Preparation technology for imidafenacin

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 ...

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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 likely to form a salt with 2-methimazole, making it lose its reactivity

Therefore, in order to make the main raw material (1) react completely under this condition, the consumption of 2-methimazole must be increased, while increasing the reaction temperature and prolonging the reaction time, which increases the consumption of raw materials and the probability of side reactions, which not only reduces the yield , and more impurities are produced, and more raw material 2-methimidazole remains, which brings great difficulties for post-processing

At the same time, in order to increase the solubility of raw materials, the more expensive aprotic polar solvent DMF or DMSO is used, which also increases the synthesis cost.

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