Efficient aprepitant preparation process

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...

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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 alcohol that is difficult to obtain as raw material, chiral alcohol ee value It is required to be more than 99%, which causes high cost and is unfavorable for industrialized production.

Since there are three chiral centers in the aprepitant molecule, namely 1R, 2R, and 3S, it brings considerable difficulty to the synthesis of high optically pure raw materials

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