Exploration of a Nitromethane-Carbonylation Strategy during Route Design of an Atropisomeric KRAS^G12C Inhibitor

Abstract

Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRASG12C inhibitor to support clinical API manufacture. Improvements to the synthesis of a chiral piperazine fragment gave reduced step count and streamlined protecting group strategy via the formation and methanol ring opening of an N-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould–Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of ortho-substituted bromo/iodo unprotected anilines.

Synthetic and Chromatographic Challenges and Strategies for Multigram Manufacture of KRASG12C Inhibitors

“…37 It was evident that milder conditions were needed for the cyclization, and hence, an extensive screen of alternative approaches to obtain S-22 or analogous compounds was initiated. 38 Providing that milder conditions to obtain S-22 could be identified, we had confidence that our "early Suzuki" approach to obtain 2 and analogous compounds described above would be a viable large scale method. However, given the disappointing racemization event, it was decided at this point that the "early Suzuki" approach (Scheme 2) did not fulfill our requirements for a process that could be used efficiently to manufacture compound 2 on large scale.…”

“…After an unproblematic separation of the atropisomers using the optimized conditions described above, the desired pure atropisomer S-24 (>99% ee) was successfully isolated on a multihundred gram scale in 46% yield. (Figures S20−S23) Next, using the same conditions as in the manufacture of 1, an S N Ar reaction of S-24 and the chiral piperazine 25 18,38 furnished compound S-26 in 76% yield (Scheme 3). An ironmediated reduction of S-26 furnished S-27, which was methylated to give compound S-28 in 77% overall yield.…”

“…To our disappointment, however, we found that a significant racemization occurred during the cyclization, providing 22 as an atropisomer mixture (Figures S13 and S14). It was evident that milder conditions were needed for the cyclization, and hence, an extensive screen of alternative approaches to obtain S - 22 or analogous compounds was initiated . Providing that milder conditions to obtain S - 22 could be identified, we had confidence that our “early Suzuki” approach to obtain 2 and analogous compounds described above would be a viable large scale method.…”

“…Next, using the same conditions as in the manufacture of 1 , an S N Ar reaction of S - 24 and the chiral piperazine 25 , furnished compound S - 26 in 76% yield (Scheme ). An iron-mediated reduction of S - 26 furnished S - 27 , which was methylated to give compound S - 28 in 77% overall yield.…”

Selective Metalation of Functionalized Quinazolines to Enable Discovery and Advancement of Covalent KRAS Inhibitors

“…The new methods accelerated not only SAR studies within medicinal chemistry but also the biological profiling of ARS-1620. Because this class of compounds continues to be important for both academic and industrial researchers, it is easy to envision additional applications of the versatile TMP-Zn bases. In a more general sense, the results presented here are a prime demonstration of the advantage of bringing process-minded chemistry teams on board relatively early during the execution of medicinal chemistry projects.…”