A kind of method for preparing midanaxin

A technology of midanacin and methylimidazole, which is applied in the field of medicine, can solve the problems of not being suitable for industrial production, high requirements for production equipment, and unsolved problems, and achieve the effects of short steps, increased yield, and favorable production

Active Publication Date: 2016-04-06
陕西步长高新制药有限公司
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The main disadvantage of this method is that the yield is low, only 32%, and a large amount of 70% sulfuric acid is used in the reaction. The thicker sulfuric acid requires higher production equipment, and there is a huge potential safety hazard in the production process. The standard, the construction of plant facilities, and the protection of the environment are all severe tests
Subsequently, Xinglin Co., Ltd. disclosed another method for preparing midanacin in Chinese patent 200580042599.4. First, 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile and 85% Phosphoric acid or concentrated hydrochloric acid reacts to generate 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile phosphate or 4-(2-methyl-1-imidazolyl)-2,2- Diphenylbutyronitrile hydrochloride, and then use 86% potassium hydroxide and isopropanol to hydrolyze 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile phosphate into amide Phosphate or hydrochloride, and then the crude product is converted into amide, recrystallized to remove impurities to obtain midanacine, the disadvantage of this method is that the yield is not high, which is 45%, and concentrated acid and alkali are used in the reaction , has high requirements for production equipment, and purification is troublesome, so it is not suitable for industrial production
[0007] In addition, some patent documents also disclose similar preparation methods, such as: the preparation methods of midanacin reported in Chinese patents 200810079474.4 and 201210254496.6 are all based on 4-(2-methylimidazol-1-yl)-2 , 2-diphenylbutyronitrile was prepared as a raw material, but it did not solve the problem
Therefore, the above four methods for synthesizing midanacin have low yields, complicated purification, and severe reaction conditions such as strong acid and strong base are used in the reaction, which have high requirements for production equipment and are not suitable for industrialized production.

Method used

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  • A kind of method for preparing midanaxin
  • A kind of method for preparing midanaxin
  • A kind of method for preparing midanaxin

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Example 1 In a 100ml three-necked flask, add 30ml of DMF, 2.73g (10mmol) of 4-chloro-2,2-diphenylbutyramide, 1.23g (15mmol) of 2-methylimidazole, heat and stir, when the reaction temperature rises to At 40°C, slowly add 3ml of 5mol / L NaOH solution dropwise, and control the reaction temperature not to exceed 45°C. After the dropwise addition is completed, the temperature is raised to 50°C, and the reaction is monitored by TLC. After stirring for 1 hour, the reaction is completed, and the reaction solution is poured into the liquid separator funnel, and then add 30ml CH to the separatory funnel 2 Cl 2 and 30ml of water, separate the organic phase and the aqueous phase, wash the camera twice with water, evaporate the organic phase to dryness under reduced pressure, and recrystallize the solid obtained by evaporation under reduced pressure with ethyl acetate to obtain 2.49 g of white powdery solid, which is collected The rate is 78%.

[0032] MS (ESI + , m / e): 320.17 [M+...

Embodiment 2

[0034] Example 2 In a 100ml three-necked bottle, add CH 2 Cl 2 30ml, 2.73g (10mmol) of 4-chloro-2,2-diphenylbutyramide, 1.23g (15mmol) of 2-methylimidazole, heat and stir, when the reaction temperature rises to 40°C, slowly add 5mol / L NaOH dropwise Solution 3ml, control the reaction temperature not to exceed 45 ° C, after the dropwise addition is completed, the temperature is raised to 50 ° C, and the reaction is monitored by TLC. After stirring for 1.5 hours, the reaction is completed. Add 30ml of water, separate the organic phase and the aqueous phase, the aqueous phase with CH 2 Cl 2 Extract twice more, combine the organic phases, evaporate the organic phases to dryness under reduced pressure, and recrystallize the solid obtained by evaporation under reduced pressure with ethyl acetate to obtain 2.39 g of white powdery solids, with a yield of 75%.

Embodiment 3

[0035] Example 3 In a 100ml three-necked bottle, add CHCl 3 30ml, 2.73g (10mmol) of 4-chloro-2,2-diphenylbutyramide, 1.23g (15mmol) of 2-methylimidazole, heat and stir, when the reaction temperature rises to 40°C, slowly add 5mol / L NaOH dropwise Solution 3ml, control the reaction temperature not to exceed 45 ° C, after the dropwise addition is completed, the temperature is raised to 50 ° C, and the reaction is monitored by TLC. After stirring for 1.5 hours, the reaction is completed. Add 30ml of water, separate the organic phase and the aqueous phase, the aqueous phase with CH 2 Cl 2 Extracted twice more, combined with a camera, the organic phase was evaporated to dryness under reduced pressure, and the solid obtained by evaporation under reduced pressure was recrystallized with ethyl acetate to obtain 2.32 g of white powdery solid, with a yield of 73%.

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Abstract

The present invention discloses a preparation method of imidafenacin. In the method, 4-chloro-2, 2-diphenylbutaneamide and 2-methylimidazole are taken as raw materials for reaction in the presence of alkali, and then ethyl acetate is used for recrystallization. The method has advantages of high yield, mild reaction condition, and simple purification and is suitable for industrialized production.

Description

technical field [0001] The technical solution of the invention belongs to the technical field of medicine, and in particular relates to a method for preparing midanacin. Background technique [0002] Midanaxin, the chemical name is 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramide, and its structure is as shown in formula (I): [0003] [0004] Midanacin is a new type of diphenylbutyramide anticholinergic drug jointly developed by Japan Ono Pharmaceutical Co., Ltd. and Kyorin Pharmaceutical Co., Ltd. It has high bladder selectivity and is used for the treatment of overactive bladder. It was launched in Japan in June 2007 . Chinese patent 94194450.6 discloses the preparation method of midanacin, which uses 4-bromo-2,2-diphenylbutyronitrile and 2-methylimidazole as raw materials to first synthesize 4-(2-methyl-1- Imidazolyl)-2,2-diphenylbutyronitrile, then hydrolyze 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyronitrile with 70% sulfuric acid at 140-150°C Form amides, after ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/56
Inventor 赵步长赵超
Owner 陕西步长高新制药有限公司
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