1H-PYRAZOLO[3,4-B]PYRIDINE

Pale Orange Solid

Hydrazine hydrate (10 mL) was added to a mixture of 2-chloro-3-formylpyridine 1 (5.00 g, 35 mmol) and p-TsOH (3.50 g, 18 mmol). The reaction mixture was stirred for 3 h at 130 °C. Upon cooling with cold water, the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSOPreparation of 1H-pyrazolo[3, 4-b]pyridine A stirred solution of 2-chloronicotinaldehyde (I-5) (5.1 g, 36 mmol) in EtOH (100 mL) and NH2NH2 (85 percent in H20, 50 mL) was heated to reflux for 24 hr. TLC (petroleum ether/ EtOAc = 1 :1) showed the reaction was complete. The mixture was concentrated and separated between H20 (100 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2S04 and concentrated in vacuo to give 1 H-pyrazolo[3, 4-b]pyridine (I-6) (4 g, 93percent) as a yellow solid.Formation of lH-pyrazolo[3, 4-b]pyridine (42)Hydrazine hydrate (64percent, 0.29 L, 5.99 mol hydrazine, 3 eq) was added dropwise to a solution of 2-fluoropyridine-3-carboxylaldehyde (0.25 kg, 1.99 mol) in EtOH (600 mL) over lhr. During the addition, a thick suspension formed, which turned into a clear red solution towards the end of the addition. The reaction mixture was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, quenched with HTo a stirred solution of 2-bromoisonicotinonitrile (500mg, 2.7mmol) in toluene (25 mL), 1 H-pyrazolo[3, 4- bjpyridine (0.6432g, 5.4mmol), and K2CO3 (1 .86g, 13.5mmol) were added followed by Cul (0.256g, 1.35mmol). The resulting solution was degassed with nitrogen for 15 minutes, and trans L/, A/-dimethylcyclohexane-1 , 2- diamine (0.192g, 1.35mmol, ) was added. The resulting reaction was heated at 110 C for 16h. The reaction mixture was evaporated under vacuum to get a crude residue that was purified by prep HPLC to afford the title compound (300 mg, 29.3 %)LC-MS (method 6): F =1.626 min; m/z = 222.01 (M+H+), To a stirred solution of 2-bromoisonicotinonitrile (500mg, 2.7mmol) in toluene (25 mL), 1 H-pyrazolo[3, 4- bjpyridine (0.6432g, 5.4mmol), and K2CO3 (1 .86g, 13.5mmol) were added followed by Cul (0.256g, 1.35mmol). The resulting solution was degassed with nitrogen for 15 minutes, and trans L/, A/-dimethylcyclohexane-1 , 2- diamine (0.192g, 1.35mmol, ) was added. The resulting reaction was heated at 110 C for 16h. The reaction mixture was evaporated under vacuum to get a crude residue that was purified by prep HPLC to afford the title compound (300 mg, 29.3 %)LC-MS (method 6): F =1.626 min; m/z = 222.01 (M+H+),

A pyrazole derivative as kinase inhibitors.