A scalable and eco-friendly total synthesis of poly(ADP-ribose) polymerase inhibitor Olaparib

Abstract

A scalable total synthesis of a potent poly(ADP-ribose) polymerase (PARP) enzyme inhibitor, Olaparib (Lynparza), approved by U.S. FDA and EMA for ovarian cancer, is disclosed. The process is operationally simple, highly atom economical and environmentally benign as compared to the existing literature route of Olaparib. Herein, we report an eco-friendly synthesis of Olaparib using commercially available inexpensive starting materials, in only four steps with 51% overall yield. This synthesis comprises the key steps of generation of conjugated enolate from 2-acetylbenzoic acid to produce α-arylated product under transition metal-free conditions followed by ring construction of the final phthalazinone scaffold affording Olaparib. An alternative synthesis of another PARP inhibitor, AZD2461, using the same protocol is also reported. Highlighting this work is the phosphonate-free synthesis, as opposed to the Horner–Wadsworth–Emmons olefination reaction utilized previously which requires the synthesis of a phosphonate precursor.