171338-33-3Relevant articles and documents
Understanding the origin of unusual stepwise hydrogenation kinetics in the synthesis of the 3-(4-fluorophenyl)morpholine moiety of NK1 receptor antagonist aprepitant
Brands, Karel M. J.,Krska, Shane W.,Rosner, Thorsten,Conrad, Karen M.,Corley, Edward G.,Kaba, Mahmoud,Larsen, Robert D.,Reamer, Robert A.,Sun, Yongkui,Tsay, Fuh-Rong
, p. 109 - 117 (2012/12/21)
An efficient and highly stereoselective one-pot Grignard addition/hydrogenation procedure is a key step in the synthesis of the NK 1 receptor antagonist aprepitant. The critical influence of pH on the nature and stability of the intermediate Grignard adducts, along with their reactivity in the hydrogenation reaction, is described. The observation of a defluorinated impurity under hydrogen-starved conditions led to mechanistic studies that revealed unusual kinetics in the hydrogenation reaction. Detailed analysis of the kinetic profiles under hydrogen-starved conditions indicated the two steps of the reaction, debenzylation of the Grignard adducts and reduction of the incipient imine, occurred in near perfect stepwise fashion wherein the debenzylation reaction was essentially complete before any imine reduction took place. Under hydrogen-saturated conditions the inhibition of the imine reduction was less complete, but the partial buildup of reactive imine intermediate led to a dramatic spike in reaction rate toward the end of reaction. Possible mechanistic rationales to explain these observation are discussed.
