合成路线1

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.