2-苯基-1-乙炔基硼酸频那醇酯

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of IId′ (10 mL, 91 mmol) in dry THF (50 mL) at −78° C. was added n-BuLi (2.5 M in n-hexane, 40 mL, 100 mmol). Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.7 mL, 91 mmol) in dry THF (100 mL) under argon atmosphere, and the reaction mixture was cooled to −78° C. The lithium acetylide from the first flask, which was cooled to −78° C., was slowly added to the second by a double-ended needle. The mixture was stirred at −78° C. for 2 hours, after which anhydrous HCl (105 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (185-200° C./15 mbar) to afford IIId (16.05 g, 76%) as a colourless oil. was slowly added to the second by a double-ended needle Then, reaction mixture was warmed to room temperature After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure the residue was purified by distillation (185-200° C./15 mbar) to afford IIId (16.05 g, 76%) as a colourless oil

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 30 mL glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (75 mg, 0.329 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated to 90° C. in an oil bath for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give the TFA salt of the title compound as a pale yellow solid (14.5 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1H), 2.05-2.12 (m, 1H), 3.49-3.66 (m, 2H), 3.76 (d, J=11.62 Hz, 1H), 3.84-4.04 (m, 2H), 4.31-4.51 (m, 3H), 7.16-7.29 (m, 1H), 7.42-7.53 (m, 3H), 7.53-7.67 (m, 2H), 7.92 (br s, 3H), 8.50 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H19FN4O2, 367. found, 367. The vessel was sealed with a cap extracted with EtOAc (2×25 mL) The combined organic phase was dried over sodium sulfate evaporated

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 30 mL glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (103 mg, 0.451 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and was extracted with EtOAc (2×50 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (32 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (br s, 3H), 1.66-1.91 (m, 5H), 3.63 (br s, 1H), 4.34-4.52 (m, 3H), 6.87 (d, J=7.07 Hz, 1H), 7.41-7.52 (m, 3H), 7.56-7.65 (m, 2H), 7.74 (br s, 3H), 8.48 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H21FN4O, 365. found, 365. The vessel was sealed with a cap was extracted with EtOAc (2×50 mL) The combined organic phase was dried over sodium sulfate evaporated

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of IId′ (10 mL, 91 mmol) in dry THF (50 mL) at −78° C. was added n-BuLi (2.5 M in n-hexane, 40 mL, 100 mmol). Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.7 mL, 91 mmol) in dry THF (100 mL) under argon atmosphere, and the reaction mixture was cooled to −78° C. The lithium acetylide from the first flask, which was cooled to −78° C., was slowly added to the second by a double-ended needle. The mixture was stirred at −78° C. for 2 hours, after which anhydrous HCl (105 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (185-200° C./15 mbar) to afford IIId (16.05 g, 76%) as a colourless oil. was slowly added to the second by a double-ended needle Then, reaction mixture was warmed to room temperature After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure the residue was purified by distillation (185-200° C./15 mbar) to afford IIId (16.05 g, 76%) as a colourless oil

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 30 mg (65 μmol) 4-[6-bromo-8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzene sulfonamide which was prepared according to intermediate example 2a, 29.5 mg 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane, 1.0 mL n-propanol, 97 μL of an aqueous 2M potassium carbonate solution, 0.85 mg triphenylphosphine, and 4.55 mg bis(triphenylphosphine)palladium (II) chloride was stirred at 120° C. for 2 hours. The solution was cooled, water added and extracted with dichloromethane. The organic phase was dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 4.6 mg (14%) of the title compound. was prepared The solution was cooled extracted with dichloromethane The organic phase was dried over sodium sulfate After filtration and removal of solvent the residue was purified by chromatography

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of IId′ (10 mL, 91 mmol) in dry THF (50 mL) at −78° C. was added n-BuLi (2.5 M in n-hexane, 40 mL, 100 mmol). Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.7 mL, 91 mmol) in dry THF (100 mL) under argon atmosphere, and the reaction mixture was cooled to −78° C. The lithium acetylide from the first flask, which was cooled to −78° C., was slowly added to the second by a double-ended needle. The mixture was stirred at −78° C. for 2 hours, after which anhydrous HCl (105 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (185-200° C./15 mbar) to afford IIId (16.05 g, 76%) as a colourless oil. was slowly added to the second by a double-ended needle Then, reaction mixture was warmed to room temperature After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure the residue was purified by distillation (185-200° C./15 mbar) to afford IIId (16.05 g, 76%) as a colourless oil