The synthesis of pasireotide is relatively straightforward, given that the chemical entity is a cyclic
peptide. The most likely scalable route closely mimics that described by the discovery authors
involving a series of conventional couplings and deprotection steps to arrive at a linear peptide which
then underwent sequential release from solid support, macrocyclization, and a global deprotection step.
Beginning from (2S,4R)-4-hydroxyproline methyl ester (110) in the scheme above, this pyrrolidine
nitrogen was first Fmoc-protected in 85% yield followed by treatment with trisphosgene and N-Boc
diaminoethane to provide the prolino carbamate shown in 49% yield over the two step sequence after a
recrystallization with ethyl acetate.
Next, commercially available Fmoc-Tyr(Bzl)-O-CH2-Ph(3-OCH3)-O-CH2-SASRIN157 resin (112)
was used as starting material in a manually operated reactor and carried through a standard protocol
consisting of repetitive cycles of N|á deprotection (piperidine/DMF, 2:8), repeated washings with DMF,
and coupling using DIC/HOBT in DMF (Schemes 2 and 3). The following amino acid derivatives
were sequentially coupled: Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-PhG-OH, proline
derivative 111 above, and finally Fmoc-Phe-OH. Couplings were continued or repeated until complete
disappearance of residual amino groups as monitored with a ninhydrin stain test. Before cleavage of the
protected linear peptide from its resin support, the Fmoc group was removed. After washings with
dichloromethane, the peptide resin was transferred into a column and the peptide fragment was cleaved
from solid support upon subjection to 2% TFA in dichloromethane. The eluate was immediately
neutralized with a saturated NaHCO3 solution which resulted in the side chain protected fragment 119
(the Scheme) was obtained in 93% homogeneity and cyclized without further purification. For
cyclization, the linear fragment was dissolved in DMF, treated with DIPEA, and then 1.5 equiv of
diphenylphosphoryl azide which resulted in the protected cyclized product obtained in good yield. For complete deprotection, the residue was dissolved at 0 ??C in aqueous TFA, and the mixture was stirred at
this temperature for 30 min. The product was then precipitated with ether containing ca. 10 equiv of
HCl, then filtered and washed with ether, and finally dried. The entire sequence produced pasireotide
(XVIII) in 20% yield from resin-bound 112.
