Synthetic method of 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride

A technology of trifluoroacetylaniline and trifluoroacetyl, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of high price and difficulty in obtaining trifluoropyruvate, and achieve reduced production costs, reduced difficulty in sewage treatment, and easy recycling The effect of treatment

Active Publication Date: 2015-10-28
LEPING RUISHENG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] But the trifluoropyruvate used in this method is difficult to obtain, and the price is expensive

Method used

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  • Synthetic method of 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride
  • Synthetic method of 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride
  • Synthetic method of 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] 37 g of 4-chloro-N-pivaloylanilide was dissolved in 350 ml of methyl tert-butyl ether, and 2.0 M n-butyllithium was dissolved in 180 ml of methyl tert-butyl ether. When the 4-chloro-N-pivaloylanilide solution was cooled to -20°C, the n-butyllithium solution was added dropwise and reacted for 2 hours. At this temperature (-20°C), 22.9 grams of trifluoroacetyl chloride gas was introduced within 30 minutes, reacted for 1 hour after the gas was introduced, and then neutralized by adding dilute hydrochloric acid until the pH was neutral, separated to obtain an organic layer, and concentrated the organic layer. layer, the residue was added with 100 milliliters of acetic acid and 50 milliliters of concentrated hydrochloric acid and heated to 75 ° C for 4 hours, cooled to 0 ° C, crystallized to obtain 42 grams of 4-chloro-2-trifluoroacetylaniline hydrate hydrochloride, yield 87 %.

Embodiment 2

[0028] Example 2: The only difference from Example 1 is that the organic solvent methyl tert-butyl ether is replaced by n-hexane, and the other processes are the same as in Example 1, which will not be repeated here, and finally crystallized to obtain 4-chloro-2 - 39 grams of trifluoroacetylaniline hydrate hydrochloride, yield 80.7%.

Embodiment 3

[0029] Example 3: The only difference from Example 1 is that the organic solvent methyl tert-butyl ether is replaced with cyclohexane, and other processes are the same as in Example 1, which will not be repeated here, and finally crystallized to obtain 4-chloro- 40 grams of 2-trifluoroacetylaniline hydrate hydrochloride, yield 82.8%.

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Abstract

The invention relates to an efavirenz intermediate synthesis method, in particular to a synthetic method of 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride, and belongs to the technical field of medicine intermediate synthesis. The synthesis method comprises the following steps that, at the low temperature, an n-butyllithium solution is added into a 4-chlorine-N-pivalic acyl aniline solution in a dropwise mode, and a 4-chlorine-N-pivalic acyl aniline bi-lithium salt solution is obtained after a reaction is finished; trifluoroacetyl chloride gas is led to the solution at the low temperature to obtain 4-chlorine-2-trifluoroacetyl-N-pivalic acyl aniline; finally, the 4-chlorine-2-trifluoroacetyl-N-pivalic acyl aniline is hydrolyzed on the acidic condition to obtain the product 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride. According to the method, the n-butyllithium serves as alkali and is basically converted into a lithium chloride solution with the high economic value after being neutralized through hydrochloric acid, recycling is facilitated, and the waste water treatment difficulty can be lowered; the low-price trifluoro-acetylchloride serves as the raw material, and the production cost can be reduced.

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 hydrate hydrochloride, and belongs to the technical field of synthesis of pharmaceutical intermediates. 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: C 14 h 9 CIF 3 NO 2 ; 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/68C07C213/00
Inventor 邓一建张吉祥乔健婷柴建陶庆生
Owner LEPING RUISHENG PHARMA CO LTD
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