Novel preparation method of ramosetron hydrochloride

A technology of ramosetron and structural formula, applied in the field of medicinal chemistry, can solve the problems of difficulty in solvent recovery, large consumption of side chain N-methyl indole and high cost, and achieves reduced consumption of N-methyl indole and easy recovery The effect of reuse and easy operation

Inactive Publication Date: 2009-05-13
TIANJIN ZHONGRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In this preparation process, the resolution yield is low (less than 20%), the consumption of side chain N-methyl indole is large, the solvent recovery is difficult, the operation is cumbersome, and the cost is higher

Method used

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  • Novel preparation method of ramosetron hydrochloride
  • Novel preparation method of ramosetron hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Preparation of 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole sulfate (method A)

[0032] Suspend 43.4 g (0.20 mol) of 5-carboxylic acid-4,5,6,7-tetrahydro-1H-benzimidazole sulfate in 500 ml of dichloroethane, add 47.6 g (0.40 mol) of thionyl chloride, Stir, heat up to 60 ° C, keep the reaction for 2 hours, evaporate the solvent under reduced pressure to obtain 36.6 g of the crude product of 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole sulfate in a yield of 36.6 g. : 77.7%, which was directly used in the following reaction without further purification.

Embodiment 2

[0033] Example 2: Preparation of 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole sulfate (method B)

[0034] 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole sulfate can also be directly prepared by reacting with a large excess of thionyl chloride. The specific method is to mix 5-formic acid-4,5, 6,7-tetrahydro-1H-benzimidazole sulfate 43.4g (0.20mol) was suspended in 238g (2.0mol) of thionyl chloride, stirred, heated to reflux, reacted for 2 hours, and concentrated under reduced pressure to recover excess amount. Thionyl chloride to obtain 42.8g of crude 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole sulfate, yield: 90.9%, which also does not require further purification, and can be directly used in the following Reaction.

Embodiment 3

[0035] Example 3: Preparation of 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride

[0036]Referring to Example 1 or 2, use 5-carboxylic acid-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride instead of 5-carboxylic acid-4,5,6,7-tetrahydro-1H-benzene Simidazole sulfate, the obtained crude product can be directly used in the following reaction without further purification.

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Abstract

The invention describes the preparation method for R-5-[(1-methyl -1H-indole -3-group) carbonyl ]- 4,5,6,7- tetrahydro -1H-benzimidazole (named Ramosetron) as 5-HT3 acceptor antagonist, and its hydrochlorate. Wherein, it uses first-resolution latter-condensation technique, reduces greatly the consumption of N- methylindole, increases total yield, and fits to industrial production.

Description

Technical field: [0001] The present invention relates to the field of medicinal chemistry, especially 5-HT 3 Receptor antagonist R-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole "ramosetron" ( Ramosetron) and the application of its hydrochloride, especially a new preparation method of ramosetron. Background technique: [0002] Ramosetron is a new type of 5-HT 3 Receptor antagonists can free serotonin from enterochromaffin cells in the digestive tract and interact with 5-HT in the afferent vagus nerve endings in the mucosa of the digestive tract. 3 Binds to receptors and exerts an antiemetic effect. In clinical practice, it mainly prevents or treats gastrointestinal symptoms such as nausea and vomiting caused by chemotherapy drugs. European Patent E.P 381422; K. Miyata et al., J. Pharm. Exper. Thera. (1991) 259(1): 15-21; Yoshitaka Fujii et al., Br. J. Ophthalmol (2001) 85: 670-672; Yoshitaka Fujii et al., Clin. Thera. (2002) 24(7): 1148-1153 re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06C07D209/12C07D235/04
Inventor 周华明李丰善
Owner TIANJIN ZHONGRUI PHARMA
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