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Bilastine preparation method

A technology of bilastine and molar ratio, which is applied in the field of preparation of bilastine, can solve the problems of cumbersome operation, harsh operating conditions, long route, etc., and achieve simple reaction operation, reduced reaction cost, high yield and purity Effect

Active Publication Date: 2016-11-23
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Due to the poor compatibility of the Grignard reaction to the group, it is necessary to use a special oxazole to protect the carboxyl group, and the yield of this step is very low
In addition, the conditions of the Grignard reaction are relatively harsh, and the requirements for anhydrous and oxygen-free are high, so it is not suitable for large-scale production
Generally speaking, the repeated protective group process makes the route too long and the cost is too high; and the use of toxic methylation reagents will also cause great harm to production personnel. Therefore, this route is not suitable for industrial production. in accordance with
[0021] In summary, the existing methods for synthesizing bilastine have harsh operating conditions, high toxicity, expensive raw materials, and cumbersome operations

Method used

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Examples

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Effect test

Embodiment 1-1

[0049] Example 1-1: Synthesis of 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (compound 3)

[0050] Add 55.2g of 2-nitroaniline (compound 1, 0.4mol) and 85.3g of 1-Boc-piperidine-4-carbaldehyde (compound 2, 0.4mol) into a mixed solvent of ethanol (3.2L)-water (80ml), and dissolve completely Add 139.3gNa 2 S 2 0 4 (0.8mol), heated to reflux, TLC followed the reaction, the reaction was complete after 8 hours, the precipitate was filtered off, the filter cake was washed with absolute ethanol (1.6L×2), and the filtrates were combined and spin-dried to obtain a precipitate. After dissolving it in ethanol, it was recrystallized from ethanol-water to obtain, 101.3g tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (compound 3), yield 84 %.

Embodiment 1-2

[0051] Example 1-2: Synthesis of 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (compound 3)

[0052] Add 55.2g of 2-nitroaniline (compound 1, 0.4mol) and 102.4g of 1-Boc-piperidine-4-carbaldehyde (compound 2, 0.48mol) into a mixed solvent of ethanol (3.2L)-water (128ml), and dissolve completely Add 174.1gNa 2 S 2 0 4 (1mol), heated to reflux, TLC followed the reaction, the reaction was complete after 8 hours, the precipitate was filtered off, the filter cake was washed with absolute ethanol (1.6L×2), and the filtrates were combined and spin-dried to obtain a precipitate. After dissolving it in ethanol, it was recrystallized from ethanol-water to obtain, 108.5g tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (compound 3), yield 90 %.

Embodiment 1-3

[0053] Example 1-3: Synthesis of 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (compound 3)

[0054] Add 55.2g of 2-nitroaniline (compound 1, 0.4mol) and 110.9g of 1-Boc-piperidine-4-carbaldehyde (compound 2, 0.52mol) into a mixed solvent of ethanol (3.2L)-water (160ml), and dissolve completely Add 208.9gNa 2 S 2 0 4 (1.2mol), heated to reflux, TLC followed the reaction, the reaction was complete after 8 hours, the precipitate was filtered off, the filter cake was washed with absolute ethanol (1.6L×2), and the filtrates were combined and spin-dried to obtain a precipitate. After dissolving it in ethanol, it was recrystallized from ethanol-water to obtain, 103.7g tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (compound 3), yield 86 %.

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Abstract

The invention discloses a Bilastine preparation method. The Bilastine preparation method includes that 2-nitroaniline which is low in price and easy to obtain is taken as a raw material which is subjected to reduction-n-cyclohexylmaleimide reaction, alkylation reaction, hydrolyzing and coupling prior to hydrolyzing to obtain Bilastine. With the method, shortcomings that harsh operation conditions, high toxicity, expensive raw materials and tedious operation in the prior art are overcome, reaction conditions in each step are moderate, and the synthetic method is simple in operation, easy to deal with, few in side products, high in yield and purity, low in production cost and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of bilastine. Background technique [0002] Bilastine is a second-generation histamine H1 receptor antagonist developed by Spain's FAES Pharmaceutical Company. It was approved by the European Union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria. This product is safe, without the sedative effect and cardiotoxicity of commonly used antihistamines. Its chemical structural formula is as follows: [0003] [0004] Researchers have successively designed and developed various synthetic methods of bilastine. Several synthetic methods have been reported for the preparation of bilastine and its key intermediates at present: [0005] Route 1: WO2009102155 reports the synthesis method of bilastine, and its synthesis route is as follows: [0006] [0007] In this method, the synthesis of the key intermediat...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D211/32C07C303/28C07C309/30C07C51/41C07C51/353C07C59/48
CPCC07C51/353C07C51/412C07C303/28C07D211/32C07D401/04C07C309/30C07C59/48
Inventor 李震颜成刚杨玉发
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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