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Preparation method for chiral 4-cyano-3-hydroxybutyrate

A hydroxybutyrate and chiral technology, which is applied in the field of preparation of chiral 4-cyano-3-hydroxybutyrate, can solve the problem that chiral ruthenium-phosphine ligands or enzymes are difficult to prepare and the product purity cannot meet the requirements , the difficulty of obtaining substrates, etc., the equipment requirements and reaction conditions are easy to achieve, suitable for large-scale production, and the cost is low.

Inactive Publication Date: 2013-12-04
SUZHOU OST ADVANCED MATERIALS +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] It is obvious that the existing synthetic method using chiral epichlorohydrin as a raw material has defects such as long route and large amount of three wastes.
The asymmetric catalytic hydrogenation method and enzymatic method of ethyl 4-chloroacetoacetate (prepared by the reaction of diketene and chlorine gas) have difficulties in obtaining substrates, difficulty in preparing chiral ruthenium-phosphine ligands or enzymes, and product purity that cannot meet the requirements. High cost and other urgent problems to be solved

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  • Preparation method for chiral 4-cyano-3-hydroxybutyrate

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preparation example Construction

[0029] The embodiment of the present invention discloses a preparation method of chiral 4-cyano-3-hydroxybutyrate, comprising the following steps:

[0030] (a) Add chiral epichlorohydrin, alcohol, and catalyst into the autoclave, feed in carbon monoxide, and conduct a heating reaction. After the reaction, refine to obtain chiral 4-chloro-3-hydroxybutyrate;

[0031] (b) adding a cyanide reagent to chiral 4-chloro-3-hydroxybutyrate for cyanation to obtain chiral 4-cyano-3-hydroxybutyrate.

[0032] The route of above-mentioned preparation method can be expressed as follows:

[0033]

[0034] In the above preparation method, due to the advanced oxo synthesis technology, the synthesis of chiral 4-chloro-3-hydroxybutyrate is realized through a one-step reaction, which meets the current development requirements of green fine chemical industry; the required raw material chiral epoxy Chloropropane rings, alcohols, and carbon monoxide are bulk chemicals, easy to obtain, and low in c...

Embodiment 1

[0040] (1) Carbonylation reaction

[0041] In an autoclave with a volume of 1 L, add 400 mL of absolute ethanol, 400 mmol of (S)-epichlorohydrin (ee>99.9%), 5.0 mmol of Co 2 (CO) 8 , 10 mmol of 3-hydroxypyridine. Seal the reactor, replace the reactor with carbon monoxide 3 times, and seal the reactor. In the Schlenk vacuum line, the reaction system was replaced three times with carbon monoxide gas at room temperature, and the pressure of CO gas was charged to 6.0 MPa. The temperature was controlled by a temperature controller to slowly rise to 60° C., reacted for 10 hours, cooled to room temperature, and unloaded.

[0042] The liquid of reaction gained is carried out qualitative analysis with Agilent 6890 / 5973 gas spectrometer, and Agilent 7890 gas chromatography carries out quantitative analysis: the conversion rate of (S)-epichlorohydrin is 99%, and (S)-4-chloro-3-hydroxyl The selectivity of ethyl butyrate is 95%. Distilled under reduced pressure to obtain 60.8 g of ethy...

Embodiment 2

[0046] (1) Carbonylation reaction

[0047] In an autoclave with a volume of 1 L, add 400 mL of anhydrous methanol, 400 mmol of (S)-epichlorohydrin (ee>99.9%), 5.0 mmol of Co 2 (CO) 8 , 5.0mmol of ZnBr 2 (pyridine) 2 . Seal the reactor, replace the reactor with carbon monoxide 3 times, and seal the reactor. In the Schlenk vacuum line, the reaction system was replaced three times with carbon monoxide gas at room temperature, and the pressure of CO gas was charged at 6.0 MPa. The temperature was controlled by a temperature controller to slowly rise to 60° C., reacted for 8 hours, cooled to room temperature, and unloaded.

[0048] The liquid obtained by the reaction is qualitatively analyzed with Agilent 6890 / 5973 gas chromatography spectrometer, and Agilent 7890 gas chromatography is used for quantitative analysis: the conversion rate of (S)-epichlorohydrin is 99.5%, and the conversion rate of (S)-4-chloro-3-hydroxy The selectivity of methyl butyrate was 91%, and 51.2 g of (...

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Abstract

The invention discloses a preparation method for chiral 4-cyano-3-hydroxybutyrate. The preparation method specifically comprises that: under the effect of a carbonylation catalyst, chiral chloropropylene oxide is taken as an initial raw material, and reacted with an alcohol and carbon monoxide for a carbonylation reaction, and corresponding chiral 4-chloro-3-hydroxybutyrate with maintained configuration is obtained and then subjected to cyanidation for preparation of chiral 4-cyano-3-hydroxybutyrate with high optical purity. Compared with conventional synthetic methods, the preparation method has the advantages of fewer steps, easily available and cheap raw materials, fewer 'three wastes (waste gas, waste water and industrial residue) ', simple post treatment, low equipment requirements, and applicability to industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of chiral 4-cyano-3-hydroxybutyrate. Background technique [0002] Statins are 3-hydroxy-3-methylglutaryl-coenzyme (3-hydroxy-3-methyglutaryl-coenzyme, HMG-CoA) reductase inhibitors. A large number of basic research and clinical trials have shown that statins not only have a powerful lipid-lowering effect, but also have "multiple effects" independent of their lipid-lowering effect, such as: improving vascular endothelial function, inhibiting inflammation and Platelet aggregation and inhibition of thrombus formation, stabilization of atherosclerotic plaque, inhibition of cardiomyocyte remodeling and cardiomyocyte apoptosis, inhibition of cardiac electrophysiological remodeling, and regulation of cardiac autonomic function. The emergence of statins is an important milestone in the history of cardiovascular disease treatment, and has become the ma...

Claims

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Application Information

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IPC IPC(8): C07C255/20C07C253/14
Inventor 陈静刘建华夏春谷许传芝
Owner SUZHOU OST ADVANCED MATERIALS
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