Overcoming Chemical Challenges in the Solid-Phase Synthesis of High-Purity GnRH Antagonist Degarelix. Part 2

The highly potent, long-acting, gonadotropin-releasing\nhormone\nantagonist Degarelix is known to be very efficient for prostate cancer\ntreatment. The synthesis of decapeptide Degarelix is complicated because\nof the presence in its sequence of several unnatural α-amino\nacids, which are prone to rearrangements and side reactions. In particular,\nthe rearrangement of the dihydroorotic (Hor) moiety with following\nhydantoin formation in the presence of bases represents one of the\nmajor problems. In this study, we describe a novel chemical strategy\nto overcome this obstacle by the use of the corresponding <i>p</i>-nitrophenylalanine derivative, which is reduced on the\nsolid support to <i>p</i>-aminophenylalanine and acylated\nwith dihydroorotic acid at the end of the solid-phase synthesis. Thus,\nthe contact of Hor with the bases required for Fmoc deprotection is\ncompletely avoided. This approach provides a superior purity of Degarelix\nwhen the synthesis is carried out in the industrial scale as well.