A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate.
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.
Department of Process Research, Merck, 16711 Autoroute Transcanadienne, Kirkland, Québec, Canada H9H 3L1. carmela_molinaro@merck.com
Carmela
C
Molinaro
Scott
S
Shultz
Amélie
A
Roy
Stephen
S
Lau
Thao
T
Trinh
Rémy
R
Angelaud
Paul D
PD
O'Shea
Stefan
S
Abele
Mark
M
Cameron
Ed
E
Corley
Jacques-Alexis
JA
Funel
Dietrich
D
Steinhuebel
Mark
M
Weisel
Shane
S
Krska
D002384:Catalysis; D003408:Cresols / Q000737:chemistry*; D003521:Cyclopropanes / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006865:Hydrogenation; D006973:Hypertension / Q000188:drug therapy; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D011725:Pyridines / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012083:Renin / Q000737:chemistry; D013237:Stereoisomerism; D000092502:Renin Inhibitors
D003408:Cresols; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; D012083:Renin; D000092502:Renin Inhibitors; C032538:4-cresol; C032727:piperidine; C571787:MK-1597