Preparation method of regorafenib

A technology of regorafenib and quantity ratio, applied in the field of preparation of regorafenib, can solve the problems of unsuitable industrial production, expensive catalyst, difficult operation, etc., and achieves reduction of production cost, saving of solvent consumption cost, and method conversion rate. high effect

Inactive Publication Date: 2018-09-21
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved by the present invention is to provide a kind of Swiss sorafenib in order to overcome the defects of complex process, difficult opera

Method used

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  • Preparation method of regorafenib

Examples

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Embodiment 1-1

[0024] The synthesis of embodiment 1-1 intermediate I

[0025] In a 100mL three-neck flask equipped with a magnetic stirring device, a thermometer and a reflux condenser, add 0.09mol of 3-fluoro-4-nitrophenol, heat and melt, add 0.10mol of KOH, and react for 10min under stirring. Add 0.10mol of 4-chloro-N-methylpyridine-2-carboxamide to the reaction system, and react with temperature control; the end point is detected by TLC, and the reaction ends in 1.5h; hot 5% NaOH solution is added to the reaction system, and the temperature is kept at 80°C After washing 3 times at ~85°C, and washing 3 times with water at the same temperature, the reaction mixture was poured into cold water while it was hot, cooled, filtered, and dried to obtain a solid. Mix the obtained solid, 1 g of activated carbon for sugar, 0.12 mmol of ferric chloride, and 50 mL of methanol in a 250 mL four-necked flask, and add 0.33 mol of 85% hydrazine hydrate dropwise at reflux temperature for 1 hour. After the ad...

Embodiment 1-2

[0026] The synthesis of embodiment 1-2 intermediate I

[0027]In a 100mL three-neck flask equipped with a magnetic stirring device, a thermometer and a reflux condenser, add 0.09mol of 3-fluoro-4-nitrophenol, heat and melt, add 0.10mol of KOH, and react for 10min under stirring. Add 0.10mol of 4-chloro-N-methylpyridine-2-carboxamide to the reaction system, and react with temperature control; the end point is detected by TLC, and the reaction ends in 1.5h; hot 5% NaOH solution is added to the reaction system, and the temperature is kept at 80°C After washing at ~85°C for 3 times and with water at the same temperature for 3 times, the reaction mixture was poured into cold water while it was hot, cooled, filtered, and dried to obtain a solid. Mix the obtained solid, 1g of activated carbon for sugar, 0.12mmol of ferric chloride, and 50mL of methanol in a 250mL four-necked flask, and add 0.30mol of 85% hydrazine hydrate dropwise at reflux temperature for 1 hour. After the dropwise ...

Embodiment 1-3

[0028] Synthesis of Example 1-3 Intermediate I

[0029] In a 100mL three-necked flask equipped with a magnetic stirring device, a thermometer and a reflux condenser, add 0.08mol of 3-fluoro-4-nitrophenol, heat and melt, add 0.10mol of KOH, and react for 10min under stirring. Add 0.09mol of 4-chloro-N-methylpyridine-2-carboxamide to the reaction system, and react with temperature control; the end point is detected by TLC, and the reaction ends in 1.5h; hot 5% NaOH solution is added to the reaction system, and the temperature is kept at 80°C After washing at ~85°C for 3 times and with water at the same temperature for 3 times, the reaction mixture was poured into cold water while it was hot, cooled, filtered, and dried to obtain a solid. Mix the obtained solid, 1g of activated carbon for sugar, 0.12mmol of ferric chloride, and 50mL of methanol in a 250mL four-necked flask, and add 0.30mol of 85% hydrazine hydrate dropwise at reflux temperature for 1 hour. After the dropwise addi...

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Abstract

The invention relates to a preparation method of regorafenib. The method comprises the following steps: heating and melting 3-fluoro-4-nitrophenol and reacting with 4-chloro-N-methylpyridine-2-formamide under the action of KOH; reducing through hydrazine hydrate to obtain an intermediate I; finally enabling the intermediate I and 3-trifluoromethyl-4-chloroaniline, and ethylene carbonate to be subjected to one-pot reaction under the catalysis of a catalyst; carrying out post-treatment to obtain a regorafenib pure product. The method provided by the invention has the advantages of high conversion rate, safety and no harms, no pollution, moderate reaction conditions, high yield and high product purity, and is applicable to industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of regorafenib. Background technique [0002] Regorafenib (regorafenib), the chemical name is 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N -Methylpyridine-2-carboxamide, developed by Bayer Healthcare in Germany, approved by the FDA in the United States, with a trade name of Stivarga. This product can inhibit a variety of kinases that promote the growth of cancer tissue, including VEGFR1-2, PDGFR-β, FGFR1 and KIT, etc., thereby inhibiting the formation of tumor angiogenesis and the proliferation of tumor cells, and is clinically suitable for the treatment of metastatic colorectal cancer . Its chemical structural formula is as follows: [0003] [0004] Several preparation methods have been reported about the synthesis of regorafenib at present, as follows: [0005] 技术方案1:专利WO2005 / 009961A、WO2008 / 89388、WO2008 / 58644、WO2011128...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 刘振腾刘新泉魏淑红高瑞照
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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