Design, synthesis, and biological evaluation of pyrazolopyrimidine-sulfonamides as potent multiple-mitotic kinase (MMK) inhibitors (part I)

One-Pot Acid-Promoted Synthesis of 6-Aminopyrazolopyrimidines from 1H-Pyrazol-5-yl-N,N-dimethylformamidines or 5-Amino-1H-pyrazole-4-carbaldehydes with Cyanamide

“…The organic extracts were dried over MgSO 4 , filtered, and concentrated under reduced pressure; then, the residue was purified by chromatography on silica gel (CH 2 Cl 2 /EtOAc = 2:8) to give pure 2g; 63% yields (64.8 mg), light-yellow solid; mp 169− 170 °C (hexane−EtOAc). 1 (35), 321 (M + , 100), 320 (40), 135 (16), 128 (11), 121 (11), 119 (10), 111 (86), 95 (20), 83 (14), 77 (26), 71 (16), 69 (27), 57 (32), 55 (14) 6-Amino-1-(4-bromophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2h). The standard procedure involved the treatment of N′-[1-(4-bromophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimidamide (1h, 107 mg, 0.27 mmol, 1.0 equiv) with cyanamide (34.1 mg, 0.81 mmol, 3.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50−60 °C with 100 W of microwave energy for 1− 2 h. When the reaction was completed, the resulting mixture was added to saturated sodium bicarbonate (15 mL) and extracted with dichloromethane (2 × 15 mL).…”

“…The organic extracts were dried over MgSO 4 , filtered, and concentrated under reduced pressure; then, the residue was purified by chromatography on silica gel (CH 2 Cl 2 /EtOAc = 9:1) to give pure 2j; 70% yields (62.8 mg), yellow solid; mp 134−135 °C (hexane−EtOAc). 1 (11), 306 (29), 286 (11), 271 (30), 77 (31). HRMS (EI) m/z: [M] + calcd for C 17 H 12 N 6 O 2 : 332.1022; Found 332.1016.…”

“…The residue solution was purified by short column chromatography on silica gel (hexane/EtOAc = 7:3) to give pure 8b; 83% yields (1.15 g), light yellow solid; mp 118−119 °C (hexane−EtOAc). 1 (22), 248 (22), 145 (12), 128 (11), 104 (12). HRMS (EI) m/z: [M] + Calcd for C 17 H 15 N 3 O: 277.1215; Found 277.1211.…”

“…The residue solution was purified by short column chromatography on silica gel (hexane/EtOAc = 6:4) to give pure 8e; 84% yields (1.23 g), yellow solid; mp 128−129 °C. (36), 297 (M + , 100), 296 (53), 177 (11), 128 (12) 5-Amino-1-(4-chlorophenyl)-3-phenyl-1H-pyrazole-4-carbaldehyde (8g). A solution of N′-[1-(4-chlorophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl-N,N-dimethyl-methanimidamide (1g, 1.73 g, 4.90 mmol, 1.0 equiv) and NaOH (0.39 g, 9.80 mmol, 2.0 equiv) in MeOH solution (45 mL) at reflux within 2−3 h. When the reaction was completed, the reaction mixture was concentrated to remove solvent, added to water (10 mL), and extracted with CH 2 Cl 2 (3 × 20 mL).…”

“…1 H NMR (CDCl 3 , 500 MHz): δ 6.00 (br, 2H), 7.43−7.49 (m, 5H), 7.64 (dd, J = 6.73, 2.02 Hz, 2H), 7.68 (dd, J = 7.90, 1.62 Hz, 2H), 9.83 (s, 1H). 13 (17), 343 (M + + 2, 100), 342 (59), 341 (M + , 98), 340 (41), 128 (11), 77 (15). HRMS (EI) m/z: [M] + Calcd for C 16 H 12 BrN 3 O: 341.0164; Found 341.0162.…”