Development of an efficient and scalable synthesis of a κ-opioid receptor agonist

ORGN 169

Arun Ghosh,, Stephane Caron2, Michel Couturier2, Keith M. DeVries2, Kristina Dupont-Gaudet2, Joel Hawkins2, Fumitaka Ito3, Janice E. Sieser2, John L. Tucker2, and Brian C. Vanderplas2. (1) Chemical Research and Development, Pfizer Global Research & Development, Groton, CT 06340-8013, (2) Chemical Research and Development, Pfizer Inc, Groton, CT 06340-8013, (3) Pfizer Global Research and Development, Pfizer Inc, 464-8601 Nagoya, Japan
Synthetic routes to the κ-opioid receptor agonist drug candidate, CJ-15,161, for large-scale production to support toxicological screening and clinical trials will be disclosed. The original discovery route was not practical for large-scale preparation and long-term manufacturing. In particular, the absence of crystalline intermediates throughout the synthesis and the lack of regioselectivity during styrene oxide ring opening by pyrrolidine proved problematic during synthetic manipulations, also the actual drug substance was an amorphous hydrochloride salt. The synthetic improvements that enabled the production of drug substance to fulfill a recent need will be presented. We will also present alternate routes to CJ-15,161 involving intermolecular N-arylation of an appropriately functionalized diamine. These diamines are obtained from the precursor α-amino acids or, more conveniently, from the corresponding 1,2-amino alcohols via 1,2,3-oxathiazolidine-2,2-dioxide. The later approach is amenable for multigram-scale preparation of CJ-15,161. Two most notable transformations in the synthetic scheme, e.g., direct amination of 4-halo benzamide as the halide counterpart, and efficient preparation of the substrate amine by dual protection/activation involving oxathiazolidine formation, may find broader application for the preparation of other N-aryl 1,2-diamine. The generality of Pd and Cu catalyzed N-arylation of oxazolidinone will also be discussed.