Method for synthesizing Nexavar

A synthesis method and compound technology, which can be applied in the fields of drug combination, antitumor drugs, organic chemistry, etc., can solve the problems of poor economy, low yield, and low compound VI synthesis yield, avoid the use of phosgene, and improve safety. and operability, improved product purity and environmental compatibility

Inactive Publication Date: 2010-03-17
SHANGHAI PUYI CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main disadvantage of using compound VI is that the synthetic yield of compound VI is very low
We can only obtain compound VI with a very low yield by using the synthetic method in the literature, which leads to only 20-30% of the synthetic yield of this process. At the same time, the purification of the product also needs the method of column chromatography separation, so the economy of this process is too high. Difference

Method used

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  • Method for synthesizing Nexavar
  • Method for synthesizing Nexavar
  • Method for synthesizing Nexavar

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 1.1 Preparation of phenyl (4-chloro-3-trifluoromethyl-phenyl)carbamate

[0043] Add compound IV (4-chloro-3-trifluoromethyl-benzene, Gaoyou Guangming Chemical Factory, chemically pure) 5g in the there-necked flask, add 50ml of dichloromethane (Shanghai Chemical Reagent Co., Ltd., chemically pure) and stir to dissolve completely, Add 4 g of pyridine (Shanghai Chemical Reagent Co., Ltd., chemically pure). A mixed solution of 10 ml of dichloromethane and 4.2 g of phenyl chloroformate (Shanghai Chemical Reagent Co., Ltd., chemically pure) was added dropwise at room temperature, and reacted for half an hour. TLC (PE: EA = 3: 1) showed that the reaction of the raw material was complete, washed once with 1N hydrochloric acid, washed three times with water, dried, filtered, weighed 7.6 g after drying, and the molar yield was 94%.

[0044] 1 H NMR (CDCl 3 , 500MHz): δ=7.1(s, 1H), 7.2(d, J=7Hz, 2H), 7.3(m, 1H), 7.4(m, 2H), 7.5(d, J=8Hz, 1H), 7.6 (d, J=8Hz, 1H), 7.8 (s, 1H). ...

Embodiment 2

[0059] 2.1 Preparation of 4-nitrophenyl (4-chloro-3-trifluoromethyl-phenyl)carbamate

[0060] Add compound IV (4-chloro-3-trifluoromethyl-benzene, Gaoyou Guangming Chemical Factory, chemically pure) 5g in the there-necked flask, add 50ml of dichloromethane (Shanghai Chemical Reagent Co., Ltd., chemically pure) and stir to dissolve completely, Add 4 g of pyridine (Shanghai Chemical Reagent Co., Ltd., chemically pure). A mixed solution of 10 ml of dichloromethane and 5.1 g of p-nitrophenyl chloroformate (Shanghai Chemical Reagent Co., Ltd., chemically pure) was added dropwise at room temperature, and reacted for half an hour. TLC (PE: EA = 3: 1) showed that the reaction of the raw material was complete, washed once with 1N hydrochloric acid, washed three times with water, dried, filtered, weighed 8.4 g after drying, and the molar yield was 92%.

[0061] 1 H NMR (CDCl 3 , 500MHz): δ=7.1(d, J=7Hz, 1H), 7.2(dd, J=7Hz, J=3Hz, 1H), 7.3(d, J=7Hz, 2H), 7.7(d, J=3Hz , 1H), 7.8 (s, 1...

Embodiment 3

[0076] 3.1 Preparation of 2-nitrophenyl (4-chloro-3-trifluoromethyl-phenyl)carbamate

[0077] Add compound IV (4-chloro-3-trifluoromethyl-benzene, Gaoyou Guangming Chemical Factory, chemically pure) 5g in the there-necked flask, add 50ml of dichloromethane (Shanghai Chemical Reagent Co., Ltd., chemically pure) and stir to dissolve completely, Add 4 g of pyridine (Shanghai Chemical Reagent Co., Ltd., chemically pure). A mixed solution of 10 ml of dichloromethane and 5.1 g of o-nitrophenyl chloroformate (Shanghai Chemical Reagent Co., Ltd., chemically pure) was added dropwise at room temperature, and reacted for half an hour. TLC (PE: EA = 3: 1) showed that the reaction of the raw material was complete, washed once with 1N hydrochloric acid, washed three times with water, dried, filtered, weighed 8.4 g after drying, and the molar yield was 92%.

[0078] 1 H NMR (CDCl 3 , 500MHz): δ=7.1(d, J=7Hz, 1H), 7.2(dd, J=7Hz, J=3Hz, 1H), 7.3(dd, J=7Hz, J=3Hz, 1H), 7.3(m , 1H), 7.6 (m, ...

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Abstract

The invention provides a method for synthesizing Nexavar. The method comprises the following steps: a, dissolving a compound II and a compound III in an organic solvent inert to the compound III and adding appropriate base; b, performing reaction at a reaction temperature between 40 and 150 DEG C so as to generate a crude Nexavar product; and c, performing conventional post-treatment on the crudeproduct, wherein R is hydrogen, methyl, nitro or chlorine; the nitro is on site 4; the methyl or the chlorine is on site 2, 3 or 4; and the compound III is prepared through the reaction of a compoundIV and phenyl chloroformate or the phenyl chloroformate containing substituents on benzene rings in an organic reaction solvent inert to chloroformate at a temperature between 10 DEG C below zero and50 DEG C. The method has the advantages of applying to the preparation of Nexavar on an industrial scale, meeting standards in pharmaceutical industrial production, improving the purity and environmental compatibility of products and improving operability, safety and yield.

Description

technical field [0001] The present invention relates to the technical field of compound preparation, in particular to the technical field of Sorafenib preparation, and more specifically, to a synthetic 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, first recorded in the patent WO0042012, the molecular formula is C 21 h 16 CIF 3 N 4 o 3 , its structural formula is shown in formula I, and its molecular weight is 464.83. The report disclosed in patent WO0042012 shows that compound I is an inhibitor of Raf kinase and can be used for treating diseases such as cancer. [0003] [0004] Patents WO0042012, WO2006034796, WO2006089150, WO2007059154, WO2007053574, US7235576 and literature (Bankston et al., Organic Process Research & Development; 2002, 6, 777-781) describe methods for the preparation of compound I, which can be illustrate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81A61P43/00A61P35/00
Inventor 王博罗宇
Owner SHANGHAI PUYI CHEM CO LTD
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