| 18% |
|
Example 31i 5-(3-Bromophenyl)-5-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)-5H-pyrrolo[3,4-b]pyridin-7-amine tert-Butyllithium (1.6 M in pentane) (1.922 mL, 3.07 mmol) was dropwise added to dry THF (10.00 mL) under argon at -100 C. 4-Bromo-2-(2,2,2-trifluoroethoxy)pyridine (0.328 g, 1.28 mmol) in dry THF (5.000 mL) was added dropwise. The mixture was stirred at -100 C. for 5 min, then N-((3-bromophenyl)(2-cyanopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (0.500 g, 1.28 mmol) in dry THF (5.000 mL) was added dropwise. The reaction mixture was stirred at -100 C. for 30 min, then at -70 C. for 2 h. Methanol (5.00 mL) was added and stirring continued for 30 min at -70 C. The cooling bath was removed and stirring continued for additional 30 min. The reaction mixture was concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (sat.) and dichloromethane (*3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was filtered through a syringe filter and purified by prep-HPLC to give 5-(3-bromophenyl)-5-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)-5H-pyrrolo[3,4-b]pyridin-7-amine (0.110 g, 18% yield): 1H NMR (400 MHz, DMSO-d6) delta ppm 8.66-8.69 (m, 1H) 8.40-8.46 (m, 1H) 8.10 (d, 1H) 7.43-7.54 (m, 3H) 7.36-7.42 (m, 1H) 7.28 (t, 1H) 7.08 (dd, 1H) 7.02 (br. s., 2H) 6.81 (dd, 1H) 4.93 (q, 2H); MS (ES+) m/z 463, 465 [M+1]+. ; Example 32i 5-(3-Bromophenyl)-5-(2-(2,2-difluoroyinyloxy)pyridin-4-yl)-5H-pyrrolo[3,4-b]pyridin-7-amine bis(2,2,2-trifluoroacetic acid) tert-Butyllithium (1.6 M in pentane) (1.922 mL, 3.07 mmol) was dropwise added to dry THF (10.00 mL) under argon at -100 C. 4-Bromo-2-(2,2,2-trifluoroethoxy)pyridine (0.328 g, 1.28 mmol) in dry THF (5.000 mL) was added dropwise. The mixture was stirred at -100 C. for 5 min, then N-((3-bromophenyl)(2-cyanopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (0.500 g, 1.28 mmol) in dry THF (5.000 mL) was added dropwise. The reaction was stirred at -100 C. for 30 min, then at -70 C. for 1 h. Hydrochloric acid (0.5 M in methanol) (7.69 mL, 3.84 mmol) was added. The mixture was stirred over night while and was allowed to reach room temperature during this time. The reaction mixture was concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (sat.) and dichloromethane (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica chromatography using 0 to 10% (3.5 M ammonia in methanol) in dichloromethane followed by prep-HPLC (Column Gemini NX C18; 21*250 mm; 5 mum; Mobilphase: 20-60% MeCN/H20+0.1% TFA; Flowrate: 20 ml/min) gave 5-(3-bromophenyl)-5-(2-(2,2-difluorovinyloxy)pyridin-4-yl)-5H-pyrrolo[3,4-b]pyridin-7-amine (0.064 g, 7% yield):1H NMR (400 MHz, DMSO-d6) delta ppm 12.28 (br. s., 1H) 10.44 (br. s., 1H) 10.08 (br. s., 1H) 8.99 (dd, 1H) 8.57 (dd, 1H) 8.29 (dd, 1H) 7.91 (dd, 1H) 7.66 (ddd, 1H) 7.47 (t, 1H) 7.40 (t, 1H) 7.24-7.33 (m, 2H) 7.19 (dd, 1H) 7.01-7.06 (m, 1H); MS (ES+) m/z 443, 445 [M+1]+. |
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