Step 3: Synthesis of 5-chloro-7-azaindole (Ib)
Under nitrogen protection, 25.0 g of 4-(2-amino-5-chloropyridin-3-yl)-2-methylbut-3-yn-2-ol, 120 mL of N-methylpyrrolidone, and 130 mL of water were added to a 500 mL double jacketed reactor. The mixture was heated to 75-80 °C (jacket temperature about 95 °C) and a vacuum of 350 mbar was applied at about 100 °C. Subsequently, 85 mL of 28% sodium hydroxide aqueous solution was slowly added dropwise over 30-45 minutes at 75-80°C. Upon completion of the dropwise addition, the dropping funnel was rinsed with 5 mL of water and the mixture was stirred at 78-81 °C overnight. The jacket temperature and vacuum need to be adjusted during stirring to maintain a steady distillate flow rate. Under typical laboratory conditions, 50 mL of the water/acetone mixture can be distilled in approximately 2 hours. Continuous water replenishment is required during the reaction to keep the reaction volume constant at about 270 mL. After the reaction is complete, the mixture is cooled to 50-55 °C and 60 mL of toluene is added. The two-phase mixture was stirred at 50-55 °C for 15-30 min, followed by standing for 15-30 min to separate the layers. After separating the aqueous layer, the aqueous layer was extracted with 3 x 50 mL of toluene at 50-55°C. The toluene layers were combined and washed with 5 x 40 mL of water at 50-55°C. The toluene layer was concentrated to dryness and the residue (17.3 g) was recrystallized with 90 mL of toluene to give 13.0 g (71% yield) of 5-chloro-7-azaindole (Ib) as light yellow crystals with an HPLC purity of 96.7% (% area).
