Method for preparing imatinib mesylate in alpha crystal form conveniently and rapidly

A technology of imatinib mesylate and crystal form, which is applied in the field of pharmaceutical chemical preparation, can solve the problems of expensive starting materials, complicated steps, complicated operations, etc., and achieve the effect of improving the utilization rate of atoms

Active Publication Date: 2014-01-01
NANJING YOUKE BIOLOGICAL MEDICAL RES +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The purpose of the present invention is to overcome the defects such as long synthetic route, complicated steps, expensive starting materials, and large pollution of acylating reagents in the synthesis of imatinib in the pri

Method used

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  • Method for preparing imatinib mesylate in alpha crystal form conveniently and rapidly
  • Method for preparing imatinib mesylate in alpha crystal form conveniently and rapidly
  • Method for preparing imatinib mesylate in alpha crystal form conveniently and rapidly

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 4-(4-methylpiperazinemethyl) benzoic acid dihydrochloride (1Kg, 3.26mol) shown in formula II, triethylamine (0.992Kg, 9.8mol), add 1,4-dioxane 6L, stir evenly, cool down to 0°C, add methanesulfonyl chloride (0.375Kg, 3.26mol) dropwise, after dropping, slowly raise the temperature to 52°C, keep the temperature for 2-3h, and monitor the reaction by TLC to obtain a mixture of acids of formula II Anhydride solution, dimethylaminopyridine DMAP (41g, 0.33mol) was added. N-(5-amino-2-methylbenzene)-4-(3-pyridyl)-2-aminopyrimidine (0.904Kg, 3.26mol) represented by formula III was dissolved in 1.6L of dimethylformamide DMF , then add 2.4L of 1,4-dioxane, slowly drop the above amine solution into the above reaction solution, keep the temperature within 53-56°C, and control the dropping time within 1.5-2h. The reaction was incubated for 2.5 hours, and the reaction was complete as monitored by TLC. Slowly lower the temperature to 20°C, add 3L of ethyl acetate to the reaction solu...

Embodiment 2

[0050] Add 4-(4-methylpiperazinemethyl)benzoic acid dihydrochloride (1.5Kg, 4.88mol) and diisopropylethylamine (1.89Kg, 14.7mol) represented by formula II to 9.2L of acetonitrile, Stir evenly, cool down to 10°C, add methanesulfonyl chloride (0.559Kg, 4.88mol) dropwise, after dropping, slowly raise the temperature to 53-54°C, keep warm for 3 hours, monitor the reaction by TLC to obtain the mixed anhydride solution of the acid of formula II , and dimethylaminopyridine DMAP (61 g, 0.5 mol) was added. N-(5-amino-2-methylbenzene)-4-(3-pyridyl)-2-aminopyrimidine (1.35Kg, 4.88mol) represented by formula III was dissolved in 2.0L of dimethylformamide DMF , then add 3.1L of acetonitrile, slowly drop the above amine solution into the above reaction solution, keep the temperature within 53-54°C, control the dropping time within 1.5-2h, after dropping, keep warm for 2h, monitor the reaction by TLC completely. Slowly lower the temperature to 30°C, add 3.5L of ethyl acetate to the reactio...

Embodiment 3

[0054] 4-(4-Methylpiperazinemethyl)benzoic acid dihydrochloride (0.8 Kg, 2.60 mol) represented by formula II, N-methylmorpholine (0.790 Kg, 7.8 mol) were added to 4.4 L of tetrahydrofuran, Stir evenly, cool down to 2°C, add methanesulfonyl chloride (298g, 2.6mol) dropwise, after dropping, slowly raise the temperature to 54-56°C, keep the temperature for 3h, and monitor the reaction by TLC to obtain the mixed anhydride solution of the acid of formula II. Dimethylaminopyridine DMAP (35.5 g, 0.29 mol) was added. N-(5-amino-2-methylbenzene)-4-(3-pyridyl)-2-aminopyrimidine (720 g, 2.6 mol) represented by formula III was dissolved in 1.1 L of dimethylformamide DMF, Then add 1.8L of tetrahydrofuran, slowly drop the above amine solution into the above reaction solution, keep the temperature within 54-56°C, and control the dropping time within 1.5-2h. completely. Slowly lower the temperature to 25°C, add 2.8 L of ethyl acetate to the reaction solution, stir evenly, filter the precip...

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Abstract

The invention relates to a method for preparing imatinib mesylate in the alpha crystal form conveniently and rapidly. The method specifically includes the steps that 4-(4-methyl piperazine methyl) benzoic acid dihydrochloride shown in the second formula and N-(5-amino-2-methyl benzene)-4-(3-pyridyl)-2-amino pyrimidine shown in the third formula serve as initial raw materials, and by using methyl sulfonyl chloride, a one-pot method is conveniently, rapidly and efficiently applied to obtain imatinib mesylate crude products; then, by re-crystallizing and adding a proper amount of seed crystals, high-purity imatinib mesylate crystals in the alpha crystal form are obtained. The preparation method is few in synthesis step, easy and convenient to operate, high in yield, high in purity of alpha crystal form of the products, low in production cost and favorable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical preparation, in particular to a convenient method for preparing α crystal form of imatinib mesylate. Background technique [0002] Imatinib mesylate, as an aniline derivative, is a specific tyrosine kinase inhibitor (tyrosine kinases inhibitors, TKI). In May 2001, it was approved by the FDA for the treatment of chronic myeloid leukemia (CML), and in 2003 it was approved by the FDA for the treatment of gastrointestinal stromal tumors (GIST). As the world's first approved tumorigenesis-related signal transduction inhibitor, the launch of imatinib mesylate has won wide acclaim from the international medical community. It not only represents a new class of anti-tumor drugs with a new mechanism of action that has Clinical application, and it indicates that the drug target is increasingly developing at the molecular level, which can be an effective way to reduce its toxic and side effec...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 史为龙闵涛车晓明张峰薛峪泉
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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