| 53% |
Stage #1: 5-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine With potassium-t-butoxide; tBuXPhos Pd G4; di-tertbutyl [2’,4’,6’-tris(propan-2-yl)-[1,1‘-biphenyl]-2-yl]phosphane In <i>tert</i>-butyl alcohol at 30℃;
Stage #2: 3,4-difluoro-phenylamine In <i>tert</i>-butyl alcohol at 30℃; |
4.1
Weighed 5-bromo-6-chloro-lH-pyrrolo[2,3-b]pyridine (944.5 mg, 4.080 mmol), t-butyl XPhos Palladacycle generation 4 (362 mg, 0.4052 mmol), potassium t-butoxide (1.372 g, 12.23 mmol), and ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl] phosphane (362 mg, 0.8525 mmol) into a 40 mL vial. Added t-butanol (21 mL) and wanned in a 30 °C heating block. Degassed with Nz for 1 minute. Added 3,4-difluoroaniline (425 pL, 4.286 mmol) and stirred at 30 °C overnight. Diluted with dichloromethane (100 mL). Washed the organics with 0.5 M HC1 aqueous solution (50 mL), and washed the aqueous phase with 10% methanol in Agent Ref. 10275.0199-00304 dichloromethane (100 mL). Combined the organic phases and dried over NaiSCU, filtered, added celite and evaporated the solvent under reduced pressure. Purification by silica gel chromatography on 80 g of Silica in a gold cartridge: (Gradient: 0-100 % ethyl acetate in heptane). Concentrated the desired fractions to dryness under reduced pressure to yield the product as a white solid, 6-chloro-N-(3,4-difluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-amine (620 mg, 53%) 1H NMR (300 MHz, DMSO-d6) 8 11.82 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.55 - 7.46 (m, 1H), 7.24 - 7.11 (m, 1H), 6.63 (ddd, J= 13.2, 7.0, 2.8 Hz, 1H), 6.53 - 6.41 (m, 2H). ESI-MS m/z calc. 279.03748, found 280.2 (M+l)+; Retention time: 0.83 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC Acquity CSH Cl 8 (2.1 x 50 mm, 1.7 pm particle) made by Waters, and a dual gradient run from 5-95% mobile phase B over 0.6 minutes. Mobile phase A = H2O (0.1 % CF3CO2H). Mobile phase B = CH3CN (0.1 % CF3CO2H). Flow rate = 0.6 mL/min, injection volume = 2.0 pL. |
| 53% |
Stage #1: 5-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine With potassium-t-butoxide; methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane; di-tertbutyl [2’,4’,6’-tris(propan-2-yl)-[1,1‘-biphenyl]-2-yl]phosphane In <i>tert</i>-butyl alcohol at 30℃;
Stage #2: 3,4-difluoro-phenylamine In <i>tert</i>-butyl alcohol at 30℃; |
4.1
Weighed 5-bromo-6-chloro-lH-pyrrolo[2,3-b]pyridine (944.5 mg, 4.080 mmol), t-butyl XPhos Palladacycle generation 4 (362 mg, 0.4052 mmol), potassium t-butoxide (1.372 g, 12.23 mmol), and ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl] phosphane (362 mg, 0.8525 mmol) into a 40 mL vial. Added t-butanol (21 mL) and wanned in a 30 °C heating block. Degassed with Nz for 1 minute. Added 3,4-difluoroaniline (425 pL, 4.286 mmol) and stirred at 30 °C overnight. Diluted with dichloromethane (100 mL). Washed the organics with 0.5 M HC1 aqueous solution (50 mL), and washed the aqueous phase with 10% methanol in Agent Ref. 10275.0199-00304 dichloromethane (100 mL). Combined the organic phases and dried over NaiSCU, filtered, added celite and evaporated the solvent under reduced pressure. Purification by silica gel chromatography on 80 g of Silica in a gold cartridge: (Gradient: 0-100 % ethyl acetate in heptane). Concentrated the desired fractions to dryness under reduced pressure to yield the product as a white solid, 6-chloro-N-(3,4-difluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-amine (620 mg, 53%) 1H NMR (300 MHz, DMSO-d6) 8 11.82 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.55 - 7.46 (m, 1H), 7.24 - 7.11 (m, 1H), 6.63 (ddd, J= 13.2, 7.0, 2.8 Hz, 1H), 6.53 - 6.41 (m, 2H). ESI-MS m/z calc. 279.03748, found 280.2 (M+l)+; Retention time: 0.83 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC Acquity CSH Cl 8 (2.1 x 50 mm, 1.7 pm particle) made by Waters, and a dual gradient run from 5-95% mobile phase B over 0.6 minutes. Mobile phase A = H2O (0.1 % CF3CO2H). Mobile phase B = CH3CN (0.1 % CF3CO2H). Flow rate = 0.6 mL/min, injection volume = 2.0 pL. |
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