Organic Process Research and Development p. 681 - 696 (2018)
Update date:2022-08-30
Topics:
Smith, Aaron C.
Kung, Daniel W.
Shavnya, Andre
Brandt, Thomas A.
Dent, Philip D.
Genung, Nathan E.
Cabral, Shawn
Panteleev, Jane
Herr, Michael
Yip, Ka Ning
Aspnes, Gary E.
Conn, Edward L.
Dowling, Matthew S.
Edmonds, David J.
Edmonds, Ian D.
Fernando, Dilinie P.
Herrinton, Paul M.
Keene, Nandell F.
Lavergne, Sophie Y.
Li, Qifang
Polivkova, Jana
Rose, Colin R.
Thuma, Benjamin A.
Vetelino, Michael G.
Wang, Guoqiang
Weaver, John D.
Widlicka, Daniel W.
Price Wiglesworth, Kristin E.
Xiao, Jun
Zahn, Todd
Zhang, Yingxin
Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds 1-3 were scaled to supply material for preclinical studies, and indole 3 was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure-activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40-50 g of 1 and 2 and 2.4 kg of 3. Multiple polymorphs of 3 were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified.
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