Practical and Scalable Manufacturing Process for the Key Intermediate of Poly(ADP-Ribose) Polymerase Inhibitor Olaparib

Abstract

Olaparib (Lynparza) is a potent, highly selective inhibitor of poly(ADP-ribose)polymerase enzymes, approved by the U.S. FDA and EMA for the treatment of ovarian cancer. Herein, we report a practical, economical, and scalable process for the synthesis of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, a key intermediate for olaparib. The low-cost industrial byproduct phthalhydrazide was used as the starting material to construct the phthalazinone moiety, which allowed access to the key intermediate by the Negishi coupling reaction. Optimization of each step has enabled the development of an environmentally benign and robust process with effective control of impurities.