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.

合成路线2

Friedel-Crafts condensation of 2-fluorobiphenyl (I) with glutaric anhydride (II) in the presence of AlCl3 gave ketoacid (III). Reduction of the ketonic group of (III) with triethylsilane in trifluoroacetic acid afforded biphenylpentanoic acid (IV), which was cyclized to the benzosuberone derivative (V) using polyphosphoric acid. Ketone reduction of (IV) by means of triethylsilane and trifluoroacetic acid provided the benzocycloheptene (VI), which was further oxidized to the isomeric ketone (VII) with chromic acid. Finally, condensation of (VII) with 5-fluoroisatin (VIII) in the presence of KOH yielded the target tetracyclic system.

合成路线3

The title hemiglutarate ester was synthesized by acylation of the known olivacine derivative (I) with glutaric anhydride (II) in pyridine, followed by conversion to the corresponding dihydrochloride salt.

合成路线4

Condensation of the known chloro pyrazolopyridine (I) with the lithium salt of 4-chlorobenzylthiol (II) produces the intermediate thioether (III) which, in the presence of excess LDA, undergoes intramolecular Claisen condensation to the pyrazolothienopyridine derivative (IV). Subsequent acylation of (IV) with glutaric anhydride (V) in acetone gives rise to the target glutarate mono-ester.

合成路线5

Acylation of 9-fluorenylmethanol (XXV) with glutaric anhydride (XXVI) yielded the glutarate mono-ester (XV). This was further activated as the pentafluorophenyl ester (XXVII) upon treatment with pentafluorophenol and DCC. Coupling of active ester (XXVII) with tripeptide (XXIV) gave rise to the glutaryl tripeptide (XXVIII).

合成路线6

Coupling of AZT (I) with Boc-Gly-OH (II) by means of dicyclohexyl carbodiimide (DCC) in the presence of dimethylaminopyridine (DMAP) in DMF followed by Boc removal by treatment with HCl/dioxane yields AZT ester (III). On the other hand, KNI-727 (IV) is condensed with glutaric anhydride (V) in THF-ether in the presence of dicyclohexylamine (DCHA) to yield the half ester of KNI-727 (VI), which is then condensed with derivative (III) by means of EDC.HCl in DMF in the presence of HOBt to furnish the target compound.

合成路线7

The reaction of triamcinolone (I) with acetone and HCl gives the corresponding acetonide (II), which is condensed with glutaric anhydride (III) in pyridine to yield the glutaric monoester (IV). Finally, this compound is condensed with mitomycin C (V) by means of CDI in THF to afford the target conjugate.

合成路线8