Acetic Acid → 5-(5-{[4-(hydroxymethyl)piperidin-1-yl]methyl}-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile

Participants

Reaction Steps

To a suspension of 5-(5-formyl-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.51 mmol) in a mixture of CH2Cl2 (10 mL) and NMP (1 mL) at room temperature under nitrogen was added 4-(hydroxymethyl)piperidine (176 mg, 1.53 mmol) followed by glacial acetic acid (153 mg, 2.55 mmol) and the reaction mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (540 mg, 2.55 mmol) was added in portions at 0° C. and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/CH2Cl2, 3% to 20%) to give 128 mg (51%) of 5-(5-{[4-(hydroxymethyl)piperidin-1-yl]methyl}-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 392 as a yellow solid and 23.8 mg of 5-[5-(hydroxymethyl)-1-benzofuran-2-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 481 as a yellow solid. Compound 392: HPLC retention time: 6.4 min.(g); melting range: 196-199° C.; and HRMS: 395.15023. Compound 481: HPLC retention time: 8.9 min.(g); MS: 395.3 (M+H); melting range: 232-234° C.; and HRMS: 395.15023.

Provenance & Evidence