Development of a Sequential Tetrahydropyran and Tertiary Butyl Deprotection: High-Throughput Experimentation, Mechanistic Analysis, and DOE Optimization

Abstract

The synthesis of compound 1 by deprotection of the THP, tert-butyl protected amino-pyrazolopyridine (2), is described. The original conditions for this transformation were conducted in a one-pot procedure and necessitated the use of large quantities of either TsOH or benzenesulfonic acid (5 equiv) and trifluoroacetic acid (10−25 equiv) and produced 1 in moderate yield (50−65%). A series of high-throughput screens of Bronstead acids, Lewis acids, and solvents was rapidly performed with the goal of identifying improved efficiency and reaction yield. Through these screens, sulfuric acid was discovered to be a suitable replacement; however, yields of 1 were still unacceptable. A decoupling of the two deprotection steps revealed that the THP byproduct resulting from removal of the THP protecting group was problematic in the subsequent removal of the tert-butyl group. Consequently, a two-step deprotection protocol was developed which, in combination with design of experiment (DOE) optimization, improved the ove...