Preparation method of regorafenib

A technology of regorafenib and quantitative ratio, which is applied in the field of preparation of regorafenib, can solve the problems of unsuitability for industrial production, expensive catalyst, difficult operation, etc., and achieve reduced production costs, mild reaction conditions, and high conversion rate of the method Effect

Inactive Publication Date: 2018-08-24
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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

Method used

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  • Preparation method of regorafenib
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  • Preparation method of regorafenib

Examples

Experimental program
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Embodiment 1-1

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

[0025] In a 250mL three-neck flask with a magnetic stirring device, a thermometer and a reflux condenser, add 0.09mol of 3-fluoro-4-nitrophenol, 0.10mol of anhydrous potassium carbonate, and 0.10mol of 4-chloro-N-methyl Pyridine-2-carboxamide, 0.003 mol of PEG-400 and 100 mL of acetonitrile were stirred with electromagnetic force, and heated to reflux in a water bath for 4 hours. Cool, filter, and evaporate acetonitrile under reduced pressure with a water pump. Mix the obtained residue, 1 g of activated carbon for sugar, 0.1 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. , Reflux 2h. After stopping the reaction, filter, wash the activated carbon with 40mL ether, and distill the filtrate to remove methanol at the same time. After evaporation, extract the still liquid with 240mL ether, combine the ether laye...

Embodiment 1-2

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

[0027]In a 250mL three-neck flask with a magnetic stirring device, a thermometer and a reflux condenser, add 0.09mol of 3-fluoro-4-nitrophenol, 0.10mol of anhydrous potassium carbonate, and 0.10mol of 4-chloro-N-methyl Pyridine-2-carboxamide, 0.003 mol of PEG-400 and 100 mL of acetonitrile were stirred with electromagnetic force, and heated to reflux in a water bath for 4 hours. Cool, filter, and evaporate acetonitrile under reduced pressure with a water pump. Mix the obtained residue, 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 0.30 mol of 85% hydrazine hydrate dropwise at reflux temperature for 1 hour. , Reflux 2h. After stopping the reaction, filter, wash the activated carbon with 40mL ether, and distill the filtrate to remove methanol at the same time. After evaporation, extract the still liquid with 240mL ether, combine the ether laye...

Embodiment 1-3

[0028] Synthesis of Example 1-3 Intermediate I

[0029] In a 250mL three-necked flask with a magnetic stirring device, a thermometer and a reflux condenser, add 0.08mol of 3-fluoro-4-nitrophenol, 0.10mol of anhydrous potassium carbonate, and 0.09mol of 4-chloro-N-methyl Pyridine-2-carboxamide, 0.002 mol of PEG-400 and 100 mL of acetonitrile were stirred with electromagnetic force, and heated to reflux in a water bath for 4 hours. Cool, filter, and evaporate acetonitrile under reduced pressure with a water pump. Mix the obtained residue, 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 0.30 mol of 85% hydrazine hydrate dropwise at reflux temperature for 1 hour. , Reflux 2h. After stopping the reaction, filter, wash the activated carbon with 40mL ether, and distill the filtrate to remove methanol at the same time. After evaporation, extract the still liquid with 240mL ether, combine the ether layers, ...

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Abstract

The invention relates to a preparation method of regorafenib. The method comprises the following steps: performing reaction on 3-fluoro-4-nitrophenol and 4-chloro-N-methyl pyridine-2-methylformamide under the effects of anhydrous potassium carbonate and PEG-400, and performing hydrazine reduction to generate an intermediate I; then performing one-pot reaction on the intermediate I, 3-trifluoromethyl-4-chlorophenylamine and dimethyl dithiocarboxylate under the effect of a catalyst, then performing post-treatment to obtain a regorafenib crude product, and further purifying the regorafenib crudeproduct to obtain a regorafenib purified product. The method disclosed by the invention has the advantages of high conversion ratio, security, no harm, no pollution, mild reaction conditions, high yield and high purity of the product; moreover, the method is suitable for 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
Inventor 刘振腾徐桂超毛慧慧高炳朋
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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