290307-40-3

624-28-2

67-64-1

290307-40-3

1. In a 2L round bottom flask, 2,5-dibromopyridine (54 g, 228 mmol) was dissolved in toluene (600 mL) to form a colorless solution. The reaction system was cooled to -78 °C and controlled to not exceed -70 °C. n-Butyllithium (2.5 M hexane solution, 100 mL, 251 mmol) was slowly added. The reaction mixture was stirred at -78 °C for 30 min before acetone (20.08 mL, 274 mmol) was quickly added. Stirring was continued for 30 min, followed by quenching the reaction with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (eluent: 20-50% ethyl acetate/heptane) to afford 2-(5-bromopyridin-2-yl)-2-propanol (42.5 g, 86% yield). 2. In a 1 L round bottom flask, 2-(5-bromopyridin-2-yl)-2-propanol (10 g, 46.3 mmol) was dissolved with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (11.87 g, 50.9 mmol) in dioxane (300 mL) and saturated aqueous sodium bicarbonate solution ( 150 mL). The reaction mixture was degassed with nitrogen and tetrakis(triphenylphosphine)palladium (2.67 g, 2.314 mmol) was added. The reaction solution was heated to reflux and thickened and then dissolved. After refluxing for 2 hours, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was partitioned with ethyl acetate and water, the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(5-(5-amino-2-methylphenyl)pyridin-2-yl)-2-propanol. 3. The above crude product was dissolved in dioxane (30 mL) and cooled to 0 °C. Sulfuric acid was added slowly through the addition funnel, initially with manual stirring until complete dissolution. The reaction was exothermic to 30°C and stirred for 30 minutes. After the completion of the reaction was monitored by LC/MS, the reaction solution was poured onto ice and extracted with ethyl acetate (2 x 200 mL). The aqueous phase was adjusted to pH 9-10 with 50% sodium hydroxide solution and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-100% ethyl acetate/heptane) to afford 4-methyl-3-(6-(prop-1-en-2-yl)pyridin-3-yl)aniline (9 g, total yield 86% in two steps). 4. 4-Methyl-3-(6-(prop-1-en-2-yl)pyridin-3-yl)aniline (9 g, 40.1 mmol) was dissolved in ethanol (100 mL) and 10% palladium carbon (0.5 g) was added. Hydrogenation was carried out at 30 psi hydrogen pressure for 2 hours. Upon completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated to afford 3-(6-isopropylpyridin-3-yl)-4-methylaniline (8 g, 88% yield).