Preparation method of regorafenib

A technology of regorafenib and quantitative ratio, applied in the field of preparation of regorafenib, can solve the problems of unsuitable industrial production, expensive catalyst, difficult operation, etc., achieve high conversion rate, reduce production cost, and high reaction yield Effect

Active Publication Date: 2018-12-14
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 operatio

Method used

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  • Preparation method of regorafenib

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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 100mmol of 4-amino-3-fluorophenol, 100mmol of anhydrous potassium carbonate, and 85mmol of 4-chloro-N-methylpyridine-2- Formamide, 2.5mmol of PEG-400 and 100mL of dichloroethane were stirred electromagnetically, and heated to reflux in a water bath for 4 hours. Cool, filter, dichloroethane was evaporated under reduced pressure with a water pump, the still liquid was extracted with 240mL ether, dried, and concentrated to obtain 21.39g of a light yellow liquid, Intermediate I, with a yield of 96.3% and a purity of 99.90%.

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 90mmol of 4-amino-3-fluorophenol, 100mmol of anhydrous potassium carbonate, and 90mmol of 4-chloro-N-methylpyridine-2- Formamide, 2mmol of PEG-400 and 100mL of dichloroethane were stirred electromagnetically, and heated to reflux in a water bath for 4 hours. Cool, filter, dichloroethane was evaporated under reduced pressure with a water pump, the still liquid was extracted with 240mL ether, dried, and concentrated to obtain 21.32g of a light yellow liquid, namely Intermediate I, with a yield of 90.6% and a purity of 99.80%.

Embodiment 1-3

[0028] Synthesis of Example 1-3 Intermediate I

[0029] In a 250mL three-neck flask with a magnetic stirring device, a thermometer and a reflux condenser, add 110mmol of 4-amino-3-fluorophenol, 100mmol of anhydrous potassium carbonate, and 80mmol of 4-chloro-N-methylpyridine-2- Formamide, 3mmol of PEG-400 and 100mL of dichloroethane were stirred electromagnetically, and heated to reflux in a water bath for 4 hours. Cool, filter, dichloroethane was evaporated under reduced pressure with a water pump, and the still liquid was extracted with 240 mL of ether, dried, and concentrated to obtain 19.59 g of a light yellow liquid, namely Intermediate I, with a yield of 93.7% and a purity of 99.76%.

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Abstract

The invention relates to a preparation method of regorafenib. The method comprises steps as follows: 4-amino-3-fluorophenol and 4-chloro-N-methylpyridine-2-formamide are subjected to ether condensation reaction under the action of anhydrous potassium carbonate and PEG-400, and an intermediate I is generated; then the intermediate I and 3-trifluoromethyl 4-chlorobenzoic acid are subjected to one-pot reaction with diphenylphosphoryl azide under the action of alkali, a crude regorafenib product is obtained and further purified, and a pure regorafenib product is obtained. The method is high in conversion rate, safe, harmless, pollution-free, high in yield and suitable for industrial production, the reaction conditions are mild, and the product purity is high.

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 刘振腾宋丽丽常志成
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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