Phosphorus oxychloride → 2,6-Dichloroquinoline

Participants

Reaction Steps

Phosphorus oxychloride (16.72 Kg) was charged to a vessel containing 6-chloroquinolin-2(1H)-one (12.50 Kg) (Prepared according to method of Johnston K. M. et al., J. Chem. Soc. Perkin Trans. 1, 1972, 1648 and references therein), benzyltrimethylammonium chloride (1.575 Kg) and 1,2-dimethoxyethane (87.8 Kg) at 70° C. 1,2-dimethoxyethane (22.5 Kg) was charged as a line rinse. The reaction was stirred at 70° C. to 75° C. for ca. 6 hours before the batch was concentrated to ca. 44 L by vacuum distillation (<40° C.). The concentrate was diluted with dichloromethane (253.1 Kg), adjusted to 38° C. to 45° C. and quenched by the addition of water (37.5 Kg) whilst maintaining the temperature at 38° C. to 45° C. After 70 minutes the batch was cooled to 25° C. to 30° C. and treated with Celite (1.30 Kg) for 40 minutes. The slurry was pressure filtered via a 1 μm filter membrane and the filtrates diluted with dichloromethane (87.5 Kg). The phases were separated and the aqueous phase extracted twice with dichloromethane (82 Kg). The combined organic extracts were washed sequentially with 5% w/w sodium hydrogen carbonate solution (37 L), water (37 Kg) and then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (96.5 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (95.4 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. The resultant slurry was stirred at 16° C. to 18° C. for 2 hours and then filtered. The filter cake was washed with isopropanol (19.7 Kg) at ca. 20° C. and then dried at up to 50° C. in vacuo to provide the subtitle compound as an off white solid (12.04 Kg).

Provenance & Evidence