反应详情

A solution of (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine (270 mg, 1.25 mmol) (from Example 9b supra) and triethylamine (1.15 mL, 840 mg, 8.30 mmol) (Aldrich) in dichloromethane (5 mL) was treated at 0° C. with a 20% solution of phosgene in toluene (2 mL, 4.15 mmol) (Fluka). After stirring for 30 minutes the mixture was filtered and the filtrate was concentrated to a small volume. Benzene (5 mL) was added and the mixture was filtered again. The filtrate was concentrated, the residue was dissolved in a small volume of anhydrous tetrahydrofuran (approx. 3 mL) and then transferred via a cannula to a −78° C. solution of (2,4-dichloro-pyrimidin-5-yl-methyl)-(4-methoxyphenyl)-amine (180 mg, 0.63 mmol) (from Example 1d supra) and n-butyllithium (2.5 M solution in hexanes, 250 μL, 0.63 mmol) (Aldrich) in anhydrous tetrahydrofuran (15 mL). The reaction mixture was allowed to slowly warm up to room temperature, stirred for 5.5 hours and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography on a silica gel column with a 0–40% ethyl acetate in hexanes gradient. The intermediate obtained from this purification was dissolved in aniline (2 mL) (Aldrich), a catalytic amount of 4-(dimethylamino)pyridine (Aldrich) was added and the resulting solution was stirred for 7 hours at 80° C. The mixture was then cooled and purified by silica gel column chromatography using a 0–40% ethyl acetate in hexanes gradient. The product from this purification was dissolved in acetonitrile (3 mL), 5% aqueous hydrofluoric acid (50 μL) was added and the mixture was stirred for 21 hours. The reaction mixture was then concentrated to a small volume and purified by silica gel column chromatography using a 0–100% tetrahydrofuran in hexanes gradient to afford the product. After a precipitation out of dichloromethane with excess of pentane, the product, (±)-1-(trans-3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, was isolated as a white solid. (Yield 23 mg, 8%).

1. filtrationwas filtered
2. concentrationthe filtrate was concentrated to a small volume
3. additionBenzene (5 mL) was added
4. filtrationthe mixture was filtered again
5. concentrationThe filtrate was concentrated
6. dissolutionthe residue was dissolved in a small volume of anhydrous tetrahydrofuran (approx. 3 mL)
7. customtransferred via a cannula to a −78° C.
8. stirringstirred for 5.5 hours
9. custompartitioned between ethyl acetate and water
10. customThe organic layer was collected
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated
14. customthe residue was purified by chromatography on a silica gel column with a 0–40% ethyl acetate in hexanes gradient
15. customThe intermediate obtained from this purification
16. stirringthe resulting solution was stirred for 7 hours at 80° C
17. temperatureThe mixture was then cooled
18. custompurified by silica gel column chromatography
19. customThe product from this purification
20. dissolutionwas dissolved in acetonitrile (3 mL)
21. addition5% aqueous hydrofluoric acid (50 μL) was added
22. stirringthe mixture was stirred for 21 hours
23. concentrationThe reaction mixture was then concentrated to a small volume
24. custompurified by silica gel column chromatography
25. customto afford the product
26. customAfter a precipitation out of dichloromethane with excess of pentane