Development of a Process to a 4-Arylated 2-Methylisoquinolin-1(2H)-one for the Treatment of Solid Tumors: Lessons in Ortho-Bromination, Selective Solubility, Pd Deactivation, and Form Control

Abstract

We here present an optimized, scalable synthesis of bromodomain and extra-terminal (BET) inhibitor BMS-986378 (CC-90010). The original route and process 1A was 7 steps with 33.8% yield and featured numerous problematic solvents, process safety concerns, difficult to scale unit operations, and challenging to control impurities. Reaction optimization to remove or mitigate these challenges resulted in our first scale-up route and process, 2A. Subsequent challenges encountered on scale-up of route and process 2A warranted the creation and implementation of an enhanced process, which eliminated dichloromethane from a phenol bromination, improved catalyst performance in the penultimate cross-coupling, and finally developed a concomitant solvent charging process for form control in the final API crystallization. The resulting scale-up route and process, 2B, was demonstrated on a >50 kg scale and afforded the final product in 49% yield over 7 steps in >99.9% assay and area purity, meeting all ICH requirements for quality.

Pd(COD)(DQ): A Stable, Versatile, and Monometallic Palladium(0) Source for Organometallic Synthesis and Catalysis

“…During our investigation, we found two examples where Pd(COD)(DQ) substantially out-performed Pd2(dba)3 (Scheme 6, left). When Pd2(dba)3 was replaced by Pd(COD)(DQ) in the Miyaura borylation to synthesize 11, [27] we observed dramatic increase in the reaction rates. While Pd2(dba)3 converted less than half of the starting material to 11 after 14 h, Pd(COD)(DQ) achieved full conversion towards the desired product within the same time period.…”

“…Left: Pd-catalyzed Miyaura borylation. [27] Yields measured by HPLC using 4-phenyltoluene as the internal standard. Right: Pd-catalyzed benzothiophene C-H arylation.…”

Suzuki–Miyaura Coupling of Aryl Nosylates with Diethanolamine Boronates

“…16 Since our attempted synthesis of 3y had given no conversion (see Table 5 ), we were unsurprised that the coupling of 2m with 1f failed as well. Inspired by another literature example on the synthesis of the antitumor candidate BMS-986378, 10h we chose the reaction of 2-quinolone 1i with ortho -methoxy boronate 2e as a model system, which afforded coupling product 8 in good yield. In the literature, homo-coupling was reported as a major problem; however, the homo-coupling product 9 was only detected at a level of ca.…”