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

A technology for the synthesis of trifluoroacetylaniline and its synthesis method, which is applied in the field of synthesis of efavirenz intermediates, can solve the problems of high price, achieve the effects of less pollution, lower energy consumption, and mild reaction conditions

Active Publication Date: 2017-03-15
SHAXING CHEM TAIZHOU CITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Document Tetrahedron, 1991,3207; J.Org.chem.63 (23), 1998,8536-8543; US5932726; Report the preparation method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate in US05925789, but In the reaction, the amount of n-butyl lithium is more than twice the molar amount of p-chloroaniline; although n-butyl lithium is not used in the preparation method reported by CN 102675125B, methyl trifluoropyruvate or ethyl trifluoropyruvate is used in its reaction. Esters, whose price is higher than n-butyllithium

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0028] Synthesis of pivalanilide

[0029]

[0030] Add 18.6g of aniline and 150mL of toluene into the reactor, cool down to 0-5°C, add 30g of 30% sodium hydroxide solution, control the temperature at 5-15°C, then add 27.8g of pivaloyl chloride dropwise, and the dropwise addition is completed in about 15 minutes , stirred at 5-15°C for 60 minutes, sampled and tested, separated after the reaction, washed the organic layer twice with water, cooled the organic phase to 0-5°C, kept it warm for 120 minutes, filtered with suction, washed the filter cake with an appropriate amount of water, and drained. After vacuum drying, 34.4 g of pivalanilide was obtained, with a yield of 97.2% and a content of 99.1%.

[0031] Synthesis of N-chloropivalanilide

[0032]

[0033] Put 35.4g of pivalanilide, 50.4g of sodium bicarbonate, 1000mL of diethyl ether and 400mL of water into the reactor, stir well so that the organic phase and the water phase are both clear liquids, then cool down to 0...

Embodiment 2

[0041] Synthesis of Acetanilide

[0042]

[0043] Add 18.6g of aniline and 150mL of toluene into the reactor, cool down to 0-5°C, then add 30g of 30% sodium hydroxide solution, control the temperature at 5-15°C, then add 17g of acetyl chloride dropwise, and the dropwise addition is completed in about 15 minutes. Stir at 5-15°C for 60 minutes, take samples for testing, separate the layers after the reaction, wash the organic layer twice with water, cool the organic phase to 0-5°C, keep it warm for 120 minutes, filter with suction, wash the filter cake with an appropriate amount of water, drain and vacuum After drying, 26.2 g of acetanilide was obtained, with a yield of 96.8% and a content of 99.2%.

[0044] Synthesis of N-Chloroacetanilide

[0045]

[0046] Put 27g of the prepared acetanilide, 50.4g of sodium bicarbonate, 1000mL of ether and 400mL of water into the reactor, stir well to make the organic phase and the water phase both clear, then cool down to 0°C, and slo...

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Abstract

The invention relates to a method for synthesizing an efavirenz intermediate, in particular to a method for synthesizing a 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate. The method includes the following steps that an acylating agent is added to aniline in an organic solvent, aniline is subjected to an acylation reaction under the alkaline condition and at the temperature of 5-15 DEG C to obtain a compound A, the compound A reacts with a chlorinating agent under the alkalescent condition to obtain a compound B, the compound B reacts with trifluoroacetic acid ethyl ester under the action of butyl lithium to obtain a compound C, the compound C and hydrochloric acid are subjected to a reflux reaction at 60-65 DEG C, and the 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate is obtained. Reaction conditions are mild, energy consumption is greatly reduced, raw materials in use are easy to obtain, cost is low, and pollution is little. The method is easy to operate, the total yield can reach 77.2%, the purity can reach 99% or above, product quality is good, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of an efavirenz intermediate, in particular to a synthesis method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate. Background technique [0002] Efavirenz, its Chinese name: 4(S)-6-chloro-4-(cyclopropylacetylene)-4-(trifluoromethyl)-benzo-1,4-dihydrooxazole- 2-ketone; English chemical name: (4S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one; Molecular formula: C14H9ClF3NO2; Molecular weight: 315.68; CAS registry number: 154598-52-4. Efavirenz is a selective non-nucleoside reverse transcriptase inhibitor (NNRTIS) of Human Immunodeficiency Virus-1 (HIV-1), developed and produced by Merck, which is used as a first-line anti-HIV drug. Competitively binds and inhibits HIV-1 reverse transcriptase (RT) activity, acts on templates, primers or nucleoside triphosphates, and has a small part of competitive inhibition, thereby preventing viral transcription and repli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C221/00C07C225/22
CPCC07C221/00C07C231/02C07C239/06C07C233/07C07C225/22
Inventor 王文秀吴金跃
Owner SHAXING CHEM TAIZHOU CITY
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