Water → HCID 21444381, compound

Participants

Reaction Steps

Potassium borohydride (3 g.) is added to 4-chloro-N-(7-chloro-1,8-naphthyridin-2-yl)-phthalimide (25.2 g.) in dioxane (500 cc.) and methanol (500 cc.). The mixture is stirred for 4 hours at a temperature of about 20° C and water (500 cc.) is then added. The precipitate is filtered off and washed with water (100 cc.) and then with a mixture (200 cc.) of equal parts of methanol and dioxane. This gives a crude product (20 g.) which is chromatographed on silica (0.05 - 0.2 mm) (6 kg.) as indicated below, the eluate being collected in fractions of 5,000 cc. Elution is carried out first with methylene chloride (10,000 cc.) and then with a mixture of methylene chloride and ethyl acetate (5/5 by volume) (40,000 cc.). This eluate, after concentration, yields (4-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6 g.) melting at 270° C. Thereafter elution is carried out with the same mixture of methylene chloride and ethyl acetate (10,000 cc.). This eluate, after concentration, gives a mixture (1.6 g.) of the isomers 4-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone and 7-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone. Finally, elution is carried out again with the same mixture of methylene chloride and ethyl acetate (20,000 cc.). This eluate, after concentration, yields 7-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (3.1 g.) melting at a temperature above 280° C.

Provenance & Evidence