Preparation method of sorafenib

A compound, the technology of p-nitrophenol, applied in the field of pharmaceutical synthesis, can solve the problems of unsuitable industrial production, expensive catalyst, difficult operation, etc., and achieve the effects of reducing production cost, mild reaction conditions, and high conversion rate of the method

Inactive Publication Date: 2018-07-13
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

[0023] The technical problem to be solved by the present invention is to provide a cable in order to overcome the defects of complex process, difficult operation, low yield, low purity, expensive catalyst and unsuitable for industrial production in the existing technology for preparing sorafenib. The preparation method of Rafenib

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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 1-1

[0034] The synthesis of embodiment 1-1 compound I

[0035] In a 250mL three-neck flask with a magnetic stirring device, a thermometer and a reflux condenser, add 0.095mol of p-nitrophenol, 0.10mol of anhydrous potassium carbonate, and 0.095mol of 4-chloro-N-methylpyridine-2-methyl Amide, 0.0025 mol of PEG-400 and 100 mL of dichloroethane were stirred with electromagnetic force, and heated to reflux in a water bath for 4 hours. Cool, filter, dichloroethane is evaporated under reduced pressure with a water pump, add 1g of activated carbon for sugar, 0.12mmol ferric chloride, 25mL ethanol and 25mL dichloroethane to the reaction flask, add 85% hydrated solution dropwise at reflux temperature Hydrazine 0.35mol, dropwise addition time 1h, after dropwise addition, reflux for 2h. After stopping the reaction, filter, wash the activated carbon with 40mL of ether, and distill the filtrate to remove ethanol and dichloroethane. After evaporation, extract the still liquid with 240mL of eth...

Embodiment 1-2

[0036] The synthesis of embodiment 1-2 compound I

[0037] In a 250mL three-neck flask with a magnetic stirring device, a thermometer and a reflux condenser, add 0.095mol of p-nitrophenol, 0.10mol of anhydrous potassium carbonate, and 0.095mol of 4-chloro-N-methylpyridine-2-methyl Amide, 0.0025 mol of PEG-400 and 100 mL of dichloroethane were stirred with electromagnetic force, and heated to reflux in a water bath for 4 hours. Cool, filter, dichloroethane is evaporated under reduced pressure with a water pump, add 1g of activated carbon for sugar, 0.12mmol ferric chloride, 25mL ethanol and 25mL dichloroethane to the reaction flask, add 85% hydrated solution dropwise at reflux temperature Hydrazine 0.30mol, dropwise for 1h, after the dropwise addition, reflux for 2h. After stopping the reaction, filter, wash the activated carbon with 40mL of ether, and distill the filtrate to remove ethanol and dichloroethane. After evaporation, extract the still liquid with 240mL of ether, co...

Embodiment 1-3

[0038] The synthesis of embodiment 1-3 compound I

[0039] In a 250mL three-neck flask with a magnetic stirring device, a thermometer and a reflux condenser, add 0.08mol of p-nitrophenol, 0.10mol of anhydrous potassium carbonate, and 0.08mol of 4-chloro-N-methylpyridine-2-methyl Amide, 0.001 mol of PEG-400 and 100 mL of dichloroethane were stirred with electromagnetic force, and heated to reflux in a water bath for 4 hours. Cool, filter, and dichloroethane are evaporated under reduced pressure with a water pump. Add 1 g of activated carbon for sugar, 0.12 mmol of ferric chloride, 25 mL of ethanol and 25 mL to the reaction flask. Add 0.30 mol of 85% hydrazine hydrate dropwise at reflux temperature. Adding time is 1h, after the addition is completed, reflux for 2h. After stopping the reaction, filter, wash the activated carbon with 40mL of ether, and distill the filtrate to remove ethanol and dichloroethane. After evaporation, extract the still liquid with 240mL of ether, combi...

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Abstract

The invention relates to a preparation method of sorafenib. The method comprises the following steps of allowing p-nitrophenol and 4-chlorine-N-picoline-2-formamide to react under the action of anhydrous potassium carbonate and PEG (polyethylene glycol)-400, generating a compound I via hydrazine hydrate reduction, allowing the compound I, 3-trifluoromethyl-4-chloroaniline and diphenyl carbonate orN,N-disuccinimidyl carbonate to give a 'one-pot' reaction by the action of a catalyst, performing post-treatment to form a sorafenib crude product, and performing further purification to form pure sorafenib. The method is high in conversion rate, safe, free from harm and pollution, mild in reaction condition, high in yield and applicable to industrial production, and can ensure high product purity.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of sorafenib. Background technique [0002] Sorafenib (sorafenib, trade name Nexavar), chemical name: 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureide]-phenoxy}- Pyridine-2-carboxylate methylamine is an orally active multi-kinase inhibitor that can inhibit tumor cell replication and tumor angiogenesis. Onyx initially discovered this new compound, and Bayer subsequently participated in the development of the drug. Later development (codenamed BAY-43-9006). Initially, researchers found that Sorafenib inhibited Raf kinase, and then found that the drug can also inhibit vascular endothelial growth factor (VEGFR), platelet-derived growth factor β receptor, FMS-like tyrosine kinase (Flt-3) , c-Kit protein and RET receptor tyrosine kinase. Its chemical structural formula is as follows: [0003] [0004] Several preparation methods that have been reported about ...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 刘振腾李志滨谢娜宋庆国
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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