Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate

A technology of trifluoroacetyl and aniline hydrochloride, which is applied in the preparation of organic compounds, chemical instruments and methods, and the production of bulk chemicals, and can solve problems such as troublesome preparation of butyllithium, incomplete recovery, and increased use costs , to achieve the effect of low price, low cost, and low cost

Active Publication Date: 2010-09-29
浙江沙星科技股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The literature Tetrahedron, 1991, 3207; J.Org.Chem.63 (23), 1998, 8536-8543; US5932726; WO9637457 reported that in the reaction of trifluoroacetylation, under the action of butyllithium, through tetramethyl Butyl ethylenediamine catalyzes the acylation reaction between pivalamide intermediate and ethyl trifluoroacetate, but the preparation of butyllithium is cumbersome

Method used

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  • Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate
  • Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate
  • Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate

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Experimental program
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Effect test

Embodiment 1

[0026] Put 80.3g (0.63mol) of p-chloroaniline and 500ml of toluene in a 1000ml flask equipped with a stirrer, dropping funnel and thermometer, cool down to 0-5°C, and put 90.8g (0.68mol) of 30% sodium hydroxide Solution, controlled at 5-15°C, add 51.1g (0.65mol) acetyl chloride dropwise, after 0.5h drop, keep warm at 5-15°C for 1h, separate layers, wash the organic layer twice, cool to -5°C and keep warm for 2h , filtered with suction, washed the filter cake with water, drained, vacuumed at -0.085Mpa, and dried below 70°C for 24 hours to obtain 103.2g of compound 4-chloro-N-acetylaniline, with a content of 99.0%, a moisture content of ≤0.3%, and a yield of 96.6%.

[0027] In this embodiment, propionyl chloride, butyryl chloride, valeryl chloride or pivaloyl chloride are used instead of acetyl chloride to achieve the same effect.

Embodiment 2

[0029] Put 80.3g (0.63mol) of p-chloroaniline and 500ml of toluene in a 1000ml flask equipped with a stirrer, dropping funnel and thermometer, cool down to 0-5°C, and put 90.8g (0.68mol) of 30% sodium hydroxide Solution, controlled at 5-15°C, add 83.2g (0.69mol) of pivaloyl chloride dropwise, after 1h dripping, keep at 5-15°C for 1h, separate layers, wash the organic layer twice, cool to -5°C and keep for 2h , filtered with suction, washed the filter cake with water, drained, vacuumed at -0.085Mpa, and dried below 70°C for 24 hours to obtain 103.8g of compound 4-chloro-N-acetylaniline, with a content of 99.3%, a moisture content of ≤0.2%, and a yield of 97.2%.

[0030] 2) Synthesis of 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate (Ⅳ)

Embodiment 3

[0032] Add 133.5g (1.0mol) of anhydrous aluminum trichloride and 200g of n-hexane into the reaction flask, stir and mix, cool down to -20°C, slowly introduce 132.5g (1.0mol) of trifluoroacetyl chloride, and mix 169.5g ( 1.0mol) of 4-chloro-2-acetylaniline was dissolved in 600g of n-hexane, and then slowly dripped into the above system at -20°C for 5.5 hours. After the addition was completed, it was naturally raised to room temperature and kept stirring for 2 hours. . After the reaction was complete, the reaction mixture was dropped into 400 g of ice water, and the temperature was controlled below 15° C., stirred for 15 min after the drop was completed, and allowed to stand to separate into layers. The organic layer was washed with water until neutral, and the aqueous layers were combined and extracted twice with 200 g of n-hexane. The organic layers were combined and concentrated to dryness under reduced pressure to obtain 270.6 g of oily N-acetyl-4-chloro-2-(trifluoroacetyl)...

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Abstract

The invention discloses a method for synthesizing a 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate, which belongs to the technical field of compound preparation methods. The method comprises the following steps of: 1) reacting parachloroaniline with acyl chloride in the presence of a methylbenzene solvent to obtain an intermediate (II); 2) dissolving the intermediate (II) in organic solvent to obtain solution, introducing trifluoro-acetyl chloride into a flask which is filled with the mixed liquor of the organic solvent and lewis acid and slowly filling the solution ofthe intermediate (II) into the flask dropwise to perform a Friedel-Crafts reaction to obtain an acylate intermediate (III), wherein a charging molar ratio of the trifluoro-acetyl chloride to the intermediate (II) is 1: 1; and 3) hydrolyzing the intermediate (II) to remove protective groups to form a salt under acid condition to obtain the 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate(IV). The method has the advantages of high safety, low cost, simple operation, less pollution, total yield of over 78.1 percent and content of more than or equal to 99.0 percent.

Description

technical field [0001] The invention belongs to the technical field of compound preparation methods, and specifically relates to the production of 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate, a key intermediate of efavirenz, an anti-AIDS drug with low cost, high safety and environmental protection resolve resolution. Background technique [0002] Efavirenz is a non-nucleoside reverse transcriptase inhibitor, which is the most effective way to treat AIDS—one of the most important drugs in the "cocktail therapy". Because of its low toxic and side effects and good therapeutic effect, it has become the first-line drug for the treatment of AIDS. Such drugs are gaining more attention from the medical industry as the number of HIV-infected people worldwide increases. Many literatures have reported the synthesis method of efavirenz before. The literature Tetrahedron, 1991, 3207; J.Org.Chem.63 (23), 1998, 8536-8543; US5932726; WO9637457 reported that in the reaction ...

Claims

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Application Information

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IPC IPC(8): C07C225/22C07C221/00
CPCY02P20/55
Inventor 黄小庭王文秀
Owner 浙江沙星科技股份有限公司
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