AZD1656 is a potent, selective glucokinase activator that progressed to Phase IIb trials for the treatment of Type II diabetes. To support the clinical trials, Process Chemistry focused on the development of a route to AZD1656 that was amenable to scaleup and deemed to be commercially viable, retaining the same building blocks as the Medicinal Chemistry synthesis. The a-resorcylate core was functionalized using a Mitsunobu reaction followed by an SNAr reaction in a sequence that differentiated the two resorcylate hydroxyl groups by protecting one of them. The synthesis of the coupling partner for the SNAr involved a highly selective decarboxylation and the control of impurities arising from the use of azetidine as a coupling partner. Downstream challenges included an amidation reaction with a pyrazine coupling partner made using a Curtius rearrangement performed in batch mode, and the development of crystallization conditions that allowed the reproducible isolation of a slow-growing polymorph of the API. The processes developed were tested as part of a 500kg manufacture of AZD1656.

Development of the glucokinase activator AZD1656: Part 2

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.