The reaction of 2,6-dichloropyridine (I) with BuLi and CO2 in THF gives 2,6-dichloropyridine-3-carboxylic acid (II) (1), which by reaction with refluxing SOCl2 yields the acyl chloride (III). The reaction of (III) with malonic ester by means of magnesium ethoxide in ethyl ether affords the nicotinoylacetic ester (IV), which is condensed with thiazol-2-amine (V) and triethylorthoformate by means of acetic anhydride providing the nicotinoyl acrylate (VI). The cyclization of (VI) by means of K2CO3 in hot dioxane gives the 7-chloro-4-oxo-1-(2-thiazolyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (VII), which is condensed with the chiral pyrrolidine (VIII) by means of triethylamine yielding the proteted intermediate (IX). Finally, this compound is deprotected and hydrolyzed with hot aqueous HCl.
The chiral intermediate, the pyrrolidine (VIII) has been obtained as follows: The optical resolution of (trans)-3-amino-1-benzyl-4-methoxypyrroloidine (rac)-(X) with D-tartaric acid gives the enathiomer (S,S)(XI), which is treated with tert-butoxycarbonyl anhydride in methanol to yield the carbamate (XII). The reduction of (XII) with LiAlH4 in THF followed by reprotection with tert-butoxycarbonyl anhydride in dichloromethane affords (S,S)-1-benzyl-3-[N-(tert-butoxycarbonyl)-N-methylamino]-4-methoxypyrrolidine (XIII), which is finally debenzylated to the target compound (VIII) by hydrogenation with H2 over Pd/C in ethanol.