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Preparation method of nilotinib

A nilotinib and condensation reaction technology, which is applied in the field of nilotinib preparation, can solve the problems of rare raw materials, high cost, and long steps, and achieve the effects of controllable production, improved product quality, and promoted development

Inactive Publication Date: 2013-08-21
SUZHOU MIRACPHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Examining the current preparation methods of nilotinib, there are problems such as rare raw materials, long steps, high cost and low yield.

Method used

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  • Preparation method of nilotinib

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Under nitrogen protection, 4-(3-pyridyl)-2-pyrimidinone (II) (1.73g, 10mmol), benzotriazol-1-yloxytris(dimethylamino) Phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 50 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 70° C., methyl 3-amino-4-methylbenzoate (III) (2.15 g, 13 mmol) and potassium tert-butoxide (1.65 g, 15 mmol) were added, and the reaction was continued for 12 hours. About half of the volume of the solvent was distilled off under reduced pressure, 30 mL of 2M sodium hydroxide was added, and the mixture was reacted at 80°C for 6 hours. Extracted 3 times with 120 mL of ethyl acetate, separated the organic phase, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL THF, 5-(4-methyl-1H-imidazol-1-yl)-3-trifluoromethylaniline (IV) (2.89 g, 12 mmol) and 1,8-di...

Embodiment 2

[0027] Under nitrogen protection, 4-(3-pyridyl)-2-pyrimidinone (II) (1.73g, 10mmol), benzotriazol-1-yloxytris(dimethylamino) Phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 50 mL. Under stirring, 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN) (1.86 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 70° C., methyl 3-amino-4-methylbenzoate (III) (2.15 g, 13 mmol) and potassium tert-butoxide (1.65 g, 15 mmol) were added, and the reaction was continued for 12 hours. About half of the volume of the solvent was distilled off under reduced pressure, 30 mL of 2M sodium hydroxide was added, and the mixture was reacted at 80°C for 6 hours. Extracted 3 times with 120 mL of ethyl acetate, separated the organic phase, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL THF, and 5-(4-methyl-1H-imidazol-1-yl)-3-trifluoromethylaniline (IV) (2.89 g, 12 mmol) and 1,5-...

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Abstract

The invention discloses a preparation method of nilotinib. The preparation method comprises the following steps of carrying out one-step condensation reaction on 4-(3-pyridyl)-2-pyrimidone (II), 3-amino-4-methyl benzoate (III) and 5-(4-methyl-1H-imidazole-1-yl)-3-trifluoromethyl phenylamine (IV) under the action of an organic alkali and a condensing agent to obtain nilotinib (I). The preparation method has the advantages that raw materials are easily available, the process is simple, conditions are mild, the environment is optimized, and quality is improved; therefore, the preparation method is suitable for industrial production and capable of promoting the economy and technology development of the raw medicine.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a method for preparing nilotinib. Background technique [0002] Nilotinib is a highly selective oral tyrosine kinase inhibitor developed by Novartis, Switzerland. Its monohydrochloride monohydrate was approved for marketing by the U.S. Food and Drug Administration (FDA) in October 2007, and its trade name is Tasigna (Daxina). It is clinically used for the treatment of chronic myelogenous leukemia that is not effective for imatinib mesylate. The drug can selectively inhibit Philadelphia chromosome-positive chronic myelogenous leukemia caused by mutations in tyrosinase and its coding gene through targeting. [0003] The chemical name of Nilotinib is: 4-methyl-3-[4-(3-pyridyl)-2-pyrimidinyl]amino-N-[5-(4-methyl-1H-imidazole-1- base)-3-(trifluoromethyl)phenyl]benzamide. [0004] [0005] Pate...

Claims

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Application Information

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IPC IPC(8): C07D401/14
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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