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Resolution method of levocetirizine chiral intermediates

A chiral intermediate, the technology of levocetirizine, is applied in the directions of organic chemistry methods, chemical instruments and methods, separation of optically active compounds, etc., to achieve the effects of easy operation, high yield and good efficiency

Active Publication Date: 2012-02-15
浙江永合新材料科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the use of chiral ionic liquids for the resolution of levocetirizine chiral intermediates has broad application prospects, but there are no similar reports at home and abroad

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 287 grams (1 mole) of 1-[(4-chlorophenyl)benzyl]piperazine and 3 moles of chiral tartrate ionic liquid into the reaction vessel, react at 50°C for 5 hours, and extract with 200 ml of toluene After the extraction, the reaction system is adjusted to pH=11-12 with 10% sodium hydroxide solution, and then extracted with 200 ml of toluene three times, combined with the toluene solution, dried with anhydrous sodium sulfate, filtered, concentrated, and crystallized with n-hexane to obtain white 52 grams of crystalline powder product, yield 36%, melting point: 94~96℃, specific rotation: [α] D ≤-21.5°(C1, toluene), optical purity: ≥99.0%, content: ≥99.0%.

Embodiment 2

[0026] Add 287 grams (1 mole) of 1-[(4-chlorophenyl)benzyl]piperazine and 1 mole of chiral lactic acid ionic liquid into the reaction vessel, react at 10°C for 10 hours, and extract with 200 ml of toluene After the extraction, the reaction system is adjusted to pH=11-12 with 10% by mass sodium hydroxide, and then extracted with 200 ml of toluene three times. The toluene solution is combined, dried with anhydrous sodium sulfate, filtered, concentrated, and normalized. Alkane crystallized to obtain 49 grams of white crystalline powder product, yield 34%, melting point: 94~96℃, specific rotation: [α] D ≤-21.5°(C1, toluene), optical purity: ≥99.0%, content: ≥99.0%.

Embodiment 3

[0028] Add 287 grams (1 mole) of 1-[(4-chlorophenyl)benzyl]piperazine and 2 moles of chiral mandelic acid ionic liquid into the reaction vessel, react at 60°C for 10 hours, and use 200 ml of toluene After extraction, the extracted reaction system is adjusted to pH=11-12 with 10% by mass sodium hydroxide solution, and then extracted with 200 ml of toluene three times, combined with the toluene solution, dried with anhydrous sodium sulfate, filtered, and concentrated , N-hexane crystallized to obtain 53 g of white crystalline powder, yield 37%, melting point: 94~96℃, specific rotation: [α] D ≤-21.5°(C1, toluene), optical purity: ≥99.0%, content: ≥99.0%.

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Abstract

A resolution method of a levocetirizine chiral intermediates belongs to the technical field of fine organic chemical engineering. The method comprises the following specific steps: adding racemic 1-[(4-chlorophenyl)benzyl]piperazine and chiral ionic liquid in a reaction container to react at 10-100 DEG C for 1-10 hours, extracting with toluene for layering, adjusting the pH value of the aqueous phase with 10wt% of sodium hydroxide solution to 11-12, extracting with toluene again, and concentrating to crystallize after the post-treatment, thus obtaining the product. The chiral ionic liquid is used as the solvent and resolving agent, the technology is easy to operate, the efficiency is high, the yield of three wastes is low, the yield of the product is more than 34%, the melting range of the product is narrow, the melting point is 94-96 DEG C, the specific rotation [alpha] D is not more than -21.5 degrees (C1, toluene), the optical purity is not less than 99.0%, and the content is not less than 99.0%. The post-treatment is convenient, the ionic liquid can be used repeatedly and the resolution method is an economical, practical, green and environmentally friendly technology.

Description

Technical field [0001] The invention relates to a method for separating levocetirizine chiral intermediates by using a chiral ionic liquid. Background technique [0002] Levocetirizine hydrochloride is a third-generation antihistamine, a single optical isomer of the second-generation antihistamine, cetirizine, and a selective H1 receptor antagonist, produced by SePracor in the United States and UCB in Belgium The company jointly developed a new chiral drug for the treatment of seasonal allergic rhinitis, perennial rhinitis, adult and juvenile chronic idiopathic measles. The anti-allergic effect is fast, strong and long-lasting. It is stronger than all existing antihistamines. It has no central nervous system side effects such as sedation and lethargy. It is a new generation of anti-allergic drugs. In 1982, UCB reported that 1-[(4-chlorophenyl)benzyl]piperazine and methyl chloroethoxyacetate were condensed and then hydrolyzed to form a salt to obtain 2-[2-[4-[ (4-Chlorophenyl)be...

Claims

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Application Information

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IPC IPC(8): C07D295/073C07B57/00
CPCY02P20/54
Inventor 张正华裴文张文成吴国忠
Owner 浙江永合新材料科技有限公司
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