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

Linear and convergent routes for the large-scale preparation of the hemator egulatory nonapeptide (Glp-Glu-Asp)(2)-DAS-(Lys)(2) (2, SK&F 107647) were i nvestigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-g ram quantities of 2. Key steps were the preparation and the coupling of tri peptide hydrochloride (HCI.H)(2)-DAS-(Lys(Z)-OBn)(2) (6, DAS = 2,7-L,L-diam inosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coup ling reagents were investigated in order to reduce the amount of epimerizat ion of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1, 2, 3-benzotri azin-3-yl-1, 1, 3, 3-tetramethyluronium tetrafluoroborate] was identified a s the condensation reagent of choice. Using this synthetic route > 97% pure final produce in an overall yield of 35% calculated on di-Boc protected 2, 7-L,L-diaminosuberic acid was prepared.