合成路线1

The reaction of 2-piperidineethanol (I) with acrylonitrile (II) gives N-(2-cyanoethyl)piperidine-2-ethanol (III), which by treatment with SOCl2 is converted into the chloronitrile (IV). The cyclization of (IV) with NaH affords 3-cyanoquinolizidine (V), which by hydrolysis with ethanol and HCl yields ethyl quinolizidine-3-carboxylate (VI). The Grignard reaction of (VI) with 2-thienylmagnesium bromide gives thienyl-3-quinolizidinyl methanol (VIII), which is dehydrated with HCl ethanol to afford 3-(di-2-thienylmethylene)quinolizidine (IX). Finally, this compound is quaternirzed with methyl bromide in acetone.

合成路线2

The Grignard condensation of oxalic acid dimethyl ester (I) with 2-thienylmagnesium bromide (II) gives 2-hydroxy-2,2-bis(2-thienyl)acetic acid methyl ester (III), which is submitted to transesterification with scopine (IV) catalyzed by Na or NaOEt, providing the corresponding ester (V). Finally, (V) is quaternized with methyl bromide in dichloromethane/acetonitrile.

合成路线3

The condensation of 2-methylcyclohexanone (I) with 2-thienyl lithium (II) or 2-thienylmagnesium bromide (III) gives cyclohexanol (IV) as a diastereomeric mixture, which was treated with Na-N3 in trichloroacetic acid to yield the azide (V). The reduction of (V) with LiAlH4 or RaNi/iPr-OH affords the corresponding amine (VI), preferentially with the cis-configuration. Finally, this compound is condensed with 1,5-dibromopentane (VII) by means of K2CO3 in acetonitrile to provide the target compound as a diastereomeric mixture. The separation of the cis- and trans- racemates has been performed by HPLC. The optical resolution was performed by a cumbersome crystallization process using CSA and di-p-toluoyltartaric acid.

合成路线4