Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor

• Published in: Organic process research & development Vol. 16; no. 12; pp. 1897 - 1904
• Main Authors: Gillmore, Adam T, Badland, Matthew, Crook, Clare L, Castro, Nieves M, Critcher, Douglas J, Fussell, Steven J, Jones, Katherine J, Jones, Matthew C, Kougoulos, Eleftherios, Mathew, Jinu S, McMillan, Lynne, Pearce, John E, Rawlinson, Fiona L, Sherlock, Alexandra E, Walton, Robert
• Format: Journal Article
• Language: English
• Published: American Chemical Society 21-12-2012
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op200238p

Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber–Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.