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.
Mesh Terms:
Adult, Binding Sites, Brain, Brain Mapping, Dose-Response Relationship, Drug, Humans, Iodine Radioisotopes, Male, Morpholines, Neurokinin-1 Receptor Antagonists, Receptors, Neurokinin-1, Single-Blind Method, Tomography, Emission-Computed
Adult, Binding Sites, Brain, Brain Mapping, Dose-Response Relationship, Drug, Humans, Iodine Radioisotopes, Male, Morpholines, Neurokinin-1 Receptor Antagonists, Receptors, Neurokinin-1, Single-Blind Method, Tomography, Emission-Computed
J. Org. Chem.
Date: Sep. 20, 2002
PubMed ID: 12227806
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