Hydrochloric Acid → Linopirdine

Participants

Reaction Steps

A slurry of 3-(4-pyridinylmethylidene)-1-phenylindolin-2-one (80 g, 0.268M) and methanol (600 mL) was cooled to 6°. Sodium borohydride pellets (0.2 g each, 3.19 g total 0.084M) were added over 20 minutes with gentle cooling. The mixture was stirred for 50 minutes, cooled to 7°, and 10N sodium hydroxide (64 mL, 0.64M) added over 11 minutes. A solution of 4-picolychloride hydrochloride (4.85 g, 0.296M) and water (160 mL) was then added over 28 minutes while maintaining a temperature of 10°-15°. Cooling was then removed, and 10N sodium hydroxide (80 mL, 0.8M) added over 10 minutes. The mixture was stirred for 2 hours and then water (580 mL) added over 45 minutes. The slurry was cooled to 10°-15°, stirred for 10 minutes, and the solids collected by filtration. The solids were then reslurried in water (450 mL), filtered, and washed with water. Drying in a vacuum oven at 85°-95° yielded 89.4 g (85%) crude title compound. Eighty-five grams of this crude product was recrystallized in isopropanol and water to yield 77.3 g of the title compound (90% recovery), m.p. 186°-188°.

Provenance & Evidence