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

  • J Pept Res. 1999 Jul;54(1):54-65. doi: 10.1034/j.1399-3011.1999.00089.x.
J Hiebl  1 ,  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
Affiliations
  • 1. Topcro Pharma Research GmbH, Linz, Austria.
PMID: 10448970 DOI: 10.1034/j.1399-3011.1999.00089.x
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.

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