Improved Synthesis of Amino Acid and Dipeptide Chloromethyl Esters Using Bromochloromethane

Abstract

Peptide chloromethyl esters are important compounds in prodrug synthesis. A simple, mild and efficient method for the synthesis of chloromethyl esters of N-blocked amino acids and dipeptides using exclusively bromochloromethane is reported. These N-blocked amino acid and dipeptide chloromethyl esters react readily with the carboxylic acid group of aspirin and with the sulfonamido group of the antimalarial sulfamethazine, to give the corresponding prodrugs.

Keywords:

• Antimalarial
• Aspirin
• Bromochloromethane
• Chloro-methyl esters
• Peptides
• Prodrugs

Acknowledgments

The authors thank Fundação para a Ciência e Tecnologia for financial support (POCTI/FCB/39218/2001). PG thanks Dr. Adelina Macedo (Chemistry Department, Faculty of Sciences, University of Porto) for FAB/Ion Trap MS spectra. Special thanks to Drs. Eliandre de Oliveira, Judit Villén and Miquel Vila (Peptide Research Laboratory, University of Barcelona) for MALDI-TOF MS analyses.