Development of a Novel Solid Support for the Economical Synthesis of Leuprolide Drug

摘要

The secretion of luteinizing hormone-releasing hormone/follicle stimulation hormone (LHRH/FSH) is under the stimulatory control of the gonadotropin releasing hormone (GnRH), a decapeptide-amide. Leuprolide, a nonapeptide with a C-terminal alkylamide moiety is an analog of LH-RH/FSH and has been approved and marketed as a drug for prostate cancer. Leuprolide has been prepared by both solution phase and solid phase methods, employing Boc/Benzyl chemistry [1-4] and Fmoc/t-butyl methodology [5-10]. During the synthesis, the C-terminal amino acid of leuprolide either has a benzyl ester group or is attached to a solid support via a benzyl ester linkage. This requires alkylaminolysis at the end of the synthesis to yield the protected leuprolide, which after acidolysis results into leuprolide. Nowadays, the most common way to synthesize peptides quickly is via solid phase approach, where the success is heavily determined by the solid support applied and its performance. Currently, there is no general rule to decide on the most convenient and effective solid support for a particular peptide synthesis. However, it is important to consider the type of chemistry to be carried out during the synthesis, resin-reagent compatibility, swelling to solvent ratio, and the length as well as the sequence of the. desired peptide.