Novel preparation method of ramosetron hydrochloride

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

Inactive Publication Date: 2006-05-03
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-formic 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 temperature for reaction for 2 hours, evaporate the solvent under reduced pressure to obtain 36.6 g of crude product of 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole sulfate, the yield : 77.7%, which can be directly used in the following reaction without further refining.

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 reacted with a large excess of thionyl chloride, and the specific method is to prepare 5-formic acid-4,5, 43.4g (0.20mol) of 6,7-tetrahydro-1H-benzimidazole sulfate was suspended in 238g (2.0mol) of thionyl chloride, stirred, heated to reflux, reacted for 2 hours, concentrated under reduced pressure to recover excess Thionyl chloride obtained 42.8g of 5-formyl chloride-4,5,6,7-tetrahydro-1H-benzimidazole sulfate crude product, yield: 90.9%, and it does not need to be further refined, 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, replace 5-formic acid-4,5,6,7-tetrahydro-1H-benzene with 5-formic acid-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride And imidazole sulfate, the resulting 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 ]- 4ú¼5ú¼6ú¼7- 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 hydrochloride thereof, especially a new preparation method of Ramosetron. Background technique: [0002] Ramosetron is a new type of 5-HT 3 Receptor antagonist, can release 5-hydroxytryptamine from enterochromaffin cells in the digestive tract, and interact with 5-HT present in the afferent vagus nerve endings in the digestive tract mucosa 3 Receptor binding, and play 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 etc., Clin. Thera. (2002) 24 (7): 1148-...

Claims

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Application Information

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