Preparation method of sorafenib

Abstract

The invention relates to a preparation method of sorafenib. The method of the invention comprises the following steps: reacting 4-chloro-3-trifluoromethyl-aniline or acid addition salts of 4-chloro-3-trifluoromethyl-aniline with an acylating chlorination reagent by a one-pot method in the presence of alkali at -10 DEG C-35 DEG C to obtain an N-chloroformyl-4-chloro-3-trifluoromethyl-aniline intermediate, and then directly allowing the intermediate to carry out an ammonolysis reaction with 4-(4-amino phenoxyl)-N-methyl-2-pyridine carboxamide to obtain sorafenib with high yield. The process is simple in operation, short in production period, and high in yield, and the obtained product has a purity of more than 98%.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a method for synthesizing a small molecule targeted drug Sorafenib, namely a 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl) - the preparation method of ureide]-phenoxy group}-pyridine-2-carboxylic acid methylamine. Background technique [0002] Sorafenib (sorafenib), chemical name: 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureide]-phenoxy}-pyridine-2-carboxylate Acid methylamine, which has a chemical structure shown in formula I, is a novel signal transduction inhibitor and multi-target anti-tumor drug jointly developed by German Bayer and Onxy companies. Sorafenib has dual anti-tumor effects: it can not only directly inhibit the proliferation of tumor cells by blocking the cell signaling pathway mediated by RAF / MEK / ERK, but also inhibit the formation of new blood vessels and Cut off the nutrient supply of tumor cells to achieve the purpose of curbing tum...

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Problems solved by technology

[0007] However, in the two preparation methods disclosed above, the genotoxic isocyanate-4-chloro-3-trifluorotoluene-phenyl ester is used, and the drug safety is potentially dangerous; and the reaction temperature needs to be strictly controlled and it takes a long time The reaction time will inevitably increase impurities and reduce the yield; WO0042012 uses concentrated sulfuric acid and hydrogen peroxide in the reaction process, and there is a potential danger of explosion during the reaction process, so it has a higher risk

[0008] In addition, although WO2009034308 also discloses the synthesis method of sorafenib, the use of potassium tert-butoxide for etherification in the disclosed preparation method will easily lead to hydrolysis and cleavage of the amide bond, thereby reducing the reaction yield and product purity, or the reaction is easy to The symmetric urea is introduced into the product and is difficult to remove, which is not conducive to industrial production and higher purity products

The sorafenib synthesis method also disclosed in WO2009054004 not only uses isocyanate-4-chloro-3-trifluorotoluene-phenyl ester which has strong mutagenic toxicity, but also needs tert-butanol due to the reaction Potassium and other strong bases can easily cause the amide bond of the intermediate to break, thereby affecting the yield and purity of the product

WO2009111061 discloses a synthetic route of sorafenib with good yield, but because the reaction requires the use of concentrated sulfuric acid, hydrogen peroxide and unstable isocyanate toxic compounds, it is also potentially unsafe; in addition, the synthetic route reaction Long steps, complex post-processing, and long production cycle; a large amount of waste liquid is generated, polluting the environment, which will greatly increase energy consumption and production costs

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