Large-scale asymmetric synthesis of a cathepsin S inhibitor.
A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.
Lorenz
Jon C
JC
Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. jon.lorenz@boehringer-ingelheim.com
Busacca
Carl A
CA
Feng
XuWu
X
Grinberg
Nelu
N
Haddad
Nizar
N
Johnson
Joe
J
Kapadia
Suresh
S
Lee
Heewon
H
Saha
Anjan
A
Sarvestani
Max
M
Spinelli
Earl M
EM
Varsolona
Rich
R
Wei
Xudong
X
Zeng
Xingzhong
X
Senanayake
Chris H
CH
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry; D002151:Calorimetry / Q000379:methods; D002384:Catalysis; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D012238:Rhodium / Q000737:chemistry; D013237:Stereoisomerism; D014508:Urea / Q000138:chemical synthesis* / Q000737:chemistry; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry
D000475:Alkenes; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D014753:Vinyl Compounds; D010165:Palladium; D014508:Urea; D012238:Rhodium; D002403:Cathepsins; C028217:cathepsin S