US 6,476,186 B1Granted

Process for preparing octreotide and derivatives thereof

AssigneeInstitute of Nuclear Energy Research

InventorsYao-Tsung Hsieh, Shiang-Rong Chang, Shyh-Yi Chyi, Hui-Lan Wu, Shu-Ling Chen, Henton Huang, Te-Wei Lee, Tian-Fu Huang

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Abstract

This invention relates a process for preparing octreotide and derivatives thereof. The starting material, Thr(ol)(tBu)-2-chlorotrityl resin is coupled with the various amino acids. The straight peptide-resin of D-Phe-Cys(Trt)-Phe-D-Trp(Boc)-Lys(Boc)-Thr(tBu)-Cys(Trt)-Thr(ol)(tBu)-2-chlorotrityl resin or D-Phe-Cys(Trt)-Tyr(tBu)-D-Trp(Boc)-Lys(Boc)-Thr(tBu)-Cys(Trt)-Thr(ol)(tBu)-2-chlorotrityl resin was obtained. Cleavage of the peptide from the resin was achieved by strong acid solution. The cleaved peptide reacted with charcoal to give disulfide-containing peptide of

Claims6

Dependent claims

A method for preparing octreotide (IA) comprising the following steps:

(1) activating Fmoc-xxx(yyy)-OH through the addition of Benzotriazolyloxytetramethyluronium hexafluorophosphate, where initially xxx is Cys and yyy is Trt;
(2) coupling said activated Fmoc-xxx(yyy)-OH with a straight chain resin, said straight chain resin initially being Thr(ol)(tBu)-2-chlorotrityl resin, to form a Fmoc-protected straight chain resin;
(3) removing said Fmoc through the addition of piperidine to form said straight chain resin;
(4) repetitively repeating steps (1), (2) and (3) in consecutive order for producing a straight chain peptide-resin compound where xxx and yyy are substituted in the following order:
xxx is Thr and yyy is tBu;
xxx is Lys and yyy is Boc;
xxx is D-Trp and yyy is Boc;
xxx is Phe and yyy is absent;
xxx is Cys and yyy is Trt;
and xxx is D-Phe and yyy is absent;
(5) cleaving said straight chain peptide-resin compound of step (4) with strong acid to obtain a straight chain peptide compound;
and
(6) reacting said straight chain peptide compound of step (5) with charcoal to obtain the octreotide (IA).

10 more elements

Dependencies are inferred from the claim text.