New method for synthesizing Ramosetron Hydrochloride

A technology of ramosetron hydrochloride and a new method, applied in the field of preparation of tetrahydrobenzimidazole derivatives, can solve problems such as unfavorable industrial production, difficult separation, purification, low yield and the like, and achieve high product yield and high quality Controllable and simple preparation method

Inactive Publication Date: 2005-11-16
天津康鸿医药科技发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the preparation method of this patent, some intermediates such as N-(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonylpyrrole and its hydrochloride are easily soluble in water, and it is difficult to pass through the experimental operation. Commonly used techniques such as extraction and recrystallization achieve the purpose of separation and purification, and the yield is low (about 30%)
In addition, in the carbonylation reaction of aromatic rings, 1,2-dichloroethane is used as the reaction solvent. This reagent belongs to the national first-class control reagent. It is highly toxic and is not conducive to industrial production. It should be avoided.

Method used

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  • New method for synthesizing Ramosetron Hydrochloride
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  • New method for synthesizing Ramosetron Hydrochloride

Examples

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preparation example Construction

[0025] Preparation of 5-carboxylate methyl benzimidazole sulfate

[0026] Add 3200ml of methanol and 304g of 5-carboxylate benzimidazole sulfate in a 5L reaction flask, add 352ml of concentrated sulfuric acid dropwise under stirring, heat and reflux for 7 hours, cool, add 20g of activated carbon, heat and reflux for 0.5 hours, heat Filtrate, concentrate the filtrate, cool to obtain white crystals, filter and dry to obtain 240g, melting point: 169-171°C, yield 74%.

[0027] Reference Example 2

[0028] Preparation of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate (II)

[0029] In a 2L autoclave, add 1200ml of acetic acid, 80g of 5-carboxylate benzimidazole methyl sulfate, 40g of 10% Pd / C (dry weight), 80°C, 60kg / cm 2 Hydrogenation reaction under certain pressure conditions for about 16 hours (until the pressure no longer changes), cooling, discharging, filtering the catalyst, and concentrating under reduced pressure to obtain a light yellow oil, adding 300ml of 6N ...

Embodiment 1

[0031] Preparation of 1-acetyl-5-carboxylic acid-4,5,6,7-benzimidazole (III)

[0032] Add 66g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate, 62.0g of triethylamine, and 300ml of acetonitrile into the reaction flask, add dropwise 36.2g of acetyl chloride, heat and reflux and stir for 4 Hours, the acetonitrile layer was concentrated to dryness under reduced pressure, cooled, 300ml of water was added dropwise, extracted with ethyl acetate, dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 70 g of brown oil, which could be directly put into the next step for reaction.

Embodiment 2

[0034] Preparation of 1-acetyl-5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole (I)

[0035] Add 70 g of acetyltetrahydrobenzimidazole, 200 ml of acetonitrile, and 40 ml of thionyl chloride into the reaction flask, heat to reflux, stir for 2 hours, and distill off part of the solvent under reduced pressure to take out excess thionyl chloride. After cooling, slowly add 53 g of tetrahydropyrrole and 100 ml of acetonitrile solution dropwise at 2°C. After the drop is complete, warm up to room temperature, stir for 2 hours, then 1 hour at 40°C, and concentrate under reduced pressure to obtain 132 g of a brown oily substance.

[0036] Add 132g of brown oil and 100g of N-methylindole to 300ml of acetonitrile, add 132g of phosphorus oxychloride, stir for 7 hours under heating and vigorous reflux, and cool to room temperature. Under cooling conditions, slowly add 660ml of water dropwise, stir with 500ml of ethyl acetate, separate layers, wash the organic layer twice wit...

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Abstract

A process for preparing the leimosiqiong hydrochoride from tetrahydrobenzoimidazole includes protecting by cycloacyl, arylcarbonylating, and acid hydrolyzing. Its advantages are high output rate (70%).

Description

technical field [0001] The invention relates to a preparation method of acylated tetrahydrobenzimidazole derivatives, more specifically a new method for synthesizing ramosetron hydrochloride. Background technique [0002] The chemical name of Ramosetron hydrochloride is (-)-5-(R)-[(3-(1-methylindolyl))carbonyl]-4,5,6,7-tetrahydrobenzene And imidazole hydrochloride, is a new type of highly selective 5-HT 3 Receptor antagonists, which work by blocking 5-HT present in the afferent vagal nerve endings in the mucous membrane of the digestive tract 3 Receptors, inhibit gastrointestinal side effects such as nausea and vomiting caused by chemotherapy drugs and surgery. Clinically, it is mainly used to prevent or treat gastrointestinal symptoms such as nausea and vomiting caused by chemotherapy drugs. [0003] Chinese patent ZL90100544.4 authorizes the preparation method of tetrahydrobenzimidazole derivatives, which uses 5-carboxylic acid benzimidazole methyl sulfate as the starti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06
Inventor 李祎亮邹美香魏文涛曹光孙歆慧张彩霞
Owner 天津康鸿医药科技发展有限公司
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