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Preparation method and application of bilastine

A technology for bilastine and bilastine methyl ester, which is applied in the field of organic compound synthesis, can solve problems such as difficult industrialized production, complex synthesis route, potential safety hazard, etc., and achieves reduction of operation steps, shortening of synthesis route, and reduction of industrialized operations. Effect

Inactive Publication Date: 2018-12-25
BEIJING THTD PHARMA TECH JOINT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the above two synthetic routes, X and R 1 Complex structure, expensive, complex synthetic route, easy to introduce impurities, difficult to purify
Moreover, the use of flammable and explosive NaH, which is not easy to be industrially produced, has potential safety hazards

Method used

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  • Preparation method and application of bilastine
  • Preparation method and application of bilastine
  • Preparation method and application of bilastine

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preparation example Construction

[0049] A preparation method of bilastine, the preparation route is as follows:

[0050]

[0051]The synthetic route of bilastine provided by the present invention shortens the synthetic route, makes the crude product of bilastine produced contain less impurities, is convenient for refining, and improves the yield of final refining, thereby reducing industrial operations and reducing cost.

[0052] The preparation method of described bilastine specifically comprises the following steps:

[0053] Using 2-methyl-2-{4-[2-(toluene-4-sulfonyloxy)-ethyl]-phenyl}-propionic acid methyl ester as starting material and 1-(2-ethoxy -Ethyl)-2-piperidin-4-yl-1H-benzimidazole is condensed into bilastine methyl ester, bilastine methyl ester is hydrolyzed into bilastine crude product in alkaline medium, and bilastine methyl ester is hydrolyzed into bilastine crude product, Rastin crude refined to get bilastine.

[0054] Preferably, the preparation method of the 2-methyl-2-{4-[2-(toluene-4...

Embodiment 1

[0079] (1) preparation of bilastine methyl ester

[0080] Dissolve 1-(2-ethoxy-ethyl)-2-piperidin-4-yl-1H-benzimidazole (27.34g, 0.1mol) and diisopropylethylamine (39g, 0.3mol) in In tetrahydrofuran (200ml), slowly add 2-methyl-2-{4-[2-(toluene-4-sulfonyloxy)-ethyl]-phenyl}-propionic acid methyl ester (28g, 0.1 mol) in tetrahydrofuran (100ml). After the addition, heat up to reflux and keep warm for 8 hours, add 100ml of water to quench the reaction, then concentrate the reaction solution, extract the concentrated reaction solution with 200ml ethyl acetate for 3 times each time, and wash the combined ethyl acetate layer with water and saturated saline Twice, dried and concentrated to give bilastine methyl ester (39.45 g, 82.6%) as a white solid.

[0081] (2) preparation of bilastine crude product

[0082] Add the bilastine methyl ester (23.88g, 0.05mol) obtained above into methanol (75ml), then add a 30% aqueous solution containing sodium hydroxide (3g, 0.075mol), and cool t...

Embodiment 2

[0086] (1) preparation of bilastine methyl ester

[0087] Dissolve 1-(2-ethoxy-ethyl)-2-piperidin-4-yl-1H-benzimidazole (27.34g, 0.1mol) and diisopropylethylamine (39g, 0.3mol) in In isopropyl ether (200ml), slowly add 2-methyl-2-{4-[2-(toluene-4-sulfonyloxy)-ethyl]-phenyl}-propionic acid methyl ester (28g , 0.1mol) in isopropyl ether solution (100ml). After the addition, heat up to reflux and keep warm for 6 hours, then add 100ml of water to quench the reaction, then concentrate the reaction solution, extract the concentrated reaction solution with 200ml ethyl acetate for 3 times each time, and wash the combined ethyl acetate layer with water and saturated saline Twice, dried and concentrated to give bilastine methyl ester (36.87 g, 77.2%) as a white solid.

[0088] (2) preparation of bilastine crude product

[0089] Add the bilastine methyl ester (23.88g, 0.05mol) obtained above into ethanol (75ml), then add a 30% aqueous solution containing sodium hydroxide (3g, 0.075mol...

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Abstract

The invention provides a preparation method and application of bilastine. Bilastine is prepared by: subjecting methyl 2-methyl-2-{4-[2-(toluene-4-sulfonyloxy)-ethyl]-phenyl}-propionate as an initial material to condensation synthesis with 1-(2-ethoxy-2-ethyl)-2-piperdine-4-yl-1H-benzimidazole to obtain bilastine methyl ester, hydrolyzing the bilastine methyl ester in an alkaline medium into crudebilastine, and refining the crude bilastine. The preparation method herein has the advantages of simple synthetic route, good accessibility of materials, good removal convenience of impurities, good safety of reaction process and the like. After the reaction route is shortened, the produced crude bilastine has fewer impurities; refining is facilitated, and refining yield can be increased; therefore, industrial operation quantity and cost are reduced; the quantity of industrial three wastes is evidently reduced; the preparation method is more economical and environmentally friendly and has fewer industrial operations.

Description

technical field [0001] The invention relates to the technical field of organic compound synthesis, in particular to a preparation method of bilastine. Background technique [0002] Bilastine, Chinese name: 2-[4-[2-[4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]piperidin-1-yl]ethyl Base] phenyl] -2-methylpropionic acid, the chemical name is 2-[4-[2-[4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl] Piperidin-1-yl]ethyl]phenyl]-2-methylpropionic acid, the structure is: [0003] [0004] It is an antihistamine with a new chemical structure developed by Spain's FAES Pharmaceutical Company. The drug has no sedative effect, no cardiotoxicity, does not interact with cytochrome P450 enzyme substrates, and has the characteristics of a strong antihistamine, which meets the current standards of the European Society of Allergy and Clinical Immunology and the impact of allergic rhinitis on asthma Standard requirements for therapeutic drugs for the treatment of allergic diseases. Bilastine is...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61P37/08
CPCA61P37/08C07D401/04
Inventor 王红平杨红瑾
Owner BEIJING THTD PHARMA TECH JOINT CO LTD
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