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Preparation method for 4-(chlorodifluoromethoxy)aniline

A kind of technology of chlorodifluoromethoxybenzene and difluoromethoxy, which is applied in the field of preparation of 4-aniline and its intermediates, chlorodifluoromethoxybenzene and 4-nitrobenzene, and can solve the problem of industrial production Difficulty, use of dangerous sulfur phosgene, etc., to achieve the effect of less impurities, less nitric acid consumption, and clean process

Active Publication Date: 2014-10-29
KINGCHEM LIAONING CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This method uses dangerous thiophosgene and bromine trifluoride, therefore, there are great difficulties in industrial production

Method used

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  • Preparation method for 4-(chlorodifluoromethoxy)aniline
  • Preparation method for 4-(chlorodifluoromethoxy)aniline
  • Preparation method for 4-(chlorodifluoromethoxy)aniline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] In a 1L stainless steel high-pressure reactor equipped with stirring and a thermometer, cool down to below 5°C, add 156g (7.8mol) of hydrogen fluoride, 156g (0.74mol) of trichloromethoxybenzene, and 0.9g of perfluorooctylsulfonyl Fluorine, heat up to 100-110°C, control the reaction pressure to 2.5-2.8MPa, and react for 4 hours. Sampling and GC detection showed that the content of 2-difluorochlorotrifluoromethoxybenzene was 81.5%. After the reaction is completed, excess hydrogen fluoride is removed by purging with nitrogen gas, and neutralized to pH=6-7 with potassium carbonate aqueous solution. Steam distillation followed by rectification gave 99 g of the product chlorodifluoromethoxybenzene with a yield of 74.9%.

Embodiment 2

[0029] In a 5L stainless steel high-pressure reactor equipped with stirring and a thermometer, cool down to below 5°C, add 780g (39mol) of hydrogen fluoride, 850g (4.02mol) of trichloromethoxybenzene, 5g of perfluorobutylsulfonyl fluoride, Raise the temperature to 100-110° C., control the reaction pressure to 2.5-2.8 MPa, and react for 4.5 hours. Sampling and GC detection showed that the content of chlorodifluorotrifluoromethoxybenzene was 79.8%. After the reaction is completed, excess hydrogen fluoride is removed by purging with nitrogen gas, and neutralized to pH=6-7 with potassium carbonate aqueous solution. Steam distillation followed by rectification to obtain 480 g of the product chlorodifluoromethoxybenzene with a yield of 72.6%.

Embodiment 3

[0031] In a 500ml three-necked flask equipped with a stirring, thermometer, and dropping funnel, add 313g (3.13mol) of 98% concentrated sulfuric acid, add 9g of water and 150g (0.84mol) of chlorodifluoromethoxybenzene, start stirring, and Add the prepared mixed acid (208g of sulfuric acid with a mass concentration of 98% and 56g of nitric acid with a mass concentration of 98%) dropwise at 15-20°C. After 1-2 hours, the dropwise addition is completed. After keeping for 2 hours, take a sample for analysis, and control the raw material ≤ 0.5% . After the analysis is qualified, the layers are static, and the spent acid is separated, and the organic phase is washed with 100 g of 5% sodium carbonate solution until neutral, and separated. The organic phase was washed with 50 g of water and separated to obtain 167 g of 4-nitrochlorodifluoromethoxybenzene, with a yield of 89%.

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Abstract

The invention relates to a preparation method for 4-(chlorodifluoromethoxy)aniline. The method includes: taking trichloromethoxybenzene as the raw material, employing hydrogen fluoride to conduct selective fluorination to obtain chlorodifluoromethoxybenzene, subjecting the chlorodifluoromethoxybenzene to nitration by a mixed acid so as to obtain 4-(chlorodifluoromethoxy)nitrobenzene, and carrying out hydrogenation reduction on the 4-(chlorodifluoromethoxy)nitrobenzene, thus obtaining the 4-(chlorodifluoromethoxy)aniline, which is an intermediate for synthesis of tumor inhibiting drugs.

Description

technical field [0001] The present invention relates to a preparation method of 4-(one chlorodifluoromethoxy)aniline and its intermediates chlorodifluoromethoxybenzene and 4-(one chlorodifluoromethoxy)nitrobenzene. Background technique [0002] 4-(Chlorodifluoromethoxy)aniline is used in the synthesis of a class of active drugs that target VEGFR-1 and VEGFR-2 and inhibit the formation of vascular tumors. For example, the synthesis of 1,3,4-oxadiazole heterocyclic compound mentioned in Bioorganic & Medicinal Chemistry Letters, 2006, 16, 19131919, see the figure below. [0003] [0004] Through literature research, the synthetic method of 4-(one chlorodifluoromethoxy) aniline is as follows: [0005] method 1: [0006] Andrew E. Feiring prepared the target compound from p-nitrophenol, carbon tetrachloride and hydrogen fluoride (J.Org.Chem., 1979, 44, 2907-2908). The yield of this method is only 45%, and the carbon tetrachloride which has been limited and toxic is used. ...

Claims

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Application Information

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IPC IPC(8): C07C217/04C07C213/02C07C43/225C07C41/22C07C201/08C07C205/37
Inventor 付立民王安钢何秉恕孙杰宋成
Owner KINGCHEM LIAONING CHEMICAL CO LTD
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