Cesium carbonate → tert-butyl [(2S)-1-({5-cyano-4-[(4,6-dimethylpyridin-2-yl)amino]pyridin-2-yl}amino)propan-2-yl]carbamate

Participants

Reaction Conditions

Reaction Steps

To a solution of 6-chloro-4-[(4,6-dimethylpyridin-2-yl)amino]pyridine-3-carbonitrile (PrepEx 1.2) (50 mg, 0.19 mmol) in 1,4-dioxane (0.8 mL) was added tert-butyl [(2S)-1-aminopropan-2-yl]carbamate hydrochloride (61 mg, 0.29 mmol) and cesium carbonate (126 mg, 0.387 mmol). The mixture was purged with argon, and then Pd2(dba)3 (4 mg, 0.004 mmol) and Xantphos (7 mg, 0.012 mmol) were added. The reaction mixture was heated to 80° C. After complete consumption of starting material (as determined by LCMS analysis), the reaction mixture was cooled to ambient temperature, filtered through CELITE (washed with chloroform), and diluted with water. The organics were separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-40% acetone/hexanes, linear gradient) to afford tert-butyl [(2S)-1-({5-cyano-4-[(4,6-dimethylpyridin-2-yl)amino]pyridin-2-yl}amino)propan-2-yl]carbamate. The isolated material was diluted with hydrochloric acid (2.0 M in dioxanes, 1 mL, 2 mmol) and stirred at ambient temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure (azeotroping with toluene). The residue was diluted with DMSO (0.5 mL). To this mixture was added hydrogen peroxide (35% solution in water, 0.020 mL, 0.23 mmol) and sodium hydroxide (4.0 N in water, 0.050 mL, 0.20 mmol). After 1 hour, the reaction mixture was filtered and purified directly by reverse phase HPLC (5-60% acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-{[(2S)-2-aminopropyl]amino}-4-[(4,6-dimethylpyridin-2-yl)amino]pyridine-3-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, CD3OD) δ 8.37 (s, 1H), 8.28 (s, 1H), 6.90 (s, 1H), 6.80 (s, 1H), 3.74-3.50 (m, 3H), 2.51 (s, 3H), 2.34 (s, 3H), 1.41 (br s, 3H).

Provenance & Evidence