ABSTRACT
A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.
Subject(s)
Cresols/chemistry , Cyclopropanes/antagonists & inhibitors , Cyclopropanes/chemical synthesis , Cyclopropanes/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperidines/chemistry , Pyridines/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Renin/antagonists & inhibitors , Catalysis , Cyclopropanes/chemistry , Enzyme Inhibitors/chemistry , Hydrogenation , Hypertension/drug therapy , Molecular Structure , Pyridines/chemistry , Renin/chemistry , StereoisomerismABSTRACT
The suitability of the Eksigent Express 800 microfluidic eight-channel HPLC instrument for multiparallel normal-phase chiral analysis in support of high-throughput pharmaceutical process research was investigated. Analysis of test mixtures containing the two enantiomers of benzoin and the closely related (R,S)-dihydrobenzoin, was carried out in a 96-well microplate, affording rapid (<2 h) and accurate assessment of enantiopurity. In a second example, use of the instrument to support high-throughput catalyst screening of the asymmetric hydrogenation of a prochiral unsaturated ester is presented, in which method development (gradient screening of four columns and two eluents, followed by optimization to afford a fast analytical method) and analysis of a 96-well microplate was carried out within a single working day. This represents a considerable improvement over conventional analysis techniques that usually take several days to complete.
