Development of a Robust Synthesis of Dactolisib on a Commercial Manufacturing Scale

Abstract

The development of the robust synthesis of quinolin-1-yl]-phenyl]propionitrile (dactolisib) on a commercial scale is described. The key step is a Pd-catalyzed Suzuki coupling of 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile to 3-quinoline boronic acid. A special focus is placed on reducing the amount of Pd catalyst used in the Suzuki coupling and purifying the crude drug substance, including removing traces of Pd.

Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry

“…Following the development of this step, the entire synthesis of PBRM was optimized, particularly regarding reducing the amount of purification needed and improving the efficiency of other reactions in the route. Baenziger and coworkers [16] from Novartis reported the development of a synthesis of dactolisib 27 [17], a dual kinase inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) currently investigated as the treatment of solid tumor forms. The coupling reaction between 25 and 26 afforded the desired product 27 and was optimized for commercial-scale manufacturing.…”

Recent Applications of Pd-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Couplings in Pharmaceutical Process Chemistry.

“…The yield for 22 was 86% in situ (Scheme 4). Baenziger and coworkers 11 from Novartis reported the development of a synthesis of dactolisib 27, 12 a dual kinase inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) currently investigated as the treatment of solid tumor forms. The coupling reaction between 25 and 26 afforded the desired product 27 and was optimized for commercial scale manufacturing.…”