A PRACTICAL AND EFFICIENT SYNTHESIS OF THE SELECTIVE NEURONAL ACETYLCHOLINE-GATED ION-CHANNEL AGONIST -(-)-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 -(-)-5-eth ynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate [(S)-2, SIB-1508Y] is described. The key steps in the process include the lithium bis(trime thylsilyl)amide-mediated acylation of N-vinylpyrrolidinone with ethyl 5-bromonicotinate, a high-yielding sodium borohydride reduction of imi ne 5, and a new heteroaryl-alkyne cross-coupling protocol for the intr oduction of the ethyne moiety in (S)-2. The preparation of enantiomeri cally pure (S)-2 was accomplished via a combination of enantioselectiv e reduction of imine 5 and crystallization of enantiomerically enriche d 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (7) as the dibenzoyl-L-t artaric acid salt.