Hydrochloric Acid → 2-(1H-Indazol-5-yloxy)-5-fluorobenzonitrile

Participants

Reaction Conditions

Reaction Steps

In a 500 mL one-necked flask containing a large magnetic stir bar, 2-(4-amino-3-methylphenoxy)-5-fluorobenzonitrile (274.5 ml, 219.6 mmol) was taken up in chloroform (0.8 M) and treated with potassium acetate (25.86 g, 263.5 mmol) at room temperature. The reaction mixture was cooled to 0° C. and treated with acetic anhydride (62.28 mL, 658.8 mmol) via addition funnel over 5 minutes. The reaction was fitted with a reflux condenser, treated with additional 100 mL chloroform, and heated to 40° C. Isoamyl nitrite (58.74 mL, 439.2 mmol) was added dropwise via an addition funnel. The addition funnel was rinsed with 60 mL+40 mL of chloroform, removed, and replaced with a glass stopper. The reaction was heated to reflux for 20 hours, cooled to room temperature, and concentrated in vacuo to a brown solid. After being dried under high vacuum for 30 minutes, the brown solid was suspended in 1 L water, stirred vigorously for 15 minutes, and filtered. The resulting orange-brown solid (83 g) was taken up in 400 mL MeOH and treated with 1.0 M hydrochloric acid (241.6 mL, 241.6 mmol) at room temperature. The mixture was fitted with a reflux condenser and warmed to 70° C. for 20 hours. The reaction was cooled to 0° C. and 1.0 M sodium hydroxide (252.6 mL, 252.6 mmol) was added, followed by water (250 mL). The resulting yellow suspension was stirred in the ice bath for 10 minutes and then allowed to settle. The suspension was filtered, washed with water (1 L), air dried, dried with latex dam, and dried under high vacuum at 40° C. for 36 hours, to provide 50.7 g (91%) of the desired product as a free-flowing tan solid. MS (APCI+) m/z 254 (M+1) detected. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br, 1H), 8.07 (s, 1H), 7.94 (dd, 1H, J=3.1 Hz, J=8.2 Hz), 7.64 (d, 1H, J=9. Hz), 7.54 (m, 2H), 7.21 (dd, 1H, J=9 Hz), 6.96 (dd, 1H, J=4.3 Hz, J=9.3 Hz).

Provenance & Evidence