A convergent, scalable process was developed for the synthesis of adamantane 11-β-hydroxysteroid dehydrogenase-1 inhibitors E-4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionylamino)adamantane-1-carboxylic acid (1) and E-4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionylamino)adamantane-1-carboxamide (2) to rapidly deliver material for development. The process was high yielding and provided 1 in 52% overall yield over six total steps with a five-step longest linear sequence and 2 in 45% overall yield over seven total steps with a six-step longest linear sequence. A process to prepare active pharmaceutical ingredient (API) of >99% purity at the kilogram scale has been developed under tight delivery timelines.
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