Recovery of a Peptide Intermediate from a Reaction Mixture Contaminated with a Large Quantity of Silicone Oil Coolant

Abstract

Accidental cracking at the bottom of a glass reactor vessel allowed silicone oil coolant to contaminate the reaction mixture of an N-terminal-free tripeptide intermediate (3) in the synthesis of a mid-sized cyclic peptide. Approximately 20 kg of silicone oil was leached from the reactor jacket and mixed with 35 kg of the reaction mixture. Our preliminary investigations showed that although the silicone oil and its degradation products could not be sufficiently removed by using heptane extraction from an acetonitrile solution of 3, these silicone-derived components could be successfully removed from an acidic aqueous solution of 3. Because 3 is an acid-sensitive N-alkylated peptide tert-butyl ester, it was essential to find an aqueous acidic solution that minimized decomposition while efficiently retaining 3 in solution. Using this approach, the silicone-derived components were reduced to a residual amount of 0.02 wt % relative to 3, with a 90% recovery of 3 from the contaminated reaction mixture.