Development of a Scalable Method for Manufacturing the Central Core of CD73 Inhibitor AB680

Abstract

AB680 is a highly potent CD73 small molecule inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Here, we report the development of a scalable and practical method for the manufacturing of the azaindazole central core. This synthesis features an N-oxide formation followed by an α-chlorination with POCl 3 leading to the formation of 4,6-dichloro-1H-pyrazolo [3,4-b]pyridine 1 in high yield and 99.5% UV purity. This method was successfully performed on multikilogram scale to support the synthesis of AB680.

Development of a Concise Process for the Synthesis of the Azaindazole Core of the CD73 Inhibitor AB680

“…Water (2.5 L) was charged, and the resulting slurry was stirred at room temperature for 0.5 h. The precipitated solids were filtered, and the cake was rinsed with water (2 × 500 mL) and dried in an oven to give 16 (640 g, 89% yield, 94.8 area% HPLC, qNMR (with 1,3,5-trimethoxybenzene as the internal standard): 92.82 wt %) as a yellow solid. The 1 H NMR data match with the literature . ESI MS [M + H] + for C 14 H 18 N 3 O 3 , calcd 276.1, found 276.1.…”

“…The precipitated solids were filtered and washed with water (2 × 1.2 L) and dried under a drying lamp to give 19 (530 g, 80% for two steps, 98.4% area% HPLC, qNMR (with 1,3,5-trimethoxybenzene as the internal standard): 88.28 wt %) as a beige solid. The 1 H NMR data match with the literature . ESI MS [M + H] + for C 14 H 14 N 3 O 3 , calcd 272.1, found 272.0.…”

“…Comparing the 1 H NMR spectrum of crude 3 to that of material purified by column chromatography suggested that most of the elusive impurities contributing to the HPLC/q-NMR purity gap are polymeric byproducts, indicated by broad 1 H NMR resonances between 3 and 7 ppm (Figure ). These impurities likely originated from the PMB deprotection step, with similar observations having been reported when this route was originally disclosed …”

“…For the decarboxylation step (Step 3, Scheme ), we took the existing procedure and sought to develop a simplified telescoped process for steps 2 and 3. As shown in Table , using crude 18 in 10 L/kg of ethanol, 23.6% of ketopiperidone 18 remained after heating the reaction at 90 °C together with 10 L/kg of water (entry 1, Table ).…”

“…The first-generation manufacturing process for 3 (Scheme ) has been disclosed previously and started with the condensation of acrylonitrile 5 , hydrazine hydrate, and arylaldehyde 6 to afford the intermediate imine (not shown). This imine was not isolated but directly converted to the corresponding pyrazole 7 via a base-promoted cyclization and subsequent redox isomerization.…”