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Preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity

A technology of ethyl hydroxybutyrate and S-4-, which is applied in the field of preparation of chemical API intermediates, can solve the problems of expensive catalysts, short process flow, and high production costs, and achieve reduced dosage, high yield, and reduced production cost effect

Active Publication Date: 2013-06-12
SHIJIAZHUANG CHIRALS CHEM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The purpose of the present invention is to provide a green, short process flow, the preparation method of optically pure S-4-chloro-3-hydroxybutyrate ethyl ester with high yield, which overcomes the preparation method of asymmetric hydrogenation reduction catalyzed by a chiral catalyst S-4-chloro-3-hydroxybutyrate ethyl ester of optical purity, the disadvantages of expensive catalyst and high production cost

Method used

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  • Preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity
  • Preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity
  • Preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity

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Embodiment 1

[0031] Preparation of nano-inorganic-organic hybrid ionic liquid materials: firstly synthesize siloxane-containing active ionic liquid, then use sodium dodecyl sulfate as a template, add sodium dodecyl sulfate in different weight ratios, and contain siloxane Based active ionic liquid, tetramethoxysilane (TMOS), reacted under different conditions to obtain nine kinds of hybrid ionic liquid materials, which can be used as immobilized materials for chiral catalysts. The reaction principle is as follows. Reaction conditions, the results are shown in Table 1.

[0032]

[0033]

[0034] Table 1

[0035]

Embodiment 2

[0037] Preparation of chiral catalyst:

[0038] (1) [RuCl 2 (COD)] n preparation of

[0039] Add 1g of ruthenium trichloride hydrate into 40 ml of absolute ethanol, stir until dissolved, and filter out the insoluble matter, then add 4.8 ml of COD into the ethanol solution, stir at room temperature for 25 h, filter with suction, wash the solid with cold acetone, Dry to give 1.22g [RuCl 2 (COD)] n, yield 89.7%.

[0040] (2) Ru 2 Cl 4 ((R)-BINAP) 2 NET 3 and Ru 2 Cl 4 ((R)-Segphos) 2 NET 3 preparation of

[0041] 0.75g [RuCl 2 (COD)] n , 2g (R)-BINAP or R-Segphos was added to 75 ml of toluene, then 1.13g triethylamine was added dropwise, refluxed for 10 h under nitrogen protection, the solvent was distilled off under reduced pressure, and the solvent was distilled off with CH 2 Cl 2 The product was washed out, filtered, and CH was distilled off under reduced pressure 2 Cl 2 , dried in vacuum to get Ru 2 Cl 4 ((R)-BINAP) 2 NET 33 2.65 grams, yield 98.0%, or...

Embodiment 3

[0043] Immobilization of Chiral Catalysts

[0044] 0.1 g Ru 2 Cl 4 ((R)-BINAP) 2 NET 3 Add it into 20ml of dichloromethane, add 1.0 g of nano-inorganic-organic hybrid ionic liquid material No. 1-9, stir for 3 hours, and spin dry to obtain immobilized chiral catalyst No. 1-9.

[0045] 0.1 g Ru 2 Cl 4 ((R)-Segphos) 2 NET 3 Add it into 20ml of dichloromethane, add 1.0 g of nano-inorganic-organic hybrid ionic liquid material No. 1-9, stir for 3 hours, and spin dry to obtain immobilized chiral catalyst No. 10-18.

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Abstract

The invention discloses a preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity. The preparation method taking ethyl 4-chloroacetoacetate as a raw material comprises the following steps of: placing ethyl 4-chloroacetoacetate and a Ru2C14 (R-BINAP or Segphos) 2NEt3 immobilized catalyst in a high-pressure kettle, wherein an alcohol solvent is adopted, the temperature is controlled at 20-100 DEG C, and the hydrogen pressure is 10-100atm, and preparing the S-4-chlorine-3-hydroxy butyric acid ethyl ester by adopting an asymmetrical hydrogenation method; and steaming out alcohol, and then steaming out the S-4-chlorine-3-hydroxy butyric acid ethyl ester, wherein the immobilized chiral catalyst can be continuously and mechanically applied. The preparation method has the advantages of low production cost, no generation of three wastes (waste water, waste gas and industrial reside) and no pollution to environments. The raw material ethyl 4-chloroacetoacetate is cheap and easily available; the yield of the S-4-chlorine-3-hydroxy butyric acid ethyl ester is high; and the product can be almost quantificationally obtained and has good optical purity and good industrialization prospect.

Description

technical field [0001] The invention relates to a method for preparing optically pure ethyl S-4-chloro-3-hydroxybutyrate, which belongs to the technical field of preparation of chemical raw material drug intermediates. Background technique [0002] Optically pure S-4-chloro-3-hydroxybutyrate ethyl ester is an important chiral intermediate for the production of atorvastatin and other statin blood lipid-regulating drugs, and is also an important raw material for the production of other chiral drugs and pesticides. Atorvastatin and other statin lipid-lowering drugs are the most sold drugs in the world at present, so it is of great significance to develop a new production process of optically pure S-4-chloro-3-hydroxybutyric acid ethyl ester. At present, there are many methods for synthesizing S-4-chloro-3-hydroxybutyric acid ethyl ester related to optical purity. The main domestic method is epichlorohydrin technology, which uses s-epichlorohydrin as raw material, through sodium...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/675C07C67/31B01J31/24
CPCY02P20/588Y02P20/50
Inventor 刘庆彬李耀峰李立斌靳晓坤温海山
Owner SHIJIAZHUANG CHIRALS CHEM CO LTD
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