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Preparation method of crude regorafenib

A technology of regorafenib and API, applied in the field of preparation of antitumor drugs, can solve the problems of uneconomical, dark color and high cost

Active Publication Date: 2019-05-24
新乡双鹭药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, the crude product is obtained by extraction or phase separation or by adding water to the reaction system to precipitate solids. Because the amino compound is oxidized by oxygen in the air, the reaction system appears brown to black purple, and it is difficult to observe the interface, resulting in low purity of the RGFN1 product. , the color is deep, and there are many impurities in the follow-up reaction, which cannot reach the quality standard of the raw material drug, and can barely reach the quality standard of the raw material drug after repeated refining, resulting in low yield, high cost, and uneconomical

Method used

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  • Preparation method of crude regorafenib
  • Preparation method of crude regorafenib
  • Preparation method of crude regorafenib

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Experimental program
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Effect test

Embodiment 1

[0023] A preparation method of regorafenib bulk drug, comprising the following steps

[0024] (1) Reaction equation:

[0025]

[0026]Under the protection of nitrogen, add 4-chloro-N-methylpyridine-2-carboxamide (abbreviated as RGFNA), 2-fluoro-4-hydroxyaniline (4-amino-3-fluorophenol) (referred to as RGFN B) and N,N-dimethylacetamide (DMA), the molar ratio of RGFNA:RGFNB:DMA is 1:1.2~1.4:1.5~1.7, the system temperature in the reactor is 25~30℃, the stirring speed is 80 Stir for 15-20min under the condition of ~130 rev / min, the jacket of the reaction kettle is heated by a circulating oil bath or steam, so that the temperature of the system in the reaction kettle rises to 100-110°C, and then dropwise add the containing Potassium tert-butoxide (t-BuOK for short) in N,N-dimethylacetamide solution, potassium tert-butoxide, N,N-dimethylacetamide solution according to RGFNA: t-BuOK: N,N-dimethylacetamide The molar ratio of dimethylacetamide solution is 1:1.1~1.3:2.5~3.5. The N,...

Embodiment 2

[0035] A preparation method of regorafenib bulk drug, comprising the following steps

[0036] (1) Reaction equation:

[0037]

[0038]Under the protection of nitrogen, add 4-chloro-N-methylpyridine-2-carboxamide (abbreviated as RGFNA), 2-fluoro-4-hydroxyaniline (4-amino-3-fluorophenol) (referred to as RGFN B) and N,N-dimethylacetamide (DMA), the molar ratio of RGFNA: RGFNB: DMA is 1:1.3:1.6, and the system temperature in the reactor is 30°C and the stirring speed is 100 rpm. For 20 minutes, the jacket of the reaction kettle was heated by a circulating oil bath or steam, so that the temperature of the system in the reaction kettle rose to 105°C, and then N ,N-dimethylacetamide solution, potassium tert-butoxide, N,N-dimethylacetamide solution according to the molar ratio of RGFNA:t-BuOK:N,N-dimethylacetamide solution is 1:1.2: 3. The N,N-dimethylacetamide solution containing potassium tert-butoxide (t-BuOK for short) needs to be prepared in advance and protected with nitrog...

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Abstract

The invention discloses a preparation method of crude regorafenib, which comprises preparing 4-(4-amino-3-trifluorophenoxy)-N-methylpyridin-2-formamide with 4-chloro-N-methylpyridin-2-formamide, 2-fluoro-4-hydroxylaniline(4-amino-3-fluorophenol) and phenyl 4-chloro-3-(trifluoromethyl)isocyanate, preparing 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamyl}amino)-3-fluorophenylamino]-N-methylpyridin-2-formamide, adding crystallizing water to obtain regorafenib (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamyl}amino)-3-fluorophenylamino]-N-methylpiridin-2-formamide monohydrate, and refiningto obtain crude regorafenib. The whole production process involves two steps of reaction and four operating processes, the yield is high, the purity is high, the content of purities is low, the molaryield is higher than 45%, and the weight yield is close to 100%.

Description

technical field [0001] The invention relates to a preparation method of a novel antineoplastic drug, in particular to a preparation method of a regorafenib bulk drug. Background technique [0002] Regorafenib is a new type of oral multikinase inhibitor, which blocks a variety of enzymes that promote tumor growth, and inhibits tumor formation, angiogenesis and tumor microenvironment formation by acting on multiple kinases in tumor cells, endothelial cells and peripheral cells . Compared with other monoclonal antibody targeted therapy drugs for colorectal cancer, the small molecular structure of regorafenib can enter the cell membrane and exert anti-tumor effect. For the treatment of metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma. Although the methods disclosed in the prior art are themselves effective for the preparation of the regorafenib compound, or the monohydrate, factors such as purity, product yield, process ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81
Inventor 刘初锋赵紫岭李明吕振培
Owner 新乡双鹭药业有限公司