合成路线1

Treatment of 5-bromo-3-pyridinecarboxylic acid (I) with thionyl chloride in 1,2-dichloroethane (DCE) gives acid chloride hydrochloride (II), which is converted to ester (III) on treatment with ethanol in DCE. Claisen condensation of ester (III) with N-vinylpyrrolidinone (IV) in the presence of littium bis(trimethylsilyl)amide followed by refluxing in aqueous hydrochloric acid gives the pyrroline (V). The reduction of pyrroline (V) with sodium borohydride in the presence of the chiral auxiliary N-carbobenzyloxy-L-proline yields the enantiomerically enriched (S)-pyrrolidine (VI) with an e.e. of 30%. This compound is reductively methylated in a mixture of aqueous formaldehyde and formic acid, and the resulting N-methylpyrrolidine (VII) is converted to the di-p-toluoyl-D-tartaric acid salt, and recrystallized from ethanol-ethyl acetate to increase the e.e. to 90%. The free amine (VII) is coupled with trimethylsilyl acetylene (VIII), in the presence of bis(triphenylphosphine)palladium dichloride, cuprous iodide, and triethylamine in THF. The resulting compound (IX) is treated with cesium carbonate in refluxing methanol to remove the trimethylsilyl group, and finally converted to the maleate salt on treatment with maleic acid in methanol.