Hydrochloric Acid → Sorafenib Impurity 43

Participants

Reaction Conditions

Reaction Steps

A mixture of 4-(4-Aminophenoxy)pyridine-2-carboxylic acid methylamide (15.0 g, 61.7 mmol) and potassium hydroxide (34.6 g, 617 mmol) in ethanol (400 mL) and water (40 mL) was stirred at 90° C. for 48 h. After cooling to RT, 2.0 N hydrochloric acid was slowly added to the reaction mixture until pH=5. The solvent was removed completely and the residue redissolved in MeOH (400 mL). After slow addition of trimethylsilylchloride (178 mL, 140 mmol, 2.27 eq) at 0° C., the reaction mixture was stirred at reflux for 24 h and cooled to RT. The mixture was filtered, and the filtrate concentrated under reduced pressure and then partitioned between DCM and water. The organic layer was then washed with 1M aqueous sodium bicarbonate solution, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was washed further with H2O and reextracted with EtOAc/Hex (1:2 v/v) to afford the desired ester (6.27 g, 42%) as a light brown solid. 1H-NMR (DMSO-d6) δ 8.51 (d, J=5.7 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.10 (dd, J=5.7, 2.7 Hz, 1H), 6.86 (dt, J=9.0, 2.4 Hz, 2H), 6.63 (dt, J=8.7, 2.4 Hz, 2H), 5.18 (br s, 2H), 3.86 (s, 3H); MS LC-MS [M+H]+=245, RT=1.04 min; TLC (75% EtOAc/hex), Rf=0.20.

Provenance & Evidence