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Novel preparation method of imidafenacin intermediate and refined product thereof

A technology for midacin and intermediates, which is applied in the field of preparing relatively pure midacin-2,2-diphenylbutyramide, which can solve the problem of low product purity

Inactive Publication Date: 2013-10-16
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] For a long time, the post-treatment solvent still remains in the product, so that the product purity is still low

Method used

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  • Novel preparation method of imidafenacin intermediate and refined product thereof
  • Novel preparation method of imidafenacin intermediate and refined product thereof
  • Novel preparation method of imidafenacin intermediate and refined product thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutanamide hydrobromide. Put 16.5 g (52 mmol) of crude 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramide into 100 mL of isopropanol, and add 8.0 mL of hydrobromic acid and isopropanol while stirring Alcohol mixed solution (volume ratio 1:1), the solid gradually dissolves and becomes a nearly colorless transparent liquid. After keeping the reaction under stirring for half an hour, 100 mL of ethyl acetate was added to the reaction solution, stirred at room temperature for 1 hour, and a solid precipitated out. Suction filtration, and rinse the filter cake with an appropriate amount of ethyl acetate. The solid was collected and dried in a blast oven at 40°C to constant weight to obtain 19.5 g of off-white 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramide hydrobromide, yield 98.9 %. M.p. 228.4-229.0°C. MS (m / z): 320[M+1] + . 1 H-NMR (DMSO- d 6 , 400 MHz) δ: 2.25 (3H, s), 2.73-2.74 (2H, m), 3.68-3.91 (2H, m), 6.81 (1H, s), 7.28-7.35...

Embodiment 2

[0026] 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutanamide. 19.5 g (0.051 mmol) of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamide acetate obtained in Example 1 was dissolved in 900 mL of water. The aqueous solution was extracted with 900 mL of ether, and the inorganic layer was collected. Add 200 mL of ethanol to the obtained aqueous solution, and add 2 mol / L of KOH aqueous solution to the system while stirring, and a solid precipitates out. After stirring for 1 h, filter with suction. The filter cake was rinsed with 40% ethanol solution and rinsed with water several times. Collect the filter cake and dry it in a blast oven at 40°C to constant weight to obtain 14.8 g of off-white 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramide with a yield of 91.0% ( Two-step total yield 90%). M.p. 192.3-193.0°C (CN101076521A 191-193°C). MS(m / z): 320[M+1] + . 1 H-NMR (DMSO- d 6 , 400 MHz) δ: 2.11 (3H, s), 2.69-2.73 (2H, m), 3.61-3.65 (2H, m), 6.75 (1H, d, J=1.0 MHz), 7.01 (1H, br s) ...

Embodiment 3

[0028] 4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutanamide. Add 116 mL of ethyl acetate to 14.5 g (0.045 mmol) of the 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramide obtained in Example 2, slowly heat to reflux, and keep Reflux for 30 min, cool to room temperature and stir for crystallization for 5 h. Suction filtration, rinse the filter cake with a small amount of ethanol, collect the filter cake and dry it in a blast drying oven at 40°C to constant weight to obtain 13.4 g of off-white 4-(2-methyl-1-imidazolyl)-2,2-di The refined product of phenylbutyramide has a yield of 92.4% (the total yield of three steps is 83.1%). M.p.192.5-193.0℃

[0029] (CN101076521A 191-193°C). MS(m / z): 320[M+1] + . 1 H-NMR (DMSO- d 6 , 400 MHz) δ: 2.11 (3H, s), 2.69-2.73 (2H, m), 3.61-3.65 (2H, m), 6.75 (1H, d, J=1.0 MHz), 7.01 (1H, br s) , 7.04 (1H, d, J=1.0 MHz), 7.34-7.49 (11H, m).

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Abstract

The invention belongs to the field of medicine chemistry, and specifically relates to a preparation method of relatively pure imidafenacin ( 4-(2-methyl-1- imidazolyl)-2,2-dibenzyl butyramide) and intermediate prepared by the method. 4-(2-methyl-1- imidazolyl)-2,2-dibenzyl butyronityile hydrolyze in the presence of alkaline to generate product, the product reacts with an inorganic acid or an organic acid to form salt, then the salt is decomposed to get rid of impurities in the product, and finally the product is recrystallized in an organic solvent to remove the residual solvent. The preparation method has the characteristics of simpleness, high yield, and good reproducibility, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing relatively pure midanacine (4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamide), and the method intermediates prepared. Background technique [0002] Overactive bladder (symptomatic overactive bladder, OAB) is a common chronic lower urinary tract dysfunction. Its incidence rate is high, the incidence rate of men over 75 years old in European and American countries is as high as 42%, and the incidence rate of women is slightly lower at 31%; the incidence rate of men over 50 years old in Beijing area in China is 16.4%, and women over 18 years old have mixed sex. The total incidence of urinary incontinence and urge incontinence is 40.4%, which seriously affects the physical and mental health of patients and reduces the quality of life. Common antimuscarinic drugs can bind part or all of the M receptors in the body with different affinities, there...

Claims

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Application Information

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IPC IPC(8): C07D233/56
Inventor 谢红玉王进敏马苏峰闫起强
Owner BEIJING VENTUREPHARM BIOTECH
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