Preparation technology for imidafenacin

A midanacin and preparation process technology, applied in the field of medicinal chemistry, can solve the problems of raising the reaction temperature, losing the reactivity, reducing the nucleophilic activity, etc., and achieves the effects of lowering the reaction temperature, improving the reactivity and shortening the reaction time.

Inactive Publication Date: 2016-03-16
KAIFENG PHARMA GRP +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above-mentioned preparation methods all adopt substitution reaction and hydrolysis reaction to carry out step by step, and there are disadvantages such as many preparation steps, high reaction temperature, long time, high consumption of raw materials, etc., especially in the first step reaction, all adopt reaction under acidic conditions, and This reaction is a nucleophilic substitution reaction, which occurs from the nucleophilic attack of the helium atom of 2-methimazole on the carbon atom connected to the halogen atom of 2-haloethyldiphenylacetonitrile. The nucleophilic activity is greatly reduced by forming a salt under the conditions, and the strong acid (HBr) generated in the reaction is more like

Method used

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  • Preparation technology for imidafenacin
  • Preparation technology for imidafenacin

Examples

Experimental program
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Effect test

Embodiment 1

[0015] Mix 160g (4mol) sodium hydroxide with 1200ml propanol, add 300g (1mol) 2-bromoethyldiphenylacetonitrile and 96g (1.2mol) 2-methimazole, and 12g polyethylene glycol 200 at room temperature, Then the reaction was stirred at 20-30°C to obtain 4-(2-methyl-1-imidazolyl)-2-2-diphenylbutyronitrile; then, the temperature was raised to 70-75°C and the reaction was continued with stirring. After the reaction is completed, lower the temperature to room temperature, neutralize the pH value of the reaction system with hydrochloric acid to 8-9, crystallize at room temperature, filter, wash, and dry to obtain the crude product of midanacine. The combined yield of the two steps of substitution and hydrolysis reaches more than 78%. Crystallization, the purity can reach more than 99.5%, which meets the requirements of product quality standards.

Embodiment 2

[0017] Mix 448g (8mol) of potassium hydroxide with 1533ml of isopropanol, add 255.5g (1mol) of 2-chloroethyldiphenylacetonitrile and 128g (1.6mol) of 2-methimazole, and 25.6g of polyethylene glycol at room temperature Alcohol 800, then stirred and reacted at 20-30°C to obtain 4-(2-methyl-1-imidazolyl)-2-2-diphenylbutyronitrile; then, the temperature was raised to 75-85°C, and the stirred reaction was continued. After the reaction is completed, lower it to room temperature, neutralize the reaction system with hydrochloric acid, bring the pH value to 8-9, crystallize at room temperature, filter, wash, and dry to obtain the crude product of midanacine. The combined yield of the two steps of substitution and hydrolysis reaches more than 78%. Recrystallized, the purity can reach more than 99.5%, which meets the requirements of product quality standards.

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Abstract

The invention discloses a preparation technology for imidafenacin and belongs to the pharmaceutical chemistry field. The method is as follows: 2-halogenated ethyl diphenylacetonitrile and 2-methyl imidazole are employed as initial raw materials, alcohol compounds are employed as a solvent, polyethylene glycol is employed as a phase-transfer catalyst, replacement and hydrolysis reactions are combined in an alkali metal hydroxide condition, and imidafenacin is prepared through one step. The technology is advantageous in that reaction steps are reduced, dosage of 2-methyl imidazole and the reaction temperature are lowered substantially, the reaction time is shortened, the synthesis yield is raised obviously, and the preparation technology is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation process of midanacin, a drug for treating overactive bladder, and belongs to the field of medicinal chemistry. Background technique [0002] Overactive bladder is a common chronic urinary tract dysfunction (OAB). The clinical manifestations are urgency, frequency and urge incontinence. was 31%. In China, the incidence rate of men over 50 years old in Beijing area is 16.4%, and the total incidence rate of urinary incontinence and urinary urgency among women over 18 years old is 40.4%. Midanacin (imidafilxin) is a drug for the treatment of overactive bladder developed by Kyorin Corporation of Japan. It was launched in Japan in June 2007. The synthesis of this product generally adopts the following synthetic route: [0003] [0004] In 1999, the synthesis of this compound reported by U.S. Patent (HS5932607) is to use (1) as a starting material, with DMF as a solvent, to react with 2-methimidazole at 150° C. for ...

Claims

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Application Information

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IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor 王瑞霞王新军崔浩张方杰方水霞赵红强罗琦刘卉朱慧峰
Owner KAIFENG PHARMA GRP
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