The reaction of 2-chloropyridine (I) with 2-(methyl-amino)ethanol (II) by heating at 150 C gives 2-[N-methyl-N-(2-pyridyl)amino]ethanol (III), which is condensed with 4-fluorobenzaldehyde (IV) by means of NaH in DMF, yielding 4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]benzaldehyde (V) (1-3). The reaction of (V) with thiazolidine-2,4-dione (VI) by means of piperidinium acetate in refluxing toluene affords 5-[4-[2-[N-methyl-N-(2-pyridyl)- amino]ethoxy]benzylidene]thiazolidine-2,4-dione (VII). Finally, this compound is reduced with H2 over Pd/C (1), Mg in methanol (2,3) or biocatalytically by incubation with whole cells of the yeast Rhodotorula rubra CBS 6469 at pH 7.5-8.0 (4-6). Under acidic conditions, pH 3.0-5.0, this microbial biotransformation is enantioselective, giving the (+)-(R)-enantiomer of rosiglitazone.
The bromination of rosiglitazone (I) with NBS in hot acetic acid gives the dibromo compound (II), which is the hydrogenated with tritium over Pd/BaSO4 in DMF/TEA to yield the target labeled compound.
The reaction of 4-fluoroiodobenzene (I) with 14C-KCN and CuI in refluxing DMF gives 4-fluorobenzonitrile (II), which is reduced with HCO2H and RaNi in DMF to yield 4-fluorobenzaldehyde (III). The condensation of (III) with the substituted ethanolamine (IV) by means of tBu-OK in DMF affords 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (V), which is condensed with thiazolidine-2,4-dione (VI) by means of piperidine acetate in refluxing toluene to provide the benzylidene-thiazolidinedione (VII). Finally this compound is hydrogenated with H2 over Pd/C in DMF to furnish the target labeled compound.