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Preparation method of bilastine important intermediate

A technology of benzimidazole and piperidine, which is applied in the field of medicinal chemistry, can solve the problems of long synthesis reaction time and achieve the effects of less side reactions, high yield and mild reaction conditions

Pending Publication Date: 2020-12-22
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the problem of long synthesis reaction time has not been overcome

Method used

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  • Preparation method of bilastine important intermediate
  • Preparation method of bilastine important intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Add 2.0 g of Compound V and 20 mL of THF to the bottle, and start stirring. Slowly add 0.8g NaH, react at room temperature for 1 hour. Add 1.0 g of tetrabutylammonium iodide and 4.1 g of bromoethyl ethyl ether, heat to reflux, and react for 1 hour. 20 mL of water was added to quench the reaction, and THF was removed by rotary evaporation. The residue was extracted with DCM 3 times, using 20 mL each time, separated, and the organic phase was collected. The organic phase was spun evaporated to remove DCM. PE 8 mL was added to the residue and stirring was started. Ice bath for 1 hour. After suction filtration, the resulting solid was air-dried at 50°C for 6-8 hours to obtain 2.3 g of compound VI as a white solid, with a yield of 92.8%.

[0018] After adding 2.8 mL of concentrated hydrochloric acid to the system, add 28 mL of deionized water and stir. Add 2.0 g of compound VI into the system and continue to stir, and react for more than 3 hours. The reaction was moni...

Embodiment 2

[0020] Add 6.0 g of Compound V and 60 mL of THF to the bottle, and start stirring. Slowly add 2.4g NaH, and react at room temperature for 1 hour. Add 3.0 g of tetrabutylammonium iodide and 4.1 g of bromoethyl ethyl ether, heat to reflux, and react for 1 hour. The reaction was quenched by adding 60 mL of water, and THF was removed by rotary evaporation. The residue was extracted with DCM for 3 times, using 60 mL each time, the layers were separated, and the organic phase was collected. The organic phase was spun evaporated to remove DCM. PE 25 mL was added to the residue and stirring was started. Ice bath for 1 hour. After suction filtration, the resulting solid was air-dried at 50°C for 6-8 hours to obtain 6.5 g of compound VI as a white solid, with a yield of 87.4%.

[0021] After adding 8.4 mL of concentrated hydrochloric acid to the system, add 84 mL of deionized water and stir. Add 6.0 g of compound VI into the system and continue to stir, and react for more than 3 h...

Embodiment 3

[0023] Add 20.0 g of Compound V and 200 mL of THF to the bottle, and start stirring. Slowly add 8.0 g of NaH and react at room temperature for 1 hour. Add 10.0 g of tetrabutylammonium iodide and 41.0 g of bromoethyl ethyl ether, heat to reflux, and react for 1 hour. 200 mL of water was added to quench the reaction, and THF was removed by rotary evaporation. The residue was extracted with DCM for 3 times, using 200 mL each time, the liquid was separated, and the organic phase was collected. The organic phase was spun evaporated to remove DCM. PE 80 mL was added to the residue and stirring was started. Ice bath for 1 hour. After suction filtration, the resulting solid was air-dried at 50°C for 6-8 hours to obtain 23.4 g of compound VI as a white solid, with a yield of 94.4%.

[0024] After adding 28.0 mL of concentrated hydrochloric acid to the system, add 280 mL of deionized water and stir. Add 20.0 g of compound VI into the system and continue to stir, and react for more...

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Abstract

According to the preparation method disclosed by the invention, the formula VI is prepared by reacting the formula V with bromoethyl ethyl ether, and a phase transfer catalyst tetrabutylammonium iodide is added, so that the reaction time is greatly shortened. the product of the formula VI is subjected to acid hydrolysis to obtain a compound II. The method is a good method for synthesizing the compound II, is mild in reaction condition, simple to operate and convenient to industrialize, and conforms to the development direction of green chemistry.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)piperidine-1-carboxylic acid tert-butyl, an important intermediate of bilastine Fat preparation. Background technique [0002] Bilastine (Formula I), chemical name 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzimidazol-2-yl]-piperidine -1-yl}ethyl)-phenyl]-2-methyl-propionic acid, CAS No. 202189-78-4, the second generation of histamine H developed by Spanish FAES pharmaceutical company 1 Receptor antagonist, compared with the original drug, its drug has good safety, no sedative effect and cardiotoxicity of commonly used antihistamine drugs, etc. It was first launched in Ireland in 2011 for the treatment of allergic rhinitis and chronic idiopathic urticaria. [0003] [0004] The synthetic route of Bilastine is generally 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (formula II ) docked with formula...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 曲振坤李恩民赵国磊
Owner BEIJING VENTUREPHARM BIOTECH
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