Preparation method for imatinib

A technology of methylphenyl and pyridine, which is applied in the field of imatinib preparation, can solve problems such as difficult purification, serious environmental pollution, and threats, and achieve the effects of lowering the reaction energy barrier, high product purity, and low energy consumption

Active Publication Date: 2017-06-16
湖南华腾医药有限公司
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0008] Chinese patent 200710067344.4 uses N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)benzamide as raw material, and 2-halo-4- Methyl-(3-pyridyl)pyrimidine reacts to produce imatinib, and the halogenating reagent used in the synthesis of 2-halogenated-4-methyl-(3-pyridyl)pyrimidine during this process, such as trichloroxy Phosphorus is a highly toxic substance, and it pollutes the environment a lot, and the production conditions need to be strictly controlled, resulting in an increase in the cost of safe production and a threat to environmental pollution, etc.
[0010] Chinese patent CN1630648A uses 3-bromo-4-methylaniline as a raw material, and realizes the ammonolysis reaction of 4-(4-methyl-piperazinyl-1-methyl) methyl benzoate with trimethylaluminum to obtain N- (4-methyl-3-bromophenyl)-4-(4-methyl-piperazinyl-1-methyl)benzamide, and finally react with noble metal palladium and pyrimidinamine to obtain imatinib, the The trimethylaluminum used in the method is a flammable chemical, which has the disadvantage of violent contact with water, and the final product produced by this method has 10% isomers, which is difficult to purify
[0022] The shortcoming of above-mentioned method is that the raw material source such as 4-(3-pyridyl)-2-aminopyrimidine is difficult, the existence of side reaction of bromination and the application of metal coupling reagents such as triethylaluminum have increased the difficulty of industrialization
[0026] The disadvantage of this method is that the reaction time is long, the temperature is high, the post-treatment is complicated, and it is difficult to realize industrialization.

Method used

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Experimental program
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Effect test

Embodiment 1

[0043] Combine 5g (12.9mmol) N-(5-iodo-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine with 3.6g (15.5mmol) 4-((4-methyl Piperazin-1-yl)methyl)benzamide was added to 90ml of dry tetrahydrofuran, and then 5.5g (25.8mmol) of potassium phosphate, 0.12g (0.65mmol) of 1,10-phenanthroline and 0.13g (0.65 mmol) cuprous iodide, stirred at room temperature in an argon atmosphere, after reacting for 4 hours, TLC point plate detection reaction was complete, filtered the reaction solution, poured the filtrate into 200ml water, precipitated solid, filtered, washed with water and acetonitrile respectively The cake was dried under reduced pressure and vacuum at 50°C to obtain 5.8 g of pale yellow-white solid imatinib with a yield of 92% and an HPLC purity of 99.4%.

Embodiment 2

[0045] Combine 25g (64.4mmol) N-(5-iodo-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine with 21.0g (90.2mmol) 4-((4-methyl Add piperazin-1-yl)methyl)benzamide to 90ml 1,4-dioxane, then add 27g (127.3mmol) potassium phosphate, 0.62g (3.2mmol) 1,10-phenanthroline and 0.13g (0.65mmol) cuprous iodide, stirred at room temperature in an argon atmosphere, after reacting for 6 hours, TLC spot plate detection reaction was complete, filtered the reaction solution, poured the filtrate into 200ml water, precipitated solid, filtered, respectively The filter cake was washed with water and acetonitrile, and vacuum-dried under reduced pressure at 50°C to obtain 26.6 g of pale yellow-white solid imatinib with a yield of 83.7% and a purity of 99.0% by HPLC.

[0046] ES-MS m / z=494[M+H + ].

[0047] 1 H NMR (DMSO-d 6 ,400MHz)δ(ppm):10.21(s,1H,NH),9.28(d,1H,4J=1.8Hz), 8.87(s,1H,NH),8.77(dd,1H,3J=4.7,4J= 1.5Hz), 8.52(d, 1H, 3J=6.9Hz), 8.47(m, 1H), 8.05(d, 1H, 4J=1.9Hz), 7.83(d, 2H, 3J=8.2Hz)...

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Abstract

The invention discloses a preparation method for imatinib. According to the method, N-(5-iodo-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine and 4-((4-methyl-piperazin-1-yl)methyl)benzamide are used as raw materials; potassium phosphate, 1,10-phenanthroline and cuprous iodide are added; a reaction at room temperature is carried out; and aftertreatment is carried out so as to obtain imatinib. The method provided by the invention overcomes the problems of wearing of equipment and high energy consumption due to a high-temperature long-time reaction and is mild in reaction conditions, easy to operate, high in yield and suitable for industrial scale-up production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of imatinib. [0002] technical background [0003] Imatinib (Imatinib) is the precursor for the preparation of imatinib mesylate, which is clinically used for the treatment of various tumors, especially for the treatment of chronic myelogenous leukemia. It was originally successfully developed by Swiss Novartis, and It was approved by the FDA in 2001. In 2002, the FDA approved the drug as a drug for the treatment of gastrointestinal stromal tumors. [0004] Imatinib, the English name is imatinib, the chemical name is 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[[4-(3-pyridine) -2-pyrimidine] amino] phenyl]-benzamide, the structural formula is as follows: [0005] [0006] There are many methods for the preparation of imatinib that have been publicly reported. [0007] method 1 [0008] Chinese patent 200710067344.4 uses N-(4-methyl-3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 陈芳军
Owner 湖南华腾医药有限公司
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