反应详情

To a stirred solution of 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (20 mg, 0.085 mmol) in 500 uL of dichloromethane at room temperature under nitrogen was added HOBt (19.5 mg, 0.128 mmol), EDCI (24.5 mg, 0.128 mmol) and DIEA (45 uL, 0.225 mmol). After 15 minutes a solution of (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A, 34 mg, 0.077 mmol) in 500 uL dichloromethane was added by pipet. After stirring overnight, the reaction was diluted to 30 mL with CH2Cl2 and washed 1×30 mL with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto Biotage 12S column and eluted initially with dichloromethane and then after about 100 mL of elution, switched to 2/98 MeOH/dichloromethane. Pure product containing fractions were pooled and concentrated to a white glass (12 mg, 21% yield). LRMS (APCI pos) m/e 667.4 (M+1). 1H NMR: (CDCl3, 400 MHz): δ 10.52 (s, 1H), 8.50 (d, 1H), 7.83 (m, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.54-7.46 (m, 4H), 7.31 (m, 1H), 7.24 (m, 1H), 7.11 (m, 2H), 6.52 (d, 1H), 4.12 (m, 1H), 3.90-3.60 (br m, 8H), 3.78 (d, 1H), 2.81 (m, 1H), 2.05 (m, 1H), 1.39 (m, 1H).

1. washwashed 1×30 mL with 10% sodium carbonate solution
2. dry with materialThe organics were dried (MgSO4)
3. filtrationfiltered
4. concentrationconcentrated
5. washeluted initially with dichloromethane
6. washafter about 100 mL of elution
7. additionPure product containing fractions