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Preparation method of nilotinib

A nilotinib and condensation reaction technology, applied in the field of nilotinib preparation, can solve the problems of rare raw materials, long steps, low yield, etc., achieve controllable production, improve product quality, and promote economic and technological effects

Inactive Publication Date: 2013-09-04
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
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  • Preparation method of nilotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 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 90° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL tetrahydrofuran, and 3-amino-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluorotolylmethyl]benzamide was added ( III) (4.86g, 13mmol) and sodium hydride (0.37g, 15mmol), the temperature was raised to 80°C, and the reaction was stirred for 5 hours, and the reaction was completed b...

Embodiment 2

[0026] 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 90° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL tetrahydrofuran, and 3-amino-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluorotolylmethyl]benzamide was added ( III) (4.86g, 13mmol) and sodium hydride (0.37g, 15mmol), the temperature was raised to 80°C, and the reaction was stirred for 5 hours, and the reaction was completed by ...

Embodiment 3

[0028] Under nitrogen protection, 4-(3-pyridyl)-2-pyrimidinone (II) (1.73g, 10mmol), benzotriazol-1-yloxytris(dimethylamino) Phosphonium hexafluorophosphate (BOP) (6.63g, 15mmol), 3-amino-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-trifluorotoluene Methyl]benzamide (III) (4.86g, 13mmol) and N,N-dimethylformamide 50mL. 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 90° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran / ethyl acetate (4:1) to obtain 3.90 g of off-white solid nilotinib (I), with a yield of 73.7%.

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Abstract

The invention discloses a preparation method of nilotinib, which comprises the following steps of: under the effect of organic base and a condensing agent, performing further condensation reaction between 4-(3-pyridyl)-2-pyrimidone (II) and 3-amino-4-methyl-N-[3-(4-methyl-1H-imidazole-1-yl)-5-trifluorotolylmethyl]benzamide (III) to obtain nilotinib (I). The preparation method disclosed by the invention has the advantages that the raw materials are easily available, the technology is simple, the conditions are mild, the environment is optimized, and the quality is improved; and moreover, the preparation method is suitable for industrial production and promotes the development of the economic technology of raw material medicines.

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 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-yl)-3-(trifluoromethyl)phenyl]benzamide. [0004] [0005] Patent Nos. WO2004 / 0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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