A convergent, multikilogram, stereoselective synthesis of 1 is described. A key fragment, (S)-3-(4-fluorobenzyl)piperidine (2) was synthesized from valerolactam in three steps using our recently discovered Ir−BDPP-catalyzed asymmetric hydrogenation. Another key fragment, (1R,2R)-2-(benzyloxycarbonylamino)cyclohexanecarboxaldehyde (3) was synthesized from meso-hexahydrophthalic anhydride in seven steps. The stereochemistry was set in the first step of this sequence via a quinidine-mediated desymmetrization of the meso-anhydride. Coupling of the fragments 2 and 3 followed by deprotection provided the penultimate 23. The active pharmaceutical ingredient (API) free base 1 was obtained by treatment of 23 with the aminothiazole fragment 4 under mild conditions.

A series of p-substituted benzyl alcohols have been oxidized to their corresponding aldehydes using aqueous hypochlorite and phase-transfer catalyst (PTC) conditions. The reaction constant, 9, has been determined to be +1.03. Possible mechanisms are suggested.

Significance: The CCR3 antagonist M is a potential treatment for asthma and allergic rhinitis. The synthesis depicted provided 20 kg of the target. Key steps include the asymmetric hydrogenation of B to C and the quinidine-mediated desymmetrization of the meso-anhydride E.Comment: Note the 172 mol-scale Curtius rearrangement using diphenylphosphoryl azide by which H was converted into carbamate I.