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|Title:||Synthesis of cyclic peptides|
|Abstract:||A process for preparing and purifying cyclic peptides having disulfide moieties in a single processing operation which simplifies synthesis and reduces production costs, yet produces high, quality yield. Higher yields are obtained by isolating the desired cyclic compound through direct ion exchange chromatography as an integral part of the single process. The improved process is particularly useful for the preparation of vasopressin and oxytocin and their respective derivatives and analogs.|
|Inventor(s):||Andersson; Lars Henrik Harald (Lund, SE), Skoldback; Jan-Ake (Malmo, SE)|
|Assignee:||Ferring AB (Malmo, SE)|
|Filing Date:||Jun 20, 1996|
|Claims:||1. A method for preparing and purifying cyclic peptide compounds containing a disulfide moiety, comprising: |
a) forming a first solution by adding to a protic solvent at neutral or acidic pH, a non-cyclic peptide containing at least two reactive, protected or non-protected sulfhydryl groups;
b) forming a second solution of iodine dissolved in a protic solvent;
c) introducing said second solution containing iodine to said first solution containing said non-cyclic peptide such that the amount of iodine present in the resulting mixture is at least about stoichiometric with respect to the sulfhydryl groups;
d) allowing the mixture resulting from step (c) sufficient time for disulfide moiety formation and conversion of said non-cyclic peptide to said cyclic peptide compound;
e) adding the mixture from step (d) containing said cyclic peptide compound directly to a separation column containing cation exchange resin;
f) eluting said cyclic peptide compound; and
g) isolating said cyclic peptide compound.
2. The method of claim 1, wherein said non-cyclic peptide in its protonated form has an acidity constant (pK.sub.a) of approximately 7.5 or higher.
3. The method of claim 1, wherein said non-cyclic peptide in its protonated form has an acidity constant (pK.sub.a) of approximately 10 or higher.
4. The method of claim 1, wherein said non-cyclic peptide in its protonated form has an acidity constant (pK.sub.a) of approximately 12 or higher.
5. The method of claim 1, wherein said non-cyclic peptide is:
6. The method of claim 1, wherein said disulfide moiety formation reaction (d) is carried out below approximately 50.degree. C.
7. The method of claim 1, wherein said second solution (b) contains a stoichiometric excess of iodine.
8. The method of claim 1, wherein said cyclic peptide compound is eluted (f) with an aqueous buffer solution selected from the group consisting of ammonium acetate, acetic acid, and combinations of ammonium acetate and acetic acid.
9. The method of claim 1, wherein said isolated cyclic peptide compound is selected from the group consisting of vasopressin and oxytocin.