Triphenylphosphine → 2,4-dimethyl-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide

温度

0 °C

A mixture of 2,4-dimethyl-thiazole-5-carboxylic acid (18.1 mg, 0.11 mmol) in dichloromethane (3.0 mL) at 25° C. was treated with triphenylphosphine (33 mg, 0.13 mmol). The reaction was cooled to 0° C. and was treated with N-chlorosuccinimide (19.9 mg, 0.15 mmol). This mixture was stirred at 0° C. for 20 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with N-chlorosuccinimide (5.0 mg, 0.04 mmol) and 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with dichloromethane (100 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×20 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 5:95 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 chloroform (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with chloroform (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 2,4-dimethyl-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (30.2 mg, 45.8%) as a white solid: EI-HRMS m/e calcd for C30H29N6O3FS (M+H)+ 573.2079, found 573.2083.

1. temperaturewas warmed to 25° C. for 20 min
2. stirringwas stirred at 25° C. for 2 d
3. washwas washed with a saturated aqueous sodium bicarbonate solution (1×20 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, 5:95 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 chloroform (100 mL)
11. washwas washed with a saturated aqueous sodium bicarbonate solution (25 mL)
12. extractionThe aqueous layer was re-extracted with chloroform (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レコード

ord-8df79b3bf55f4b3ab45a19fca64f5914

出典データセット

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07135475B2