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Process of preparing troipisetron

A preparation technology of tropisetron, which is applied in the field of preparation technology of antiemetic drug tropisetron, can solve the problems such as the inevitable by-product hydrogen chloride gas generation, and achieve simple operation, high yield and good selectivity Effect

Inactive Publication Date: 2009-06-24
北京成宇化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method still uses oxalyl chloride as an acylating reagent, and a large amount of by-product hydrogen chloride gas is unavoidable, and there are still obvious deficiencies as a large-scale production process.

Method used

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  • Process of preparing troipisetron
  • Process of preparing troipisetron
  • Process of preparing troipisetron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Indole-3-carboxylic acid (16.1 g, 0.1 mol), 2-chloro-1,3-dimethylimidazoline chloride (11.4 g, 0.1 mol), and tropinol (14.1 g, 0.1 mol) were dissolved in In ethyl acetate (200 ml), triethylamine (10.1 g, 0.1 mol) was added dropwise with stirring, and reacted at room temperature for 12 hours. Add water (60 ml), adjust pH=9-10 with 15% sodium hydroxide, wash with water until neutral, and dry. Concentrate to obtain light yellow solid product, add absolute ethanol (300 milliliters), after dissolving, add concentrated hydrochloric acid under cooling, make pH=2~3, carry out vacuum distillation to obtain tropisetron hydrochloride crude product, filter, anhydrous Ethanol was recrystallized to obtain 24.3 g of a white crystalline product (purity determined by liquid chromatography was greater than 99.76%), yield 76.1%; melting point: 283-285° C., and the spectrum of the product was consistent with literature reports.

Embodiment 2

[0026] Indole-3-carboxylic acid (16.1 g, 0.1 mol), 2-chloro-1,3-dimethylimidazoline chloride (13.7 g, 0.12 mol), tropinol (14.1 g, 0.1 mol) were dissolved in In ethyl acetate (200 ml), triethylamine (15.2 g, 0.15 mol) was added dropwise with stirring, and reacted at room temperature for 18 hours. Add water (60 ml), adjust pH=9-10 with 15% sodium hydroxide, wash with water until neutral, and dry. Concentrate to obtain light yellow solid product, add absolute ethanol (300 milliliters), after dissolving, add concentrated hydrochloric acid under cooling, make pH=2~3, carry out vacuum distillation to obtain tropisetron hydrochloride crude product, filter, anhydrous Ethanol was recrystallized to obtain 25 g of a white crystalline product (purity determined by liquid chromatography was greater than 99.84%), with a yield of 78.3%; melting point: 283-285°C.

Embodiment 3

[0028] Indole-3-carboxylic acid (16.1 g, 0.1 mol), 2-chloro-1,3-dimethylimidazoline chloride (11.4 g, 0.1 mol), and tropinol (14.1 g, 0.1 mol) were dissolved in Pyridine (7.9 g, 0.1 mol) was added dropwise into ethyl acetate (200 ml) with stirring, and reacted at room temperature for 12 hours. Add water (60 ml), adjust pH=9-10 with 15% sodium hydroxide, wash with water until neutral, and dry. Concentrate to obtain light yellow solid product, add absolute ethanol (300 milliliters), after dissolving, add concentrated hydrochloric acid under cooling, make pH=2~3, carry out vacuum distillation to obtain tropisetron hydrochloride crude product, filter, anhydrous Ethanol was recrystallized to obtain 21.7 g of a white crystalline product (purity determined by liquid chromatography was greater than 99.25%), with a yield of 68.1%; melting point: 283-285°C.

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Abstract

The invention relates to a synthesis process for preparing tropisetron by using 2-chloro-1,3-dimethylimidazoline chloride as a condensing agent. Under the action of imidazoline chloride and an organic base, react indole-3-carboxylic acid and tropinol at room temperature for 12 to 24 hours in an inert solvent, and undergo cooling, filtering, washing and other processing steps to obtain the target Product tropisetron; the molar ratio that the above-mentioned indole-3-carboxylic acid, tropinol and 2-chloro-1,3-dimethylimidazoline chloride carry out condensation reaction is: 1: 1~2: 1~3; Preferably it is 1:1 to 1.5:1 to 1.5. The synthesis process of the invention is safe, pollution-free, easy to operate, high in product yield and good in purity, and can meet the requirements of pharmaceutical production.

Description

technical field [0001] The invention belongs to the production field of fine chemical products, and in particular relates to a preparation process of an antiemetic drug tropisetron. Background technique [0002] The chemical name of Tropisetron hydrochloride is endo-1H-indole-3-carboxylic acid-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester hydrochloride, It is a highly selective 5-HT3 receptor antagonist, which is suitable for the prevention and treatment of nausea and vomiting caused by chemotherapy, radiotherapy and surgery in children and adults. Its chemical structure is shown in figure 2 . [0003] As an existing preparation method, in U.S. Patent (US4797406, US4789673), it is introduced to react with indole-3-formic acid and oxalyl chloride, and obtain 3-indoleformyl chloride with methylene chloride and n-hexane, and then react with tropinol The reaction of lithium tropine alkoxide generated under the activation of n-butyllithium is followed by post-treatment to obtain t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D221/00C07D209/00
Inventor 宋宇王道林王玉平
Owner 北京成宇化工有限公司
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