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A kind of preparation method of azasetron hydrochloride

A technology of azasetron hydrochloride and aminoquinuclidine hydrochloride, which is applied in the field of medicine, can solve problems such as difficult removal of by-products, environmental and equipment pollution, unfavorable production methods, etc., to achieve mild reaction conditions, avoid pollution, and yield high rate effect

Active Publication Date: 2016-06-01
YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, the thionyl chloride used in the route 1 is used as an acylating reagent, which has great pollution to the environment and equipment; the highly toxic reagent ethyl chloroformate is used in the route 2, and the route 2 needs to be reacted at -20°C and chromatographic column separation and purification, which is not conducive to the production of the method; the condensation reagent DCC is used in route three, and the generated by-product DCU is not easy to remove

Method used

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  • A kind of preparation method of azasetron hydrochloride
  • A kind of preparation method of azasetron hydrochloride

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Effect test

Embodiment 1

[0080] In a 500ml three-necked flask, add 150ml of water and 12g (0.3mol) of sodium hydroxide, stir until the solid is completely dissolved, then add 100ml of ethanol, cool down to 20°C, add 6-chloro-4-methyl-3,4-di Hydrogen-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid methyl ester 25.5g (0.1mol), stirring reaction for 3h, the reaction is completed, cooling below 10°C, dilute hydrochloric acid to adjust the pH value to 2 , filtered, and dried to obtain off-white solid of 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, 21.9g, yield The rate is 91%.

[0081] 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid (12.0g, 0.05mol), triethyl phosphite ( Add 10.0g, 0.062mol), 2,2'-dithiodibenzothiazole (20.0g, 0.062mol) and tetrahydrofuran (100ml) into a dry reaction flask, stir at room temperature for 1h, and control the temperature in an ice-water bath below 20°C. A solution of triethylamine (8.6ml) in tetrahydrofuran (20ml) was added dr...

Embodiment 2

[0087]In a 500ml three-neck flask, add 200ml of water and 12g (0.3mol) of sodium hydroxide, stir until the solid is completely dissolved, then add 100ml of ethanol, cool down to 21°C, add 6-chloro-4-methyl-3,4-di Hydrogen-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid methyl ester 25.5g (0.1mol), stirred for 3h, the reaction was completed, cooled below 10°C, dilute hydrochloric acid to adjust the pH value to 1 ~2, filtered and dried to give off-white solid of 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, 20.9g , yield 86.7%.

[0088] 6-chloro-4-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid (12.0g, 0.05mol), triethyl phosphite ( Add 9.7g, 0.06mol), 2,2'-dithiodibenzothiazole (19.4g, 0.06mol) and tetrahydrofuran (100ml) into a dry reaction flask, stir at room temperature for 1h, and control the temperature in an ice-water bath below 20°C. A solution of triethylamine (8.6ml) in tetrahydrofuran (20ml) was added dropwise. After dropping, r...

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Abstract

The invention discloses a method for preparing azasetron hydrochloride. The method comprises the following steps: hydrolyzing 6-chloro-4-methyl-3-oxo-3,4- dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester which serves as an initial material to prepare carboxylic acid; condensing with 2,2'-dibenzothiazyl disulfide under the action of triethylamine and triethyl phosphite to prepare active ester of carboxyl-2-benzothiazolyl thioester; directly condensing with a 3-aminoquinuclidine alkaline aqueous solution without separation, and salifying to prepare the azasetron hydrochloride. The method can be used for avoiding multiple steps of reaction and pollution to environment, has mild reaction condition and relatively high yield, and is suitable for industrialization.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of azasetron hydrochloride. Background technique [0002] Azasetron hydrochloride, alias N-(1-azabicyclo2.2.2oct-8-yl)-6-chloro-4-methyl-3-oxo-3,4-di-2H-1,4 -Benzoxazine-8-carboxamide hydrochloride, CASNo.:123040-16-4; Molecular formula: C l7 h 20 ClN 3 o 3 HCl, the structural formula is: [0003] [0004] It is used to prevent and treat nausea and vomiting caused by tumor chemotherapy, radiotherapy and surgery, and is a 5-HT3 receptor antagonist with high efficiency, high selectivity, safe use and low side effects. [0005] There are few reports about the synthetic method of azasetron hydrochloride, which are mainly divided into the following three routes: [0006] Route 1: Patent US4892872, literature (China Industry Journal, 2006, 37 (1), 1-3) and literature (Chinese Journal of Medicinal Chemistry, 200, 10 (2): 138-140), all with 6-chloro-4 -Methyl-3-oxo-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 李元波谢义鹏曹康平王强伍普华王颖周芯宇
Owner YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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