Synthesis method of imatinib and imatinib mesylate

Abstract

The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis technology, in particular to a synthesis technology of imatinib and its medicinal mesylate suitable for large-scale industrial production. Background technique [0002] Imatinib mesylate (STI 571) is a successful tyrosine kinase inhibitor researched by Novartis, Switzerland, for chronic myeloid leukemia (CML) and gastrointestinal stromal cell tumor (GIST) )Treatment. In May 2001, imatinib mesylate was approved by the FDA for marketing, and its trade name is Glivec. It is currently an isolated drug in the United States, Japan, and Europe, and it is a first-line drug for the treatment of leukemia. The chemical name of imatinib mesylate is 4-[(4-methyl-1-piperazine)methyl]-4-[4-methyl-3-[[4-(3-pyridyl)-2 -pyrimidinyl]amino]-phenyl]benzamide methanesulfonate, the chemical structure is: [0003] [0004] There are many domestic and foreign literature reports on the synthetic method of ...

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Problems solved by technology

[0004] There are many domestic and foreign literature reports about the synthetic method of Gleevec. The earliest report is found in European patent EP564409 (the route is as follows), which uses 2-methyl-5-nitroaniline as raw material, and 3-dimethylamino-1 -(3-pyridyl)-2-propen-1-one reacts into a pyrimidine ring, and then prepares imatinib through palladium-carbon catalytic reduction and amidation. The main disadvantages of this method are: 1. Forming a pyrimidine ring and amidation The yield of two steps is low, 2. Catalyzed hydrogenation has potential safety hazard in large-scale industrial production 3. Acylating agent also needs five-step synthesis, therefore, whole process route is long, yield is low, raw material utilization rate is low, and production cost High, poor economy and does not meet the requirements of green chemistry

[0006] Chinese patent CN200810033189.9 (the route is as follows) uses N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide as raw material and 4-Methyl-(3-pyridyl)-2-pyrimidinone can obtain imatinib under the action of condensing agent and alkali, but the condensing agent is expensive, low temperature needs to be controlled, post-treatment is only washed with water, and the product impurities are difficult to remove and other shortcomings, not conducive to industrial production

[0011] The synthetic method disclosed in Chinese patent CN03803556.1 is to use 3-bromo-4-methylaniline as raw material to obtain imatinib by using trimethylaluminum aminolysis, and then obtain imatinib by palladium catalyst and BINAP ligand. The disadvantage of this method is that the final There are isomers in the product, which increases the difficulty and cost of separation and purification; the flammable chemical trimethylaluminum and expensive palladium catalyst are used to catalyze hydrogenation, which brings potential safety risks to large-scale industrial production; in addition, the ligand BINAP The price is also more expensive; these have increased the cost of industrialization, making the process less economical

[0013] 此外,CN200710067344.4,、WO2006071130、WO2008098949、 WO2009151899、US2010076189、US2008255138、WO2008070350、 US20080207904等专利以及A Facile TotalSynthesis of Imatinib Base and Its Analogues(Organic Process Research&Development 2008,12, 490–495)、甲磺酸伊马 The synthesis of Tini (Chinese Journal of Pharmaceutical Sciences, 2008, 43 (3), 228-229) and other documents have proposed new methods or improved the synthesis of Gleevec, but there are still many shortcomings, such as using highly toxic, Reagents that are harmful to the environment, or expensive catalysts, have harsh reaction conditions, long process routes, high raw material costs, high pollution, high energy consumption, long production cycles, cumbersome and complicated post-processing, and low product purity. Methyl imatinib is difficult to remove, and the total yield is low, which will increase the difficulty and cost of industrial production and reduce the economics of industrialization

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