Reaction Steps
3-(4-(tert-butyldimethylsilyl)-5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (132.7 g, 348 mmol) was dissolved in anhydrous THF (265 mL). Imidazol-1-yl(trimethyl)silane (254 mL) was added followed by (2R)-3-methyl-2-(piperazin-2-yl)butan-2-ol (90 g, 522 mmol). The mixture was divided into four glass pressure vessel's and the sealed containers heated and stirred at 95° C. for 48 hours. The crude mixtures were cooled, combined and diluted with ethyl acetate (1.7 L). The solution was washed with saturated sodium bicarbonate (2×500 ml). The combined aqueous layers were back-extracted with ethyl acetate (500 ml). The combined organics were washed with brine (500 ml), dried over MgSO4, filtered and concentrated in vacuo to give a viscous brown oil. The diastereoisomers were separated on silica gel (10-100% ethyl acetate containing 2% triethylamine in petroleum ether). This gave the required (S,R)-diastereoisomer as a yellow foam (125.3 g, 59%); 1H NMR (CDCl3) 0.01 (9H, s), 0.42 (6H, s), 0.78-0.89 (15H, m), 1.09-1.13 (3H, m), 1.74 (1H, m), 2.61 (1H, m), 2.80-2.99 (4H, m), 3.12 (1H, m), 3.45 (1H, d), 3.69 (1H, d), 7.12 (1H, m), 8.55 (1H, m), 8.81 (1H, m), 12.75 (1H, brs); 19F NMR (decoupled) −108.9; MS ES 605.2 (M+). The (R,R)-diastereoisomer was isolated as a yellow foam (27.5 g, 13%); 1H NMR (CDCl3) 0.00 (9H, s), 0.38 (6H, m), 0.76-0.80 (15H, m), 0.85 (3H, s), 1.85 (1H, m), 2.50 (1H, m), 2.90-3.13 (4H, m), 3.42 (1H, m), 3.56 (1H, m), 3.91 (1H, m), 7.08 (1H, m), 8.51 (1H, m), 8.76 (1H, m), 12.70 (1H, brs); 19F NMR (decoupled) −109.0; MS ES 605.2 (M+).
