Synthesis
GENERAL STEPS: 5-bromo-3-(trifluoromethyl)pyridin-2-amine (180 g) was mixed with 1,4-dioxane (3600 mL) in a flask and stirred. Bis(pinacolato)diboron (284.47 g), potassium acetate (109.95 g) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (18 g) were added sequentially at 25-30 °C. The reaction mixture was heated to 95-100 °C and maintained for 15-16 hours. After completion of the reaction, it was cooled to 25-30 °C, filtered through a bed of diatomaceous earth and the filter bed was washed with ethyl acetate (1800 mL). The filtrate was concentrated under reduced pressure to give the crude product 2-amino-3-(trifluoromethyl)pyridine-5-boronic acid pinacol ester (450 g).
Purification step: the crude product was dissolved in methanol (1800 mL), activated carbon (45 g) and silica gel (60-120 mesh, 450 g) were added, and stirred at 25-30 °C for 1 hour. The mixture was filtered through a bed of diatomaceous earth and washed with methanol (450 mL). The filtrate was slowly added to cold water (6750 mL) over a period of 1 hour, maintaining the temperature at 0-5 °C. The precipitate was collected by filtration and washed with cold water (900 mL). The wet solid was dried at 45-50 °C to give purified 2-amino-3-(trifluoromethyl)pyridine-5-boronic acid pinacol ester (209 g).
Yield: 97.47%.
Purity: 98.43%.
1H NMR (300 MHz, DMSO-d6): δ 8.38 (s, 1H), 7.80 (s, 1H), 6.92 (s, 2H), 1.27 (s, 12H).
MS: m/z 289.1 (M + 1)
References
[1] Patent: WO2015/145369, 2015, A1. Location in patent: Page/Page column 37
[2] Patent: WO2012/34526, 2012, A1. Location in patent: Page/Page column 36-37
[3] Patent: US2013/190307, 2013, A1. Location in patent: Paragraph 0172; 0173
[4] Patent: WO2010/8847, 2010, A2. Location in patent: Page/Page column 147-148
[5] Patent: WO2008/12326, 2008, A1. Location in patent: Page/Page column 69
