Abstract
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 Pl-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 P255 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.
NSTL