Development of a Rapid Scale-Up Synthesis of (S)-N-(8-((2-Amino-2,4-dimethylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-2-yl)acetamide, a Potent Adaptor-Associated Kinase 1 Inhibitor

Abstract

(S)-N-(8-((2-Amino-2,4-dimethylpentyl)­oxy)-5H-chromeno­[3,4-c]­pyridin-2-yl)­acetamide (1) is a potent adaptor-associated kinase 1 inhibitor, which may have the potential to treat neuropathic pain and other neurological disorders including schizophrenia, Parkinson’s disease, bipolar disorder, and Alzheimer’s disease. For preclinical studies, a substantial amount of high-quality material was required. The original discovery route for the preparation of this compound suffered from scale-up issues that included a very low-yielding C–O coupling step and the use of expensive and toxic reagents. This paper describes a rapid scale-up synthesis accomplished in eight steps, which involves the coupling of phenol 17 with oxathiazolidine 18 as the key transformation.

Amphiphilic Polyfluorinated Amino Ethers from Cyclic Sulfamidates

“…However, the reaction of cyclic sulfamidates was reputed as challenging with “classic” alkoxides. Indeed, strong oxygen nucleophiles such as sodium methoxide turned out to be reluctant partners in this reaction. − Phenoxide and derivatives are weaker bases than alkoxides and a class of oxygen nucleophiles that has demonstrated synthetic utility in the ring opening of cyclic sulfamidates. − We surmised that the electron-withdrawing property of fluorine atoms in polyfluorinated alkoxides could impart appropriate nucleophilicity to allow smooth reaction with cyclic sulfamidates.…”

Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain

“…To overcome this synthetic difficulty, the cyclic sulfonamide 38 derived from 35 was used to simultaneously activate the OH group and protect the NH 2 group and thereby enable efficient coupling. Scheme describes a practical route to access chiral cyclic sulfonamide 38 from the previously disclosed intermediate ( S )- 36 . The double bond was reduced, and the Cbz group was removed in one pot to afford intermediate 37 .…”

Synthesis of 5H-chromeno[3,4-c]pyridine derivatives through ruthenium-catalyzed [2 + 2 + 2] cycloaddition

“…For example, a series of functionalized 5 H -chromeno[3,4- c ]pyridines have recently proved to be an efficient dual ROCK1 and ROCK2 inhibitor (Scheme 1a). 2 In this case, the nature of the functional chain bound to the chromenopyridine unit plays a key role in the ROCK inhibition process. 11 C-labeled radioligands involving chromeno[3,4- c ]pyridin-5-one scaffolds were also used in in vivo PET studies for the analysis of the dopamine D4 receptor subtype (Scheme 1b).…”