Reaction Steps
In a 100 mL round-bottomed flask, HBTU (112 mg, 0.29 mmol), Hunig's base (0.20 ml, 1.13 mmol) and 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) were combined with DMF (3.0 ml) to give a light yellow solution. 2-Amino-1-(tetrahydro-2H-pyran-4-yl)propan-1-ol (72 mg, 0.45 mmol) was added and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc. The reaction mixture was poured into 50 mL sat NaHCO3 and extracted with EtOAc (2×50 mL). The organic layers were combined and washed with H2O (2×50 mL) then dried over MgSO4 and concentrated in vacuo to provide the crude material. The product was purified by flash chromatography (silica gel, 80 g, 20% to 50% EtOAc in hexanes) to provide 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-hydroxy-1-methyl-2-(tetrahydro-pyran-4-yl)-ethyl]-amide as two discreet diastereomers (arbitrarily assigned). Diastereomer A (30 mg, 22%) as a white powder: 1H NMR (300 MHz, CDCl3) δ ppm 9.20 (m, 1H), 8.68 (dd, J=8.69, 5.29 Hz, 1H), 8.41 (d, J=9.44 Hz, 1H), 8.27 (s, 1H) 6.96-7.13 (m, 2H) 5.70 (s, 2H) 4.54-4.67 (m, 1H) 4.06-4.20 (m, 4H) 3.87-4.04 (m, 2H) 3.56-3.65 (m, 2H) 3.42 (d, J=6.80 Hz, 1H) 3.21-3.39 (m, 2H), 2.53 (d, J=4.15 Hz, 1H) 1.85 (d, J=12.84 Hz, 2H) 1.76 (ddd, J=11.52, 7.93, 3.97 Hz, 1H), 1.33-1.56 (m, 5H), 0.75-1.04 (m, 2H), −0.05 (s, 9H). Diastereomer B (70 mg, 53%) as a white powder: 1H NMR (300 MHz, CDCl3) δ ppm 9.21 (s, 1H) 8.42-8.61 (m, 2H) 8.27 (s, 1H) 6.96-7.15 (m, 2H) 5.51-5.76 (m, 2H) 4.40-4.64 (m, 1H) 3.93-4.24 (m, 3H) 3.62-3.83 (m, 2H) 3.50-3.62 (m, 2H) 3.26-3.50 (m, 2H) 2.70 (d, J=5.29 Hz, 1H) 1.92-2.10 (m, 2H) 1.14-1.84 (m, 5H) 0.67-1.07 (m, 2H) −0.33-0.16 (m, 9H).
