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Recycling method of levorotation camphorsulfonic acid serving as clopidogrel resolving agent

A technology for clopidogrel camphorsulfonate and clopidogrel resolving agent, which is applied in the fields of chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., and can solve the difficulties in separation of L-camphorsulfonic acid, poor optical purity, and technical problems. Complexity and other issues, to achieve the effect of low production cost, short time and high optical purity

Inactive Publication Date: 2012-05-30
ZHEJIANG LANGHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] With the development of optically active chiral drugs, the application of camphorsulfonic acid is becoming more and more extensive. At present, the separation of L-camphorsulfonic acid is more difficult than D-camphorsulfonic acid, the process is complicated, the optical purity is poor, the cost is high and the pollution is serious.

Method used

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  • Recycling method of levorotation camphorsulfonic acid serving as clopidogrel resolving agent
  • Recycling method of levorotation camphorsulfonic acid serving as clopidogrel resolving agent

Examples

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Effect test

Embodiment 1

[0024] Example 1 Dissolve 30 g of clopidogrel camphorsulfonate in 120 ml of ethyl acetate and 60 ml of water mixture, adjust the pH value to 8 with saturated sodium carbonate solution, separate the organic layer, and extract the aqueous layer twice with 30 ml of ethyl acetate , discard the ethyl acetate layer, acidify the aqueous layer with concentrated sulfuric acid, adjust the pH value to 0.5, then concentrate and evaporate to dryness to obtain 24 g of solid, add 75 ml of methyl ethyl ketone to the solid and heat to 60 ° C to dissolve the solid, filter, and analyze the filtrate at room temperature crystallized for 12 hours, filtered with suction, and dried the filter cake to obtain 16g of L-camphorsulfonic acid, melting point: 192-193°C, optical rotation: -22.3° (589nm, c=20, H 2 (25°C), yield: 92.0%.

Embodiment 2

[0025] Example 2 Dissolve 30 g of clopidogrel camphorsulfonate in 90 ml of ethyl acetate and 30 ml of water mixture, adjust the pH value to 9 with saturated sodium bicarbonate solution, separate the organic layer, and extract the aqueous layer with 40 ml of ethyl acetate for two Next, discard the ethyl acetate layer, acidify the aqueous layer with concentrated hydrochloric acid until the pH value reaches 1.5, then concentrate and evaporate to dryness to obtain 20 g of a solid, add 160 ml of acetone to the solid and heat to 50 ° C to dissolve the solid, filter, and crystallize the filtrate at room temperature for 10 hour, suction filtration, after the filter cake was dried, 15.5g of L-camphorsulfonic acid was obtained, melting point: 192-194°C, optical rotation: -22.5° (589nm, c=20, H 2 (25°C), yield: 89.1%.

Embodiment 3

[0026] Example 3 Dissolve 30 g of clopidogrel camphorsulfonate in 45 ml of ethyl acetate and 15 ml of water mixture, adjust the pH value to 9 with saturated potassium bicarbonate solution, separate the organic layer, and extract the aqueous layer with 40 ml of ethyl acetate for two The second time, discard the ethyl acetate layer, acidify the aqueous layer with concentrated phosphoric acid until the pH value reaches 3, then concentrate and evaporate to dryness to obtain 25 g of solid, add 50 ml of ethyl acetate to the solid and heat to 50 ° C to dissolve the solid, filter, and analyze the filtrate at room temperature crystallized for 5 hours, filtered with suction, and dried the filter cake to obtain 15.8 g of L-camphorsulfonic acid, melting point: 193-195°C, optical rotation: -21.8° (589nm, c=20, H 2 (25°C), yield: 90.8%.

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Abstract

The invention discloses a recycling method of levorotation camphorsulfonic acid serving as a clopidogrel resolving agent, which belongs to the technical field of fine chemistry industry. The method comprises the following steps of: 1) adding clopidogrel camphorsulfonate into a certain amount of ethyl acetate and water mixed solution, mixing fully and uniformly, and performing alkaline treatment with saturated inorganic salt solution; 2) acidifying a water layer with strong acid, concentrating and evaporating to dryness to obtain a solid, adding an organic solvent, heating until concentrated solution is dissolved, and filtering to remote inorganic salt; and 3) cooling and crystallizing filtrate for 5 to 12 hours and performing suction filtration to obtain the levorotation camphorsulfonic acid. The method has a simple recycling process and short time. Further resolution indicates that an obtained product has high optical purity, recovery ratio of over 89 percent, low production cost anda good economic benefit, is easy to operate, is nontoxic and environmentally-friendly, and is suitable for mass industrial production.

Description

technical field [0001] The invention belongs to the technical field of fine chemicals, and in particular relates to a method for recovering L-camphorsulfonic acid, a clopidogrel resolution agent, which is easy to operate and has a high recovery rate. Background technique [0002] Clopidogrel (Clopidogrel), chemical name (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester, is A platelet inhibitor, which was successfully researched and developed by the French company Sanofi (Sanofi) in 1986. Its sulfate salt is used clinically. The chemical structure of its trade name is Plavix: [0003] [0004] The structure of clopidogrel contains a chiral center and has two chiral isomers, of which only (+)-(S)-clopidogrel and its salts have physiological activity. Since (+)-(S)-clopidogrel is a chiral compound containing a chiral center, the target chiral isomer can be obtained by chiral synthesis or chiral resolution. The separation of enantiomers ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C309/19C07C303/44
Inventor 林邦平洪秀云黄明孙
Owner ZHEJIANG LANGHUA PHARMA
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