Condensation of 7-hydroxy-1,8-naphthyridin-2-amine (I) with phthalic anhydride (II) in refluxing acetic acid gives N-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide (III), which is treated with refluxing POCl3 to yield the 7-chloro derivative (IV). Reduction of compound (IV) with KBH4 in dioxane affords 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (V), which is condensed with 5-methyl-2-hexanone (VI) by means of NaH in DMF to give (?-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one (VII) (racemic pagoclone). The treatment of (VII) with NaOH in dioxane/water yields the racemic benzoic acid (VIII). Optical resolution of racemic (VIII) by means of (+)-ephedrine or cinchonine affords the (+)-isomer (IX), which is finally cyclized to the chiral (+)-indolinone derivative pagoclone by means of SOCl2 and imidazole in dichloromethane.
The isoindolinone (VII) (racemic pagoclone) can also be obtained by reaction of isoindolinone (V) with SOCl2 in DMF to provide 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)isoindolin-1-one (X), which is condensed with 3-oxo-6-methylheptanoic acid ethyl ester (XI) by means of NaH in DMF to yield 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindolin-1-yl-6-methyl-3-oxoheptanoic acid ethyl ester (XII). Finally, this compound is decarboxylated to the indolinone (VII) by means of LiCl in refluxing DMSO/water. The racemic benzoic acid (VIII) can also be obtained by hydrolysis of the heptanoic ester (XII) with concentrated sulfuric acid to give the corresponding free acid (XIII), which is finally decarboxylated and hydrolyzed by means of NaOH in water.
The optical resolution of racemic pagoclone (VII) can also be performed by reaction with (-)-(1R,2R,3S,5R)-pinanediol (XIV) by means of PPTS in refluxing dichloroethane to give the ketal (XV) as a diastereomeric mixture separated by crystallization. Finally, hydrolysis of the desired diastereomer (XVI) with 12N HCl affords the (+)-enantiomer, pagoclone.
The condensation of 2-amino-7-hydroxy-1,8-naphthyridine (I) with 5,6-dihydro-1,7-dithiin-2,3-dicarboxylic acid anhydride (II) in biphenyl-diphenyl ether at 230 C gives 5,7-dioxo-8-(7-hydroxy-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (III), which by reaction with POCl3 at 100 C is converted to the corresponding 7-chloro derivative (IV). Partial reduction of (IV) with KBH4 in methanol yields 6-(7-chloro-1,8-naphthyridin 2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (V), which is condensed with 4-chlorocarbonyl-1-(tert-butoxycarbonyl)piperazin (VI) by means of NaH in DMF affording 5-[(4-tert-butoxycarbonylpiperazin-1-yl)carbonyloxy]-6-(7-chloro-1,8-naphthyndin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (VII) Deprotection of (VII) by means of trifluoroacetic acid gives 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-[(piperazin-1-yl)carbonyloxy]-2,3,6,7-tetrahydro-5H-1,4-dithino[2,3-c]pyrrole (VIII), which is finally acetylated with propionic acid (IX) by means of dicyclohexylcarbodiimide in methylene chloride. The piperazine derivative (VI) is prepared as follows: The condensation of piperazine (X) with tert-butyl azidoformate (XI) in aqueous HCl gives 1-(tert-butoxycarbonyl)piperazine (XII), which is then condensed with phosgene in anhydrous toluene.