Oxalic Acid → 2-(7-Bromo-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one

Participants

Reaction Conditions

Reaction Steps

The procedure described in Example 4 is followed but starting with 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (8 g.) in anhydrous dimethylformamide (240 cc.), sodium hydride (50% dispersion in mineral oil) (1.2 g.) and 1-chlorocarbonyl-4-methylpiperazine (4.1 g.) in anhydrous dimethylformamide (40 cc.). After stirring at 26° C. for 18 hours, the reaction mixture is poured into ice-water (1,500 cc.). The insoluble matter (7.3 g.) is filtered off and dissolved in a mixture (73 cc.) of methylene chloride and ethyl acetate (80-20 by volume). The solution obtained is passed through a column of silica gel (73 g.). Elution is first carried out with a mixture (5,750 cc.) of methylene chloride and ethyl acetate (80-20 by volume); the corresponding eluates are discarded. Elution is then carried out with pure ethyl acetate (1,250 cc.) and then with a mixture (1,250 cc.) of ethyl acetate and methanol (50--50 by volume); the corresponding eluates are combined and concentrated to dryness. A residue (3 g.) is obtained which is dissolved in ethanol (90 cc.). A solution of oxalic acid (0.53 g.) in ethanol (10.5 cc.) is added to the solution obtained. The mixture is stirred for 1 hour and the precipitate which forms is filtered off and washed with ethanol (6 cc.). A product (1.8 g.), melting at 260° C., is thus obtained and is treated with a saturated solution of sodium bicarbonate (50 cc.) and methylene chloride (40 cc.). The organic layer is isolated by decanting, dried over anhydrous potassium carbonate and concentrated to dryness. A residue weighing 1.2 g. is obtained and is recrystallised from ethanol (80 cc.). 2-(7-Bromo-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1yl)carbonyloxy-isoindolin-1-one (0.9 g.), melting at 225°-230° C., is thus obtained.

Provenance & Evidence