Methane → Tonapofylline

HRID 480167Notes

Reaction equation

HRID 480167 reaction equation
[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30].O1CCCC1.C>O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]

Participants

5

Reactant 3

HCID 297MethaneHCID 8028TetrahydrofuranHCID 670791013-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid

Product 1

HCID 216466Tonapofylline

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid, (XIII, Example 89, 1.934 kg), tetrahydrofuran (11.875 l), water (0.625 l) and activated charcoal (0.100 kg) are mixed and stirred at 16 to 25° for 30 minutes and then filtered. The filter cake is washed with THF (0.500 l). A separate flask is charged with palladium on carbon (10%, 0.130 kg) and the filtered tetrahydrofuran/water mixture of the starting material. The flask is placed under reduced pressure and purged with nitrogen. The reduced pressure/nitrogen purge is repeated twice. The flask and contents are placed under reduced pressure and purged twice with hydrogen. The mixture is vigorously stirred under an atmosphere of hydrogen at 20° C. for 3 hours. The reaction vessel is evacuated and purged with nitrogen three times. The contents are filtered through celite (0.500 kg) and the filter cake washed with tetrahydrofuran (2×0.500 l). The solvent is removed under reduced pressure at 40 to 45°. Aqueous acetonitrile (50%, 7.540 l) is added to the residue and the slurry is aged at 15 to 25°, with stirring, for 3 hours. The slurry is cooled to between 0 and 5° and filtered. The filter cake is washed with aqueous acetonitrile (50%, 1.93 l), transferred to drying trays and dried at 50 to 60° under reduced pressure for 24 hours to give the title compound.

Workup

  1. filtrationfiltered
  2. washThe filter cake is washed with THF (0.500 l)
  3. additionA separate flask is charged with palladium on carbon (10%, 0.130 kg)
  4. additionthe filtered tetrahydrofuran/water mixture of the starting material
  5. custompurged with nitrogen
  6. customThe reduced pressure/nitrogen purge
  7. custompurged twice with hydrogen
  8. stirringThe mixture is vigorously stirred under an atmosphere of hydrogen at 20° C. for 3 hours
  9. customThe reaction vessel is evacuated
  10. custompurged with nitrogen three times
  11. filtrationThe contents are filtered through celite (0.500 kg)
  12. washthe filter cake washed with tetrahydrofuran (2×0.500 l)
  13. customThe solvent is removed under reduced pressure at 40 to 45°
  14. additionAqueous acetonitrile (50%, 7.540 l) is added to the residue
  15. customis aged at 15 to 25°
  16. stirringwith stirring, for 3 hours
  17. temperatureThe slurry is cooled to between 0 and 5°
  18. filtrationfiltered
  19. washThe filter cake is washed with aqueous acetonitrile (50%, 1.93 l)
  20. customto drying trays
  21. customdried at 50 to 60° under reduced pressure for 24 hours

Sources & evidence

ORD record
ord-47761542ecff42e1a469000e2dcaabc2
Source dataset
uspto-grants-2003_11
Patent number
US06649600B1

Reaction notes

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