合成路线1

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.

合成路线2

2-Chloropyridine (I) was condensed with (S)-prolinol (II) to furnish the pyridinylpyrrolidine (III). Subsequent alkylation of the hydroxyl group of (III) with 4-fluorobenzaldehyde (IV) using NaH in hot DMF gave ether (V). Knoevenagel condensation of (V) with 2,4-thiazolidinedione (VI) in the presence of benzoic acid and piperidine afforded the required benzylidene thiazolidine, which was finally treated with maleic acid in acetone to yield the title maleate salt.

合成路线3

The condensation of 2-chloropyridine (I) with ethyl trifluoroacetate (II) by means of LDA in THF gives 2-chloro-3-(trifluoroacetyl)pyridine (III), which is condensed with 4-fluoroaniline (IV) by means of refluxing aqueous acetic acid to yield the diarylamine (V). The cyclization of (V) by means of concentrated H2SO4 affords 7-fluoro-5-hydroxy-5-(trifluoromethyl)-5,10-dihydro-benzo[b]-1,8-naphthyridine (VI), which is dehydrated in THF to give 7-fluoro-5-(trifluoromethyl)benzo[b]-1,8-naphthyridine (VII). The condensation of (VII) with cyclopropylmethanol (VIII) by means of anhydrous HCl in dichloromethane yields the 5-(cyclopropylmethoxy)-7-fluoro-5-(trifluoromethyl)-5,10-dihydro-benzo[b]-1,8-naphthyridine (IX), which is oxidated by means of MCPBA in dichloromethane to afford the N-oxide (X) (1, 2). Finally, this racemic compound is submitted to chiral HPLC to obtain the target enantiomer (1).

合成路线4

合成路线5

Metalation of 2-chloropyridine (I) with BuLi in the presence of N,Ndimethylethanolamine in hexane at –78 °C, followed by condensation with N-methoxy-N,1-dimethylpiperidine-4-carboxamide (II) in hexane provides (6-chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone (III). Condensation of chloropyrimidine derivative (III) with benzophenone imine, Pd2dba3, BINAP and t-BuONa in refluxing toluene yields compound (IV), which by hydrolysis with HCl in THF furnishes (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (V). N-Acylation of amine (V) with 2,4,6-trifluorobenzoyl chloride (VI), optionally in the presence of Et3N in THF or refluxing 1,4-dioxane, generates lasmiditan (VII), which is finally treated with NH4Cl in MeOH or HCl in refluxing i-PrOH .