| 73.65% |
With pyridine; bromine; In dichloromethane; at 0℃; for 2h;Inert atmosphere; |
A mixture of 7-azaindoline (4 g, 33.29 mmol), pyridine (4 mL), and DCM (40 mL) was added Br2 (1.72 mL, 33.29 mmol) in DCM (24 mL) using an additional funnel under ice bath in nitrogen and stirred for 2 hours. The reaction was then quenched with water and extracted with ethyl acetate (30 ml x 3). The organic layer was collected, dried over anhydrous MgS04, and concentrated in vacuo to yield a dark brown product, which was purified by a flash column over silica gel (ethyl acetate : n-hexane = 2 : 1, Rf = 0.63) to afford 1 (4.88 g, 73.65%) as a yellow solid. *H-NMR (500MHZ, CDCI3): delta 3.06 (t, /= 8.5 Hz, 2H), 3.64 (t, /= 8.5 Hz, 2H), 7.31 (s, IH), 7.85 (s, IH). |
| 48% |
|
Preparation Example R-4. 5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine described in Preparation Example R-3 (15mg, 0.13mmol) and N-bromosuccinimide (24mg, 0.14mmol) were dissolved in N,N-dimethylformamide (0.5mL), and the solution was stirred for 15 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and the title compound (12mg; 60mumol, 48%) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 2.98 (2H, t, J=8.8Hz), 3.48 (2H, t, J=8.8Hz), 6.60 (1 H, s), 7.37 (1 H, d, J=1.1 Hz), 7.71 (1 H, d, J=2.4Hz). |
| 43% |
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 3h; |
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (5.00 g, 41.6 mmol) was dissolved in DMF (140 mL) and N-bromosuccinimide (8.89 g, 49.9 mmol) After that, the reaction was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was evaporated, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 1:1)Intermediate 7 (3.60 g, 18.1 mmol,Yield 43%). |
| 36% |
|
Preparation Example O-1. 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 1H-Pyrrolo[2,3-b]pyridine (1.0g, 8.46mmol) and 10% palladium-carbon (500mg) were dissolved in a mixture of formic acid (10mL) and triethylamine (10mL), and the solution was stirred at 70C for 17 hours. To this reaction mixture was further added 10% palladium-carbon (270mg), and the mixture was stirred at 70C for 2 hours. The reaction mixture was cooled to room temperature, then an aqueous solution of 5N sodium hydroxide was added thereto, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate : methanol = 10 : 1), and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614mg, 5.11mmol, 60%) was obtained as a pale yellow solid. The resulting 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614mg, 5.11mmol) and N-bromosuccinimide (1.09g, 6.13mmol) were dissolved in N,N-dimethylformamide (12mL), and the solution was stirred for 2.5 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane : ethyl acetate = 3 : 1), and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (370mg, 1.86mmol, 36%) was obtained as a white solid. The resulting 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (345mg, 1.73mmol), zinc cyanide (305mg, 2.60mmol) and tetrakis(triphenylphosphine)palladium(0) (200mg, 0.173mmol) were dissolved in dimethylsulfoxide (7mL), and the solution was stirred at 120C for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water and ethyl acetate were added to the reaction solution, the organic layer was separated, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate), and the title compound (167mg, 1.15mmol, 66%) was obtained as a light brown solid. 1H-NMR Spectrum (DMSO-d6) delta (ppm) : 3.01 (2H, t, J=8.6Hz), 3.58 (2H, t, J=8.6Hz), 7.46 (1 H, s), 7.63 (1 H, s), 8.10 (1 H, s). |
| 36 - 48% |
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2.5 - 15h;Product distribution / selectivity; |
Preparation Example O-1. 2,3-Dihydro-1H-pyrrolo[2,3-]pyridine-5-carbonitrile 1H-Pyrrolo[2,3-b]pyridine (1.0g, 8.46mmol) and 10% palladium-carbon (500mg) were dissolved in a mixture of formic acid (10mL) and triethylamine (10mL), and the solution was stirred at 70C for 17 hours. To this reaction mixture was further added 10% palladium-carbon (270mg), and the mixture was stirred at 70C for 2 hours. The reaction mixture was cooled to room temperature, then an aqueous solution of 5N sodium hydroxide was added thereto, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate : methanol = 10 : 1), and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614mg, 5.11mmol, 60%) was obtained as a pale yellow solid. The resulting 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614mg, 5.11mmol) and N-bromosuccinimide (1.09g, 6.13mmol) were dissolved in N,N-dimethylformamide (12mL), and the solution was stirred for 2.5 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane : ethyl acetate = 3 : 1), and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (370mg, 1.86mmol, 36%) was obtained as a white solid. The resulting 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (345mg, 1.73mmol), zinc cyanide (305mg, 2.60mmol) and tetrakis(triphenylphosphine)palladium(0) (200mg, 0.173mmol) were dissolved in dimethylsulfoxide (7mL), and the solution was stirred at 120C for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water and ethyl acetate were added to the reaction solution, the organic layer was separated, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate), and the title compound (167mg, 1.15mmol, 66%) was obtained as a light brown solid. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 3.01 (2H, t, J=8.6Hz), 3.58 (2H, t, J=8.6Hz), 7.46 (1 H, s), 7.63 (1 H, s), 8.10 (1H, s).; Preparation Example R-4.5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine described in Preparation Example R-3 (15mg, 0.13mmol) and N-bromosuccinimide (24mg, 0.14mmol) were dissolved in N,N-dimethylformamide (0.5mL), and the solution was stirred for 15 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 5 : 1), and the title compound (12mg, 60mumol, 48%) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 2.98 (2H, t, J=8.8Hz), 3.48 (2H, t, J=8.8Hz), 6.60 (1 H, s), 7.37 (1 H, d, J=1.1 Hz), 7.71 (1 H, d, J=2.4Hz). |
| 35% |
|
Step 2; A solution of Br2 (2.78 ml, 8.64 g, 54 mmole) in dry dichloromethane (40 ml) was added dropwise over a period of 1 h 45 min to a stirred and cooled (-10C) solution of 2.3-dihydro-1H-pyrrolo[2,3-b]pyridine (6.5 g,54 mmole) in a mixture of dry dichloromethane (60 ml) and pyridine (6 ml). The suspension was stirred at 0C for 2 hrs, poured into a mixture of NaHCO3 (120 ml) and saturated aqueous Na2S2O3 (15 ml) and extracted with a solution of ethyl acetate/methanol (3X200 ml). The organic layers were concentrated to afford 3.7 g of 5-bromo- 2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine (2) after purification by flash chromatography using dichloromethane as eluent (35% yield). 1H NMR (400 MHz, DMSO-D6) delta ppm 2.98 ( t, J = 8.54 Hz, 2H ) 3.48 (t, J=8.55 Hz, 2H) 6.58 (bs, 1 H) 7.37(s,1 H) 7.71 (s,1 H) |
|
With N-Bromosuccinimide; In chloroform; |
Step A 7-Aza-5-bromoindoline See Van Der Plas et al., Tetrahedron 1989, 45, 803, and Taylor et al. ibid. 1987, 43, 5145. NBS (2.71 g, 15.2 mmol) was added to a stirred solution of 7-azaindoline (1.83 g, 15.2 mmol, in chloroform (200 mL). After 1 h, the reaction mixture was washed with 10% sodium metabisulfite solution, dried (Na2SO4), filtered through a pad of silica (eluding with ethyl acetate) and evaporated in vacuo to give the title compound: 1H NMR (CDCl3) delta 3.09 (t, J=8.5 Hz, 2H), 3.74 (t, J=8.5 Hz, 2H), 5.00 (br s, 1H), 7.32 (s, 1H), 8.13 (s, 1H). |
|
With N-Bromosuccinimide; In chloroform; |
Step A 7-Aza-5-bromoindoline See Van Der Plas et al., Tetrahedron 1989,45, 803, and Taylor et al. ibid. 1987, 43, 5145. NBS (2.71 g, 15.2 mmol) was added to a stirred solution of 7-azaindoline (1.83 g, 15.2 mmol, in chloroform (200 mL). After 1 h, the reaction mixture was washed with 10% sodium metabisulfite solution, dried (Na2SO4), filtered through a pad of silica (eluding with ethyl acetate) and evaporated in vacuo to give the title compound: 1H NMR (CDCl3) delta 3.09 (t, J=8.5 Hz, 2H), 3.74 (t, J=8.5 Hz, 2H), 5.00 (br s, 1H), 7.32 (s, 1H), 8.13 (s, 1H). |
|
With bromine; sodium bromide; In dichloromethane; at 20 - 25℃; for 5.5h; |
The above-mentioned 1st-step synthesis of the 7-aza-indoline, 300 ml dichloromethane, 4g of sodium bromide is added to 1L round-bottom flask mixing and stirring in the, room temperature next adds by drops 48g bromine, 30 minutes after the dropping, after dropping temperature to 25 C, keeping the temperature constant and start timing stirring reaction 5h;After the reaction is ended 0.2mol/L of the washing 3 times, the organic phase is dried by anhydrous sodium sulfate, filtered, evaporated to dryness, to obtain 5-bromo-7-aza-indoline |
| 130 kg |
With hydrogen bromide; dihydrogen peroxide; at 20 - 30℃; for 5h;Large scale; |
Control the temperature below 20 degrees Celsius, dihydro-7-azaindole 120kg dissolved in 1200kg of hydrogen bromide dubbed the solution,Control the temperature of 20-30 degrees Celsius, slowly dropping hydrogen peroxide 120kg, add the continued reaction for 5 hours, and then to the reaction solution by adding sodium hydroxide to adjust, and then filtered, washed, centrifuged 0.5 hours, dried product 130kg dihydro-5-bromine -7-azaindole. |
|
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 1h; |
l,3-Dibromo-5,5-dimethylhydantoin (9.64 g) was added to a mixture of 2,3-dihydro- lH-pyrrolo[2,3-6]pyridine (8.1 g), 4-toluenesulphonic acid monohydrate (1.03 g) and methylene chloride (550 ml) and the resultant mixture was stirred at ambient temperature for 1 hour. The reaction solution was decanted from a black tar. The organic solution was washed with an 0.2M aqueous sodium thiosulphate solution (2 x 250 ml) and with brine, dried over magnesium sulphate and evaporated. There was thus obtained 5-bromo-2,3-dihydro- lH-pyrrolo[2,3-6]pyridine (4.05 g); 1H NMR Spectrum: (DMSOd6) 2.99 (t, 2H), 3.47-3.52 (m, 2H), 6.58 (s, IH), 7.38-7.39 (m, IH), 7.72 (t, IH). Mass Spectrum; M+H+ 199 and 201. |
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