Diisopropylethylamine → 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

HRID 1685213Notes

Reaction equation

HRID 1685213 reaction equation
Cl[C:2]1[C:7]([CH2:8][C:9]([O:11]CC)=O)=[C:6]([Cl:14])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.O.CN(C=O)C>[Cl:14][C:6]1[C:7]2[CH2:8][C:9](=[O:11])[N:29]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=3[O:25][CH3:24])[C:2]=2[N:3]=[CH:4][N:5]=1

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 5972502,4-DimethoxybenzylamineHCID 56592985Ethyl 2-(4,6-dichloropyrimidin-5-yl)acetate

Product 1

HCID 569717344-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-oneYield 77.9%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
26.5 °C

Procedure

Charge 175 L of DMF and ethyl 2-(4,6-dichloropyrimidin-5-yl)acetate (25 kg) into a reactor at RT. Charge 17.55 Kg of DIPEA into the reactor over a period of 5-10 minutes while maintaining the temperature at 25-28° C. Cool the contents of the reactor to 10-15° C. and stir the reaction for 5-10 minutes. Charge 20.8 Kg of 2,4-Dimethoxybenzylamine into the reactor by while maintaining the temperature at 10-15° C. Heat the reaction slowly to a temperature of 60-65° C. and stir 3 hours. Cool the reaction slowly to 25-28° C. and add 250 L of water into the reactor while maintaining the temperature at 10-15° C. Stir the reaction mass for 10-15 minutes then heat the reaction to 25-28° C. Charge 125 L of DCM into the reaction, stir for 15 minutes and separate the layers. Wash the aqueous layer with 75 L of DCM. Wash the combined organic layers with 75 L of 1N HCl solution followed by water (100 L) and finally with 15% brine (100 L). Distill the organic layer under vacuum at 45-50° C. Charge 50 L of Hexane into the reaction at 45-50° C. and distill the reaction under vacuum at 45-50° C. (2×). Cool the reaction to 0-5° C. and stir for 30 minutes. Filter the resulting solid and wash the wet cake with 50 L of chilled n-Hexane (0-5° C.). Dry the resulting solids under vacuum at 40-45° C. Charge toluene (375 L) the dried solids and 1.025 Kg of para-Toluene to a reactor. Heat the reaction to 85-90° C. for 2 h. Cool the reaction to 80-85° C. and adjust the pH to 6.5-7.0 by adding 10% Sodium bicarbonate solution. Distill the reaction under vacuum at 45-50° C. Cool the contents of the reactor to 25-28° C., charge 3×L of Toluene into the reaction and heat to 85-90° C. Stir for 1 hour then cool the contents of the reactor to 25-28° C. Further cool to 0-5° C. and filter the solids. Wash the wet cake with 75 L of chilled Toluene (0-5° C.). Slurry the solids with 75 L of chilled water (0-5° C.) and filter. Wash the wet cake with 37.5 L of chilled water (0-5° C.) and dry the material under vacuum at 40-45° C. to afford 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (26.5 Kg, 73% yield, 98.89% purity by HPLC).

Workup

  1. temperatureCool the contents of the reactor to 10-15° C.
  2. customthe reaction for 5-10 minutes
  3. temperaturewhile maintaining the temperature at 10-15° C
  4. temperatureHeat
  5. customthe reaction slowly to a temperature of 60-65° C.
  6. stirringstir 3 hours
  7. temperatureCool
  8. customthe reaction slowly to 25-28° C.
  9. temperaturewhile maintaining the temperature at 10-15° C
  10. stirringStir the reaction mass for 10-15 minutes
  11. temperaturethen heat
  12. customthe reaction to 25-28° C
  13. custominto the reaction
  14. stirringstir for 15 minutes
  15. customseparate the layers
  16. washWash the aqueous layer with 75 L of DCM
  17. washWash the combined organic layers with 75 L of 1N HCl solution
  18. distillationDistill the organic layer under vacuum at 45-50° C
  19. additionCharge 50 L of Hexane
  20. custominto the reaction at 45-50° C.
  21. distillationdistill
  22. customthe reaction under vacuum at 45-50° C. (2×)
  23. temperatureCool
  24. customthe reaction to 0-5° C.
  25. stirringstir for 30 minutes
  26. filtrationFilter the resulting solid
  27. washwash the wet cake with 50 L of chilled n-Hexane (0-5° C.)
  28. customDry the resulting solids under vacuum at 40-45° C
  29. temperatureHeat
  30. customthe reaction to 85-90° C. for 2 h
  31. temperatureCool
  32. customthe reaction to 80-85° C.
  33. distillationDistill
  34. customthe reaction under vacuum at 45-50° C
  35. temperatureCool the contents of the reactor to 25-28° C.
  36. custominto the reaction
  37. temperatureheat to 85-90° C
  38. stirringStir for 1 hour
  39. temperaturethen cool the contents of the reactor to 25-28° C
  40. temperatureFurther cool to 0-5° C.
  41. filtrationfilter the solids
  42. washWash the wet cake with 75 L of chilled Toluene (0-5° C.)
  43. customwith 75 L of chilled water (0-5° C.)
  44. filtrationfilter
  45. washWash the wet cake with 37.5 L of chilled water (0-5° C.)
  46. customdry the material under vacuum at 40-45° C.

Sources & evidence

ORD record
ord-554256da5c8e4665830583adafdaf252
Source dataset
uspto-grants-2012_04
Patent number
US08148387B2

Reaction notes

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