Development of a Synthesis of Kinase Inhibitor AKN028

Abstract

The novel tyrosine kinase inhibitor AKN028 has demonstrated promising results in preclinical trials. An expedient protocol for the synthesis of the compound at kilogram scale is described, including an S N Ar reaction with high regioselectivity and a Suzuki coupling. Furthermore, an efficient method for purification and removal of residual palladium is described.

A broadly applicable quantitative relative reactivity model for nucleophilic aromatic substitution (SNAr) using simple descriptors

“…As a test of the ESP/EA model's potential utility in real-world synthetic planning, we sought to validate its predictions against S N Ar reactions used to prepare clinical candidate active pharmaceutical ingredients (APIs). These include recent reports on branebrutinib, 134 an EGFR T790 M inhibitor, 135 a Nav1.7 inhibitor, 136 a tyrosine kinase inhibitor, 137 an SRI/5-HT 2A antagonist, 138 an RoRγ inverse agonist, 139 and merestinib 140 ( Fig. 12 ).…”

Palladium Extraction Following Metal-Catalyzed Reactions: Recent Advances and Applications in the Pharmaceutical Industry

“…Several more case studies of the successful use of functionalized silicas and resins have been reported by pharmaceutical companies, demonstrating their utility and applicability on an industrial scale. − An additional benefit exhibited by functionalized silica scavengers is the ease of metal recovery via incineration. This is a favorable property, as metal catalysts typically account for approximately 5–20% of total manufacturing costs; hence, recovery and potential recycling of the metal are highly beneficial in making the process as economical as possible .…”

Natural Products–Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry

“…Eszopiclone Insomnia [24,25] Zopiclone Treatment of sleep disorders [26] Cephalostatin 1 Anticancer [27,28] Favipiravir Antiviral (approved in Japan, influenza; FDA clearance, COVID-19) [29][30][31] (-)-Barrenazine A Anticancer [32] (-)-Barrenazine B Anticancer [32] Alocasin A Anticancer [33] AKN-028 Acute myeloid leukemia [34,35] Acute myeloid leukemia [34,35] Botryllazine Anticancer [36,37] Phenazine-1-carboxylic acid Antibacterial [38] 2-Bromo-1-hydroxy phenazine Antibacterial [39] Griseolutein A Antibacterial [40] HP-14 Biofilm-eradicating agent [41] Iodinin Antibacterial [42] Myxin Antibacterial [43] Quinoxidine Antibacterial [44] Dioxidine Antibacterial [44] Anticancer [36,37] Phenazine-1-carboxylic acid Botryllazine Anticancer [36,37] Phenazine-1-carboxylic acid Antibacterial [38] 2-Bromo-1-hydroxy phenazine Antibacterial [39] Griseolutein A Antibacterial [40] HP-14 Biofilm-eradicating agent [41] Iodinin Antibacterial [42] Myxin Antibacterial [43] Quinoxidine Antibacterial [44] Dioxidine Antibacterial [44] Antibacterial [38] 2-Bromo-1-hydroxy phenazine Botryllazine Anticancer [36,37] Phenazine-1-carboxylic acid Antibacterial…”