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Abstract

A large-scale process is described herein for preparing a cyclic peptide as described, comprising solid phase peptide synthesis of a linear peptide and cleaving it from the resin; oxidizing cysteine residues to form an intramolecular disulfide bond; and isolating the cyclic peptide, wherein:

(i) coupling uses diisopropylcarbodiimide and ethyl cyanohydroxyiminoacetate and/or N-hydroxybenzotriazole;(ii) cleaving comprises contacting the peptide with a solution comprising TFA and dithioerythritol and/or dithiothreitol;(iii) the peptide is precipitated after cleaving without prior concentration of the peptide by evaporation;(iv) oxidizing comprises contacting an aqueous solution comprising at least 5 mg/mL peptide with hydrogen peroxide;(v) isolating comprises loading the peptide on a reverse phase chromatography at up to 40 grams/kg column, and elution from the column;(vi) isolating comprises lyophilization, followed by grinding the peptide; and/or(vii) substitution of the resin is at least 0.3 milliequivalents/gram, and/or the resin is a Rink aminomethylstyrene resin.

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First Claim