反应详情

To a mixture of (+)-(1R,3R)-4-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (710 mg, 1.73 mmol) (from Example 27d supra) in anhydrous tetrahydrofuran (50 mL) at 0° C. was added in portions lithium aluminum hydride (196 mg, 5.19 mmol) (Aldrich). The slurry that resulted was allowed to slowly warm up to room temperature and after stirring for 5.5 hours was poured in portions to a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was then collected, dried over sodium sulfate, filtered and concentrated to a solid residue that was dissolved in dichloromethane (50 mL). To this solution was added manganese dioxide (1.5 g, 17.30 mmol) (Aldrich) and the resulting slurry was stirred for 3.5 hours and then filtered. The solids were washed with tetrahydrofuran (approximately 30 mL) and the combined filtrate was concentrated to a residue that was dissolved in benzene (60 mL). That solution was treated with p-anisidine (180 mg, 1.49 mmol) (Aldrich) and p-toluenesulfonic acid mono-hydrate (25 mg) (Aldrich) and refluxed using a Dean Stark apparatus overnight. The mixture was then cooled, partitioned between ethyl acetate and water and the organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (50 mL) and the solution that resulted was cooled at 0° C. To this solution was added lithium aluminum hydride (150 mg, 4.08 mmol) in small portions and the slurry that formed was allowed to slowly warm up to room temperature. After stirring overnight the slurry was poured in portions into a mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated and the residue was purified by chromatography on a silica gel column with a 0–30% ethyl acetate in hexanes gradient. The intermediate obtained from that purification was then dissolved in dichloromethane (80 mL) and that solution was treated with triethylamine (490 μL, 0.35 g, 3.47 mmol) (Aldrich) and cooled at 0° C. This was followed by a dropwise addition of a 20% phosgene in toluene solution (570 μL, 1.16 mmol) (Fluka). The reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 1 hour and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a silica gel column with a 0–30% ethyl acetate in hexanes gradient. The intermediate from this purification was dissolved in tetrahydrofuran (50 mL). This solution was then treated with 3-chloroperoxy-benzoic acid (75%, 320 mg, 1.43 mmol) (Aldrich) stirred overnight and partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a solid residue. This residue was dissolved in aniline (3 mL) (Aldrich) and stirred at 75° C. for 16.5 hours. The mixture was then cooled, and purified by silica gel column chromatography with a 0–20% diethyl ether in toluene gradient to give (−)-(1R,3R)-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 152 mg, 68%).

1. customThe slurry that resulted
2. customThe organic layer was then collected
3. dry with materialdried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated to a solid residue that
6. dissolutionwas dissolved in dichloromethane (50 mL)
7. stirringthe resulting slurry was stirred for 3.5 hours
8. filtrationfiltered
9. washThe solids were washed with tetrahydrofuran (approximately 30 mL)
10. concentrationthe combined filtrate was concentrated to a residue that
11. dissolutionwas dissolved in benzene (60 mL)
12. temperaturerefluxed
13. customa Dean Stark apparatus overnight
14. temperatureThe mixture was then cooled
15. custompartitioned between ethyl acetate and water
16. customthe organic layer was collected
17. dry with materialdried over sodium sulfate
18. filtrationfiltered
19. concentrationconcentrated
20. dissolutionThe residue was dissolved in anhydrous tetrahydrofuran (50 mL)
21. customthe solution that resulted
22. temperaturewas cooled at 0° C
23. customthe slurry that formed
24. temperatureto slowly warm up to room temperature
25. stirringAfter stirring overnight the slurry
26. customThe organic layer was collected
27. dry with materialdried over sodium sulfate
28. filtrationfiltered
29. concentrationconcentrated
30. customthe residue was purified by chromatography on a silica gel column with a 0–30% ethyl acetate in hexanes gradient
31. customThe intermediate obtained from that purification
32. temperaturecooled at 0° C
33. stirringThe reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 1 hour
34. custompartitioned between ethyl acetate and water
35. customThe organic layer was collected
36. dry with materialdried over sodium sulfate
37. filtrationfiltered
38. concentrationconcentrated
39. customThe residue was purified by chromatography on a silica gel column with a 0–30% ethyl acetate in hexanes gradient
40. customThe intermediate from this purification
41. dissolutionwas dissolved in tetrahydrofuran (50 mL)
42. stirringstirred overnight
43. custompartitioned between ethyl acetate and saturated aqueous potassium carbonate solution
44. customThe organic layer was collected
45. dry with materialdried over sodium sulfate
46. filtrationfiltered
47. concentrationconcentrated to a solid residue
48. dissolutionThis residue was dissolved in aniline (3 mL) (Aldrich)
49. stirringstirred at 75° C. for 16.5 hours
50. temperatureThe mixture was then cooled
51. custompurified by silica gel column chromatography with a 0–20% diethyl ether in toluene gradient