Integration of a Highly Selective Demethylation of a Quaternized Ergoline into a One-Pot Synthesis of Pergolide

We have developed a high-yielding one-pot synthesis of pergolide (10) from dihydrolysergol (1), which was isolated as pergolide mesylate (6, Permax), a semisynthetic ergot alkaloid marketed for the adjunctive treatment of Parkinson's disease. The process involved the formation of quaternized amine intermediates, followed by a highly selective demethylation and thioether formation via thiomethoxide ion. A novel tandem chromatography procedure was used to remove closely related byproducts, which included an unexpected and unusual thiomethyl ether homologue of pergolide.