Efficient Synthesis of NK₁ Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation

Abstract

An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.

Novel rearrangements of an N-oxide degradate formed from oxidation of a morpholine acetal substance P antagonist

“…The intervention of the [1,3] sigmatropic rearrangement is a rare event during the course of a Claisen rearrangement. 11 However, such rearrangement has recently been witnessed also in the synthesis of an NK 1 receptor antagonist Aprepitant, 12 which also contains the cis-2-alkoxy-3-arylmorpholine core. The degradation products (3,4,5,6) of N-oxide 2 can be well explained by these elimination/addition mechanisms, and the subsequent rearrangements.…”

Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model

“…The effect of the cyclooxygenase inhibitor indomethacin and the nonselective nitricoxide (NO) synthase inhibitor N G -monomethyl-L-arginine monoacetate (L-NMMA) on capsaicin-induced dermal vasodilation were also assessed by infusing dosages in the human forearm that have previously been shown to be effective in antagonizing vasodilating prostaglandins and NO, respectively (Smits et al, 1995;de Hoon et al, 2003). Because there is no infusible formulation of a SP antagonist available, the potent SP antagonist aprepitant was given orally, and capsaicin-induced vasodilation was measured on the left arm preaprepitant and on the right arm 4 h after dosing aprepitant (T max ) (Brands et al, 2003;Patel and Lindley, 2003). Because in the latter part of the study protocol measurements of dermal perfusion on both arms were not simultaneously performed, the diurnal reproducibility of the capsaicin-induced DBF response was evaluated by adding a control period in which no treatment was given, but only capsaicin was applied once in the morning on the left arm and 4 h later, in the afternoon, on the right arm.…”

Enantioselective hydrosilylation of prochiral ketones catalyzed by chiral BINAP-copper(I) complexes

“…This alcohol is also of special interest for the development of some recent NK-1 antagonists including aprepitant (Fig. 2) [15]. As anticipated, the excellent enantioselectivity displayed by CuCl/NaOt-Bu/BINAP system seems to be limited to aryl alkyl ketones.…”