N-Hydroxyphthalimide → 2-[3-(4-Morpholinyl)propoxy]-1H-isoindole-1,3(2H)-dione

Participants

Reaction Conditions

Reaction Steps

N-(3-Morpholinopropoxy)phthalimide may be obtained in the following manner: solution of 3-morpholinopropanol (27.5 g), N-hydroxyphthalimide (30.2 g) and triphenylphosphine (47.2 g) in tetrahydrofuran (400 cc) is cooled to a temperature in the region of 0° C. and ethyl azodicarboxylate (37.65 g) is added in the course of 1 hour 30 minutes. The solution obtained is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The residue is taken up with ethyl acetate (500 cc) and the suspension obtained is filtered. The filtrate is extracted with N aqueous hydrochloric acid solution (200 cc). The aqueous phase is separated after settling has taken place and then extracted 3 times with ethyl acetate (600 cc in total). The aqueous phase is brought to a pH in the region of 10 by adding N aqueous sodium hydroxide solution and is extracted 3 times with ethyl acetate (300 cc in total). The organic extracts are combined, washed 3 times with distilled water (150 cc in total), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. A crude product (25.8 g) is thereby obtained, which is chromatographed on a column 8 cm in diameter containing silica (0.060 mm) (1 kg). The column is eluted with pure ethyl acetate, collecting 500-cc fractions. The first 12 fractions are discarded; the next 48 fractions are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. N-(3-Morpholinopropoxy)phthalimide (15.5 g) is thereby obtained in the form of white crystals, m.p. 98° C. 3-Morpholinopropanol may be obtained according to O. HROMATKA, Ber., 75, 131, (1942).

Provenance & Evidence