Preparation method of NK1 receptor antagonist

Abstract

The invention discloses a preparation method of an NK1 receptor antagonist. According to the invention, chiral resolution adopts a mixed solvent, CaCl2 is added for a reaction in an alkaline environment, CaCl2 does not participate in the reaction but needs to be added in advance for better devitrification, water is added for quenching after the reaction is finished, and CaCl2 is dissolved at the same time, so devitrification efficiency is further improved; and then 5-hydroxymethyl-2,4-dihydro-[1,2,4]triazin-3-one is used as a raw material for synthesis of aprepitant under the catalysis of DBU at room temperature.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of an NK1 receptor antagonist. Background technique [0002] The chemical name of aprepitant is 5-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluoro Phenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one, the structure is as follows: [0003] [0004] Aprepitant was approved by the FDA in 2003 for the treatment of chemotherapy-induced vomiting and was the first marketed NK1 receptor antagonist. [0005] In the structure of aprepitant, there are 3 chiral centers, and an important chiral intermediate is included in its preparation route. The chiral intermediate also has 3 chiral centers, and the structure is as follows: [0006] [0007] It has been reported in the literature that the above-mentioned chiral intermediates are synthesized by asymmetric hydrogenation catalytic method using high-pressure hydrogen as a ...

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Problems solved by technology

[0010] The method has high yield, good optical purity, and mild reaction conditions, but the required chiral catalyst is not easy to obtain, and the preparation requires column chromatography purification, and the operation is complicated

[0011] In the process of preparing aprepitant from the above chiral intermediates, most of the prior art uses 5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one or 5-bromo Methyl-2,4-dihydro-[1,2,4]triazol-3-one undergoes alkylation reaction to prepare aprepitant, the reaction conditions are mild, but it needs to react for more than 10 hours, and the reaction time is relatively long long, the yield is low, and the crude product obtained needs to be further refined, as patent CN109467552A discloses a kind of preparation technology of aprepitant, with 5-bromomethyl-2,4-dihydro-[1,2,4] Triazol-3-one is used as a raw material to prepare aprepitant, which needs to be reacted at 30-35°C for 12-15 hours, and the purity after separation and purification is 99.8%.

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