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Alcaftadine intermediate preparation method

A catadine and intermediate technology, which is applied in the field of compound preparation, can solve the problems of unsuitable industrialization and enlargement, large environmental pollution, high equipment corrosiveness, etc., and achieves easy industrial production, easily available raw materials, and short synthesis routes. Effect

Active Publication Date: 2015-08-26
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] We try to use N-methyl-4-piperidine formic acid to carry out acyl chloride synthesis N-methyl-4-piperidine carboxylic acid chloride, but yield is only 40-50%, and this reaction needs to use thionyl chloride, reaction and During the post-treatment process, a large amount of acid gas is released, causing serious environmental pollution and corrosiveness to equipment, so it is not suitable for industrial scale-up
[0013] So finding more economical synthetic methods is always a challenge

Method used

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Examples

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Effect test

Embodiment 1

[0032] Preparation of [4-(1-methylpiperidine)][2-(1-phenethyl-1H-imidazole-)] ketone

[0033] Under the protection of nitrogen, dissolve 17.2g (0.1mol) of benethylimidazole in 170mL of tetrahydrofuran, stir and cool to below -40℃, add dropwise 2.5mol / L n-butyllithium n-hexane solution 50mL (0.125mol), and then drop Add 15.7 g (0.1 mol) of methyl 1-methylpiperidine-4-carboxylate, keep stirring at low temperature, monitor by TLC until the reaction is complete, and add glacial acetic acid. The reaction solution was poured into purified water and stirred evenly, extracted with ethyl acetate, the organic layer was separated, dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The obtained oil was added with isopropanol and stirred to precipitate a solid, which was suction filtered and dried to obtain 25.3 g of an off-white solid with a yield of 85.1%. HPLC purity: 98.7%

[0034] 1H NMR 1H NMR (400MHz, CDCl3, TMS): δ7.12...

Embodiment 2

[0036] Preparation of [4-(1-methylpiperidine)][2-(1-phenethyl-1H-imidazole-)] ketone

[0037] Under the protection of nitrogen, dissolve 17.2g (0.1mol) of benethylimidazole in 170mL of tetrahydrofuran, stir and cool down to below -40℃, add dropwise 2.5mol / L n-butyl lithium n-hexane solution 50mL (0.125mol), drip to completion Then, 17.1 g (0.1 mol) of ethyl 1-methylpiperidine-4-carboxylate was added dropwise, and stirring was maintained at low temperature. TLC monitored until the reaction was complete, and glacial acetic acid was added. The reaction solution was poured into purified water and stirred evenly, extracted with ethyl acetate, the organic layer was separated, dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The obtained oily state was stirred with isopropanol to precipitate a solid, which was suction filtered and dried to obtain 24.9 g of an off-white solid with a yield of 83.7% and an HPLC purity of ...

Embodiment 3

[0039] Preparation of [4-(1-methylpiperidine)][2-(1-phenethyl-1H-imidazole-)] ketone

[0040] Under the protection of nitrogen, dissolve 17.2g (0.1mol) of benethylimidazole in 170mL of tetrahydrofuran, stir evenly, cool to below -40°C, dropwise add 2.5mol / L n-butyl lithium n-hexane solution 50mL (0.125mol), Then 18.5 g (0.1 mol) of isopropyl 1-methylpiperidine-4-carboxylate was added dropwise, and the stirring was continued to be maintained at a low temperature. TLC monitored until the reaction was complete, and glacial acetic acid was added. The reaction solution was poured into purified water and stirred evenly, extracted with ethyl acetate, the organic layer was separated, dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The obtained oily substance was added with isopropanol and stirred to precipitate a solid, which was filtered and dried to obtain 26.8 g of off-white solid, yield 90.1%, HPLC purity: 99.2%

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Abstract

The invention relates to a preparation method of a histamine H1 receptor antagonist alcaftadine key intermediate [4-(1-methylpiperidine)][2-(1-phenethyl-1H-imidazole-)]-methanone. According to the method, N-methyl-4-piperidine carboxylate is adopted as a raw material, and is subjected to a condensation reaction with phenethyl imidazole under an alkaline condition. With the method, the synthesizing process is simplified, three-waste generation is reduced, the raw material and the reagents are cheap and are easy to obtain, and yield is high. The method is more suitable for industrialized productions.

Description

Technical field [0001] The present invention relates to a preparation method of a compound, in particular to a histamine H1 receptor antagonist-a key intermediate of Alcaftadine [4-(1-methylpiperidine)][2-( 1-Phenethyl-1H-imidazole-)] ketone preparation method. Background technique [0002] Alcaftadine, trade name: Lastacaft, is a new histamine H1 receptor antagonist developed by Vistakon Pharmaceuticals. In 2010, the FDA approved it for the treatment of itching caused by allergic conjunctivitis, and it was launched in 2011. [0003] The synthetic route of acatadiene is mainly the synthetic process reported in the patent document WO1992022551. The process has a key intermediate I, namely [4-(1-methylpiperidine)][2-(1-phenethyl-1H) -Imidazole-)] ketone, the structural formula of intermediate I is as follows: [0004] [0005] Patent document WO1992022551 prepares intermediate I with ethyl N-formate-4-piperidinoyl chloride and phenethyl imidazole as starting materials, through conde...

Claims

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Application Information

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IPC IPC(8): C07D401/06
CPCC07D401/06
Inventor 宁东波朱毅陈彦陈国华
Owner WUHAN WUYAO SCI & TECH
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