Preparation method of urea compound

Abstract

The invention relates to a preparation method of a urea compound, belongs to the technical field of pharmacy and in particular relates to a preparation method of sorafenib. The preparation method comprises the following steps: forming a mixed solution by using 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide solids, a solvent and water; stirring, and then removing a water layer; and reacting with 4-chloro-3-trifluoromethyl-phenyl isocyanate to prepare a target product namely sorafenib. According to the preparation method, a reactant is mixed with water to remove alkali and avoid the generation of impurities, thereby obtaining a high-purity product; and the preparation method is simple to operate and easy to control, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of urea compounds, belonging to the technical field of pharmacy. Background technique [0002] Sorafenib (Sorafenib), chemical name: 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy}pyridine-2-carboxamide, its structure As shown in the following formula (I): It is a multi-target anti-tumor drug with dual anti-tumor effects, and can directly inhibit the proliferation of tumor cells by blocking the cell signal transduction pathway mediated by RAF / MEK / ERK, It can also block the formation of tumor neovascularization by inhibiting VEGF and platelet-derived growth factor (PDGF) receptors, and indirectly inhibit the growth of tumor cells. It is a multi-kinase inhibitor; it has been approved for its p-toluenesulfonate Forms used to treat diseases such as renal cell carcinoma and hepatocellular carcinoma: [0003] [0004] In prior art such as US7235576, WO2009111061, the preparation of Sorafenib is mai...

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Problems solved by technology

In these methods, either it takes a long reaction time to react completely; or use a strong base and then react with 4-chloro-3-trifluoromethyl-phenylisocyanate to easily generate a symmetrical urea impurity, which is difficult to remove and affects the product. The purity and yield; or use 4-chloro-3-trifluoromethylaniline reaction, need to use N,N'-carbonyldiimidazole (CDI) to activate first, but N,N'-carbonyldiimidazole is easy to decompose in water However, it affects the reaction and has high requirements on the production environment; while using other activators and then reacting to obtain the final product increases the reaction steps and increases the production cost

In addition, in the patent application CN102311384, the method of salting the intermediate 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide and then freeing it and then performing subsequent reactions to obtain the final product is adopted. This method increases the reaction steps, the operation is loaded down with trivial details, is unfavorable for industrialized production

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