Preparation method for nilotinib

A nilotinib and compound technology, which is applied in the field of preparation of nilotinib, can solve the problems of high cost and long steps of synthetic nilotinib route, and achieve the goal of reducing preparation cost, increasing yield and short synthesis route Effect

Active Publication Date: 2015-08-26
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0022] The main purpose of the present invention is to provide a kind of preparation method of nilotin

Method used

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  • Preparation method for nilotinib
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  • Preparation method for nilotinib

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preparation example Construction

[0039] As described in the background technology section, to solve the problems of long route and high cost of synthesizing nilotinib in the existing technology. In order to solve this problem, the present invention provides a kind of preparation method of Nilotinib, and this preparation method comprises the following steps: compound A and 3-(4-methyl-1H-imidazol-1-yl)-5- (Trifluoromethyl) aniline is subjected to carbonyl insertion amination reaction to obtain an amination product; and the above amination product is subjected to R group deprotection treatment to obtain nilotinib; wherein, compound A has a structure shown in formula I:

[0040]

[0041] In formula I, the R group includes but not limited to benzyl, -COCF 3 , -CHO or -CO 2 R', wherein the R' group includes but is not limited to C 1 ~C 10 Alkyl, C 1 ~C 3 Alkoxyethyl or C 7 ~C 19 Aralkyl.

[0042]The present invention innovatively applies the carboxylation reaction to the synthetic route of nilotinib. S...

Embodiment 1

[0060] Dimethylformamide (1 L), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (aromatic amine, 0.54 mol), (5 -Bromo-2-methylphenyl(4-(pyridin-3-yl)pyrimidin-2-yl)-tert-butyl carbamate (0.648mol), 1,1'-bis(diphenylphosphino)dicene Iron dichloride palladium dichloromethane complex (0.016mol), triphenylphosphine (0.032mol), phenol (2.5g, 0.027mol), triethylamine (1.62mol) and 4A molecular sieve (100g) were stirred evenly. Introduce nitrogen to replace the air, then introduce carbon monoxide to replace the nitrogen and make the pressure in the kettle reach 0.8MPa. Heat up to 90-105°C for reaction. After 42 hours of reaction, a product system containing aminated product is obtained. Cool the product system to 50 Below ℃, evacuate carbon monoxide and replace with nitrogen.

[0061] The above product system was diluted with methyl tert-butyl ether (1 L), and molecular sieves were filtered off to obtain a filtrate. Add mass concentration to the filtrate and be 1% K 2 CO ...

Embodiment 2

[0063] To the autoclave was added dimethylformamide (10 mL), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (aromatic amine, 4.5 mmol), (5 -Bromo-2-methylphenyl(4-(pyridin-3-yl)pyrimidin-2-yl)-tert-butyl carbamate (5.4mmol), 1,1'-bis(diphenylphosphino)dicene Iron dichloride palladium dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) are stirred evenly.Burse into nitrogen Replace the air, then introduce carbon monoxide to replace the nitrogen and make the pressure in the kettle reach 0.8MPa. Heat up to 90-105°C for reaction. After 72 hours of reaction, a product system containing aminated product is obtained. Cool the product system to below 50°C, Evacuate carbon monoxide and replace with nitrogen.

[0064] The above system was diluted with methyl tert-butyl ether (10 mL), and molecular sieves were filtered off to obtain a filtrate. Add mass concentration to the filtrate and b...

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Abstract

The invention provides a preparation method for nilotinib. The preparation method comprises the following steps: producing a carbonyl insertion amination reaction of a compound A and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenylamine, and obtaining an amination product; performing R group deprotection treatment on the amination product, and obtaining nilotinib, wherein the compound A has a structure as shown in a formula I, in the formula I, R is selected from benzyl, -COCF3, -CHO or -CO2R', and R' is C1-C10 alkyl, C1-C3 alkoxy ethyl or C7-C19 aralkyl. The preparation method is short in synthetic route and mild in reaction condition, and due to the adoption of special raw materials, the preparation method reduces the process cost while increasing the carbonyl yield.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of nilotinib. Background technique [0002] Nilotinib is a potent and precise second-generation tyrosine kinase inhibitor, applicable to adult patients with chronic myeloid leukemia in chronic phase or accelerated phase who have previously been treated (including imatinib). Patients were positive for the resistant or intolerant Philadelphia chromosome. [0003] In the existing research, many patents and literatures have recorded different synthetic methods of nilotinib. [0004] Route 1: The vast majority of existing patents and documents use 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline as a raw material and 4-methyl-3 Nilotinib was obtained by coupling -(4-(pyridin-3-yl)pyrimidin-2-ylamino)benzoic acid or its derivatives. [0005] [0006] route one [0007] R 1 for H, R 2 is OH, Cl, alkoxy or aralkyl; or R 1 for OH, R 2 For tert-but...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 洪浩詹姆斯·盖吉李九远李常峰黄高超
Owner ASYMCHEM LAB TIANJIN
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