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温度

0 °C

A mixture of 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid (71 mg, 0.46 mmol) in dichloromethane (2.5 mL) at 0° C. was treated with triphenylphosphine (145 mg, 0.55 mmol) and N-chlorosuccinimide (74 mg, 0.55 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 10 min. At this time, the reaction was treated with a solution of 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (400 mg, 0.92 mmol) in dichloromethane (2.5 mL). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The aqueous layer was re-extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL). The water layer was re-extracted with dichloromethane (2×50 mL). The organic layers were combined and dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in vacuo for 24 h to afford 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (169 mg, 65%) as a white solid: (ES)+-HRMS m/e calcd for C31H32N7O3F (M+H)+ 570.2623, found 570.2619.

1. temperaturewas warmed to 25° C. for 10 min
2. stirringThe reaction was stirred at 25° C. for 24 h
3. washwas washed with a saturated aqueous sodium bicarbonate solution (1×50 mL)
4. extractionThe aqueous layer was re-extracted with dichloromethane (2×50 mL)
5. dry with materialThe combined organics were dried over magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customFlash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded impure product
9. customThe resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min)
10. concentrationconcentrated in vacuo
11. additionThe resulting residue was diluted with dichloromethane (50 mL)
12. washwas washed with a saturated aqueous sodium bicarbonate solution (50 mL)
13. extractionThe water layer was re-extracted with dichloromethane (2×50 mL)
14. dry with materialdried with magnesium sulfate
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. customThe resulting solid was dried in vacuo for 24 h