Carbon Dioxide → 4-(2-Amino-6-chloropyrimidin-4-yl)-N-(tert-butoxycarbonyl)-L-phenylalanine

Participants

Reaction Conditions

Reaction Steps

To a 5-L three-necked flask with a thermometer controller, a mechanical stirrer, and a condenser protected under N2 was charged EtOH (570 g), THF (1330 g), boronic acid 7 (100 g, 255.6 mmol, 1.0 eq.), 2-amino-4,6-dichloropyrimidine 126 g (768.3 mmol, 3.0 eq.), PPh3 (0.87 g, 3.32 mmol, 1.3 mol %) and Pd(OAc)2 (0.373 g, 1.66 mmol, 0.65 mol %). The flask was then degassed by three vacuum/nitrogen fill cycles and stirred at about 10-20° C. for about 10-20 minutes. To the stirring solution was added an aqueous solution of KHCO3 (92 g, 918.9 mmol, 3.6 eq in 579 g of water) over about 30-50 minutes to control the evolution of CO2 gas). The flask was then degassed again by three vacuum/nitrogen fill cycles. The resulting solution was then refluxed at about 68˜72° C. for 21˜23 hours and the reaction was determined to be complete base on HPLC analysis. The reaction mixture was concentrated to ˜750 mL under reduced pressure at 35˜40° C. and then flushed with water (300 mL×2). The concentrated solution was diluted with water (600 g) and stirred for 15˜30 minutes at 20˜25° C. After filtration, the filter cake was washed with water (200 g×2). The filtrate was extracted with EtOAc (500 g×2). The combined EtOAc layer was washed with water (300 g). THF (1000 g) and toluene (730 g) were then added to the combined aqueous layer and the mixture was acidified to pH 2.5˜3.5 with 6 N HCl (−100 g) at 20˜25° C. The layers were separated and NaCl (500 g) was added to the aqueous layer then extracted with EtOAc (400 g). The combined organic layer was treated with active carbon (50 g) at 65˜68° C. for 8˜10 hours twice. The resulting mixture was concentrated under vacuum to ˜300 mL at 30˜40° C. and then flushed with toluene (500 g). The resulting mixture was cooled to 0˜5° C. and stirred for 60˜80 minutes at 0˜5° C., and then filtered. The wet cake was washed with toluene (43 g) and dried in vacuum oven at 40˜45° C. for 12 hours to afford 82.3 g of the monochloride toluene solvate 8 as an off-white solid in 66% yield corrected for 80 w % purity (96.3 A %).

Provenance & Evidence