Efficient aprepitant preparation process

A preparation technology of aprepitant, which is applied in the field of high-efficiency preparation technology of aprepitant, can solve the problems of high cost, low yield, long reaction route, etc., and achieve low manufacturing cost, high yield and good drug effect Effect

Inactive Publication Date: 2017-07-21
SICHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The final oily product obtained by this route is extremely difficult to purify, the reaction route is long, and the yield is low, which is very unfavorable for environmental protection
[0006] JOrg Chem, 2002,67 (19): 6743-6747 reports a kind of method utilizing chiral induction method to synthesize aprepitant, but this method needs to use the chiral alcoh

Method used

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Embodiment

[0028] A high-efficiency preparation process of aprepitant of the present invention comprises the following process steps:

[0029] (1) With (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-methoxy 2R-[1R-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3S-(4-fluorophenyl)-4-(N-methoxy Carbonyl-2-aminoethylhydrazone)-morpholine;

[0030] (2) Using 2R-[1R-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3S-(4-fluorophenyl)-4-(N-methoxycarbonyl-2- Aminoethylhydrazone)-morpholine prepares the crude product of aprepitant;

[0031] (3) Refining the crude product of aprepitant to obtain the finished product of aprepitant.

[0032] Wherein, the concrete process of described step (1) is:

[0033] 1) Fill the 100L reactor with nitrogen, add dimethyl sulfoxide, (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy ]-3-(4-fluorophenyl)-morpholine hydrochloride and xylene, stir to dissolve, add potassium carbonate, stir at 20-25°C, then add (AR-3)2-(2-chloro-1- Iminoeth...

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Abstract

The invention discloses an efficient aprepitant preparation process. The preparation process comprises the steps that firstly, a 2R-[1R-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy)-3S-(4-fluorophenyl)-4-(N-methoxycarbonyl group-2-aminohydrazonyl)-morpholine is prepared from a (2R,3S)-2-[(1R)-1-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy]-3-(4-fluorophenyl)-morpholine hydrochloride; an aprepitant crude is prepared from the 2R-[1R-[3,5-difluoromethyl/trifluoromethyl phenyl] ethoxy)-3S-(4-fluorophenyl)-4-(N-methoxycarbonyl group-2-aminohydrazonyl)-morpholine; then the aprepitant crude is refined and an aprepitant finished product is obtained. According to the efficient aprepitant preparation process, the prepared aprepitant has the advantages of high recovery rate, good efficacy, low cost of the whole process, safety and no pollution.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a high-efficiency preparation process of aprepitant. Background technique [0002] Aprepitant (Aprepitant, trade name: Emend), chemical name: 5-[[2-(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy ]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, the structural formula is as follows: [0003] [0004] Aprepitant is the first NK1 receptor antagonist approved by the U.S. FDA. Its new mechanism of action makes it different from previous serotonin receptor blockers. Come to the gospel. [0005] The synthesis method of aprepitant was first seen in the patent application with the publication number WO9516679A1. This method uses the rare unnatural amino acid L-p-fluorobenzylglycine as a raw material, which is cyclized with the highly toxic substance 1,2-dibromoethane at high temperature and reacted with After the end, excess dibromoethane was dis...

Claims

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Application Information

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IPC IPC(8): C07D413/06
CPCC07D413/06
Inventor 朱玮杨敏侯述成
Owner SICHUAN PHARMA
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