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s-3-cyclohexenecarboxylic acid and its purification method

A technology of cyclohexenecarboxylic acid and S-3-, which is applied in organic chemistry methods, separation/purification of carboxylic acid compounds, organic chemistry, etc., can solve the problem of inability to synthesize edoxaban, unsatisfactory purification purity, and many influencing parameters and other problems, to achieve the effect of facilitating large-scale industrial production, highlighting substantive characteristics, and simple refining methods

Active Publication Date: 2022-08-05
ZHENGZHOU INST OF CHIRAL DRUGS RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The molecular structure of 3-cyclohexenecarboxylic acid has chiral properties because it contains a chiral carbon atom. Among them, S-3-cyclohexenecarboxylic acid is the raw material of anticoagulant Edoxaban, and R-3-cyclohexene Ethylene carboxylic acid cannot synthesize Edoxaban; at the same time, the purity requirements of raw materials and intermediates are relatively high in drug synthesis, and the physical and chemical properties of chiral enantiomers are very close, so it is difficult to separate
Although the above methods can be used to purify S-3-cyclohexenecarboxylic acid, there are many influencing parameters in the purification process and the purification degree is not ideal

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The present embodiment provides a method for purifying S-3-cyclohexenecarboxylic acid, and the specific steps include:

[0024] Dissolve 1.26kg of crude S-3-cyclohexenecarboxylic acid and 1.28kg of R-a-phenethylamine in ethyl acetate, heat up to 70°C, stir and reflux for 1h, cool to 20°C after the reaction, filter and dry to obtain 2.32 kg of S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt. The crude S-3-cyclohexenecarboxylic acid refers to S-3-cyclohexenecarboxylic acid with an ee value of less than 97%.

[0025] Dissolve the S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt with ethanol at 80°C, cool down to 40°C for crystallization for 0.5h after dissolving, repeat the above operation 3 times after filtration; obtain recrystallized material ;

[0026] Add 3.7kg of methylene chloride, 5.5kg of water and the recrystallized material to the reaction vessel successively, add hydrochloric acid dropwise to maintain pH 2, stir at room temperature for 1h, collec...

Embodiment 2

[0031] The present embodiment provides a method for purifying S-3-cyclohexenecarboxylic acid, and the specific steps include:

[0032] According to the ratio of the molar ratio of S-3-cyclohexenecarboxylic acid crude product and R-a-phenethylamine to 1:1.5, the materials were weighed respectively, and then the weighed S-3-cyclohexenecarboxylic acid crude product and the weighed R-a- Phenethylamine was dissolved in ethyl acetate, heated to 90 °C, stirred and refluxed for 2 h, cooled to 30 °C after the reaction, filtered and dried to obtain S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt. The crude S-3-cyclohexenecarboxylic acid refers to S-3-cyclohexenecarboxylic acid with an ee value of less than 97%.

[0033] Dissolve the S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt with ethanol at 80°C, cool down to 40°C for crystallization for 0.5h after the dissolution, repeat the above operation 3 times after filtration; obtain recrystallized material ;

[0034] Add 4.6...

Embodiment 3

[0037] The present embodiment provides a method for purifying S-3-cyclohexenecarboxylic acid, and the specific steps include:

[0038] According to the ratio of the molar ratio of S-3-cyclohexenecarboxylic acid crude product and R-a-phenethylamine to 1:1, the materials were weighed respectively, and then the weighed S-3-cyclohexenecarboxylic acid crude product and the weighed R-a- Phenylethylamine was dissolved in ethyl acetate, heated to 70°C, stirred and refluxed for 2h, cooled to 25°C after the reaction, filtered and dried to obtain S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt;

[0039] Dissolve the S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt with ethanol at 85°C, cool down to 40°C for crystallization for 0.5h after dissolving, and repeat the above operation 3 times after filtration; obtain a recrystallized material ;

[0040]4.3kg of dichloromethane, 6.2kg of water and the recrystallized material were successively added to the reaction vessel, hydroch...

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Abstract

The invention provides a method for purifying S-3-cyclohexenecarboxylic acid, the specific steps comprising: mixing crude S-3-cyclohexenecarboxylic acid, R-a-phenethylamine and ethyl acetate, stirring under reflux, filtering Obtain S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt, wherein, described S-3-cyclohexenecarboxylic acid crude product refers to the S-3-cyclohexenecarboxylic acid with ee value less than 97%; The S-3-cyclohexenecarboxylic acid-R-a-phenethylamine salt and ethanol are mixed, crystallized and filtered to obtain a recrystallized material; methylene chloride, water and the recrystallized material are mixed and stirred, and the The organic layer is collected after the liquid, and the organic layer is subjected to distillation treatment to obtain S-3-cyclohexenecarboxylic acid. The method for purifying S-3-cyclohexenecarboxylic acid provided by the invention can make the ee value of the prepared S-3-cyclohexenecarboxylic acid reach more than 99%, and simultaneously the resolving agent R-phenethylamine is recycled ,save costs.

Description

technical field [0001] The invention relates to the technical field of S-3-cyclohexenecarboxylic acid synthesis, in particular to a kind of S-3-cyclohexenecarboxylic acid and a purification method thereof. Background technique [0002] The molecular structure of 3-cyclohexenecarboxylic acid has chiral properties because it contains a chiral carbon atom, wherein S-3-cyclohexenecarboxylic acid is the raw material of the anticoagulant edoxaban, and R-3-cyclohexene is the raw material of edoxaban. Edoxaban cannot be synthesized from enoic acid; at the same time, the purity of raw materials and intermediates is required in drug synthesis, and the physical and chemical properties of chiral enantiomers are very similar, making it difficult to separate. Existing chiral enantiomers are usually obtained by the following three methods to obtain single enantiomer chiral compounds: [0003] (1) Chiral source synthesis method: using a single enantiomer of a chiral compound as a raw mater...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/42C07C61/08C07C209/86C07C211/27
CPCC07C51/42C07C209/86C07B2200/07C07C61/08C07C211/27
Inventor 邓照西
Owner ZHENGZHOU INST OF CHIRAL DRUGS RES CO LTD
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