To a stirred solution of azaindoline 5 (7.00 g, 35.2 mmol) in CH2C12 (664 ML) was added activated MnO2 (3.06 g, 35.2 MMOL), AND PROGRESS of the reaction was monitored BY LH EMR of reaction aliquots. After 3 days the mixture was filtered through A pad of silica, and the pad was washed with EtOAc. The filtrates were concentrated to afford the azaindole 27 (6. 98 g, 100 percent) as A brown solid. 1H NMR data as in Method 1.The 84.8 g of the 5-bromo-7-azaindoline product obtained in step 4 was dissolved in 400 mL of toluene, 221.5 g of manganese dioxide was added, Heating reflux reaction 4h;Step 6) The reaction solution obtained in Step 5 was cooled to room temperature, filter, The filter cake was washed twice with dichloromethane, Combine organic phase, dry, Concentrated 5-bromo-7-azaindole crude product, The product was crystallized from a petroleum ether-ethyl acetate mixed solution of ΡΕ / ΕΑ = 10: 1 to give 75 g of 5-bromo-7-azaindole, Yield 90percent.a) 30g (0.151mol) of 5-bromo-7-azaporphyrin, 60g of activated carbon fiber catalyst, 264g of xylene into the reaction flask, stirring evenly, to obtain a reaction mixture G;b) The reaction mixture G at 100 °C, oxygen flow 200mL/min, reaction 8h, chromatographic monitoring of the disappearance of raw materials;c) Filtration, filter out activated carbon fiber catalyst, obtain organic layer H, recover solvent, get 5-bromo-7-azaindole crude product, recrystallize from methanol to obtain product 25.37g, yield 85.43percent, content ≥99percent .To the autoclave was added 100 kg of dihydro-5-bromo-7-azaindole, 100 kg of manganese dioxide and 950 kg of glacial acetic acid, Control the temperature of 80-90 degrees Celsius, reaction 2h, then the reaction solution cooled to 20 degrees Celsius, filtered, washed with water, centrifuged for 0.5 hours, dried product 5 - bromo-7-azaindole 82kg.Step 3; To a stirred solution of 5-bromo- 2, 3-dihydro- 1H-pyrrolo[2, 3-b]pyridine (3.4 g, 17 mmole) in 30 ml of toluene was added activated MnOPreparation Example R-5. 5-Bromo-2, 3-dihydro-1H-pyrrolo[2, 3-b]pyridine (600mg, 3.01mmol) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone described in Preparation Example R-4 (753mg, 3.31 mmol) was dissolved in toluene (15mL), and the solution was refluxed for 40 minutes under nitrogen atmosphere. The reaction solution was cooled to room temperature, water and ethyl acetate were added thereto, the organic layer was partitioned, 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 (260mg, 1.32mmol, 44percent) was obtained as a white solid. In the 250 ml flask is sequentially added in 50 ml ethanol and 5 - bromo -1 - hydrogen pyrrolo [2, 3 - the b] pyridine -2 - ketone (4.2g, 20 mmol), Sn powder (4.7 g, 40 mmol) and 5 mol/L hydrochloric acid (14 ml), 40 °C stirring for 2 hours, the reaction is completed, to remove the ethanol, add 50 ml of water residue is completely dissolved, saturatedNaHCOb) Preparation of 5-bromo-7-azaindole from isolated 4-(2-Amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol; A 1000 mL double-jacket reactor (under a nitrogen atmosphere) is charged with 80.0 g 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol, 320 mL N-methylpyrrolidone and 330 mL water. The mixture is heated to 75 to 80° C. and a vacuum of ca 350 mbar is applied. The solution is then treated at 75 to 80° C. within 30 to 45 minutes with 181 mL sodium hydroxide (28percent in water). The dropping funnel is rinsed with 5 mL water and the mixture stirred at 78 to 81° C. for 15 to 20 hours. During stirring the jacket temperature and the vacuum have to be adjusted such that the internal temperature is 78 to 81° C. and a slight steadily distillate flow is guaranteed. When the volume in the reactor has reached approx. 800 mL water is continuously added to keep the volume constant for the rest of the reaction time. In-process control. Upon complete conversion, the reaction mixture is concentrated to a volume of approx. 700 mL and then cooled to 50 to 55° C. The mixture is treated at this temperature with 200 mL toluene. The biphasic mixture (ca. 900 mL) is stirred at 50 to 55° C. for 15 to 30 minutes and the layers are then allowed to separate for 15 to 30 minutes. The aqueous layer is separated and then extracted at 50 to 55° C. with 3.x.140 mL, totally with 420 mL toluene. The combined toluene layers are washed at 50 to 55° C. with 2.x.100 mL, totally with 200 mL water. The toluene layer is concentrated under reduced pressure at 45 to 55° C. until a residual volume of 450 to 500 mL is obtained. The residue is treated at 50 to 55° C. with 225 g ethyl acetate and the resulting solution is washed at 50 to 55° C. with 3.x.150 mL, totally with 450 mL water. From the organic layer, water and ethyl acetate are azeotropically distilled off with toluene under reduced pressure at 45 to 55° C. At the end of the distillation a volume of 600 to 700 mL is adjusted. The mixture is heated to 90 to 95° C. and stirred until a clear solution is obtained. The solution is treated with 2.0 g activated charcoal (Norit SX) and the resulting mixture stirred for 15 to 30 minutes at 90 to 95° C. The charcoal is removed by a hot filtration at 90 to 95° C. The first reactor, the filter and the transfer pipes are washed with 3.x.100 mL, totally with 300 mL toluene. The filtrate is concentrated under reduced pressure to a volume of approx. 400 mL. The resulting suspension is heated to 90 to 100° C. to obtain a clear solution. The solution is cooled to -5 to -10° C. within 7 to 10 hours and the resulting suspension stirred at this temperature for additional 3 to 5 hours. The crystals are filtered off and washed in two portions with 120 mL toluene (pre-cooled to <0° C.). The wet crystals are dried at 55 to 65° C./<30 mbar until constant weight. Yield: 46.5 g (75percent) of slightly yellow crystals with an assay of 100.1percent (m/m).To a stirred solution of the TBS derivative 26 (1.01 g, 3.3 mmol) in MeOH (10 mL) was added a 10percent solution of HCl in MeOH (7 mL). After 8 min the solvents were evaporated and the residue was partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted with AcOEt (3x). The combined organic solutions were dried (MgSO4), concentrated and purified by PTLC with CH2CL2 : MeOH=95: 5 as eluent to afford the bromo derivative 27 (0.60 g, 94 percent). H NMR (400 MHz; CDCl3) 8 6.47 (dd, J = 2.0, 3.5 Hz, 1H), 7.37 (dd, J = 2.5, 3.5 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8. 36 (d, J = 2.0 Hz, 1H), 10.24 (br s, NH).To a solution of N-(5-bromo-3-trimethylsilanylethynyl-pyridin-2-yl)-acetamide (4.75 g, 15.26 mmol) in THF (90 ml) was added dropwise a 1 M solution of tetra-n-butyl ammonium fluoride in THF (30.5 ml, 30.5 mmol). After stirring at reflux for 15 hours, the reaction mixture was concentrated in vacuo and water was added. The aqueous layer was extracted three times with dichloromethane with, and the combined extracts were directly adsorbed on silica gel. Purification by flash chromotography on silica gel with a gradient of ethyl acetate/hexanes afforded 2.29 g of a beige solid. Recrystallization from ethyl acetate/hexanes provided the title compound as light beige flakes (1.33 g). Further purification of the filtrate on silica gel with a gradient of ethyl acetate/hexanes afforded more of the title compound as a crystalline powder (675 mg) for a combined yield of 2.01 g; 67percent. Step 3: A solution of 10a (440 g, 1.63 mol) in t-butanol (5 L) was treated with potassium t-butoxide (732 g, 6.54 mol). The reaction was heated at reflux for 12 hours. Progress of the reaction was monitored by HPLC. First, quick trimethylsilyl deprotection occurs, over time the t-butyl enol is noted in the HPLC. Once the HPLC indicates that all material is converted to the enol, the reaction is cooled to room temperature and concentrated hydrochloric acid (1 L) is added. The reaction is again brought to reflux and stirred for 12 hours. Once the reaction is determined to be complete by HPLC, the reaction is cooled to room temperature, poured into water (5 L) and filtered through a bed of Celite (diatomaceous earth). The aqueous solution is then diluted with water (5 L) and made basic by the addition of 50percent sodium hydroxide. The mixture is extracted with ethyl acetate (3.x.6 L). The organics are washed with water (4 L) and saturated sodium chloride (4 L), dried over sodium sulfate and solvent removed under reduced pressure to a thick slurry. The slurry is filtered and solids washed with 50percent methyl t-butyl ether/heptane (500 mL). The pale yellow solid 11a are dried in a vacuum oven to constant weight, 192 g (60percent); Example 85-bromo-7-azaindole (12, via Sonogashira reaction)SiMe.1112A solution of 2-Amino-3-iodo-5-bromopyridine (1 1 ) in toluene was degassed with argon and then treated with PdCIExample 2bSynthesis of 5-bromo-7-azaindole (1)150 mL of LDA (2.0 M in THF, 0.30 mol) was added into a flask and cooled to -30° C. Then 24.2 g (0.10 mol) of the compound of formula (4) was dissolved in 121 mL of dry THF and the solution was slowly added (within about 2 h) to keep the reaction at constant temperature for 5-6 h until the disappearance of the compound (4) was shown by HPLC analysis. Then, 37.2 mL (0.65 mol) of acetic acid in 90 mL of THF was slowly added and the resulting solution was further vigorously stirred for 10 min. Then, 150 mL of water was injected until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with 4.x.100 mL of hot toluene (40° C.). The organic phases were combined and THF was removed under vacuum at 45° C. The residual toluene solution was washed with 3.x.150 mL of water and 2.x.150 mL of saturated sodium chloride solution, and then dried over 8 g magnesium sulfate for 1 h. After filtration, the mixture was concentrated under vacuum to furnish 22 g of a black, sticky oil. This oil was heated in 40 mL toluene until complete dissolution, and was then cooled to room temperature. The mixture was kept at this temperature for 10 h and then cooled and kept at 0° C. for 2 h for crystallization. After filtration, the solid was washed by a small amount of toluene and dried at 50° C. for 8 h to furnish 2.8 g of the title compound (I) with a HPLC purity of >99percent. All filtrates were combined and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate 10:1 as eluent to afford additional 2.2 g of the title compound (I) with a purity of >98.9percent (HPLC). In total 5.0 g (26percent) of 5-bromo-7-azaindole (1) were obtained.Example 2b: Synthesis of 5-bromo-7-azaindole (1):150 mL of LDA (2.0 M in THF, 0.30 mol) was added into a flask and cooled to -30°C. Then 24.2 g (0.10 mol) of the compound of formula (4) was dissolved in 121 mL of dry THF and the solution was slowly added (within about 2 h) to keep the reaction at constant temperature for 5-6 h until the disappearance of the compound 4 was shown by HPLC analysis. Then, 37.2 mL (0.65 mol) of acetic acid in 90 mL of THF was slowly added and the resulting solution was further vigorously stirred for 10 min. Then, 150 mL of water was injected until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with 4x 100 mL of hot toluene (40°C). The organic phases were combined and THF was removed under vacuum at 45°C. The residual toluene solution was washed with 3x 150 mL of water and 2x 150 mL of saturated sodium chloride solution, and then dried over 8 g magnesium sulfate for 1 h. After filtration, the mixture was concentrated under vacuum to furnish 22 g of a black, sticky oil. This oil was heated in 40 mL toluene until complete dissolution, and was then cooled to room temperature. The mixture was kept at this temperature for 10 h and then cooled and kept at 0°C for 2 h for crystallization. After filtration, the solid was washed by a small amount of toluene and dried at 50°C for 8 h to furnish 2.8 g of the title compound (1) with a HPLC purity of >99 percent. All filtrates were combined and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate 10: 1 as eluent to afford additional 2.2 g of the title compound (1) with a purity of >98.9 percent (HPLC). In total 5.0 g (26percent) of 5-bromo-7-azaindole (1) were obtained.
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