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Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride

A technology of benzoic hydrochloride and methylpiperazine is applied in the field of green synthesis technology of 4-benzoic acid, an important intermediate of imatinib, can solve the problem of high market price, achieve good environmental protection, many steps, The effect of short reaction steps

Inactive Publication Date: 2015-09-16
武汉利宝瑞医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The above-mentioned intermediate 7 is an important intermediate raw material for the synthesis of imatinib mesylate, but the synthetic method of this intermediate has not been reported in detail in relevant literature, so the market price is relatively high

Method used

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  • Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride
  • Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride
  • Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Dissolve p-cyanobenzyl chloride (1g, 6.6mmol) in a mixed solvent of ethanol and water (10mL, ethanol:water=2:1 in the mixed solvent), add methylpiperazine (1.2eq, 0.792g, 7.92mmol ), heating the reaction at 70°C for 1-2 hours, cooling to room temperature, recovering most of the ethanol to obtain 4-(4-methyl-1-piperazinyl)benzonitrile, adding sodium hydroxide (6eq , 1.584g, 39.6mmol), heat the reaction at 70°C, after the reaction is complete, cool to room temperature, slowly add dilute hydrochloric acid dropwise to pH = 1 in an ice bath, add sodium chloride to saturation, cool to precipitate a solid, filter , and dried to obtain 4-(4-methylpiperazin-1-ylmethyl)benzoic acid hydrochloride (2.0 g).

[0032] Such as figure 1 As shown, there is a product peak at about 4.098min, which is consistent with the peak retention time reported in the literature, showing that the compound is correct. By the area normalization method, the purity of the product can be as high as 99.8%....

Embodiment 2

[0037]Dissolve p-cyanobenzyl chloride (13.5g, 89.1mmol) in a mixed solvent of ethanol and water (135mL, ethanol:water=2:1 in the mixed solvent), add methylpiperazine (1.2eq, 10.7g, 106.9 mmol), heated reaction at 100°C, the reaction time was 1-2 hours, cooled to room temperature, reclaimed most of the ethanol, obtained 4-(4-methyl-1-piperazinyl) benzonitrile, added sodium hydroxide ( 6eq, 21.4g, 534.6mmol), heat the reaction at 100°C, after the reaction is complete, cool to room temperature, slowly add dilute hydrochloric acid dropwise to pH = 1.5 in an ice bath, add sodium chloride to saturation, cool to precipitate a solid, Filter and dry to obtain 4-(4-methylpiperazin-1-ylmethyl)benzoic acid hydrochloride (27g).

Embodiment 3

[0039] Dissolve p-cyanobenzyl chloride (111g, 723.6mmol) in a mixed solvent of ethanol and water (1120mL, ethanol:water=2:1 in the mixed solvent), add methylpiperazine (1.2eq, 87.9g, 879.1mmol ), heat the reaction at 90°C, the reaction time is 1-2 hours, cool to room temperature, recover most of the ethanol to obtain 4-(4-methyl-1-piperazinyl) benzonitrile, add sodium hydroxide (6eq , 175.8g, 4396mmol), heat the reaction at 90°C, after the reaction is complete, cool to room temperature, slowly add dilute hydrochloric acid dropwise to pH = 2 in an ice bath, add sodium chloride to saturation, cool to precipitate a solid, filter, After drying, 4-(4-methylpiperazin-1-ylmethyl)benzoic acid hydrochloride (220 g) was obtained.

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Abstract

The invention relates to a green synthesis process of 4-(4-methylpiperazin-1-ylmethyl) benzoic acid. The process comprises the following steps: according to a stoichiometric molar ratio, p-cyanobenzylchloride is dissolved in a mixed solvent of ethanol and water; methylpiperazine is added; a heating reaction is carried out under a certain temperature; the material is cooled to room temperature, and most ethanol is recovered, such that 4-(4-methyl-1-piperazinyl) benzonitrile is obtained; sodium hydroxide is added, and reflux is carried out; when the reaction is finished, the material is cooled to room temperature; in an ice bath, dilute hydrochloric acid is dropped slowly until the material is acidic; sodium chloride is added until the sodium chloride is saturated; cooling is carried out, such that solid is precipitated; and filtering and drying are carried out, such that 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride is obtained. The method provided by the invention has the following advantages: 1, the method is simple and easy to operate; reaction steps are short; the raw materials are cheap and easy to obtain; an overall yield and product purity are greatly improved compared to prior arts; 2, the method has good environment friendliness, and no toxic gas is released during the reaction processes; 3, with the method, post treatment is simple to operate and is highly efficient.

Description

technical field [0001] The invention relates to the field of antitumor drugs, in particular to a green synthesis process of 4-(4-methylpiperazin-1-ylmethyl)benzoic acid, an important intermediate of imatinib. Background technique [0002] Imatinib mesilate, chemical name 4-(4-methylpiperazinyl-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl) ) pyrimidine-2-amino]-benzamide methanesulfonate. Imatinib mesylate is a small molecule tyrosine kinase (TK) inhibitor, its mechanism of action is to target the bcr / abl receptor subtype of tyrosine kinase, selectively bind to the bcr / abl protein tyrosine kinase catalyzed Competitively prevents tyrosine kinases from binding to ATP in the nucleotide-binding pocket of the region. It can recognize the inactivation conformation of the activation loop of tyrosine kinase, and specifically bind to it, prevent autophosphorylation and phosphorylation of tyrosine kinase substrate, reduce the activity of tyrosine kinase, inhibit or control the occurrence of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/155
CPCC07D295/155
Inventor 秦华利陈小清郝建宏冷静熊峰尚振鹏
Owner 武汉利宝瑞医药科技有限公司
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