Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two S_NAr Reactions, Oxidation and Suzuki Coupling

Abstract

A sustainable second-generation process for GDC-0134 was developed with a particular focus on safety and greenness, while complying with strong specifications to supply pivotal clinical studies. Through these efforts, we discovered solvents to replace the solvents classified as substances of very high concern by the REACH regulation in two SNAr steps. We further established a safer and faster way to oxidize the sulfanyl to the sulfonyl intermediate by dosing H2O2 at higher temperatures, reducing accumulation while minimizing uncontrolled H2O2 decomposition. The reaction conditions for the Suzuki coupling and the second SNAr were modified to increase the selectivity in these two steps. A change in the solvent for the final crystallization allowed operation at higher concentrations and delivery of a highly pure active pharmaceutical ingredient (API). The new improved process reduced the process mass intensity by approximately 40% and was successfully used to produce 150 kg of GDC-0134.

Kilo-Scale Electrochemical Oxidation of a Thioether to a Sulfone: A Workflow for Scaling up Electrosynthesis

“…Instead, an improvement in process safety could be attained via in situ electrochemical generation of substoichiometric quantities of oxidants (i.e., mediated oxidation), thus reducing the amount present in the reaction at any given time. Because of the prevalence of sulfone moieties within APIs (Scheme A) − and as leaving groups in synthetic routes, , we chose the oxidation of a thioether to a sulfone as our model reaction.…”

Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis

“…The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01056. Kinase panel, crystal data collection and refinement statistics, 1 H NMR spectra, 19 F-NMR spectra, LC spectra, and MS spectra (PDF)…”

“…5 Of the type I inhibitors reported, most are defined by an amino-pyridine hinge-binding motif. When coupled with diverse heterocycles (pyridine GNE-3511, 11 pyrazole GNE-8505, 17 imidazole 3, 18 and pyrimidine GDC-0134), 19 these amino-pyridine inhibitors (Figure 1) 20 have been shown to be potent against DLK/LZK with favorable in vivo properties. Notably, GDC-0134 (4) has also completed phase 1 clinical studies in ALS patients.…”

Synthesis of Adagrasib (MRTX849), a Covalent KRASG12C Inhibitor Drug for the Treatment of Cancer

“…Compound 11, in turn, could be prepared from an appropriately activated pyrimidone (13a or 13b) via another S N Ar reaction. 13,14 Ketoester 17 could be obtained using conventional chemistry and would serve as starting material for the construction of the tetrahydropyridopyrimidine core. 15 The synthesis began with the preparation of ketoester 17 via a three-step through process.…”

“…We conceived that penultimate 9 could be prepared from compound 11 and chiral piperazine 12 via a S N Ar reaction. Compound 11 , in turn, could be prepared from an appropriately activated pyrimidone ( 13a or 13b ) via another S N Ar reaction. , Ketoester 17 could be obtained using conventional chemistry and would serve as starting material for the construction of the tetrahydropyrido­pyrimidine core …”