The general procedure for the synthesis of 3-(2-chloropyrimidin-4-yl)-1-methylindole from 2,4-dichloropyrimidine and N-methylindole is as follows:
Intermediate 7: Synthesis of 3-(2-chloropyrimidin-4-yl)-1-methylindole
40g of 2,4-dichloropyrimidine and 200mL of 1,2-dimethoxyethane (DME) were added to a 1L three-neck flask and stirred until complete dissolution. After cooling the reaction system to 10-15°C, 45 g of anhydrous ferric chloride (FeCl3) was added rapidly and in batches, controlling the reaction temperature to not exceed 35°C. Stirring of the reaction mixture was continued for 15 minutes after each portion of FeCl3 was added. Subsequently, 52.8 g of N-methylindole was slowly added dropwise to the reaction system. After the dropwise addition, the reaction mixture was slowly heated to 50°C and stirred at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography (TLC) until the reaction was completed.
Upon completion of the reaction, the mixture was cooled to 5-10°C and about 300 mL of a mixture of methanol and water (1:2 by volume) was slowly added dropwise, at which time a large amount of viscous solid precipitated. The reaction mixture was filtered, the solid product was collected and the filter cake was washed twice with methanol. Finally, the resulting solid was dried under reduced pressure at 50°C to give the target product in 85% yield.
