Hydrochloric Acid → 4,4'-(6-Chloropyrimidine-2,4-diyl)dimorpholine

HRID 709522

Reaction equation

HRID 709522 reaction equation
Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[OH2:16].Cl>C1(C)C=CC=CC=1>[Cl:9][C:4]1[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:16][CH2:12][CH2:11]2)[CH:5]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 8083MorpholineHCID 773782,4,6-Trichloropyrimidine

Product 1

HCID 6863344,4'-(6-Chloropyrimidine-2,4-diyl)dimorpholineYield 91.9%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent3×

Conditions

Temperature
83 °C

Procedure

Prepare a solution of 22 g (0.12 mol) of 2,4,6-trichloropyrimidine 1, in 95.2 g (110 mL) of toluene and charge it to the 125 mL addition funnel. Charge a nitrogen-flushed 500 mL round bottom 4-neck flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet/outlet with 62.7 g (63 mL, 0.72 mol) of morpholine 2, 95.2 g (110 mL) of toluene and 44 g (44 mL) of water. Add the toluene solution of 1 over 10 minutes. Heat the reaction mixture to 83±3° C. Stir at 83±3° C. for 2 h. Check the progress of the reaction. Cool to 30±3° C. Transfer the 2-phase mixture to a 1 L separatory funnel. Separate the phases. Wash the organic phase (top) twice with 200 mL (2×100 mL) of warm (30° C.) water. Separate the phases after each wash. Transfer the organic (top) phase back to the 500 mL reaction flask that equipped with a condenser, heating mantle, thermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet/outlet. Stir and add 50.0 mL of 10.0 N aqueous hydrochloric acid solution. Heat the solution to 53±3° C. and stir for 12-18 h. Check the progress of the reaction. Cool to 22±3° C. Transfer the 2-phase mixture to a 1 L separatory funnel. Separate the phases. Transfer the aqueous (bottom) phase to a 500 mL round bottom 4-neck flask equipped with a cooling bath, thermocouple, addition funnel, pH probe, mechanical stirrer and nitrogen inlet/outlet. Stir and cool to 0±3° C. Add 85.0 g of 25% aqueous sodium hydroxide solution by drops over 30 minutes, maintaining a batch temperature of 10±10° C. throughout the addition. Warm to 20±3° C. and stir for 30 minutes. Isolate the solids by vacuum filtration. Wash the cake with 3×100 mL of water. Dry the solids (55° C., 30 mbar) for 24 hours to afford 30.9 g (91.9% yield) of 3 as a white crystalline solid.

Workup

  1. additionto the 125 mL addition funnel
  2. additionCharge a nitrogen-
  3. customflushed 500 mL round bottom 4-neck flask
  4. customthat equipped with a condenser
  5. temperatureheating mantle
  6. customthe progress of the reaction
  7. temperatureCool to 30±3° C
  8. customSeparate the phases
  9. washWash the organic phase (top) twice with 200 mL (2×100 mL)
  10. temperatureof warm (30° C.) water
  11. customSeparate the phases after each wash
  12. customback to the 500 mL reaction flask
  13. customthat equipped with a condenser
  14. temperatureheating mantle
  15. additionthermocouple, 125 mL addition funnel, mechanical stirrer and nitrogen inlet/outlet
  16. stirringStir
  17. temperatureHeat the solution to 53±3° C.
  18. stirringstir for 12-18 h
  19. customthe progress of the reaction
  20. temperatureCool to 22±3° C
  21. customSeparate the phases
  22. customTransfer the aqueous (bottom) phase to a 500 mL round bottom 4-neck flask equipped with a cooling bath
  23. additionthermocouple, addition funnel
  24. stirringStir
  25. temperaturecool to 0±3° C
  26. additionAdd 85.0 g of 25% aqueous sodium hydroxide solution by drops over 30 minutes
  27. temperaturemaintaining a batch temperature of 10±10° C.
  28. additionthroughout the addition
  29. temperatureWarm to 20±3° C.
  30. stirringstir for 30 minutes
  31. customIsolate the solids
  32. filtrationby vacuum filtration
  33. washWash the cake with 3×100 mL of water
  34. customDry the solids (55° C., 30 mbar) for 24 hours

Sources & evidence

ORD record
ord-3b45c0c9004c4f3ea54c48d8c4d6bfaa
Source dataset
uspto-grants-2015_11
Patent number
US09181215B2

Linked notes

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