LM-1554 is synthesized by condensation of 2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo[b]thiophene (I) with chloroacetonitrile (III) in the presence of dry hydrogen chloride gas followed by basification. Alternatively, 2-amino-3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophene (IV) can be condensed with chloroacetonitrile (III) under the above reaction conditions. The condensation of (I) with chloroacetamide (II) in the presence of an equivalent of phosphorus oxychloride in chloroform followed by basification also yields LM-1554.
By reaction of 2-aminobenzophenones (I) with bromoacetyl halide (II) or tosyloxyacetyl halide (VI) to give, respectively, 2-(bromoacetylamino)benzophenones (III) or 2-(tosyloxyacetylamino)benzophenones (VII), which are treated with ethanolamine (IV) to give the compounds (V), which with acetic acid in ethanol give the desired compounds. These compounds can also be obtained from (III) and (VI) without isolation of (V)
The synthesis of nitidine chloride was first reported in 1973. The procedure was based on the synthesis of dihydronitidine, which involves hydrocyanation of the corresponding chalcone, followed by hydrolysis, reduction and cyclization to the 2-aryl tetralone. Leukart reaction of the tetralone followed by ring closure with phosphorus oxychloride and catalytic dehydrogenation yields the benzo[c]phenanthridine nucleus. Methylation and quarternization with methyl sulfate followed by anion exchange with sodium chloride forms the chloride salt of the desired compound. Several other syntheses of nitidine chloride have also been reported. These include: a) synthesis of the intermediates by a different route; b) photocyclization of bromobenzamide from 5-aminonaphthalene to phenanthridine; and c) condensation of homophthalic anhydride and the Schiff base to form the 3-arylisoquinoline. Many analogues of nitidine chloride, including fagaronine. The tetramethoxy analogue, the indenoisoquinoline derivative, etc., possess significant antineoplastic activity.