Preparation method of efavirenz intermediate

A technology of efavirenz and intermediates, which is applied in the field of organic synthesis, can solve the problems of complex organic ligand structure, cumbersome operation, and harsh reaction conditions, and achieve the advantages of recycling, shortening the process flow, and mild process conditions. Effect

Inactive Publication Date: 2017-07-28
WUHAN INSTITUTE OF TECHNOLOGY
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  • Abstract
  • Description
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Problems solved by technology

[0008] The synthetic efavirenz key intermediate of this method has the following disadvantages: (1) used reagents such as Me 3 SiCF 3 、Me 4 NF, n-Bu 4 NF and the like are expensive, which is not conducive to industrial production; (2) the selected organic ligand has a complex structure, high cost, and the effect of the reaction is not good; (3) the entire reaction process is long, time-consuming, harsh reaction conditions, cumbersome operation, Not conducive to the promotion of industrialization;

Method used

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  • Preparation method of efavirenz intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0027] At 12°C, 52.36g of organic ligand (1R,2S)-1-phenyl-2-(1 -Toluene solution of -pyrrolidinyl)-1-propanol and 74.2g of zinc trifluoromethanesulfonate were stirred and reacted at this temperature for 2 hours. After the reaction was completed, the temperature was raised to 18°C. Then, a mixture of 25.47g cyclopropynemagnesium chloride and 80mL 2-methyltetrahydrofuran was added to the above solution, stirred at this temperature for 1 hour, then cooled to -10°C, and 43.11g 1-(5-chloro-2- Nitrophenyl)-2,2,2-trifluoroethanone, and the mixture was stirred at -10°C for 20 hours. After the reaction was completed, 400 mL of saturated ammonium chloride solution was added to quench the reaction, and the organic phase and the aqueous phase were separated by toluene extraction. The organic phase was directly concentrated and dried to obtain 83mL of the oil phase of (S)-1-(5-chloro-2-nitrophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol , it was added to 1500mL of tetrahydrofuran ...

Embodiment 2

[0029] At 12°C, 35.04g of organic ligand (1R,2S)-1-phenyl-2-(1 -Toluene solution of -pyrrolidinyl)-1-propanol and 49.48g of zinc trifluoromethanesulfonate were stirred and reacted at this temperature for 2 hours. After the reaction was completed, the temperature was raised to 18°C. Then add a mixture of 19.18g cyclopropynylmagnesium bromide and 70mL 2-methyltetrahydrofuran to the above solution, stir at this temperature for 1 hour, then cool down to -10°C, add 1-(5-chloro-2- Nitrophenyl)-2,2,2-trifluoroethanone (28.74 g), and the mixture was stirred at -10°C for 22 hours. After the reaction was completed, 300 mL of saturated ammonium chloride solution was added to quench the reaction, and the organic phase and the aqueous phase were separated by toluene extraction. The organic phase was directly concentrated and dried to obtain 78 mL of (S)-1-(5-chloro-2-nitrophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol as an oil phase, it was added to 1000mL of tetrahydrofuran and ...

Embodiment 3

[0031]At 12°C, add 30.12g organic ligand (1R,2S)-1-phenyl-2-(1 The toluene solution of -pyrrolidinyl)-1-propanol and 42.34g of zinc trifluoromethanesulfonate were stirred and reacted at 23°C for 2 hours. After the reaction was completed, the temperature was raised to 18°C. Then, a mixed solution of 18.38g cyclopropynemagnesium chloride and 80g 2-methyltetrahydrofuran was added to the above solution, stirred at this temperature for 1 hour, then cooled to -10°C, and 1-(5-chloro-2-nitro 23.95 g of phenyl)-2,2,2-trifluoroethanone, and the mixture was stirred at -6°C for 22 hours. After the reaction was completed, 260 mL of saturated ammonium chloride solution was added to quench the reaction, and the organic phase and the aqueous phase were separated by toluene extraction. The organic phase was directly concentrated and dried to obtain an oil phase of 71 mL of (S)-1-(5-chloro-2-nitrophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol , add it to 800mL of tetrahydrofuran and me...

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Abstract

The invention relates to a preparation method of an efavirenz intermediate. The method comprises the following steps of reacting a zinc salt or copper salt with an organic ligand (1R, 2S)-1-phenyl-2-(1-pyrrolidyl)-1-propyl alcohol in an organic solvent, adding a cyclopropylene reagent; stirring at a constant temperature for 2h and adding 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoro-ethanone, completing stirring reaction, adding a proton source for quenching reaction and separating an organic phase from an aqueous phase through extraction; and adding an oil phase which is obtained through direct concentration and drying of the organic phase to a solution of tetrahydrofuran and methyl alcohol at a certain ratio, and then adding acetic acid and iron powder, stirring and filtering the obtained mixture through kieselguhr, washing, drying, carrying out vacuum concentration and purifying to obtain an efavirenz key intermediate. The 1-(5-chloro-2-nitrophenyl)-2,2,2-trifluoro-ethanone is utilized for participating in reaction, so that the method is short in process, mild in condition, simple in operation, green, environment-friendly and low in cost.

Description

technical field [0001] The invention relates to a preparation method of an efavirenz intermediate, belonging to the technical field of organic synthesis. Background technique [0002] Efavirenz (Efavirenz) is an anti-HIV virus drug developed by Merck, which is known to be effective in the treatment of human immunodeficiency virus (HIV) by targeting the activity of HIV reverse transcriptase. Its Chinese name is (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazine-2 - Ketone, the chemical structure of which is shown in the following formula. [0003] [0004] Efavirenz is produced from the intermediate (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol and triphosgene Obtained by cyclization reaction. The structure of the efavirenz intermediate is shown below: [0005] [0006] In view of the medical value and social significance of efavirenz, the synthesis of its intermediates is very important, and there ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C215/70
CPCC07C213/02C07C201/12C07C215/70C07C205/19
Inventor 吴广文胡争朋熊奇邹杨熊泽
Owner WUHAN INSTITUTE OF TECHNOLOGY
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