Stereoselective Process for a CCR3 Antagonist

Abstract

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.

Fast Reductive Amination by Transfer Hydrogenation “on Water”

“…[1,2] One of the best ways for producing amines is the reduction of imino C=N bonds, [1a,c, 2n,q,s] which are most conveniently obtained from the condensation of carbonyl compounds with amines. [1b, 2t] Borane hydride reduction has been used in a number of industrial applications, [3] for example, synthesis of a CCR3 antagonist [4] and an antiangiogenic tyrosine kinase inhibitor. Reductive amination (RA) exploits imines in situ generated from carbonyl compounds and amines, alleviating the problematic imine isolation.…”

“…2h,p,s–u In most of the RA reactions developed, stoichiometric boron hydride reduction and heterogeneous hydrogenation dominate the scene 1b. 2t Borane hydride reduction has been used in a number of industrial applications,3 for example, synthesis of a CCR3 antagonist4 and an antiangiogenic tyrosine kinase inhibitor 5. However, the use of a stoichiometric amount of boron hydrides generates copious amounts of waste and is associated with other problems, such as toxicity issues with NaBH 3 CN and the inability to aminate aromatic ketones with NaBH(OAc) 3 , two most widely used hydrides in RA 2t.…”

Chemical‐Reductant‐Free Electrochemical Deuteration Reaction using Deuterium Oxide

“…A series of deuterium‐substituted amino acids were prepared (Scheme a), such as α‐amino acid derivative 2 bg , β‐amino acid derivative 2 bh , and a DOPA precursor 2 bi . A deuterated building block of CCR3 antagonist 2 bj was synthesized . With α,β‐unsaturated acid as starting material, d2‐isobuprofen 2 bk was prepared for the first time.…”

Cinchona Alkaloids in Asymmetric Organocatalysis

“…For instance, Yue and coworkers used it in the preparation of a CCR3 antagonist on a 35-kilogram scale. 283 Likewise, Hamerak et al applied the above-mentioned procedure to the opening of 3-isobutylglutaric anhydride with cinnamyl alcohol, yielding the key intermediate for the asymmetric synthesis of pregabalin. 284 Starting from a prochiral anhydride featuring an exocyclic methylene group, Mittendorf and co-workers developed a four-step asymmetric synthesis of b-amino acid BAY 10-8888.…”