title: Large-scale asymmetric synthesis of a cathepsin S inhibitor.
abstract: 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.
authors.affiliation: Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. jon.lorenz@boehringer-ingelheim.com
authors.forename: Jon C
authors.initials: JC
authors.lastname: Lorenz
authors.forename: Carl A
authors.initials: CA
authors.lastname: Busacca
authors.forename: XuWu
authors.initials: X
authors.lastname: Feng
authors.forename: Nelu
authors.initials: N
authors.lastname: Grinberg
authors.forename: Nizar
authors.initials: N
authors.lastname: Haddad
authors.forename: Joe
authors.initials: J
authors.lastname: Johnson
authors.forename: Suresh
authors.initials: S
authors.lastname: Kapadia
authors.forename: Heewon
authors.initials: H
authors.lastname: Lee
authors.forename: Anjan
authors.initials: A
authors.lastname: Saha
authors.forename: Max
authors.initials: M
authors.lastname: Sarvestani
authors.forename: Earl M
authors.initials: EM
authors.lastname: Spinelli
authors.forename: Rich
authors.initials: R
authors.lastname: Varsolona
authors.forename: Xudong
authors.initials: X
authors.lastname: Wei
authors.forename: Xingzhong
authors.initials: X
authors.lastname: Zeng
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: 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
chemical_list: D000475:Alkenes; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D014753:Vinyl Compounds; D010165:Palladium; D014508:Urea; D012238:Rhodium; D002403:Cathepsins; C028217:cathepsin S