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Process for the preparation of imatinib and intermediates thereof

A technology of phenyl and compound, which is used in the field of preparation of imatinib and its intermediates, which can solve problems such as time-consuming, unsuitable for industrial applications, and no economic advantages

Inactive Publication Date: 2009-09-09
F I S FAB ILTALIANA SINTETICI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, many steps have time-consuming and difficult inspection work-ups, so they are not suitable for industrial applications
In addition, N,N-dimethylformamide dimethyl acetal is an expensive reactant, making this synthetic method very economically unfavorable

Method used

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  • Process for the preparation of imatinib and intermediates thereof
  • Process for the preparation of imatinib and intermediates thereof
  • Process for the preparation of imatinib and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] Example 1: 4-methyl-N3-[4-(3-pyridyl)-2-pyrimidinyl]-1,3-phenylenediamine 8

[0196] Suspend 16 g of the sodium salt of β-oxo-3-pyridinepropanal with an HPLC purity of 99% (A%) and a salt content (residue on ignition) of 25% in 115 mL of n-butanol under an inert atmosphere and 11.7 g (2-methyl-5-aminophenyl)guanidine. 9 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. 6 g of potassium hydroxide were added in portions and the mixture was refluxed for 18 hours, removing water with a Dean Stark apparatus. Once the conversion was complete, the suspension was cooled and the organic layer was washed with water. The organic layer was concentrated to a small volume and toluene was added. Filtration of the precipitate yielded 15.5 g of product with 99.2% HPLC purity (A%) under drying, by LC-MS and 1 H-NMR for identification.

[0197] LC-MS: [M+1] + =278.

[0198] 1 H-NMR (300MHz, DMSO-d 6 ): δ(ppm)2.02(s, 3H); 4.85(s, 2H); 6.31(d,...

Embodiment 2

[0199] Example 2: 1-(5-amino-2-methylphenyl)-3-[(3-oxo-3-(3-pyryl)-1-prop-1-enyl)guanidine 22

[0200] Suspend 10 g of the sodium salt of β-oxo-3-pyridinepropionaldehyde with a HPLC purity of 99% (A%) and a salt content (residue on ignition) of 25% in 80 mL of isopropanol under an inert atmosphere . 24 mL of 15% isopropanol hydrochloride solution was added, and the mixture was stirred at room temperature for 1 hour. 7 g of (2-methyl-5-aminophenyl)guanidine were added in portions, and the mixture was stirred at room temperature for 12 hours. Once the conversion was complete, the precipitate was filtered and dried to yield 13.5 g of product with 98% HPLC purity (A%) and 30% salt content (residue on ignition), identified by LC-MS.

[0201] LC-MS: [M+1] + =296.

Embodiment 3

[0202] Example 3: N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine 1 (R 1 = NO 2 )

[0203] Under an inert atmosphere, in 50 mL of toluene, 5 g of sodium salt of β-oxo-3-pyridinepropanal and 8 mL of isopropanol hydrochloride. 3.7 g of (2-methyl-5-nitrophenyl)guanidine were added, and the mixture was stirred at room temperature for 1 hour. The mixture was refluxed for 18 hours and the water was removed using a Dean Stark apparatus. Once the conversion is complete, the suspension is cooled to 10 °C and the precipitate is filtered; the precipitate is triturated in warm water, which yields 2.5 g of product with 96% HPLC purity (A%) upon filtration and drying by GC-MS for identification.

[0204] MS m / e (int.rel.): 307 (M+) (100); 292 (76); 260 (63); 246 (38).

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Abstract

Tthe present invention provides a process for the preparation of 4-methyl-N3- [4- (3-pyridinyl) -2- pyrimidinyl] -1, 3-benzenediamine and analogues thereof, intermediates useful for the synthesis of Imatinib, or 4- [ (4-methyl-l-piperazinyl) methyl] -N- [4-methyl-3- [ [4- (3- pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide.

Description

technical field [0001] The object of the present invention is a method for the preparation of 4-methyl-N-3-[4-(3-pyridyl)-2-pyrimidinyl]-1,3-phenylenediamine and its analogues, using In Imatinib or 44(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidine Base] amino] phenyl] benzamide synthesis intermediate. Background technique [0002] Imatinib mesylate, a molecule of formula 9, is an important drug used in the treatment of chronic myeloid leukemia. [0003] [0004] Its preparation was first described in EP 564409 to Novartis and is summarized in Scheme 1 below. The document does not report the yields of the various preparative operations. [0005] plan 1 [0006] [0007] However, WO 2006 / 071130 reports that the overall yield of imatinib does not exceed 15% using this synthesis method. In addition, many steps have time-consuming and difficult inspection work-ups, so they are not suitable for industrial applications. Furthermore, N,N-dimeth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/55C07D213/58C07D401/04
Inventor 亚历桑德拉·法尔基恩尼奥·格伦迪历罗卡多·莫特利马里诺·斯帝瓦雷罗
Owner F I S FAB ILTALIANA SINTETICI SPA
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