Preparation method of sorafenib

A technology of trifluoromethyl and aniline, applied in the field of medicine and chemical industry, can solve the problems of long reaction time, long production cycle, unsafety and the like, and achieve the effects of simplified operation steps, short reaction route and good controllability

Active Publication Date: 2014-04-16
QILU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 difficul

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  • Preparation method of sorafenib
  • Preparation method of sorafenib
  • Preparation method of sorafenib

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Experimental program
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Embodiment 1

[0045] Add 103ml of acetonitrile and 10.3g (34.8mmol) triphosgene to a 2000mL reaction flask, stir to dissolve, control the temperature to 10°C, add dropwise 20g (102.3mmol) of 4-chloro-3-trifluoromethyl-aniline, 200mL of acetonitrile and 14.5ml of triethylamine, after stirring for 3 hours, dropwise added 22.4g (92.0mmol) of compound III (ie 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide , the same below), 14.5ml of triethylamine and 224ml of acetonitrile mixture solution, temperature control to 10 ℃, stirring reaction for 3h, adding 500ml of water to the reaction system, stirring at room temperature for 2h, suction filtration, washing, drying to obtain 36g Rafenib, yield 84.3%, HPLC purity 98.6%.

Embodiment 2

[0047] Add 1L ethyl acetate and 100g (0.505mol) diphosgene to a 10L reactor, stir to dissolve, control the temperature to 20°C, add dropwise 194g (0.992mol) 4-chloro-3-trifluoromethyl-aniline, A mixed solution composed of 1.9L ethyl acetate and 141ml triethylamine was stirred for 2 hours; a mixed solution composed of 217g (0.893mol) compound III, 141ml triethylamine and 2.2L ethyl acetate was added dropwise, and the temperature was raised to 30°C. Stir the reaction for 2 hours; add 5.1L saturated saline to the reaction system, stir and wash, separate liquids, stir the organic phase at room temperature for 2 hours, suction filter, wash, and dry to obtain 355g of Sorafenib, with a yield of 85.5% and a purity of 98.3% by HPLC .

Embodiment 3

[0049] Add 1L tetrahydrofuran and 100g (0.337mol) triphosgene to a 10L reactor, stir to dissolve, cool down to 0°C, then dropwise add 194g (0.992mol) 4-chloro-3-trifluoromethyl-aniline, 1.9L tetrahydrofuran and a mixed solution composed of 141ml triethylamine, stirred and reacted for 4h. Then, a mixed solution consisting of 217g (0.893mol) of compound III, 2.2L of tetrahydrofuran and 141ml of triethylamine was added dropwise to the reaction solution, the temperature was controlled to 5°C, and the reaction was stirred for 4h. 5.1L of water was added to the reaction system, and stirred at room temperature for 2h. , Suction filtration, washing, drying, obtain 361g Sorafenib, yield 87.0%, HPLC purity 98.1%.

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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...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 张进王丙忠林栋范传文
Owner QILU PHARMA
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