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Preparation method of imidafenacin

A technology of imidazole and methylimidazole, which is applied in the field of preparation of midanacin, a new drug for the treatment of overactive bladder, can solve the problems of deflagration, many impurities, and complex components of the final product.

Inactive Publication Date: 2014-06-25
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (I) When preparing the precursor 4-bromo-2.2-diphenylbutyronitrile (3), sodium amide, which is extremely active in chemical properties and easy to deflagrate, has caused problems in production safety and environmental protection
[0010] (II) The condensation reaction between 4-bromo-2.2-diphenylbutyronitrile (3) and 2-methylimidazole is difficult, so a high temperature of 150 ° C is required, and the tube is sealed and pressurized for 30 hours. The catalyst triethylamine used in the molecule There are also nitrogen atoms that can undergo nucleophilic reactions, which may cause side reactions with the raw material 4-bromo-2.2-diphenylbutyronitrile (3), so 2-methylimidazole should be added in excess, resulting in complex components and impurities in the final product. more, must be separated and purified by column chromatography
Not suitable for industrial production

Method used

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  • Preparation method of imidafenacin
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  • Preparation method of imidafenacin

Examples

Experimental program
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example 1

[0023] Preparation of 1-(2-bromoethyl)-2-methyl-1H-imidazole (5)

[0024] 1,2-Dibromoethane (50ml), 2-methylimidazole (2.5g, 30.5mmol), tetrabutylammonium bromide (TBAB) (0.5g) and K 2 CO 3 (3.6g) and KOH (4.6g) were sequentially added into a 100ml three-neck flask, stirred and heated to 50°C for 7h. After cooling to room temperature, the reaction solution was filtered, the filtrate was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. Concentrate, add a mixed solvent of isopropyl ether and ethyl acetate (3:1) and stir to dissolve and crystallize to obtain 5.1 g of the product, with a yield of 88.5%, mp.79-80°C.

[0025] Preparation of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile hydrochloride (2)

[0026] Diphenylacetonitrile (5.8g, 30mmol) and 50% KOH aqueous solution (15ml), dimethylsulfoxide (DMSO) (100ml), tetrabutylammonium bromide (TBAB) (0.9g) and toluene 50ml were added to the reaction bottle, stirred at 40°...

example 2

[0032] Preparation of 1-(2-bromoethyl)-2-methyl-1H-imidazole (5)

[0033] 1,2-dibromoethane (50ml), 2-methylimidazole (2.5g, 30.5mmol), tetrabutylammonium chloride (0.43g) and Na 2 CO 3 (2.8g) and NaOH (3.3g) were sequentially added into a 100ml three-neck flask, stirred and heated to 40°C for 5h. After cooling to room temperature, the reaction solution was filtered, the filtrate was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. Concentrate, add a mixed solvent of isopropyl ether and ethyl acetate (3:1) and stir to dissolve and crystallize to obtain 4.9 g of the product, with a yield of 85.1%, mp.79-80°C.

[0034] Preparation of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile hydrochloride (2)

[0035] Diphenylacetonitrile (5.8g, 30mmol) and 50% NaOH aqueous solution (15ml), dimethyl sulfoxide (DMSO) (100ml), tetrabutylammonium chloride (0.8g) and toluene 50ml were added to the reaction flask, Stir at 40 °C for 0.5 ...

example 3

[0041] Preparation of 1-(2-bromoethyl)-2-methyl-1H-imidazole (5)

[0042] 1,2-Dibromoethane (50ml), 2-methylimidazole (2.5g, 30.5mmol), benzyltriethylammonium chloride (TEBA) (0.35g) and Na 2 CO 3 (2.8g) and NaOH (3.3g) were sequentially added into a 100ml three-neck flask, stirred and heated to 45°C for 4h. After cooling to room temperature, the reaction solution was filtered, the filtrate was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. Concentrate, add isopropyl ether and ethyl acetate mixed solvent (3:1) and stir to dissolve and crystallize to obtain 5.0 g of product, yield 86.8%, mp.79-80°C.

[0043] Preparation of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile hydrochloride (2)

[0044] Diphenylacetonitrile (5.8g, 30mmol) and 50% KOH aqueous solution (15ml), dimethylsulfoxide (DMSO) (100ml), benzyltriethylammonium chloride (TEBA) (0.66g) and toluene 50ml were added To the reaction flask, stirred at 40 ° C fo...

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Abstract

The invention discloses a method for preparing 4-(2-methyl-1H-imidazole-1-yl)-2,2-diphenyl butyrylamide (1). The target product of the method is a new drug imidafenacin for treating overactive bladder. The invention provides a new synthetic route and a new preparation method; and the new method is simple and convenient to operate, mild in reaction conditions, easy to control, high in yield, good in product purity, free of pollution on the environment and suitable for industrial mass production.

Description

technical field [0001] The invention relates to a preparation method of midanacin, a new drug for treating overactive bladder technical background [0002] Imidafenacin is a new type of highly bladder-selective diphenylbutyramide anticholinergic drug jointly developed by Japan Ono Pharmaceutical Co., Ltd. and Kyorin Pharmaceutical Co., Ltd. It blocks the contraction of choline on the detrusor muscle, making the detrusor Muscle relaxant, used to treat overactive bladder. Approved for listing in Japan in June 2007 [0003] Overactive bladder is one of the common clinical manifestations of voiding dysfunction, manifested as frequency, urgency, and nocturia, with or without urge incontinence. With the increasing proportion of my country's aging population in the total population, as well as the increase in diabetes, cerebral thrombosis, and nervous system damage diseases, the incidence of overactive bladder is also increasing year by year, seriously affecting the physical and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor 赵世明李玲韩世磊
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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