反应详情

A mixture of (±)-4-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl-amino]-2-methylsulfanyl-pyrimidine-5-carbaldehyde (700 mg,1.90 mmol) (from Example 13a supra), p-anisidine (230 mg, 1.90 mmol) (Aldrich) and p-toluenesulfonic acid mono-hydrate (50 mg) (Aldrich) in benzene was refluxed using a Dean-Stark apparatus for 6 hours. The mixture was then cooled and partitioned between ethyl acetate and saturated aqueous potassium carbonate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was then dissolved in anhydrous tetrahydrofuran (60 mL) and to this solution at 0° C. was added in small portions lithium aluminum hydride (216 mg, 5.70 mmol) (Aldrich). The slurry that formed was allowed to slowly warm up to room temperature and after overnight stirring was poured slowly into a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was purified by HPLC using 50% diethyl ether in hexanes as the elution solvent. The intermediate obtained from this purification was dissolved in dichloromethane (100 mL), followed by addition of triethylamine (500 μL, 660 mg, 6.52 mmol) (Aldrich) and cooled at 0° C. A 20% phosgene in toluene solution (640 μL, 1.31 mmol) (Fluka) was then added dropwise and the resulting mixture was stirred for 30 minutes at 0° C. and 1 hour at room temperature. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to a residue that was purified by chromatography on a silica gel column with a 0–60% ethyl acetate in hexanes gradient to give (±)-1-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 543 mg, 57%).

1. temperaturewas refluxed
2. customfor 6 hours
3. temperatureThe mixture was then cooled
4. custompartitioned between ethyl acetate and saturated aqueous potassium carbonate
5. customThe organic layer was collected
6. dry with materialdried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated
9. dissolutionThe residue was then dissolved in anhydrous tetrahydrofuran (60 mL) and to this solution at 0° C.
10. customThe slurry that formed
11. customThe organic layer was collected
12. dry with materialdried over sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. customThe residue was purified by HPLC
16. customThe intermediate obtained from this purification
17. temperaturecooled at 0° C
18. stirringthe resulting mixture was stirred for 30 minutes at 0° C. and 1 hour at room temperature
19. customThe mixture was then partitioned between ethyl acetate and water
20. customThe organic layer was separated
21. dry with materialdried over sodium sulfate
22. filtrationfiltered
23. concentrationconcentrated to a residue that
24. customwas purified by chromatography on a silica gel column with a 0–60% ethyl acetate in hexanes gradient