反应详情

To a solution of (R)-2-methylsulfanyl-4-(tetrahydrofuran-3-ylamino)-pyrimidine-5-carboxylic acid ethyl ester (1.0 g, 3.55 mmol) (from Example 11a supra) at 0° C. in anhydrous tetrahydrofuran (60 mL) was added in portions solid lithium aluminum hydride (400 mg, 10.65 mmol) (Aldrich). The resulting slurry was allowed to slowly warm up to room temperature. After overnight stirring the slurry was poured slowly into a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give the crude reduction product. This crude intermediate was dissolved in dichloromethane (30 mL) and treated with manganese dioxide (2.9 g, 34.27 mmol) (Aldrich). After stirring for 2 hours the solids were filtered, washed with tetrahydrofuran (approx. 30 mL), the combined filtrate was concentrated and the residue was dissolved in toluene (40 mL). The solution was then treated with p-anisidine (470 mg, 3.77 mmol) (Aldrich), a catalytic amount of p-toluenesulfonic acid mono-hydrate (Aldrich) was added and the mixture was heated at reflux using a Dean-Stark apparatus for 3 hours. The mixture was then cooled and partitioned between ethyl acetate and saturated aqueous potassium carbonate. The ethyl acetate layer was collected, dried over sodium sulfate, filtered, and concentrated to a residue that was then dissolved in tetrahydrofuran (40 mL). The resulting solution was treated at 0° C. with lithium aluminum hydride (390 mg, 10.28 mmol) (Aldrich). The slurry was allowed to slowly warm to room temperature and after stirring for 13.5 hours was poured slowly into a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated and the resulting residue was purified by silica gel column chromatography using a 0–70% ethyl acetate in hexanes gradient. The intermediate isolated from this purification was dissolved in tetrahydrofuran (50 mL). Triethylamine (1 mL) (Aldrich) was added and the solution was cooled to 0° C. Followed a dropwise addition of 20% phosgene in toluene solution (1.3 mL, 2.71 mmol) (Fluka) and stirring at 0° C. for 1.5 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by chromatography on a silica gel column with a 0–40% ethyl acetate in hexanes gradient. The intermediate isolated from this purification was dissolved in tetrahydrofuran (50 mL) and the resulting solution was cooled at 0° C. and treated with 3-chloroperoxybenzoic acid (75%, 1.13 g, 4.93 mmol) (Aldrich). The reaction mixture was allowed to slowly warm up to room temperature and after stirring overnight was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in aniline (10 mL) (Aldrich), a catalytic amount of aniline hydrochloride (Aldrich) was added and the resulting solution was stirred for 4.5 hours at 95° C. The mixture was then cooled and purified by silica gel column chromatography using a 0–100% ethyl acetate in hexanes gradient to afford the product. Trituration with pentane yielded (R)-3-(4-methoxy-phenyl)-7-phenylamino-1-(tetrahydrofuran-3-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 740 mg, 50%).

1. customThe organic layer was separated
2. dry with materialdried over sodium sulfate
3. filtrationfiltered
4. concentrationconcentrated
5. customto give the crude reduction product
6. stirringAfter stirring for 2 hours the solids
7. filtrationwere filtered
8. washwashed with tetrahydrofuran (approx. 30 mL)
9. concentrationthe combined filtrate was concentrated
10. dissolutionthe residue was dissolved in toluene (40 mL)
11. temperaturethe mixture was heated
12. temperatureat reflux
13. customfor 3 hours
14. temperatureThe mixture was then cooled
15. custompartitioned between ethyl acetate and saturated aqueous potassium carbonate
16. customThe ethyl acetate layer was collected
17. dry with materialdried over sodium sulfate
18. filtrationfiltered
19. concentrationconcentrated to a residue that
20. dissolutionwas then dissolved in tetrahydrofuran (40 mL)
21. temperatureto slowly warm to room temperature
22. stirringafter stirring for 13.5 hours
23. customThe organic layer was separated
24. dry with materialdried over sodium sulfate
25. filtrationfiltered
26. concentrationconcentrated
27. customthe resulting residue was purified by silica gel column chromatography
28. customThe intermediate isolated from this purification
29. temperaturethe solution was cooled to 0° C
30. stirringstirring at 0° C. for 1.5 hours
31. customThe mixture was then partitioned between ethyl acetate and water
32. customThe organic layer was collected
33. dry with materialdried over sodium sulfate
34. filtrationfiltered
35. concentrationconcentrated to a residue that
36. customwas purified by chromatography on a silica gel column with a 0–40% ethyl acetate in hexanes gradient
37. customThe intermediate isolated from this purification
38. temperaturethe resulting solution was cooled at 0° C.
39. temperatureto slowly warm up to room temperature
40. stirringafter stirring overnight
41. customwas partitioned between ethyl acetate and water
42. customThe organic layer was collected
43. dry with materialdried over sodium sulfate
44. filtrationfiltered
45. concentrationconcentrated
46. dissolutionThe residue was dissolved in aniline (10 mL) (Aldrich)
47. additiona catalytic amount of aniline hydrochloride (Aldrich) was added
48. stirringthe resulting solution was stirred for 4.5 hours at 95° C
49. temperatureThe mixture was then cooled
50. custompurified by silica gel column chromatography
51. customto afford the product