Preparation method of urea compound

A technology of compound and mixed solution, which is applied in the field of preparation of urea compounds, can solve the problems of affecting the reaction, easy to decompose, cumbersome operation, etc.

Active Publication Date: 2015-06-03
SUNSHINE LAKE PHARM CO LTD
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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 producti

Method used

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Embodiment Construction

[0007] The contriver finds through research, uses N-methyl-4-chloro-2-pyridinecarboxamide to react with 4-aminophenol in the presence of a strong base, and it is easy to make the resulting product 4-(4-aminophenoxy)-N -Methyl-2-pyridinecarboxamide contains a small part of base, and the existence of this small part of base makes 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide and 4-chloro- 3-trifluoromethyl-phenylisocyanate generates a symmetrical urea impurity in the reaction process, its structure is shown in the following formula (A), it is difficult to remove from Sorafenib, affecting the quality of the target product Sorafenib and yield; and the compound 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide solid is mixed with water, treated, and then with 4-chloro-3-trifluoromethyl- The phenylisocyanate reaction can avoid a large amount of production of the impurity (A), and can obtain the product Sorafenib with high yield and high purity;

[0008]

[0009] On the one h...

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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...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 李东明王小江
Owner SUNSHINE LAKE PHARM CO LTD
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