Understanding the Origin of Unusual Stepwise Hydrogenation Kinetics in the Synthesis of the 3-(4-Fluorophenyl)morpholine Moiety of NK₁ Receptor Antagonist Aprepitant

Abstract

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 hydrogenstarved 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 hydrogensaturated 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.

Comparative performance evaluation and systematic screening of solvents in a range of Grignard reactions

“…In addition to the broad applications on a research scale, Grignard reactions have also been adapted to a large scale and are the pivotal steps in the manufacture of numerous complex molecules. From a pharmaceutical perspective, the Grignard reaction has been employed as a key step in numerous syntheses such as that of tramadol, 3 ravuconazole, 4 naproxen, 5 ibuprofen, 6 aprepitant, 7 droloxifene, 8 and tamoxifen 9 ( Fig. 1).…”

“…2.2.1 Aryl Grignard reactions for benzyl alcohol. The use of aryl Grignard reagents in organic chemistry is also well established in the literature, and has been exploited in the synthesis of a number of important pharmaceutical compounds such as naproxen, 5 emend (aprepitant), 7 droloxifene, 8 and tamoxifen. 9 It is another important transformation we have selected for the investigation of the solvent effect.…”

Grignard Reagents as Niche Bases in the Synthesis of Pharmaceutically Relevant Molecules

“…This fact is borne out among others by the numerous applications of Grignard reaction in the pharmaceutical industry, e.g. for the large scale manufacturing of such essential drugs as tramadol, [2] tamoxifen, [3] ravuconazole, [4] clotrimazole, [5] naproxen, [6] aprepitant, [7] ibuprofen, [8] droloxifene [9] and mefloquine [10] . In most uses of Grignard reagents, a successful reaction outcome relies on not only the readiness with which organomagnesium nucleophiles react with diverse functional groups, but also the effective elimination or sequestering of moieties with an active hydrogen atom.…”

Scale-down of Heterogeneous Catalytic Reduction Using a Bubble Column: Controlled Mass Transfer down to 3 cm3 Working Volume

“…A range of examples confirms the generality of this principle with respect to olefin and ketone hydrogenation. 2−4 Merck workers also encountered the effect in the catalytic hydrogenation of an imine, in which some defluorination of an aryl fluoride occurred under "hydrogen starved" conditions, 5 and were able to devise satisfactory manufacturing conditions based on a knowledge of the volumetric mass transfer coefficient under operating conditions. In the hydro-dechlorination of a benzyl chloride, dimerization instead of reduction occurred under hydrogen starved conditions.…”