acetoxy-4-bromobutanoic acid (90 g, 0.4 mol) and To methanol (1.2 L, 1.2 mol) was added 1.0 M tetrabut...

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Abstract

The present invention relates to a process for preparing (R)-4-cyano-3-hydroxybutyric acid ester products and more particularly, to a process for preparing optically pure (R)-4-cyano-3-hydroxybutyric acid ester products expressed by formula (1) in high yield by performing cyanation and sequential esterification of (S)-3,4-epoxybutyric acid salt as a starting material. In said formula, R represents linear or branched alkyl group with 1-4 carbon atoms or benzyl group. (R)-4-cyano-3-hydroxybutyric acid ester with more than 90% of yield and 99.8% of optical purity.

Description

technical field [0001] The present invention and the new process for preparing (R)-4-chloro-3-hydroxybutyrate products particularly relate to (S)-3,4-epoxybutyrate as raw materials through chlorination and sequence esterification Thereafter, an optically pure (R)-4-cyano-3-hydroxybutyrate product represented by the following formula (1) was prepared in high yield. R in the formula represents a straight chain or branched chain alk(hydrocarbon) group or phenyl group containing 1-4 carbon atoms. Background technique [0002] Photoactive (R)-4-cyano-3-hydroxybutyrate represented by the following formula (1) is a key intermediate product for the production of hypolipidemic agents. Various methods for the preparation of hypolipidemic agents using photoactive (R)-4-cyano-3-hydroxybutyrate have been reported, as described below. [0003] US Patent No. 4,681,893 describes a process for the preparation of the hypolipidemic agent, atorvastatin, from (R)-4-cyano-3-hydroxybutyrate. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07B53/00C07C253/00C07C255/20
CPCC07C253/00C07B2200/07C07C255/20
Inventor 卢炅渌柳昊成金暻逸李源章黄大一
Owner LOTTE FINE CHEM CO LTD
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