Zhang Fuli
2012
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Journal
Chinese Journal of Pharmaceuticals
Abstract
(2R,3S) -2-[(R) -1 -[3,5-di-(Trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl) morpholine hydrochloride,the key intermediate of aprepitant,was synthesized from 4-methoxybenzaldehyde(3) by reductive amination with 2-aminoethanol to afford 2-(4-methoxybenzylamino) ethanol(4).Compound 4 underwent annulation with glyoxylic acid to yield 2-hydroxy-4-(4-methoxybenzyl) morpholin-3-one(5).After esterification of 5 with trifluoroacetic anhydride to provide 6,6 was condensed with(R)-1-[3,5-di-(trifluoromethyl)phenyl]ethanol(7),and compound 8 was subjected to crystallization-induced diastereomeric transformation under delicate basic condition,and followed by Grignard reaction,deprotection and salification with an overall yield of about 18%(based on 3).