合成路线1

The synthesis of metabolites M-III, M-IV and M-V of pioglitazone has been reported: a) Synthesis of metabolite M-IV: The reduction of 5-acetyl-2-methylpyridine (I) with NaBH4 in cooled ethanol gives the corresponding 1-hydroxyethyl derivative (II), which is protected with chloromethyl methyl ether and NaH in DMF yielding the methoxymethyl ether (III). The hydroxymethylation of (III) with aqueous formaldehyde at 150-60 C affords the ethanol (IV), which is condensed with 4-fluoronitrobenzene (V) by means of NaH in cooled DMF giving 5-[1-(methoxymethoxy)ethyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine (VI). The reduction of the nitro group of (VI) with H2 over Pd/C in ethyl acetate yields the corresponding amino compound (VII), which is diazotized with NaNO2 in aqueous HBr and condensed with methyl acrylate (VIII) by means of Cu2O to afford the 2-bromopropionate derivative (IX). The cyclization of (IX) with thiourea (X) by means of sodium acetate in refluxing ethanol gives the intermediate iminothiazolidinone (XI), which without isolation, is treated with refluxing 2N HCl to give metabolite M-IV. b) Synthesis of metabolite M-III: By oxidation of metabolite M-IV with the pyridine.sulfur trioxide complex in ethanol/dichloromethane/triethylamine