反应详情

4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (IX, Example 85a, 1 wt) and tetrahydrofuran (11 vol) are mixed under nitrogen. Borane.tetrahydrofuran complex (1 M) in THF (5.1 vol) is added at such a rate as to maintain the internal temperature between 10 to 20°. The mixture is stirred at 10 to 20° for 17 to 20 hours until all of the acid (X) is consumed (TLC; dichloromethane/methanol, 9/1, visualization UV then potassium permanganate). Methanol (4.2 vol) is added to the reaction, prior to heating at reflux for 45 to 75 min. The reaction is cooled to between 15 and 40° and the solvent removed by reduced pressure at 40 to 45°. The residue is partitioned between ethyl acetate (16.6 vol) and hydrochloric acid (1 M, 2.5 vol) and the aqueous layer is removed with any undissolved solid material. This mixture is clarified and the residual organic phase from the filtration of the aqueous layer/solid mixture is combined with the bulk organic phase. Saturated sodium hydrogen carbonate (2.5 vol) is added and the layers separated, retaining any solids with the aqueous phase. This aqueous phase/solid mixture is filtered and the residual organic phase from these mother liquors is combined with the bulk organic phase. The combined organic phases are washed with saline (2.5 vol), the layers are separated and any residual solid is retained with the aqueous phase. The aqueous phase/solid mixture is filtered and any organic in the mother liquors from the filtration is combined with the bulk organic phase, dried with magnesium sulphate (0.5 wt) for 5 to 15 mins, filtered, washed with ethyl acetate (1 vol) and the solvent removed under reduced pressure at 40 to 45° to give the title compound.

1. temperatureto maintain the internal temperature between 10 to 20°
2. customis consumed (TLC
3. additionMethanol (4.2 vol) is added to the reaction
4. temperatureto heating
5. temperatureat reflux for 45 to 75 min
6. temperatureThe reaction is cooled to between 15 and 40°
7. customthe solvent removed by reduced pressure at 40 to 45°
8. customThe residue is partitioned between ethyl acetate (16.6 vol) and hydrochloric acid (1 M, 2.5 vol)
9. customthe aqueous layer is removed with any undissolved solid material
10. filtrationthe residual organic phase from the filtration of the aqueous layer/solid mixture
11. additionSaturated sodium hydrogen carbonate (2.5 vol) is added
12. customthe layers separated
13. filtrationThis aqueous phase/solid mixture is filtered
14. washThe combined organic phases are washed with saline (2.5 vol)
15. customthe layers are separated
16. filtrationThe aqueous phase/solid mixture is filtered
17. filtrationany organic in the mother liquors from the filtration
18. dry with materialdried with magnesium sulphate (0.5 wt) for 5 to 15 mins
19. filtrationfiltered
20. washwashed with ethyl acetate (1 vol)
21. customthe solvent removed under reduced pressure at 40 to 45°