Process for manufacturing peptide

A large-scale process of preparing a cyclic peptide having SEQ ID NO:

• 1, or a pharmaceutically acceptable salt thereof, the process comprising:
• (a) sequentially coupling amino acids and 4-fluorobenzoic acid to a resin by solid phase peptide synthesis, thereby obtaining a linear peptide coupled to said resin;
• (b) cleaving said linear peptide from said resin, thereby obtaining a free linear peptide;
• (c) oxidizing cysteine residues of said linear peptide to form an intramolecular disulfide bond, thereby obtaining the cyclic peptide having SEQ ID NO:
• 1 in solution;
• and
• (d) isolating the cyclic peptide having SEQ ID NO:
• 1, or a pharmaceutically acceptable salt thereof,
• wherein:
• (i) said coupling is effected using diisopropylcarbodiimide (DIC) in combination with ethyl cyanohydroxyiminoacetate and/or N-hydroxybenzotriazole;
• (ii) said cleaving is effected by contacting said linear peptide coupled to said resin with a solution comprising trifluoroacetic acid (TFA) and a scavenger selected from the group consisting of dithioerythritol (DTE) and dithiothreitol (DTT);
• (iii) the process further comprises precipitating said free linear peptide after said cleaving without concentrating said free linear peptide by evaporation prior to said precipitating;
• (iv) said oxidizing is effected by contacting an aqueous solution comprising said linear peptide at a concentration of at least 5 mg/mL with hydrogen peroxide;
• (v) said isolating comprises loading said cyclic peptide on a reverse phase chromatography column at a concentration of no more than 40 grams cyclic peptide per kg of said column, and eluting said cyclic peptide from said column;
• (vi) said isolating the cyclic peptide having SEQ ID NO:
• 1 comprises lyophilization, and the process further comprises grinding said cyclic peptide following said lyophilization;
• and/or
• (vii) a degree of substitution of said resin is at least 0.3 milliequivalents per gram and/or said resin is a Rink aminomethylstyrene resin.