Reaction Steps
[4-Amino-3-(1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid dihydrochloride (79 g, 0.238 mol) and 1-(4-chloro-3-methoxyphenyl)piperazine dihydrochloride (71.3 g, 0.238 mol) were suspended in anhydrous DMF (793 mL) and cooled in an ice bath. N,N-diisopropylethylamine (290 mL, 1.67 mol) was added and the mixture was stirred at room temperature until all solids dissolved to form a brown solution. HCTU (113.23 g, 0.273 mol) was added in portions over 10 min while maintaining the internal temperature below 20° C. After 3 h, the reaction mixture was poured slowly into a flask of vigorously stirred ice water (6 L) to give a suspension, which was stirred for 1 h, filtered, and washed with saturated NaHCO3 (500 mL×2) and water (500 mL×2). The solid was purified by trituration in refluxing MeCN (2×500 mL) to provide 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]ethanone (90.5 g, 81% yield, >98% pure by LC-MS). 1H NMR (400 MHz, d6-DMSO) δ 13.0 (s, 1H), 10.14 (d, 1H, J=3.7 Hz), 8.16 (s, 1H), 7.95 (d, 1H, d, J=3.7 Hz), 7.25 (dd, 1H, J=1.03 and 1.36 Hz), 7.20 (d, 1H, J=8.8 Hz), 7.16 (s, 1H), 6.70 (d, 1H, J=2.4 Hz), 6.52 (dd, 1H, J=2.4 and 8.8 Hz), 5.37 (s, 2H), 3.83 (s, 3H), 3.74 (t, 2H, J=4.8 Hz), 3.58 (t, 2H, J=4.8 Hz), 3.28 (t, 2H, J=4.8 Hz), 3.17 (t, 2H, J=4.8 Hz). 13C NMR (100.6 MHz, d6-DMSO) δ 165.3, 159.0, 157.3, 155.7, 155.5, 151.6, 141.2, 136.6, 130.3, 128.7, 119.0, 111.9, 109.0, 101.9, 98.0, 56.7, 49.4, 48.9, 48.8, 44.7, 42.1; IR (KBr) 3219, 2937, 1682, 1638, 1594, 1567 cm−1; MS (ES) m/z 468.1 (M+H+). Anal. Calcd for C21H22N9O2Cl-0.85 H2O: C, 52.20; H, 4.94; N, 26.09; Cl, 7.34. Found: C, 51.92; H, 4.68; N, 26.44; Cl, 7.18.
