title: Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.
abstract: Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)2-DAS-(Lys)2 (2, SK&F 107647) were investigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2. Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)2-DAS-(Lys(Z)-OBn)2 (6, DAS-2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl-1,1,3,3-tetrameth yluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.
authors.affiliation: Topcro Pharma Research GmbH, Linz, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Hiebl
authors.forename: D P
authors.initials: DP
authors.lastname: Alberts
authors.forename: A F
authors.initials: AF
authors.lastname: Banyard
authors.forename: K
authors.initials: K
authors.lastname: Baresch
authors.forename: H
authors.initials: H
authors.lastname: Baumgartner
authors.forename: I
authors.initials: I
authors.lastname: Bernwieser
authors.forename: P K
authors.initials: PK
authors.lastname: Bhatnagar
authors.forename: M
authors.initials: M
authors.lastname: Blanka
authors.forename: M
authors.initials: M
authors.lastname: Bodenteich
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.forename: P M
authors.initials: PM
authors.lastname: Esch
authors.forename: H
authors.initials: H
authors.lastname: Kollmann
authors.forename: I
authors.initials: I
authors.lastname: Lantos
authors.forename: K
authors.initials: K
authors.lastname: Leitner
authors.forename: G
authors.initials: G
authors.lastname: Mayrhofer
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.forename: A
authors.initials: A
authors.lastname: Rio
authors.forename: F
authors.initials: F
authors.lastname: Rovenszky
authors.forename: D
authors.initials: D
authors.lastname: Stevenson
authors.forename: K D
authors.initials: KD
authors.lastname: Tubman
authors.forename: K
authors.initials: K
authors.lastname: Undheim
authors.forename: H
authors.initials: H
authors.lastname: Weihtrager
authors.forename: W
authors.initials: W
authors.lastname: Welz
authors.forename: K
authors.initials: K
authors.lastname: Winkler
mesh_terms: D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry*
chemical_list: D007202:Indicators and Reagents; D009842:Oligopeptides; D010446:Peptide Fragments; C086049:SK&F 107647