Triphenylphosphine → HCID 58739261, compound

Temperature

0 °C

A mixture of 5-methyl-isoxazole-4-carboxylic acid (7.3 mg, 0.05 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with triphenylphosphine (17 mg, 0.06 mmol). This mixture was cooled to 0° C. and then was reacted with N-chlorosuccinimide (10 mg, 0.07 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL). The 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 (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 5-methyl-isoxazole-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 (7.6 mg, 24.4%) as an off-white solid: EI-HRMS m/e calcd for C29H27N6O4F (M+) 542.2078, found 542.2083.

1. temperaturewas warmed to 25° C. for 20 min
2. stirringThe reaction was stirred at 25° C. for 18 h
3. washwas washed with a saturated aqueous sodium bicarbonate solution (1×10 mL)
4. dry with materialThe organics were dried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customFlash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded impure product
8. customThe resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min)
9. concentrationconcentrated in vacuo
10. additionThe resulting residue was diluted with dichloromethane (100 mL)
11. washwas washed with a saturated aqueous sodium bicarbonate solution (25 mL)
12. extractionThe aqueous layer was re-extracted with dichloromethane (1×50 mL)
13. dry with materialThe combined organics were dried over magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe resulting solid was dried in vacuo for 24 h

ORD record

ord-a4bcf1db04c24b0cbe309a3412a0817a

Source dataset

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07135475B2