Method for preparing bilastine

A compound, ethyl technology, applied in the field of drug synthesis, can solve problems such as difficult removal of impurities, increased post-processing difficulty, and fracture

Inactive Publication Date: 2020-12-22
山东齐环医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this preparation method, a strong base is used to hydrolyze the oxazole ring in step 3, which can also easily...

Method used

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  • Method for preparing bilastine
  • Method for preparing bilastine
  • Method for preparing bilastine

Examples

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preparation example Construction

[0027] In a more preferred preparation scheme, bilastine is prepared by reacting the compound represented by formula I with 2-chloroethyl ether.

[0028] In some embodiments of the above-mentioned preferred preparation method, the preparation method of bilastine is prepared by reacting the compound shown in formula I with 2-chloroethyl ether, and the reaction is shown in the following formula:

[0029]

[0030] The preparation method is as follows:

[0031] 2-(4-{2-[4-(1H-benzimidazol-2-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid (Formula I shown compound), DMF and sodium hydride were mixed and reacted for a period of time, then 2-chloroethyl ether was added, and the heating reaction was continued. After the reaction, the pH value of the reaction system was adjusted to neutral by glacial acetic acid, and a white solid was obtained by filtration, which was the ratio Rustin.

[0032] In this series of embodiments, the 2-(4-{2-[4-(1H-benzimidazol-2-yl)-piperid...

Embodiment 1

[0059] In this embodiment, a kind of 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-1-methanol Base-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole, 2-(4-{2-[ 4-(1H-benzimidazol-2-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid is an intermediate bilastine preparation method, the The preparation method is shown in the following formula:

[0060]

[0061] Step 1: Preparation of 2-[1-(2-{4-[1-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl] -Phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole

[0062] 20.1g 2-piperidin-4-yl-1H-benzimidazole, 41.6g 2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl )-1-methyl-ethyl]-phenyl}-ethyl p-toluenesulfonate, 11.7g of sodium carbonate, 50ml of DMF were put into the reaction flask, and heated to 80°C for 2 hours. Add 100ml of deionized water, filter, and air-dry the filter cake at 70°C for 3 hours to obtain 35.5g of white solid. Yield 79.8%.

[0063] Step 2: Preparation of ...

Embodiment 2

[0068] The difference from Example 1 is that another method for preparing 2-(4-{2-[4-(1H-benzimidazol-2-yl)-piperidin-1-yl]-ethyl Base}-phenyl)-2-methyl-propionic acid method:

[0069] 40.0g 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]- Phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxyl-ethyl)-1H-benzimidazole, 60ml ethanol, 10ml concentrated hydrochloric acid are put into the reaction flask and heated to The reaction was refluxed for 5 hours. After the reaction, the pH value was adjusted to 7 with 4 mol / L sodium hydroxide, filtered, and the filter cake was washed with water, and dried at 70° C. for 3 hours to obtain 31.8 g of a white solid. Yield 90.3%.

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Abstract

The invention particularly relates to a method for preparing bilastine, which comprises the following steps of reacting 2-(4-{2-[4-(1H-benzimidazole-2-yl)-piperidine-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid serving as a key intermediate with 2-chloroethyl ether to prepare bilastine. The invention further provides a scheme for preparing the above intermediate from 2-[1-(2-{4-[1-(4, 4-dimethyl-4, 5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidine-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole, or 2-piperidine-4-yl-1H-benzimidazole or 2-methyl-2-{4-[2-(toluene-4-sulfonyloxy)-ethyl]-phenyl}-methyl propionate. The synthesis process provided by the invention has the characteristics of easily available raw materials, simple operation, high yield and avoidance of impurity generation,and is convenient for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of bilastine. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Bilastine, the chemical name is 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzimidazol-2-yl]-piperidine- 1-base} ethyl)-phenyl]-2-methyl-propionic acid, the structure is shown in the following formula: [0004] [0005] Bilastine is an oral non-sedating histamine H1 receptor antagonist developed by Spain's FAES Pharmaceutical Company. It was approved by the European Union in August 2012 for the treatment of allergic rhinitis and urticaria. The compound acts selectively on peripher...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 厉建超王锴男王田雨王明卿
Owner 山东齐环医药科技有限公司
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