Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction
A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.
Zhao, Matthew M.,McNamara, James M.,Ho, Guo-Jie,Emerson, Khateeta M.,Song, Zhiguo J.,Tschaen, David M.,Brands, Karel M. J.,Dolling, Ulf-H,Grabowski, Edward J. J.,Reider, Paul J.,Cottrell, Ian F.,Ashwood, Michael S.,Bishop, Brian C.
p. 6743 - 6747
(2007/10/03)
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