Sodium hydride → 2-[3-(4-Phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide

Participants

Reaction Conditions

Reaction Steps

A solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (4.9 g) in dimethylformamide (20 cc) is added to a solution of the sodium salt of 2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide (obtained by heating, after the evolution of gas has ceased, a solution of 4-bromo-5-isoquinolylsulphonamide (4.1 g) in dimethylformamide (25 cc) and a suspension of sodium hydride (0.85 g) in an 80% dispersion in vaseline oil in dimethylformamide (50 cc) at 110° C. for 2 hours and 30 minutes) cooled to 20° C. The reaction medium is heated for 2 hours at 100° C., then poured into a mixture of water (300 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×300 cc), dried over magnesium sulphate and concentrated to dryness. The residue is purified by chromatography on a silica column under a slight overpressure of nitrogen, eluting with ethyl acetate and then with a mixture of ethyl acetate and ethanol vol). 2-[3-(4-Phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide (1.4 g) is obtained in the form of a yellow oil. 1.8 g of this product are purified with a second, similar chromatography stage to give 2-[3-(4-phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide (1.6 g) (Rf =0.27; support: silica gel; eluant: ethyl acetate-ethanol (9-1 vol)). This product is dissolved in ethyl acetate (100 cc) before adding a 3 N solution of hydrochloric acid in isopropyl oxide (5 cc). The precipitate is centrifuged, washed with ethyl acetate and dried under vacuum (0.1 mm Hg) at 35° C. 2-[3-(4-Phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide dihydrochloride (1.6 g) is obtained in the form of a yellow (amorphous) solid.

Provenance & Evidence