Abstract
Abstract(−)‐Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6‐step synthesis of (−)‐finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (−)‐finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.
Highlights
Abstract: (À)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes
Because of these significant short comings, we were interested in developing an enantioselective synthesis of this challenging molecule
With the amino alcohol (4) in hand, we investigated the enantioselective [4+2]-cyclization with acetoacetamide 5 using a broad array of chiral phosphoric acids
Summary
Abstract: (À)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. E) (R)-TRIP (10 mol %), acetoacetamide (3.0 equiv), 4 molecular sieves, toluene, 110 8C, 24 hours; ee of the product was determined by chiral SFC. As catalyst (Scheme 1, see the Supporting Information for further details).
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