Method for preparing anti-tumor medicine imatinib

Abstract

The invention relates to a method for preparing an anti-tumor medicine imatinib, which comprises the following steps of: performing amidation-condensation two-step 'one pot' reaction on 4-methyl-3-bromaniline (V), 4-(chloromethyl) benzoyl chloride (IV) and N-methyl piperazine to directly obtain a key intermediate N-(4-methyl-3-bromophenyl)-4-(4-methyl piperazin-1-methyl)-benzamide (III); and performing nucleophilic substitution on the N-(4-methyl-3-bromophenyl)-4-(4-methyl piperazin-1-methyl)-benzamide (III) and 4-(3-Pyridinyl)-2-aminopyrimidine (II) to obtain the imatinib (I). The method hasthe advantages that: the process is reasonably designed, expensive reagents are not used, the reaction yield is high, raw materials are low in cost, the operation is simple and convenient, rigorous reaction conditions are absent, and the method is suitable for mass production.

Description

【Technical field】 [0001] The invention relates to the technical field of medicine manufacturing, in particular to a synthesis method for preparing antitumor drug imatinib. 【Background technique】 [0002] Imatinib (Imatinib, I), chemical name: 4-[(4-methylpiperazinyl-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl) -2-pyrimidinyl] amino] phenyl] benzamide, American Chemical Abstracts registration number CAS: 152459-95-5, the structure of imatinib is as follows: [0003] [0004] Imatinib is a tyrosine kinase inhibitor antineoplastic drug developed by Swiss Novartis, which was approved by the U.S. Food and Drug Administration (FDA) in May 2001 for the treatment of chronic myelogenous leukemia ( CML for short), was approved in February 2002 for the treatment of gastrointestinal stromal cell tumors (GIST for short), and has the advantages of rapid onset, strong metastasis, and small side effects. [0005] Looking at the preparation methods of imatinib can be summarized as the followi...

AI Technical Summary

Problems solved by technology

Its disadvantages are: the operation is increased, the yield is still not high, and the side reaction between the diaryl secondary amine and the acid chloride cannot be avoided;

Its disadvantages are: it belongs to the linear synthesis route, the reaction steps are relatively long, the guanidine group and pyrimidine ring need to be formed in the main reaction process, the yield is low, and the final condensation reaction needs to use expensive palladium / carbon catalyst, which increases the raw and auxiliary materials. the cost of;

Its disadvantages are: it belongs to the linear synthesis route, and the reaction steps are relatively long. In the main reaction process, cyanamide needs to be used to synthesize the guanidinium group, and the final cyclization yield is low, the reaction time is long, and the reaction of raw materials is not complete;

Its shortcoming is: the preparation of 4-(3-pyridyl)-2-halogen pyrimidine is loaded down with trivial details, needs to use highly toxic reagent phosphorus oxychloride

Its disadvantages are: the condensing agent for the preparation of amides by ammonolysis is trimethylaluminum, which is a highly flammable chemical with difficult sources and extremely dangerous for large-scale use

In its final nucleophilic substitution reaction, the document uses an expensive organopalladium catalyst, which also leads to the final product containing so-called 10% isomers, which need to be removed by reverse phase chromatography, which increases the difficulty and cost of separation and purification. The synthesis process is difficult to have industrial value;

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