Pagoclone - Anxiolytic GABA-A/BZD site partial agonist

Pagoclone has been obtained by several related ways: 1) Condensation of 7-hydroxy-1,8-naphthyridin-2-amine (1) with phthalic anh ydride (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 af fords 2-(7-chloro-1,8-naphthyridin-2-yi)-3-hydroxyisoindolin-1 -one (V) (1, 2), which is condensed with 5-methyl-2-hexanone (VI) by means of NaH in DM F to give (+/-)-2-(7-chloro-1,8-naphthyridin-2-yi)-3-(5-methyl-2-oxohexyl)i soindolin-1 -one (VII) (racemic pagoclone) (3).The treatment of (VII) with NaOH in dioxane/ water yields the racemic benzoic acid (VI H) (4-6). Optica l resolution of racemic (VIII) by means of (+)-ephedrine (4, 5) or cinchoni ne (6, 7) affords the (+)-isomer (IX), which is finally cyclized to the chi ral (+)-indolinone derivative pagoclone by means of SOCl2 and imidazole in dichloromethane (4-7). Scheme 1. 2) The isoindolinone (VII) (racemic pagoclone) can also be obtained by reac tion 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-oxohep tanoic acid ethyl ester (XII). Finally, this compound is decarboxylated to the indolinone (VII) by means of LiCl in refluxing DMSO/water (3) Scheme 2. 3) The racemic benzoic acid (VIII) can also be obtained by hydrolysis of th e heptanoic ester (XII) with concentrated sulfuric acid to give the corresp onding free acid (XIII), which is finally decarboxylated and hydrolyzed by means of NaOH in water (6, 7). Scheme 2. 4) 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 ref luxing dichloroethane to give the ketal (XV) as a diastereomeric mixture se parated by crystallization. Finally, hydrolysis of the desired diastereomer (XVI) with 12N HCl affords the (+)-enantiomer, pagoclone (8). Scheme 3.