Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor

New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.

pubs.acs.org

Translation of Nickel-Catalyzed C(sp2)–C(sp3) Cross-Electrophile Coupling to Non-Amide Solvents

The cross-electrophile coupling of organobromides is widely utilized in organic synthesis but generally requires undesirable amide solvents (e.g., DMF, DMA, and NMP). We report that the combination of...

doi.org

Cross-Electrophile Coupling to Form Sterically Hindered C(sp2)–C(sp3) Bonds: Ni and Co Afford Complementary Reactivity

The formation of sterically hindered C(sp2)–C(sp3) bonds could be a useful synthetic tool but has been understudied in cross-electrophile coupling. Here, we report two methods that couple secondary alkyl bromides with aryl halides that contain sterically hindered C–X bonds: 1) ortho-substituted aryl bromides with nickel catalysts and 2) di-ortho-substituted aryl iodides with cobalt catalysts. Stoichiometric experiments and deuterium labeling studies show that 1) [Co] is better than [Ni] for oxidative addition of di-ortho-substituted Ar–I and 2) [Co] is better than [Ni] for radical capture/reductive elimination steps with di-ortho-substituted arenes. For both metals, Ar–H side products observed in reactions with low-yielding di-ortho-substituted aryl iodides appear to arise from Ar• formation and hydrogen-atom transfer from the solvent. While the origins of the differences in scope are not yet understood, these studies demonstrate a previously unknown complementarity between nickel and cobalt in cross-electrophile coupling.

doi.org

Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Triflates with Alkyl Halides: Mechanism-Informed Design of More General Conditions

Aryl triflates make up a class of aryl electrophiles that are available in a single step from the corresponding phenol. Despite the known reactivity of nickel complexes for aryl C–O bond activation of phenol derivatives, nickel-catalyzed cross-electrophile coupling using aryl triflates has proven challenging. Herein, we report a method to form C(sp2)–C(sp3) bonds by coupling aryl triflates with alkyl bromides and chlorides using phenanthroline (phen) or pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN)-ligated nickel catalysts. The scope of the reaction is demonstrated with 38 examples (61 ± 14% average yield). Mechanistic studies provide a rationale for the conditions used and a roadmap for further applications of cross-electrophile coupling. First, the rate of alkyl radical generation is controlled by maintaining the majority of alkyl halide as the alkyl chloride, which is unreactive, and utilizing a dynamic halide exchange process to adjust the concentration of reactive alkyl bromide or iodide. Second, the challenge of using electron-rich aryl triflates appears to be due to off-cycle transmetalation to form unproductive aryl zinc reagents. The optimal PyBCamCN ligand together with LiCl avoids this deleterious transmetalation step.

doi.org

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous liga...

pubs.acs.org