5-Chloro-7-azaindole

Yellow powder

Step 3: Synthesis of 5-chloro-7-azaindol (Ib); A 500 mL double-jacket reactor (under a nitrogen atmosphere) is charged with 25.0 g 4-(2-amino-5-chloro-pyridin-3-yl)-2-methyl-but-3-yn-2-ol, 120 mL N-methylpyrrolidone and 130 mL water. The mixture is heated to 75 to 80° C. (ca. 95° C. jacket temperature) 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 85 mL sodium hydroxide (28percent in water). The dropping funnel is rinsed with 5 mL water and the mixture stirred at 78 to 81° C. over night. During stirring the jacket temperature and the vacuum have to be adjusted such that a slight steadily distillate flow is guaranteed. In a typical lab experiment approx. 50 mL of water/acetone are distilled off in 2 hours. During the reaction, water is continuously added to keep the volume constant at approx. 270 mL. Upon complete conversion, the reaction mixture is cooled to 50 to 55° C. The mixture is treated at this temperature with 60 mL toluene. The biphasic mixture 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.50 mL with toluene. The combined toluene layers are washed at 50 to 55° C. with 5.x.40 mL with water. The toluene layer is concentrated to dryness. The residue (17.3 g) is crystallized from 90 mL toluene to afford 13.0 g (71percent) of 5 chloro-7-azaindol (Ib) as slightly yellow crystals with a purity of 96.7percent (area).Compound 41 (4.37 g, 0.0164 mol) was dissolved in THF. Molecular sieve (lOg of 3A) was added followed by TBAF (32.75 mL, 0.0328). The reaction mixture was stirred for 5 h at rt. Diluted with ethyl acetate and washed several times with water, brine and the organic layer was dried and concentrated in vacuo to an oil that was subjected to flash chromatography (30percent EtOAc-70percent hexanes) to give 02.3 g (90percent) of the desired material 42. 1H NMR DMSO d6 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 6.5 (s, 1H).(6) The 5-chloro-7-azaindoline obtained in step (5), manganese dioxide was added to toluene, 5-chloro-7-azaindoline, Manganese dioxide, toluene weight ratio of 17:45:80, heated to 60 ° C and refluxed for 3 hours, cooled to room temperature after the product was filtered, The filter cake was washed three times with trichloromethane. The combined filtrates were evaporated to dryness and recrystallized from methyl acetate to give 5-chloro-7-azaindole.Third Step A solution of potassium tert-butoxide (36g, 320mol) in N-methylpyrrolidone (70ml) was heated to 80°C under nitrogen. A solution of 5-chloro-3-(trimethyl-silanylethynyl)-pyridin-2-ylamine (2) (36g, 160mol) in NMP (200ml) was added dropwise via a dropping funnel. The reaction mixture was stirred at 80°C for a further fifty minutes. The reaction mixture was allowed to cool to room temperature. Brine (500ml) was added to the reaction mixture and extracted with diethyl ether (5 x 200mol). The combined organic were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography, using as eluent pentane/EtOAc 0percent to 40percent, and further recrystallised from cyclohexane to afford the title compound (10g, 41percent). 1H NMR (CDCl3) 6.5 (1H, s), 7.4 (1H, s), 8.0 (1H, s), 8.2 (1H, s), 10.4-10.6 (1H, brs). MS (ES+) 153.Into a 10000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of potassium t-butoxide (446.3 g, 3.98 mol, 2.00 equiv) in NMP (1300 mL). This was followed by the addition of a solution of 5-chloro-3-(2- (tratne lsilyl)em^ (446.3 g, 1.98 mol, 1.00 equiv) in NMP (2500 mL) dropwise with stirring at 80°C over 3 hours. After stirred for 60 min at 80°C in an oil bath, the reaction mixture was cooled to 40°C and diluted with 7500 mL of brine. The resulting solution was extracted with 5x3000 mL of ether. The organic layers were combined, washed with 2x3000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE to EtOAc:PE (1-30). This resulted in 120 g (40percent) of 5-chloro-1H-pyrrolo[2, 3-b3pyridine as a yellow solid.