合成路线1

Compound (XII) is finally condensed with piperazine-ethanol (XIII) in refluxing butanone. The separation of the trans isomer is performed by precipitation of the oxalate, treatment with dimethyl-amine in water and extraction with ether.

合成路线2

1) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) gives the intermediate benzylidene derivative (VII), which is finally cyclized with methyl 3-aminocrotonate (VIII) in refluxing isopropanol.

合成路线3

2) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The reaction of acetoacetate (V) with NH3 in ethanol gives the corresponding aminocrotonate (IX), which is then cyclized with methyl (3-nitrobenzylidene)acetoacetate (VI) [prepared from methyl acetoacetate (X) and 3-nitrobenzaldehyde (VI)] in refluxing isopropanol.

合成路线4

Lithiation of 2-chloro-N-methylbenzamide (I) using sec-butyllithium and tetramethyl ethylenediamine, followed by addition of the resulting organolithium derivative to 3-bromo-4,5-dimethoxybenzaldehyde (II) produced hydroxy amide (III), which was cyclized to lactone (IV) upon refluxing with HCl/dioxan. Reduction of the lactone function of (IV) employing DIBAL yielded lactol (V). The intermediate isobenzofuran generated by acidic treatment of lactol (V) experienced a Diels-Alder addition with dimethyl fumarate (VI) to afford adduct (VII). Subsequent aromatization of (VII) to give naphthalene (VIII) was carried out by treatment with boron trifluoride etherate in hot acetonitrile. Selective saponification of the less hindered ester group of (VIII) provided acid (IX). After coupling of (IX) with N-(2-hydroxyethyl)piperazine (X) by means of DCC and HOBt, the title compound was converted to the hydrochloride salt.

合成路线5

Ullmann condensation between o-chlorobenzoic acid (I) and p-anisidine (II) produces the diphenylamine carboxylic acid (III), which is further cyclized to the 2-methoxyacridone (IV) by heating in polyphosphoric acid. N-Alkylation of acridone (IV) with 1-bromo-4-chlorobutane (V) in the presence of KOH under phase-transfer conditions furnishes the N-(chlorobutyl)acridone (VI). Finally, nucleophilic substitution of the chloro group of (VI) with N-(2-hydroxyethyl)piperazine (VII) gives rise to the title compound.

合成路线6

合成路线7