Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate

A technology of trifluoroacetylphenyl and trifluoroacetyl, which is applied in the field of compound preparation and can solve the problem of high price

Active Publication Date: 2016-07-20
SHAXING CHEM TAIZHOU CITY
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  • Abstract
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  • Claims
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Problems solved by technology

The synthetic method of efavirenz has been reported in literature before: literature Tetrahedron, 1991,3207; J.Org.chem.63 (23), 1998,8536-8543; US5932726; 4-chloro-2- (Trifluoroacetyl) aniline hydrochloride hydrate preparation method, but in the reaction, the amount of n-butyllithium is more than twice the molar amount of p-chloroaniline; although n-butyllithium is not used in the preparation method reported by CN102675125B, But use methyl trifluoropyruvate or ethyl ester in its reaction, its price is also higher than n-butyllithium, for this reason, urgently need to develop a 4-chloro-2 that cost is low, and yield is high, suitable for industrialized production -The preparation method of (trifluoroacetyl) aniline hydrochloride hydrate

Method used

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  • Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate
  • Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate
  • Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate

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Embodiment 1

[0019] A method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate, specifically comprising the steps:

[0020] ①Synthesis of 4-chloro-N-phthalic anilide: Add 12.8g of p-chloroaniline, 102mL of toluene and 16.3g of phthalic anhydride to the reactor connected to the water separator, heat up to 110-120°C, Reflux for 1.5 hours, TLC monitoring, the reaction is complete, lower the temperature to 30-35°C, add 50mL of water, separate layers, wash the toluene layer with 100mL of water twice, cool down to -5-0°C, stir for 2 hours, suction filter, filter The cake was rinsed with an appropriate amount of water, drained, and the solid was vacuum-dried at 70°C to obtain 23.2 g of 4-chloro-N-phthalanilide, with a yield of 95.1% and a content of 99.2%.

[0021] ② Synthesis of N-(4-chloro-2-trifluoroacetylphenyl)-phthalamide: In the reactor, under the protection of nitrogen, add 25.8g of 4-chloro-N-phthalamide , 258mL of methyl tert-butyl ether, 11.6g of tetramethylethyl...

Embodiment 2

[0024] A method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate, specifically comprising the steps:

[0025] ①Synthesis of 4-chloro-N-phthalic anilide: Add 12.8g of p-chloroaniline, 102mL of toluene and 14.8g of phthalic anhydride to the reactor connected to the water separator, heat up to 110-120°C, Reflux for 1.5 hours, TLC monitoring, the reaction is complete, lower the temperature to 30-35°C, add 50mL of water, separate layers, wash the toluene layer with 100mL of water twice, cool down to -5-0°C, stir for 2 hours, suction filter, filter The cake was rinsed with an appropriate amount of water, drained, and the solid was vacuum-dried at 70°C to obtain 21.9 g of 4-chloro-N-phthalanilide, with a yield of 90% and a content of 99.0%.

[0026] ② Synthesis of N-(4-chloro-2-trifluoroacetylphenyl)-phthalamide: In the reactor, under the protection of nitrogen, add 25.8g of 4-chloro-N-phthalamide , 258mL of methyl tert-butyl ether, 11.6g of tetramethylethylen...

Embodiment 3

[0029] A method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate, specifically comprising the following steps, 1. the synthesis of 4-chloro-N-phthalanilide: in a water separator connected Add 12.8g of p-chloroaniline, 51mL of toluene, and 16.3g of phthalic anhydride into the reactor, raise the temperature to 110-120°C, reflux for 1.5 hours, monitor by TLC, after the reaction is complete, cool down to 30-35°C, add 50mL of water, and divide layer, the toluene layer was washed twice with 100 mL of water, cooled to -5 ~ 0 ° C, stirred for 2 hours, filtered with suction, the filter cake was rinsed with an appropriate amount of water, and dried, and the solid was vacuum-dried at 70 ° C to obtain 4- Chloro-N-phthalanilide 19.5g, yield 80%, content 98.5%.

[0030] ② Synthesis of N-(4-chloro-2-trifluoroacetylphenyl)-phthalamide: In the reactor, under the protection of nitrogen, add 25.8g of 4-chloro-N-phthalamide , 258mL of methyl tert-butyl ether, 11.6g of tetr...

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Abstract

The invention discloses a method for preparing a 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate, and belongs to the field of compound synthesis. P-chloroaniline serves as a raw material, the method includes the following steps that 1, the p-chloroaniline and acid anhydride are reacted to obtain 4-chlorine-N-phthaloyl aniline; 2, the 4-chlorine-N-phthaloyl aniline and trifluoroacetic acid ethyl ester are reacted under the effect of butyl lithium to obtain N-(4-chlorine-2 trifluoroacetyl phenyl)-phthalic diamide; 3, after the N-(4-chlorine-2 trifluoroacetyl phenyl)-phthalic diamide and hydrazine hydrate are heated and subjected to reflux in absolute ethyl alcohol, hydrochloric acid and glacial acetic acid are added, and the 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate is obtained. The method is easy to operate, low in cost and suitable for industrial production, and the total yield is up to 82.2%.

Description

technical field [0001] The invention belongs to the field of compound preparation methods, in particular to a preparation method of 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate. Background technique [0002] 4-Chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate is a key intermediate of the anti-AIDS drug efavirenz, which is a selective non-nucleoside reversal agent for human immunodeficiency virus (HIV-1) Recording enzyme inhibitors, and the combination of efavirenz and other anti-HIV drugs can treat HVI-1 infection, and the therapeutic effect is good. It has become the first-line drug for the treatment of AIDS. The synthetic method of efavirenz has been reported in literature before: literature Tetrahedron, 1991,3207; J.Org.chem.63 (23), 1998,8536-8543; US5932726; 4-chloro-2- (Trifluoroacetyl)aniline hydrochloride hydrate preparation method, but in the reaction, the amount of n-butyllithium is more than twice the molar amount of p-chloroaniline; although n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48C07C213/00C07C215/68
CPCC07C213/00C07D209/48C07C215/68
Inventor 王文秀吴金跃
Owner SHAXING CHEM TAIZHOU CITY
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