Alkylation of methyl 4-(acetylamino)-2-hydroxybenzoate (I) with propargyl bromide (II) in the presence of K2CO3 in refluxing acetonitrile gave propargyl ether (III), and subsequent chlorination with N-chlorosuccinimide in DMF yielded (IV). Then, a Claisen-type rearrangement of (IV) in boiling diphenyl ether furnished the benzopyran (V), which was hydrogenated over Pt/C to give dihydrobenzopyran (VI). Subsequent treatment of (VI) with 4 N KOH produced the hydrolysis of both ester and amide functions, affording acid (VII). Treatment of dicyclopropyl ketone (VIII) with HCl gas provided 1,7-dichloro-4-heptanone (IX). Cyclization of (IX) with cyanoacetic acid in a two-phase system of aqueous ammonia and n-hexane gave bicyclic intermediate (X), which upon decarboxylation yielded nitrile (XI). Subsequent hydrogenation in the presence of Raney-Ni and NaOH furnished 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (XII) (3). The title compound was then obtained by coupling of acid (VII) with amine (XII) using carbonyldiimidazole (CDI), followed by conversion to the hemifumarate salt.

Alkylation of methyl 4-(acetylamino)-2-hydroxybenzoate (I) with propargyl bromide (II) in the presence of K2CO3 in refluxing acetonitrile gave propargyl ether (III), and subsequent chlorination with N-chlorosuccinimide in DMF yielded (IV). Then, a Claisen-type rearrangement of (IV) in boiling diphenyl ether furnished the benzopyran (V), which was hydrogenated over Pt/C to give dihydrobenzopyran (VI). Subsequent treatment of (VI) with 4 N KOH produced the hydrolysis of both ester and amide functions, affording acid (VII). Treatment of dicyclopropyl ketone (VIII) with HCl gas provided 1,7-dichloro-4-heptanone (IX). Cyclization of (IX) with cyanoacetic acid in a two-phase system of aqueous ammonia and n-hexane gave bicyclic intermediate (X), which upon decarboxylation yielded nitrile (XI). Subsequent hydrogenation in the presence of Raney-Ni and NaOH furnished 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (XII) (3). The title compound was then obtained by coupling of acid (VII) with amine (XII) using carbonyldiimidazole (CDI), followed by conversion to the hemifumarate salt.

Alkylation of methyl 4-(acetylamino)-2-hydroxybenzoate (I) with propargyl bromide (II) in the presence of K2CO3 in refluxing acetonitrile gave propargyl ether (III), and subsequent chlorination with N-chlorosuccinimide in DMF yielded (IV). Then, a Claisen-type rearrangement of (IV) in boiling diphenyl ether furnished the benzopyran (V), which was hydrogenated over Pt/C to give dihydrobenzopyran (VI). Subsequent treatment of (VI) with 4 N KOH produced the hydrolysis of both ester and amide functions, affording acid (VII). Treatment of dicyclopropyl ketone (VIII) with HCl gas provided 1,7-dichloro-4-heptanone (IX). Cyclization of (IX) with cyanoacetic acid in a two-phase system of aqueous ammonia and n-hexane gave bicyclic intermediate (X), which upon decarboxylation yielded nitrile (XI). Subsequent hydrogenation in the presence of Raney-Ni and NaOH furnished 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (XII) (3). The title compound was then obtained by coupling of acid (VII) with amine (XII) using carbonyldiimidazole (CDI), followed by conversion to the hemifumarate salt.