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  • Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.

Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.

The journal of peptide research : official journal of the American Peptide Society (1999-08-17)
J Hiebl, D P Alberts, A F Banyard, K Baresch, H Baumgartner, I Bernwieser, P K Bhatnagar, M Blanka, M Bodenteich, T Chen, P M Esch, H Kollmann, I Lantos, K Leitner, G Mayrhofer, R Patel, A Rio, F Rovenszky, D Stevenson, K D Tubman, K Undheim, H Weihtrager, W Welz, K Winkler
PMID10448970
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.