Preparation method of intermediate cyclopropyl acetylene of anti-AIDS (acquired immune deficiency syndrome) drug efavirenz

A cyclopropylacetylene, anti-AIDS technology, applied in the direction of dehydrohalogenation preparation, hydrocarbon production from halogen-containing organic compounds, phosphorus halide/oxyhalide, etc., can solve the problem of cooling liquid temperature not being too low, crystallization, decompression precision Distillation vacuum limit and other issues

Inactive Publication Date: 2018-08-24
JIANGSU YUXIANG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, the melting point of phosphorus oxychloride is 1.25°C, and it may crystallize during the cooling process. The temperature of the cooling liquid should not be too low, and the vacuum degree during vacuum distillation is also limited.

Method used

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  • Preparation method of intermediate cyclopropyl acetylene of anti-AIDS (acquired immune deficiency syndrome) drug efavirenz
  • Preparation method of intermediate cyclopropyl acetylene of anti-AIDS (acquired immune deficiency syndrome) drug efavirenz

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Add ethylcyclohexane (500ml) and phosphorus pentachloride (204.1g, 0.98mol) into a 1000ml reaction flask, add 2g of triethylamine, start stirring, adjust the temperature to 40-50°C, then add cyclopropane dropwise methyl ketone (84.1 g, 1 mol), the dropwise addition was completed, and the temperature was kept for 1 hour. The reaction solution obtained above is rectified under reduced pressure, the pressure is controlled at 3.8-4.0kPa, the reflux ratio is 2, the temperature of the kettle is controlled to be ≤80°C, the fraction with the temperature of the tower top ≤30°C is collected, and the by-product phosphorus oxychloride produced by the reaction is recovered ; The residual liquid in the tower kettle was transferred to a 1000ml reaction flask, and 120 grams of triethylamine was added to the above reaction flask, the temperature was raised to reflux temperature, and the temperature was kept for 1 hour. Atmospheric distillation obtained 60.1 grams of α-chlorovinylcyclopr...

Embodiment 2

[0028]Add chlorobenzene (500ml) and phosphorus pentachloride (218.7g, 1.05mol) into the reaction flask, add 2g of triethylamine, start stirring, adjust the temperature to 30-40°C, then add cyclopropylmethyl ketone dropwise (84.1 g, 1 mol), the dropwise addition was completed, and the temperature was kept for 2 hours. The obtained reaction solution is rectified under reduced pressure, the pressure is controlled at 2.5-2.7kPa, the reflux ratio is 3, the temperature of the kettle is controlled to be ≤ 70°C, the fraction with the temperature at the top of the tower ≤ 25°C is collected, and the by-product phosphorus oxychloride produced by the reaction is recovered; The residual liquid in the tower kettle was transferred to a 1000ml reaction flask. Add 120 grams of triethylamine in above-mentioned reaction bottle, be warming up to reflux temperature, keep warm for 10 hours. Atmospheric distillation to obtain 62.5 grams of α-chlorovinyl cyclopropane; using reactive distillation tec...

Embodiment 3

[0030] Add ethylbenzene (500ml) and phosphorus pentachloride (220.5 grams, 1.06mol) into the reaction flask, add 2 grams of pyridine, start stirring, adjust the temperature to 20-30°C, then add cyclopropyl methyl ketone (84.1 gram, 1mol), the dropwise addition was completed and incubated for 3 hours. The obtained reaction solution is rectified under reduced pressure, the pressure is controlled at 2.5-2.7kPa, the reflux ratio is 3, the temperature of the kettle is controlled to be ≤70°C, the fraction with the temperature of the tower top ≤25°C is collected, and the by-product phosphorus oxychloride produced by the reaction is recovered; The residual liquid in the tower kettle was transferred to a 1000ml reaction flask. Add 120 grams of triethylamine in above-mentioned reaction bottle, be warming up to reflux temperature, keep warm for 10 hours. Distill at atmospheric pressure to obtain 64.8 grams of α-chlorovinyl cyclopropane; adopt reactive distillation technology, add 125 gr...

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Abstract

The invention discloses a preparation method of intermediate cyclopropyl acetylene of anti-AIDS (acquired immune deficiency syndrome) drug efavirenz. The preparation method comprises the steps of performing a reaction in an organic solvent by taking cyclopropyl methyl ketone as a raw material and phosphorus pentachloride as a chlorinating agent by the action of a catalyst to generate alpha, alpha-dichloroethyl cyclopropane and phosphorus oxychloride, performing decompressed rectification to remove phosphorus oxychloride, removing part of hydrogen chloride from alpha, alpha-dichloroethyl cyclopropane by the action of triethylamine to generate alpha-chlorovinyl cyclopropane, and further removing part of hydrogen chloride by the action of strong base to generate cyclopropyl acetylene. Phosphorus oxychloride is removed by the decompressed rectification; the generation of much phosphorus wastewater due to hydrolysis of phosphorus oxychloride in ice water is avoided; recovered phosphorus oxychloride can be comprehensively utilized by simple rectification; waste gas, wastewater and industrial residue are reduced; the cost is lowered; cyclopropyl acetylene is prepared from alpha-chlorovinyl cyclopropane via a reaction rectification technology; and the method has the advantages of high conversion rate, good selectivity, low energy consumption and the like, and is suitable for industrialproduction.

Description

technical field [0001] The invention relates to the technical field of synthesis of cyclopropylacetylene, in particular to a preparation method of an anti-AIDS drug efavirenz intermediate cyclopropylacetylene. Background technique [0002] Efavirenz (also known as DMP266), the chemical name is (4s)-6-chloro-(cyclopropylacetylene)-4-(trifluoromethyl)-benzo-1,4-dihydrooxazole-2 -ketone. This medicine is developed by Merck Company of the United States, and has been approved by the U.S. Food and Drug Administration (FDA) in 1999. This medicine is recognized as the most effective medicine against and treating HIV-virus. Cyclopropylacetylene is the necessary raw material for the synthesis of this drug, so the efficient and green synthesis of cyclopropylacetylene has also attracted the attention of chemists. [0003] Cyclopropylacetylene was first synthesized and produced through cyclization of chloropentyne under the action of butyllithium. Due to the high price and dangerous u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C1/30C07C13/04C01B25/10
CPCC01B25/10C07C1/30C07C17/25C07C2601/02C07C13/04C07C22/00
Inventor 黄剑阮旭波程云涛张治国陈中兵程红伟
Owner JIANGSU YUXIANG CHEM
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