Five-membered ring systems: thiophenes and selenium/tellurium analogs and benzo analogs

Evolution of the Manufacturing Route towards a Key Benzothiophen‐2‐yl‐Boronic Acid Building Block of Rogaratinib

“…In mitigation, charcoal was added to the reactionmixture, thus preventing the palladium build-up and enabling removal by filtration during work-up. 9 Unfortunately the use of less than 2 mol-% palladium catalyst led to incomplete conversion. Although a stalled reaction could be restarted and brought to completion by addition of more catalyst, such a high loading in an early step was deemed unfeasible.…”

“…During the Rogaratinib project, boronic acid 3 was produced in multiple campaigns via different synthetic routes to methyl-methoxy-benzothiophene 4 (Scheme 2). [7][8] [9] The initial demand for preclinical supply was met using the drug discovery route in a kilo-lab setting and delivered building block 3 on hundred-gram scale (Scheme 3). This route started from 2-methoxy-4-methyl aniline 6, which was converted to the corresponding thiophenol 5.…”