Practical asymmetric synthesis of aprepitant,a potent human NK-1 receptor antagonist,via a stereoselective Lewis acid-catalyzed trans acetalization reaction |
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Authors: | 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 |
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Institution: | Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK. matthew_ahao@merck.com |
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Abstract: | 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. |
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