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.