Nintedanib impurity and preparation method and application thereof
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A technology of nintedanib, impurity reference substance, applied in the direction of organic chemistry, etc., can solve the problem that impurities are not reported in literature and so on
Inactive Publication Date: 2016-06-29
HAINAN SIMCERE PHARMA CO LTD +1
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[0010] This impurity has not been reported in the literature at home and abroad
Method used
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Embodiment 1
[0035] Preparation of 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide
[0036]
[0037] N-methyl-4-nitroaniline (10g, 0.066mol) and ethyl acetate (40mL) were mixed and stirred, heated to 60°C, chloroacetyl chloride (9.2g, 0.081mol) was added dropwise, and refluxed for 5 hours. Cool down, add 30 mL of n-heptane dropwise, filter, and dry the solid in vacuum. Yield 11.5g (yield 76.6%), HPLC purity 98.6%, MS (m / z): 229 ((M+H) + .
Embodiment 2
[0039] Preparation of N-methyl-N-(4-nitrophenyl)-2-(4-nitrophenylamine)acetamide
[0040]
[0041] 2-Chloro-N-methyl-N-(4-nitrophenyl)acetamide (6.9g, 0.0302mol), 4-nitroaniline (4.3g, 0.0311mol), potassium iodide (5.1g, 0.0307mol ), N,N-diisopropylethylamine (3.9g, 0.0302mol) and toluene (50mL) were mixed and stirred, heated at 100°C for 3 hours, cooled, added 50ml of water, stirred, filtered, and dried in vacuum. Yield 6.8g, (yield 68.2%), HPLC purity 99.2%, MS (m / z): 331 (M+H) + .
Embodiment 3
[0043] Preparation of 2-chloro-N-(2-(methyl(4-nitrophenyl)amine)-2-oxoethyl)-N-(4-nitrophenyl)acetamide
[0044]
[0045] N-methyl-N-(4-nitrophenyl)-2-(4-nitrophenylamine)acetamide (6g, 0.018mol), ethyl acetate (60mL) and chloroacetyl chloride (2.37g , 0.021mol) were mixed and stirred, heated to 60°C, and reacted for 6 hours. Cool down, filter, and dry the solid in vacuo. Yield 3.9g (yield 53.3%), HPLC purity 98.7%, MS (m / z): 407 (M+H) + .
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Abstract
The invention relates to a nintedanib impurity represented by the formula VI and a preparation method thereof. The preparation method comprises that with N-methyl-4-nitroaniline as a starting material, the compound is obtained through the steps of acylation, substitution, acylation, substitution, reduction, substitution reactions and the like. The compound and an intermediate compound represented by the formula V can be used as reference substances for detection of nintedanib raw materials and preparation related substances.
Description
technical field [0001] The invention relates to a nintedanib impurity and a preparation method and application thereof. Background technique [0002] Nintedanib is a new orally effective angiogenesis inhibitor developed by Boehringer Ingelheim. The structure of nintedanib is shown below: [0003] [0004] The synthetic method of nintedanib has been reported in CN100351235C and CN101883755B, and intermediate N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) is used in the synthetic process Acetamide, wherein, CN101883755B specification page 15 to 16 discloses the synthetic route of this intermediate as follows: [0005] [0006] The inventor finds unexpectedly, when starting material N-methyl-4-nitroaniline contains impurity 4-nitroaniline, through follow-up reaction, intermediate N-(4-aminophenyl)-N-methyl- 2-(4-Methylpiperazin-1-yl)acetamide may contain impurities of formula V. [0007] [0008] In the process of preparing nintedanib through subsequent reac...
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