A kind of preparation method of Sorafenib

A technology for sorafenib crude product and compound, which is applied in the fields of sorafenib preparation and pharmaceutical compound preparation, can solve the problems of severe reaction, high industrial production danger, use of highly toxic raw materials, etc., and achieves the effect of simple process.

Active Publication Date: 2017-05-10
哈药集团股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The reaction needs to be carried out at a high temperature of 90°C, and the reaction time is as long as 5 hours. The reaction of the 4-chloro-3-trifluoromethylphenyl isocyanate used is too violent and difficult to control
[0008] Chinese patent CN101671299A discloses a preparation method of sorafenib, the reaction raw material uses the highly toxic compound phenyl chloroformate, the industrial production is dangerous and not friendly to the environment
[0011] Although the existing technology can synthesize Sorafenib, there are generally disadvantages such as high temperature reaction, use of highly toxic raw materials, and uncontrollable reaction.

Method used

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  • A kind of preparation method of Sorafenib
  • A kind of preparation method of Sorafenib
  • A kind of preparation method of Sorafenib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Preparation of compound III (4-chloro-3-trifluoromethylphenylcarbamoyl imidazole)

[0034] Dissolve 2.0kg of compound IV (4-chloro-3-trifluoromethylaniline) in 17.0L of 1,2-dichloroethane, stir, add 2.3kg of compound V (N,N'-carbonyldiimidazole), Raise the temperature to 50°C, react for 10h, and then transfer to room temperature for 1h. Filter, wash twice with 1,2-dichloroethane, filter dry, and vacuum-dry at 40°C to obtain 1.6kg of compound III (4-chloro-3-trifluoromethylphenylcarbamoyl imidazole) with a purity of 99.2% , yield 85%.

Embodiment 2

[0035] Embodiment 2 prepares Sorafenib crude product

[0036] Add 200L of ethyl acetate and 18.7kg of compound III to the reaction tank, stir and raise the temperature to 25°C, then add 9.8kg of compound II, keep stirring at 25°C for 3h, cool down to 20°C to grow crystals for 2h after the reaction, filter, and use acetic acid Wash twice with ethyl ester, filter dry, and vacuum-dry at 40°C to obtain 17.2 kg of crude sorafenib with a purity of 99.18% and a yield of 91.1%.

Embodiment 3

[0037] Embodiment 3 prepares Sorafenib crude product

[0038] Add 200L of dichloromethane and 18.7kg of compound III to the reaction tank, stir and heat up to 35°C, then add 9.8kg of compound II, keep stirring at 35°C for 2h, cool down to 20°C to grow crystals for 2h after the reaction, filter, and use two Wash twice with methyl chloride, filter dry, and vacuum-dry at 40° C. to obtain 16.9 kg of crude Sorafenib with a purity of 99.20% and a yield of 90.22%.

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Abstract

The invention discloses a novel method for synthesizing sorafenib. The method comprises the following steps: using a (4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide) compound II and a (4-chloro-3-trifluoromethylphenyl-carbamoyl-imidazole) compound III as raw materials, and reacting in an organic solvent inert to the compound III to produce a sorafenib crude product; then, dissolving the sorafenib crude product by the organic solvent and an organic or inorganic acid, and adding a solvent into which sorafenib is difficult to dissolve to enable the sorafenib to be separated out, so as to obtain a sorafenib pure product. The novel method is simple in technical process, ensures high product purity, facilitates operation and is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to the technical field of preparation of pharmaceutical compounds, in particular to the technical field of Sorafenib preparation, and more specifically, to a synthesis method and a purification method of Sorafenib. Background technique [0002] Compound 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide, also known as Rafenib, the molecular formula is C 21 h 16 CIF 3 N 4 o 3 , the molecular weight is 464.83, and the structural formula is formula Ⅰ. [0003] [0004] Sorafenib is a multikinase inhibitor indicated for the treatment of gastrointestinal stromal tumors and metastatic renal cell carcinoma that do not respond to or are intolerant to standard therapy. Sorafenib has dual anti-tumor effects: on the one hand, it can directly inhibit tumor growth by inhibiting the RAF / MEK / ERK signaling pathway; on the other hand, it can block tumor angiogenesis by inhibiti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 赵玉新王喜军牟春福王硕冰石成刘金红张婷婷
Owner 哈药集团股份有限公司
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