Process for synthesizing imatinib

A synthesis method and imatinib technology, applied in the field of pharmaceutical compound synthesis, can solve the problems of difficulty in purification, instability, long reaction time, etc., and achieve the effects of being beneficial to industrial production, mild reaction conditions, and improved yield

Active Publication Date: 2009-08-05
FUJIAN SOUTH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its biggest shortcoming is: 1) owing to use cyanamide to synthesize guanidine group, and cyanamide is low boiling point, very volatile, thereby the yield of guanidine group is low and unstable; 2) the synthetic yield of pyrimidine ring is low , the reaction time is long, and the reaction of raw materials is not complete
Its biggest disadvantage is that 1) the trimethylaluminum used is a flammable chemical, which reacts violently with water; 2) the final product has 10% isomers, which is difficult to purify
The halogenated reagent used in the synthesis of 2-halo-4-methyl-(3-pyridyl)-pyrimidine, such as phosphorus oxychloride, belongs to highly toxic substances and has a great impact on the environment

Method used

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  • Process for synthesizing imatinib
  • Process for synthesizing imatinib
  • Process for synthesizing imatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] In a 500ml dry four-neck flask, add 250ml of tetrahydrofuran, 33.8g of N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide and 17.3 g of 4-methyl-(3-pyridyl)-2-pyrimidinone, stirring and dissolving, cooling to 0 degrees, adding (benzotriazole-1-oxyl)-tris(dimethylamino)phosphonium hexa Fluorophosphate (BOP) 50g and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) 16g. Slowly raise the temperature to 25° C. and react overnight. After detecting the completion of the reaction, the tetrahydrofuran was concentrated and the obtained solid was washed with water and dried to obtain 45 g of imatinib, with a yield of 91.0%.

[0036] The spectral data are as follows:

[0037] 1 H NMR (500M, DMSO) δ: 10.2(s, 1H), 9.30(s, 1H), 8.99(s, 1H), 8.72(d, J=4.0Hz, 1H), 8.57(s, 1H), 8.53 (s, 1H), 8.11(s, 1H), 8.00(s, 1H), 7.98(s, 1H), 7.58-7.51(m, 4H), 7.44(d, J=4.3Hz, 1H), 7.22( d, J=8.1Hz, 1H), 3.70(s, 2H), 3.50-3.25(m, 2H), 3.20-2.90(m, 4H), 2.81(s, 3H), 2.40(s, 3H), 2.24 ...

Embodiment 2

[0040] In a 500ml dry four-necked flask, add 250ml of acetonitrile, 33.8g of N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide and 17.3 g of 4-methyl-(3-pyridyl)-2-pyrimidinone, stirring and dissolving, cooling to 0 degrees, adding (benzotriazole-1-oxyl)-tris(dimethylamino)phosphonium hexa Fluorophosphate (BOP) 50g and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) 16g. Slowly raise the temperature to 25° C. to react overnight. After detecting the completion of the reaction, concentrate the acetonitrile, wash the obtained solid with water, and dry to obtain 44 g of imatinib, with a yield of 89.0%. Spectral data ditto.

Embodiment 3

[0042] In a 5000ml dry four-necked bottle, add toluene 2500ml, N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide 338g and 173 g of 4-methyl-(3-pyridyl)-2-pyrimidinone, 500 g of tripyrrolidinylphosphonium bromide hexafluorophosphate (PyBrOP) and 160 g of triethylamine were added under stirring. After reacting overnight, the toluene was concentrated after detecting the completion of the reaction, and the obtained solid was washed with water and dried to obtain 445 g of imatinib, with a yield of 90.0%. Spectral data ditto.

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Abstract

The invention discloses a method for synthesizing imatinib. The method comprises that: N-(4-methyl-3-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide is used as a raw material, and reacts with 4-methyl-(3-pyridyl)-2-pyrimidone under actions of a polypeptide condensation agent and an organic alkali so as to generate the imatinib. The method has the advantages of mild reaction conditions, easy operation, high reaction yield and suitability for industrialized production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical compounds, in particular to a synthesis method of imatinib. Background technique [0002] Imatinib mesylate is a signal transduction inhibitor (formerly STI571) successfully researched by Novartis after 7 years of hard work. It is the first approved tumorigenesis-related signal transduction inhibitor in the world. Imatinib mesylate has obtained the status of an orphan drug in the United States, the European Union and Japan, and was approved by the U.S. Food and Drug Administration (FDA) on May 10, 2001, for the treatment of α-interferon (interfer on-alfa) patients with chronic myelogenous leukemia in the blast crisis phase, accelerated phase, or chronic phase of treatment failure. [0003] The chemical name of Imatinib is: 4-(4-methylpiperazinyl-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl)pyrimidine- 2-amino]-benzamide, the structural formula is as follows: [0004] [0005] Imatinib ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 沈鑫廖立新林复兴何晓杨继东詹华杏
Owner FUJIAN SOUTH PHARMA CO LTD
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