Green preparation method of pazopanib hydrochloride

Abstract

The invention belongs to the technical field of pharmaceutical chemistry synthesis and particularly relates to a green preparation method of pazopanib hydrochloride. The method comprises the steps ofallowing o-toluidine and N-chlorosuccinimide to give a chlorination reaction to form 2-methyl-5-chlorine-aniline, allowing 2-methyl-5-chlorine-aniline to react with a nitrous acid compound to form 6-chlorine-2H-indole hydrochloride, performing N methylation reaction to form N-methyl-6-chlorine-2H-indole, performing 3-delta carbon alkylation reaction in the presence of dimethyl sulfoxide to form 2,3-dimethyl-6-chlorine-2H-indazole, allowing 2,3-dimethyl-6-chlorine-2H-indazole to react with 2-chlorine-4-amino-pyrimidine and methyl iodide to form N-(2-chloropyrimidine-4)-N-methyl-2,3-dimethyl-2H-indazole-6-amine, and at last, allowing N-(2-chloropyrimidine-4)-N-methyl-2,3-dimethyl-2H-indazole-6-amine to react with 3-sulfamate-4-methyl-aniline to form pazopanib hydrochloride. The method is lowin raw material price, simple to operate and low in operational risk, and avoids generation of waste acid; and a reaction yield and purity are high.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a green preparation method of pazopanib hydrochloride. Background technique [0002] Pazopanib, chemical name 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl]amino]-2- Toluenesulfonamide, a multi-target tyrosine kinase inhibitor developed by GlaxoSmithKline (GSK) in the UK, in addition to inhibiting vascular endothelial growth factor receptors (VEGFR)-1, 2 and 3 , but also inhibit PDGFR, c-kit and FGFR and other tyrosine kinases. The function of pazopanib is to inhibit the phosphorylation of the above-mentioned kinase itself, inactivate the kinase, and then inhibit angiogenesis, so as to achieve the purpose of "starving" the tumor. As a targeted drug for vascular tumors, pazopanib mainly has the following advantages: 1. Since the genes of vascular endothelial cells are relatively stable, drug resistance is not easy to deve...

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Problems solved by technology

[0003] At present, the preparation method of multiple pazopanib has been reported both at home and abroad, for example: 1, Chen Yan, Fang Zheng, Wei Ping etc. report on the China Pharmaceutical Industry Journal with o-ethylaniline as the initial raw material, through nitration, ring formation, Synthesis of key intermediate 6-[N-(2-chloro-4-pyrimidinyl)methylamino]-2,3-dimethyl-2H through 6-step reactions including methylation, reduction, nucleophilic substitution and methylation -indole, then obtain pazopanib hydrochloride in nucleophilic substitution and salification; but the used reagent stannous chloride belongs to highly toxic and highly polluting reagents, which is not conducive to production; 2, with 3-methyl- 6-nitro-1H-indazole is used as the starting material, and pazopa is prepared through 5 steps of N-methylation, nitro reduction, nucleophilic substitution, N-methylation, nucleophilic substitution / salt formation, etc. Nitrate hydrochloride; this method is the same as route 1, all need to carry out nitration reaction, use concentrated sulfuric acid and concentrated nitric acid to carry out nitration reaction, will produce a large amount of waste acid liquid, the domestic environmental protection pressure is very big at present, waste acid liquid needs very complicated The process is environmentally friendly, which is unfavorable to production costs; 3. HarrisP.A., Boloor A., ​​Cheung M. reported the key intermediate 6-[N-(2-chloro-4-pyrimidinyl)methylamino] on J.M.C. The synthesis method of -2,3-dimethyl-2H-indole uses o-ethylaniline as the initial raw material, and undergoes 4-step reactions such as nitration, ring formation, nitro reduction, and nucleophilic substitution with 2,4-dichloropyrimidine. Synthetic 6-[N-(2-chloro-4-pyrimidinyl)methylamino]-2,3-dimethyl-2H-indole, this method has a serious shortcoming, is exactly in the reaction with 2,4-di When chloropyrimidine undergoes nucleophilic substitution, since 2,4-dichloropyrimidine contains two relatively active chlorines, substitution reactions can occur, and by-products are prone to occur, and the by-products are relatively similar in chemical and physical properties due to their similar structures. It is not easy to remove by conventional means such as recrystallization, which will seriously affect product quality; for the synthesis of intermediate 3-methyl-6-nitro-2H-indazole, the current industrial method is to use 2-ethyl-5-nitro Aniline is obtained by reacting under the action of acetic acid and sodium nitrite. The yield of this method is very high, and the molar yield can reach 98%, but acetic acid is needed as a solvent, and the dosage is very, very large. Divided by vacuum distillation, it needs to be neutralized with alkaline water in the post-treatment process, resulting in a large amount of industrial wastewater

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