This patent application publication describes a method for preparing a tripeptide that does not require the step of isolating and purifying the intermediate peptides produced after completion of each reaction. The method also does not require protecting groups.
In the reaction sequence, a carboxylic acid is reacted as a triethylammonium salt with a chloroformate to form the carbonate. This step uses triethylamine as the base and also serves as a nucleophilic catalyst and does not use phase-transfer catalysis.
Frankly, in our opinion, PTC could be used in this step to replace the 1.5 equivalents of triethylamine with catalytic triethylamine and less expensive stoichiometric carbonate or hydrogen carbonate. That would potentially save money and greatly reduce the hassle of liberating so much triethylamine from its hydrochloride for recovery and recycle or for disposal.
The inventor is explicit in citing the use of a hydrophobic solvent that forms two phases with water, which is preferable for a PTC system, especially when using water-sensitive compounds in order to protect them from hydrolysis.
In the second step, the inventor notes that a phase-transfer catalyst can be used to react the unprotected nitrogen of proline with the carbonate. The inventor cites 9 possible quaternary ammonium cations, three possible quaternary phosphonium cations, five crown ethers and a few polyethylene glycols as suitable for the second reaction. The inventor chose CTAB (cetyl trimethyl ammonium chloride) as the phase-transfer catalyst for the second reaction. In principle, CTAB could be acting as a surfactant and not a phase-transfer catalyst. The formation of emulsions is not reported so it is possible that CTAB is indeed acting as a phase-transfer catalyst and not as an emulsifier.
The inventor produced two different tripeptides using this method. The second example produced Boc-Gly-Pro-Gly-Pro-Gly-Val-Leu-OH and also used CTAB as the phase-transfer catalyst.
This publication definitely has interesting aspects.
