反应详情

To 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.9 g, 3.42 mmol), 2-fluoroethanol (0.3 mL, 5.13 mmol) triphenylphosphine (1.35 g, 5.13 mmol) in THF (22.5 mL) at 0 C is added DIAD (1.0 mL, 5.13 mmol) in drops over 5 min. After 20 min the reaction mixture is allowed to warm to 25 C. After 18 h the mixture is concentrated in vacuo, absorbed onto silica gel using ether and chromatographed on silica gel eluting with hexane/ethyl acetate. 3-(6-Chloro-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane was obtained as a yellow solid (560 mg). MS m/z=312 (M+H). This material (550 mg) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (583 mg), aq. Na2CO3 (1.3 mL, 2M), and tetrakis triphenylphosphine palladium (50-100 mg) in 1:1 toluene:ethanol (11 mL). The reaction mixture was heated in a microwave at 12° C. for 20 min. It was then dissolved in CH2Cl2 and chromatographed on silica gel using hexane/ethyl acetate as the eluant to give 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a white foam (0.51 g). MS m/z=369 (M+H). A solution of this material (500 mg, 1.36 mmol) and triethylamine (0.95 mL) in dichloromethane was treated with triphosgene (202 mg, 0.68 mmol). After 30 min one tenth of the solution was treated with excess methylamine (2N in THF). Reverse phase HPLC gave the title compound (29 mg) MS m/s=426.2 (M+H).

1. temperatureto warm to 25 C
2. concentrationAfter 18 h the mixture is concentrated in vacuo
3. customabsorbed onto silica gel
4. customchromatographed on silica gel eluting with hexane/ethyl acetate