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Method for synthesizing Imatinib

A synthetic method, imatinib technology, applied in the field of organic synthesis, can solve problems such as difficult purification, easy volatility, and great environmental impact, and achieve the effects of industrial production, mild reaction conditions, and clean and complete reactions

Active Publication Date: 2010-06-16
FUJIAN SOUTH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But all there is following shortcoming in these two routes: 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) pyrimidine ring The synthesis yield is low, the reaction time is long, and the raw material reaction 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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  • Method for synthesizing Imatinib
  • Method for synthesizing Imatinib
  • Method for synthesizing Imatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1 imatinib,

[0036] In a 500ml dry four-necked flask, add 250ml of tetrahydrofuran, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-1, 27.7g of 3-phenylenediamine and 4-( 25g of 4-methylpiperazine-1-methyl)-methyl benzoate, stirred and dissolved, added 10g of sodium methoxide, heated at 70°C to reflux for overnight reaction, detected the completion of the reaction and concentrated the tetrahydrofuran, washed the obtained solid with water, and dried to obtain Imatinib 45g, yield 91.0%.

[0037] The spectral data are as follows:

[0038] 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 (s, 3H). 13 C NMR (125M, DMSO) δ: 164.9, 161.3, 161.1, 159.4, 150.8, 147.7, 137.7, 137.1, 134.9, 134.3, 132.3, 129.9, 129.1, 127.7, 1...

Embodiment 2

[0041] In a 5000ml dry four-neck flask, add 3000ml of dichloromethane, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-1,3-phenylenediamine 277g and 4- (4-Methylpiperazine-1-methyl)-ethyl benzoate 270g, after stirring and dissolving, add 100g of sodium methoxide, heat at 40°C and reflux reaction overnight, after detecting the completion of the reaction, concentrate the toluene, wash the obtained solid with water, and dry 455g of imatinib was obtained, with a yield of 92.0%. Spectral data ditto.

Embodiment 3

[0043]In a 5000ml dry four-necked flask, add toluene 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-1,3-phenylenediamine 277g and 4-(4 -Methylpiperazine-1-methyl)-benzyl benzoate 450g, after stirring and dissolving, add 200g of sodium ethoxide, heat to 50°C and react overnight, after detecting the completion of the reaction, concentrate the toluene, wash the obtained solid with water, dry to obtain Matinib 445g, yield 90.0%. Spectral data ditto.

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Abstract

The invention discloses a method for synthesizing Imatinib, comprising the following steps: under the action of alkali, 4-methyl-N-3-(4-pyridine-3-radix-pyrimidine-2-radix)-1,3-phenylenediamine shown in the formula (I) reacts with 4-(4-methylpiperazine-1-methyl)-benzoate shown in the formula (II) in an aprotic inorganic solvent to form the Imatinib shown in the formula (III), namely 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl) pyrimidine-2-amino]-benzamide. In the above chemical structure general formula, R represents fatty alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl containing 1-10 carbon atoms. The invention provides the new method for synthesizing Imatinib, which has mild reaction conditions and high yield and is environment-friendly.

Description

technical field [0001] The invention belongs to the field of organic synthesis, 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] The synthetic route of imatinib ...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61P35/02
Inventor 沈鑫林复兴何晓杨继东詹华杏
Owner FUJIAN SOUTH PHARMA CO LTD
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