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Preparation method of nilotinib

A technology of nilotinib and methyl, applied in the field of nilotinib preparation, can solve the problems of rare raw materials, high cost, long steps, etc., and achieve the effects of controllable production, improved product quality, and promotion of development.

Inactive Publication Date: 2013-09-11
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

[0024] Under nitrogen protection, 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid (II) (3.06g, 10mmol), benzotriazepam Azol-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 60° 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 of tetrahydrofuran, 5-(4-methyl-1H-imidazol-1-yl)-3-trifluoromethylaniline (3.13 g, 13 mmol) and sodium hydride (0.37 g, 15 mmol) were added, and the temperature was raised to 80° C., stirred for 5 hours, and TLC monitored the completion of the r...

Embodiment 2

[0026] Under nitrogen protection, 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid (II) (3.06g, 10mmol), benzotriazepam Azol-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 60° 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 of tetrahydrofuran, 5-(4-methyl-1H-imidazol-1-yl)-3-trifluoromethylaniline (3.13 g, 13 mmol) and sodium hydride (0.37 g, 15 mmol) were added, and the temperature was raised to 50° C., stirred for 5 hours, and TLC monitored the completion of the rea...

Embodiment 3

[0028] Under nitrogen protection, 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid (II) (3.06g, 10mmol), benzotriazepam Azol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.63g, 15mmol), 5-(4-methyl-1H-imidazol-1-yl)-3-tri Fluoromethylaniline (3.13 g, 13 mmol) and N,N-dimethylformamide 50 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (4.56 g, 30 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 60° 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 4.32 g of off-white solid nilotinib (I), with a yield of 81.7%.

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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 a one-step condensation reaction of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amino]benzoic acid (II) and 5-(4-methyl-1H-imidazole-1-yl)-3-trifluoromethyl phenylamine (III) to obtain nilotinib (I). The preparation method disclosed by the invention has the advantages of easily-available raw materials, simple process, mild conditions, environment optimization and quality improvement, 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 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] Worl...

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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