[Synthesis]
In a round-bottomed flask equipped with a stirrer, thermometer and reflux condenser, 135 mL of anhydrous tetrahydrofuran (THF), 20 g (0.169 mol) of N,N,N',N'-tetramethylethylenediamine, and 15.7 g (0.068 mol) of 2-BOC-amino-4-chloropyridine were added sequentially. The reaction mixture was cooled to -78°C and 68 mL of a 2.5 M hexane solution of n-butyllithium was slowly added dropwise, keeping the reaction temperature constant. After the dropwise addition was completed, stirring was continued at -78°C for 30 min. Subsequently, 15 g (0.2 mol) of N,N-dimethylformamide (DMF) was added, keeping the temperature at -78°C. After the reaction was completed for 1 h, the cooling was stopped, and the reaction mixture was allowed to warm up naturally to room temperature and stirring was continued for 1 h. The reaction was then continued for 1 h. After the reaction was completed, the reaction mixture was allowed to warm up naturally to room temperature. Upon completion of the reaction, 30 mL of methanol and 150 mL of aqueous ammonium chloride were added sequentially under cooling conditions and allowed to stand for 30 minutes. 1000 mL of water and 500 mL of dichloromethane were added to the reaction mixture and the mixture was transferred to a partition funnel to separate the organic layer. The aqueous layer was re-extracted once with 200 mL of dichloromethane. The organic layers were combined, washed with water and dried over anhydrous sodium sulfate. The dichloromethane was removed by distillation under reduced pressure and the residue was dissolved in 200 mL of dichloromethane. Under stirring and cooling conditions, 50 mL of 1,4-dioxane solution in 4 M hydrochloric acid was added to the solution and allowed to stand at room temperature for 5 h. The progress of the reaction was monitored by thin layer chromatography (TLC). Upon completion of the reaction, 200 mL of dichloromethane was added and the excess acid was neutralized with 2 M sodium hydroxide solution. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. Finally, the product was purified by column chromatography using dichloromethane as eluent to give 9.6 g (55% yield) of 2-amino-4-chloronicotinaldehyde. |