(92b) Boc Deprotections: Simple Reactions, Complex Processes

Tert-butyloxycarbonyl (boc) protecting groups are ubiquitous throughout chemical syntheses. They are often used to protect primary amines from unwanted reactions within a chemical synthesis, enabling selective functionalization of a substrate into the desired compound. Boc groups are often cleaved in the presence of strong acids, releasing CO₂ and isobutylene as gaseous by-products. While the chemistry itself is straightforward, the formation of the primary amine in the presence of strong acid often leads to immediate salt formation; depending on the complexity of the molecule, this can quickly result in a complex form space.

In this talk, we will discuss the penultimate step in the synthetic route to repotrectinib, a tyrosine kinase inhibitor approved by the FDA in 2023 to treat patients with non-small cell lung cancer with ROS1 gene fusions and/or solid tumors with NTRK gene fusions. The penultimate step of the synthetic sequence is a “simple” boc-deprotection in acetonitrile/water utilizing HCl as the acid catalyst. Detailed kinetic models were developed for the reaction; the desired reaction is 2^nd order in acid concentration, consistent with literature precedent, and the only process-related impurity forms through a background decarboxylation reaction with a non-monotonic dependence on acid concentration. While the chemical transformation was “simple”, the same could not be said about the form space, which consisted of mono- and bis-HCl salts, including both anhydrous and monohydrate forms. The bis-HCl salts were preferred by the project team, as the HCl concentrations required to achieve the mono-HCl salt resulted in significant levels of product degradation. Competitive slurries revealed the bis-HCl monohydrate to be thermodynamically favored across the proposed processing landscape, but the bis-HCl anhydrous form was kinetically favored to nucleate during the reaction. A combination of high-throughput screening, data-rich experimentation, and kinetic modeling guided process development to isolate the bis-HCl monohydrate directly from the reaction mixture in high quality and >90% yield.