Use of Phosphazene Base BTPP for Phosphorylative Activation in the Scale-Up of BET Inhibitor GSK525762

In this article, an improved synthesis of a key triazole intermediate in the synthesis of bromo- and extra-terminal domain (BET) inhibitor GSK525762 (1) is described, which avoids the need for the formation of a thioamide intermediate for the key methyltriazolo[1,4]benzodiazapine formation. Conditions for a phosphorylative activation of lactam 4 were identified through the extensive screening of reagents and solvents, where a number of phosphazene bases were found to have unmatched activity. Development efforts focused on the use of phosphazene base P1-t-Bu-tris(tetramethylene) (BTPP) with diethyl chlorophosphoridate (DECP) and culminated in the demonstration of the new process at a 750 g scale. The resulting synthetic route avoids the use of thiolating agent P₂S₅ and isolation of the resulting thioamide while delivering 1 in exceptional purity with a reduced number of steps, resulting in a higher yield and improved throughput over the previous process.