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Synthetic method of 4-chloro-3-(trifluoromethyl)phenyl isocyanate

A technology of benzene isocyanate and trifluoromethyl chlorobenzene, applied in the field of medicine, can solve the problems of iron sludge waste residue being difficult to handle, easy to generate isomer impurities, requiring higher temperature, etc., and achieves reduction of environmental protection pressure, low risk, high temperature and the like. cost effect

Active Publication Date: 2020-03-17
SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the main preparation route of 4-chloro-3-(trifluoromethyl)benzene isocyanate is to use ortho-chlorobenzotrifluoride as the starting raw material, through concentrated nitric acid / concentrated sulfuric acid mixed acid nitration to obtain nitrated compound, and then through iron powder / ethanol The system is reduced to an amide, and then reacted with triphosgene to obtain the target product. The nitrification process of this process requires high temperature, which is risky and easy to produce isomer impurities; the use of iron powder as an electron donor in the reduction process will produce iron sludge and waste residues that are difficult to handle. Environmental protection issues, and hydrogen will be produced during the reaction process, which will bring safety hazards

Method used

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  • Synthetic method of 4-chloro-3-(trifluoromethyl)phenyl isocyanate
  • Synthetic method of 4-chloro-3-(trifluoromethyl)phenyl isocyanate
  • Synthetic method of 4-chloro-3-(trifluoromethyl)phenyl isocyanate

Examples

Experimental program
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Effect test

Embodiment 1

[0045] (1) In a 500ml three-neck flask, add 100g of o-chlorobenzotrifluoride and 200g of acetic anhydride and mix well, add 65g of concentrated nitric acid dropwise at a controlled temperature of 10-12°C, keep stirring for 3 hours after dropping, add 5% aqueous sodium hydroxide solution Adjust the pH to 8.0, separate the layers after washing, and collect 120.7 g of the organic phase;

[0046] (2) the organic phase obtained in step (1), 1g activated carbon, 7.5gFeCl 3 ·6H 2 O was added to 200 g of ethanol, mixed uniformly and then heated to reflux, and 86.5 g of hydrazine hydrate solution with a mass fraction of 80% was added dropwise, and the addition was completed within 3 hours. After the dropwise addition was completed, filter while hot, distill the filtrate to remove ethanol under normal pressure, add 1,2-dichloroethane for extraction and layering, and collect the organic phase;

[0047] (3) Add 65.7g of triphosgene and 1g of DMAP into 1,2-dichloroethane, stir until diss...

Embodiment 2

[0053] (1) In a 500ml three-neck flask, add 100g of o-chlorobenzotrifluoride and 220g of acetic anhydride and mix well, add 68g of concentrated nitric acid dropwise at a controlled temperature of 10-12°C, keep stirring for 3.5h after dropping, add 5% sodium hydroxide The pH of the aqueous solution was adjusted to 7.8, the layers were separated after washing, and 123.1 g of the organic phase was collected;

[0054] (2) the organic phase obtained in step (1), 1g activated carbon, 9.6gFeCl 3 ·6H 2 O was added to 200 g of ethanol, mixed uniformly and then heated to reflux, and 88.2 g of hydrazine hydrate solution with a mass fraction of 80% was added dropwise, and the addition was completed within 3 hours. After the dropwise addition is completed, filter while it is hot, evaporate the ethanol from the filtrate under normal pressure, add dioxane for extraction and layering, and collect the organic phase;

[0055] (3) Add 65.7g of triphosgene and 1g of pyridine into dioxane, stir ...

Embodiment 3

[0058] (1) In a 500ml three-necked flask, add 100g of o-chlorobenzotrifluoride and 210g of acetic anhydride and mix well, add 69g of concentrated nitric acid dropwise at a controlled temperature of 12-14°C, keep stirring for 4 hours after dropping, add 5% sodium hydroxide aqueous solution Adjust the pH to 7.5, separate the layers after washing, and collect 119.7 g of the organic phase;

[0059] (2) the organic phase obtained in step (1), 1g activated carbon, 8.4gFeCl 3 ·6H 2 O was added to 200 g of ethanol, mixed uniformly and then heated to reflux, and 83.9 g of hydrazine hydrate solution with a mass fraction of 80% was added dropwise, and the addition was completed within 3.5 hours. After the dropwise addition was completed, filter while it was hot, evaporate the ethanol from the filtrate under normal pressure, add chloroform for extraction and layering, and collect the organic phase;

[0060] (3) Add 65.7g of triphosgene and 1g of DMF into chloroform, stir until dissolved...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of 4-chloro-3-(trifluoromethyl)phenyl isocyanate. Chlorobenzotrifluoride, acetic anhydride andconcentrated nitric acid react to obtain 4-nitro-2-chlorotrifluoromethylbenzene, the 4-nitro-2-chlorotrifluoromethylbenzene, activated carbon, FeCl36H2O and hydrazine hydrate react to obtain 4-chloro-3-trifluoromethylaniline, and 4-chloro-3-trifluoromethylaniline, triphosgene and a catalyst react to obtain 4-chloro-3-(trifluoromethyl)phenyl isocyanate. According to the invention, in a nitration process, an acetic anhydride / concentrated nitric acid system is used for replacing a traditional nitric acid / sulfuric acid mixed acid system, the reaction can be completed at a low temperature by utilizing the strong nitration effect of acetyl nitrate, the risk is low, and more nitration impurities are few; in a reduction process, a FeCl36H2O / activated carbon / hydrazine hydrate system is used for replacing a traditional iron powder reduction process, so that generation of a large amount of iron mud waste residues is avoided, and the environmental protection pressure is reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a synthesis method of 4-chloro-3-(trifluoromethyl)phenylisocyanate. Background technique [0002] 4-Chloro-3-(trifluoromethyl)phenylisocyanate is an important pharmaceutical intermediate, mainly used in the synthesis of anticancer drug Sorafenib. Sorafenib is the first oral multi-kinase inhibitor that targets serine / threonine kinases and receptor tyrosine kinases on tumor cells and tumor blood vessels. These two kinases affect tumor cell proliferation and Angiogenesis, two activities that are critical in tumor growth. These kinases include RAF kinase, VEGFR-2 (vascular endothelial growth factor receptor), VEGFR-3, PDGFR-β (platelet-derived growth factor receptor), KIT, and FLT-3 (of the type III tyrosine kinase receptor family ). Sorafenib is a multi-target bio-targeted new drug jointly developed by Bayer and ONYX. The U.S. FDA approved Sorafenib for the treatment...

Claims

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Application Information

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IPC IPC(8): C07C263/10C07C265/12C07C209/36C07C211/52C07C201/08C07C205/12
CPCC07C263/10C07C209/365C07C201/08C07C265/12C07C211/52C07C205/12
Inventor 蔡会敏赵奇韩强李珊珊赵文勇
Owner SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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