The condensation of 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (I) with 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (II) by means of BuLi in THF gives 7-[hydroxy[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (III), which is treated with acetic anhydride in pyridine, yielding the corresponding acetoxy derivative (IV). Elimination of acetic acid from (IV) in hot toluene affords the corresponding methylene derivative (V), which is hydrogenated with H2 over Pd/C in DMF/ethanol giving 10-methyl-7-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-ylmethyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (VI). Finally, this compound is deprotected in hot acetic acid/water. In order to obtain the (+)-enantiomer, the racemic mixture is treated with either (-)-di-p-toluyl-L-tartaric acid or (+)-di-p-toluyl-D-tartaric acid. The mixture of diastereomeric salts is separated by fractional crystallization. The pure (+)-enantiomer is obtained by treatment of the corresponding tartrate salt with NaHCO3 or NaOH in water. Finally, the (+)-free base is treated with HCl in methanol.
A new synthesis of FK-1052 has been described: The cyclization of 2-methylcyclohexane-1,3-dione (I) with phenylhydrazine (II) by means of sulfuric acid in toluene gives 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (III), which is condensed with 5-methyl-1-(triphenylmethyl)imidazole-4-carbaldehyde (IV) by means of lithium diisopropylamide (LDA) in THF to yield 7-[hydroxy[5-methyl-1-(triphenylmethyl)imidazol-4-yl]methyl]-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (V). The acylation of (V) with acetic anhydride in pyridine affords the corresponding acetate (VI), which by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is converted to the methylene derivative (VII). Finally, this compound is hydrogenated and deprotected by hydrogenolysis with H2 over Pd/C in acetic acid. In order to obtain the (+)-enantiomer, the racemic mixture is treated with (+)-di-p-toluoyl-D-tartaric acid, and the mixture of diastereomeric salts is separated by fractional crystallization. The (+)-enantiomer is obtained by treatment of the corresponding tartrate salt with 2N NaOH. Finally, the (+)-free base is converted to the hydrochloride by treatment with HCl in EtOH and recrystallization from MeOH/ether.
A new synthesis of FK-1052 has been performed by two closely related ways: 1) The reaction of 2-methylaniline (I) with glutaric anhydride (II) gives the corresponding glutarimide (III), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide in CCl4 to the bromomethyl derivative (IV). The reaction of (IV) with triphenylphosphine yields the phosphonium bromide (V), which, by an intramolecular Wittig reaction with 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF affords 6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (VI). The condensation of (VI) with 5-methyl-1-(triphenylmethyl)imidazole-4-carbaldehyde (VII) by means of lithium diisopropylamide (LDA) in THF gives the condensed methanol derivative (VIII), which is acetylated with acetic anhydride and pyridine to the acetoxy compound (IX), and converted into the olefine (X) by reaction with DBU in toluene. Elimination of the triphenylmethyl group of (X) with aqueous acetic acid gives 7-(5-methyl-1H-imidazol-4-ylmethylene)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (XI), which is hydrogenated over Pd/C and ammonium formate in THF/water to afford the saturated compound (XII). Optical resolution of (XII) with di-p-toluyl-D-tartaric acid as usual, gives the (+)-enantiomer (XIII), which is treated with paraformaldehyde and dimethylamine in aqueous acetic acid to yield the (+)-dimethylaminomethyl compound (XIV). Finally, the dimethylamino group is eliminated with Pd/C and ammonium formate in THF/ethanol/water. 2) The final steps of the preceding sequence can also be performed in reverse order: The racemic compound (XII) is first treated with paraformaldehyde and dimethylamine as before to give the racemic dimethylaminomethyl compound (XVI), which is deaminated with Pd/C and ammonium formate as before to the racemic FK-1052 (XVI). Finally, this compound is submitted to optical resolution with di-p-toluyl-D-tartaric acid as before.