Hydrochloric Acid → 5,7-Dichloro-1,6-naphthyridine

Participants

Reaction Conditions

Reaction Steps

Phosphorus oxychloride (3 vol) is charged to the reactor at 30±5° C. followed by 1,6-naphthyridin-5,7(6H,8H)-dione (1 eq), tetramethylammonium chloride (1.05 eq) and a rinse of phosphorus oxychloride (0.5 vol). The mixture is heated to 103.5±3.5° C. and stirred for a minimum of 36 h. The reaction is then cooled to 60±5° C. and sampled. On receipt of a successful sample, toluene (4 vol) is added and the mixture concentrated to 2-3 volumes by distillation under vacuum (NLT 650 mm of Hg) and temperature<60° C. Additional toluene (2 vol) is added and again the mixture distilled under vacuum to 2-3 vols. This toluene addition/distillation cycle is repeated once more then the mixture is cooled to 47.5±2.5° C. and treated with tetrahydrofuran (8 vol) and ethyl acetate (8 vol). The mixture is cooled to 30±5° C. and poured into 15% aq. sodium carbonate (15 vol) which has been pre-cooled to 5.0±5.0° C. Additional tetrahydrofuran (3 vol) is added along with ethyl acetate (3 vol) in order to rinse out the initial reaction vessel. Whilst still at 5±5° C. the mixture is slowly treated with further 15% aqueous sodium carbonate solution (5 vol) and stirred for 15-30 min. The temperature is increased to 22.5±2.5° C. and the pH adjusted to 7-8 by addition of either 15% aqueous sodium carbonate solution or dilute HCl. Ethyl acetate (5 vol) is added followed by celite. The mixture is stirred then filtered. The celite bed is washed with ethyl acetate (2×2 vol). The filtrate is distilled at <55° C. under vacuum (NLT 650 mm of Hg) down to 30±5 volumes. Water (2 vol) is added and the distilled again down to ˜30 vols. This water addition/distillation cycle is repeated until the tetrahydrofuran, toluene and ethyl acetate content are each NMT 3.0% by GC (% w/w). At that point, water (10 vol) is added and the mixture heated to 42.5±2.5° C. and stirred for 30-60 min. The product is isolated by filtration at 42.5±2.5° C. and washed with water (2×3 vol). The cake is sucked dry then offloaded and charged to a separate reactor. Water (20 vol) is added and the suspension heated to 42.5±2.5° C. and stirred for 30-60 min 42.5±2.5° C. The product is filtered and washed with water (2×3 vol), sucked dry then transferred to a vacuum oven and further dried at 52.5±2.5° C. under vacuum (NLT 650 mm of Hg) for 8±2 h.

Provenance & Evidence