合成路线1

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.