5-Bromo-2-fluoropyridine-3-carboxaldehyde

Intermediate 1; Preparation of 5-bromo-1H-pyrazolo[3, 4-b]pyridine; a) 5-bromo-2-fluoro-3-pyridinecarbaldehyde; Following the procedure described in WO2006015124 and trituration of the crude product in hexanes instead of crystallization from cyclohexane afforded the title compound as an off-white solid (68percent). MS (ES)+ m/e 203.8, 205.7 [M+H]A solution of lithium di-iso-propylamine (5 mL, 35 mmol) in anhydrous THF (40 mL) was cooled to -78° C. under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30 mmol) was added. The mixture was then stirred at -78° C. for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at -78° C. for 90 min. N-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspension at -78° C. and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10percent (w/v) aqueous solution of citric acid. The mixture was warmed to room temperature and distributed between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude product from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g, 52percent yield) as pale beige flaky crystals. Preparation of 3-Methyl-5-(4, 4, 5, 5-tetramethyl-[1 , 3, 2]dioxaborolan-2-yl)-1 H-pyrazolo[3, 4-b]pyridine (79) Diisopropylamine (2.6ml, 25mmol) was dissolved in tetrahydrofuran (100ml), 2.5M solution of butyllithium in tetrahydrofuran (10ml, 25mmol) was slowly added dropwise at 0 and then the mixture was stirred for 1 minute. A solution of 5-bromo-fluoro-2-pyridine (4.0g, 22.7mmol) in tetrahydrofuran (20ml) was slowly added dropwise at -78 and stirred for 30 minutes. Ethylformate (2.8ml, 34mmol) was added dropwise and then the mixture was stirred for 10 minutes at -78. After completion of the reaction, 1N hydrochloric acid solution was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.1g, 88percent).Example D-1 : Preparation of (2S)-1-(4-(1-isopropyl-3-(1H-pyrazolo[3, 4-b]pyridin-5-yl)-1H-pyrazol-4- yl)pyrimidin-2-ylamino)propan-2-ol Step 1: Synthesis of 5-bromo-2-fluoro-pyridine-3-carbaldehyde.[0217] A solution of lithium di-zso-propylamine (5 mL, 35 mmol) in anhydrous THF (40mL) was cooled to -78 °C under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30mmol) was added. The mixture was then stirred at -78 °C for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at -78 °Cfor 90 min. 7V-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspensionat -78 °C and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10 percent (w/v) aqueous solution of citric acid. The mixture waswarmed to room temperature and distributed between water and dichloromethane. Theaqueous phase was extracted three times with dichloromethane and the organic phases werecombined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crudeproduct from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g, 52percent yield) as pale beige flaky crystals.A mixture of Into two parallel 30 ml sealed tubes, each was placed