4-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

Synthesis

1. A solution of 70% mCPBA (11.54 g, 66.87 mmol) in ethyl acetate (25 mL) was added dropwise to a solution of 7-azaindole (5 g, 42.3 mmol) in ethyl acetate (40 mL) at 0°C while maintaining good agitation. After addition, the mixture was stirred at room temperature for 1-2 hours until the ingredients were completely consumed. The mixture was cooled, filtered and washed with ethyl acetate to give a solid product. The solid was dissolved in 50 mL of water and adjusted to pH 9.5-10.5 with 30% K2CO3 solution (16 mL) to produce a precipitate. The mixture was stirred at room temperature for 1 h. After cooling, the mixture was filtered and washed with a small amount of cold water to give 2.484 g of 1H-pyrrolo[2,3-b]pyridine 7-oxide (Formula 12, 43.8% yield). ms (m/z): 135.1 (MH+). 2. A solution of methylsulfonic anhydride (6.066 g, 34.82 mmol) and acetonitrile (11.7 mL) was added dropwise to a 0 °C solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (2.3333 g, 17.41 mmol) and tetramethylammonium bromide (4.023 g, 26.12 mmol) in DMF (11.7 mL). After stirring for 45 minutes, DMF (11.7 mL) was added dropwise to the mixture and then stirred overnight at room temperature. Ice water (35 mL) was added to the mixture and then adjusted to pH 7 with 10N NaOH (4.66 mL). after stirring at room temperature, a precipitate was formed, filtered and washed with water to afford 1.891 g of 4-bromo-1H-pyrrolo[2,3-b]pyridine (Formula 13, 55% yield). mS (m/z): 197 (MH+). nMR (DMSO-d6) showed 69% impurities, probably 4,6-dibromo compounds based on LC/MS analysis. 3. A n-butanol (2 mL) solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (197 mg, 1 mmol), dimethylamine hydrochloride (88 mg, 1.079 mmol), and paraformaldehyde (33 mg, 1.1 mmol) was heated for 1.25 h at 120°C. The solvent was removed and the residue was heated for 1.25 h at 120°C. After removal of the solvent, the residue was treated with ice water and a few drops of concentrated hydrochloric acid. After washing with ether, the aqueous layer was alkalized with saturated aqueous NaHCO3 solution and then extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated to give 106 mg of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethylamine (formula 14, 42% yield). ms (m/z): 254.2 (MH+). 4. a solution of 1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethylamine (341 mg, 1.34 mmol) and hexamethylenetetetramine (190 mg, 1.34 mmol) in 66% propionic acid (0.8 mL) was added dropwise to a refluxing solution at 120°C. The reaction mixture was heated for 2-4 hours. The reaction mixture was heated for 2-4 hours and monitored by MS. After cooling, it was treated with water (4 mL) and filtered to afford 238 mg of 4-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (Eq. 15, 79% yield). ms (m/z): 225.0 (MH+). 5. Sodium hydride (60%, 27.4 mg, 0.686 mmol) was added batchwise to a 0°C suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (128.6 mg, 0.572 mmol) in 5 mL DMF and 1 mL THF. After stirring for 20 min, methyl iodide (39.2 μL, 0.6292 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 2.5 hours. The solvent was evaporated and the residue was treated with dichloromethane, filtered and dried. After further treatment with hexane, it was filtered and washed with hexane to give a beige solid, which was recrystallized from chloroform and hexane to give 102 mg of 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (Eq. 16, 74% yield). ms (ESI): m/z 239 (M+H). 6. 4-Bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (38 mg, 0.159 mmol), phenylboronic acid (38.8 mg, 0.318 mmol) and tetrakis(triphenylphosphine)palladium(0) (27.6 mg, 0.0238 mmol) were mixed together in a mixture of saturated sodium carbonate (0.37 mL) and 1,2-dimethoxyethane ( 1.4 mL) The mixture was heated to 120°C in microwave and kept for 20 min. It was filtered through a silica gel pad and washed with a 5% MeOH solution of ethyl acetate. After evaporating the solvent, acetonitrile was added to the residue and the bright yellow solid was removed by filtration. The filtrate was concentrated to give 51.4 mg of 1-methyl-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (formula 17, Ar=phenyl, 76% yield). mS (ESI): m/z 237 (M+H).

References

[1] Patent: US2009/298820, 2009, A1. Location in patent: Page/Page column 36-37
[2] Patent: WO2010/30727, 2010, A1. Location in patent: Page/Page column 120