Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.
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.
Hiebl
J
J
Topcro Pharma Research GmbH, Linz, Austria.
Alberts
D P
DP
Banyard
A F
AF
Baresch
K
K
Baumgartner
H
H
Bernwieser
I
I
Bhatnagar
P K
PK
Blanka
M
M
Bodenteich
M
M
Chen
T
T
Esch
P M
PM
Kollmann
H
H
Lantos
I
I
Leitner
K
K
Mayrhofer
G
G
Patel
R
R
Rio
A
A
Rovenszky
F
F
Stevenson
D
D
Tubman
K D
KD
Undheim
K
K
Weihtrager
H
H
Welz
W
W
Winkler
K
K
D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry*
D007202:Indicators and Reagents; D009842:Oligopeptides; D010446:Peptide Fragments; C086049:SK&F 107647