Synthesis of a potent cathepsin s inhibitor labeled with deuterium and carbon-14.
Morpholine-4-carboxylic acid {(S)-1-[4-cyano-1-(3-morpholin-4-yl-propyl)-piperidin-4-ylcarbamoyl]-4,4- dimethyl-hexyl}-amide, (1) is a potent reversible and selective cathepsin S inhibitor. Deuterium labeled (1) was prepared in four steps in 62% overall yield from [2H8]- morpholine and chiral acid (6). Carbon-14 labeled (1) was obtained in two steps using sodium [14C]-cyanide in a modified Strecker reaction followed by amide bond formation with acid (6) in 74% overall radiochemical yield. The phosphate salt of this compound was produced by treatment with phosphoric acid in methanol in 97% yield.
Boehringer Ingelheim Pharmaceuticals, Research and Development Center, Ridgefield, CT 06877-0368, USA. bachir.latli@boehringer-ingelheim.com
Bachir
B
Latli
Matt
M
Hrapchak
Jon C
JC
Lorenz
Carl A
CA
Busacca
Chris
C
Senanayake
D002250:Carbon Radioisotopes / Q000737:chemistry*; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003903:Deuterium / Q000138:chemical synthesis*; D009025:Morpholines / Q000138:chemical synthesis*; D010880:Piperidines / Q000138:chemical synthesis*
D002250:Carbon Radioisotopes; D009025:Morpholines; D010880:Piperidines; C579620:morpholine-4-carboxylic acid (1-(4-cyano-1-(3-morpholin-4-ylpropyl)piperidin-4-ylcarbamoyl)-4,4-dimethylhexyl)amide; C037574:morpholine; D003903:Deuterium; D002403:Cathepsins; C028217:cathepsin S