A practical and efficient synthesis of the selective neuronal acetylcholine-gated ion channel agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate (SIB-1508Y)

An efficient, high-yielding synthetic procedure for the preparation of the novel neuronal acetylcholine-gated ion channel agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate [(S)-2, SIB-1508Y] is described. The key steps in the process include the lithium bis(trimethylsilyl)amide-mediated acylation of N-vinylpyrrolidinone with ethyl 5-bromonicotinate, a high-yielding sodium borohydride reduction of imine 5, and a new heteroaryl-alkyne cross-coupling protocol for the introduction of the ethyne moiety in (S)-2. The preparation of enantiomerically pure (S)-2 was accomplished via a combination of enantioselective reduction of imine 5 and crystallization of enantiomerically enriched 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (7) as the dibenzoyl-L-tartaric acid salt.