Acetic Acid → HCID 22595831, compound

HRID 1784116Notes

Reaction equation

HRID 1784116 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[N:16]([O-])=O.[Na+].C(O)(=O)C.[OH-].[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[ClH:8].[ClH:8].[NH2:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[C:4]([NH2:9])[N:3]=1

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 8083MorpholineHCID 14798Sodium HydroxideHCID 24489Sodium DithioniteHCID 674322,4-Diamino-6-chloropyrimidineHCID 23668193Sodium Nitrite

Product 1

HCID 22595831HCID 22595831, compoundYield 141.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent3×

Conditions

Temperature
21 °C

Procedure

In a 10 L 4-neck flask equipped with a mechanical stirrer, a thermometer and a heating mantle was placed 2,6-diamino-4-chloropyrimidine (870.5 g; 6.0 mol) In water (3190 ml). To the stirred resulting white suspension was added morpholine (1113 g; 12.8 moles) in one portion. The temperature raised from 14 to 28° C. and the mixture was heated until at 75° C. a clear solution was obtained and refluxed for 16 hours. After complete conversion of the starting material (controlled by HPLC analysis) the reaction mixture was cooled to room temperature and NaNO2 (465 g, 6.74 mole) was added in three portions. No heat effect was observed but the product precipitated out of the mixture. During subsequent dropwise addition of acetic acid (600 g, 9.0 moles) the mixture became so thick that faster stirring and additional water (850 mL) were necessary to achieve a well mixable suspension. A temperature raise from 15 to 28° C. was measured. After stirring for 2 hours, HPLC analysis showed complete conversion. The mixture was then allowed to cool down to room temperature and transferred to a 20 L flask. To the add (pH 4) purple slurry was added water (3500 mL) and then an aqueous NaOH solution (165 g in 825 mL) in order to neutralise to pH 7. The suspension was cooled down to 10-12° C. in an ice-water bath and Na2S2O4 (4.68 kg, 26.9 moles) was added in portions of about 500 g at 5 minutes intervals. A temperature raise to 30° C. was observed. The mixture was left stirring overnight at room temperature before being analysed (HPLC: 99.3% conversion). The suspension was filtered over filter cloth and the wet cake was washed with 2.77 L water leaving 1.5 kg of wet material which was slurried in isopropanol (10.2 L) and to the suspension was added dropwise 36% HCl/H2O (1.16 L) during which the temperature raised from 15 to 30° C. Subsequent heating of the slurry to 40° C. afforded an almost clear solution and crystallisation started suddenly showing an exotherm to 50° C. The suspension was cooled down to room temperature before the suspension was filtered over filter cloth. The wet cake was again slurried in isopropanol (5.0 L), again filtered over filter cloth and dried at 40° C. in vacuo (200 mbar) for several days. According to this procedure was obtained 1.2 kg (yield 54.1%) of 2,5,6-triamino-4-morpholino-pyrimidine dihydrochloride with a purity above 99.9% and characterised as follows: UV (MeOH, nm): 225, 254.

Workup

  1. customIn a 10 L 4-neck flask equipped with a mechanical stirrer
  2. customTo the stirred resulting white suspension
  3. temperaturethe mixture was heated until at 75° C. a clear solution
  4. customwas obtained
  5. temperaturerefluxed for 16 hours
  6. temperatureAfter complete conversion of the starting material (controlled by HPLC analysis) the reaction mixture was cooled to room temperature
  7. customthe product precipitated out of the mixture
  8. temperatureA temperature raise from 15 to 28° C.
  9. stirringAfter stirring for 2 hours
  10. temperatureto cool down to room temperature
  11. customtransferred to a 20 L flask
  12. additionTo the add (pH 4) purple slurry
  13. temperatureThe suspension was cooled down to 10-12° C. in an ice-water bath
  14. temperatureA temperature raise to 30° C.
  15. waitThe mixture was left
  16. stirringstirring overnight at room temperature
  17. filtrationThe suspension was filtered
  18. filtrationover filter cloth
  19. washthe wet cake was washed with 2.77 L water leaving 1.5 kg of wet material which
  20. additionwas added dropwise 36% HCl/H2O (1.16 L) during which the temperature
  21. temperatureraised from 15 to 30° C
  22. temperatureSubsequent heating of the slurry to 40° C.
  23. customafforded
  24. customan almost clear solution and crystallisation
  25. customexotherm to 50° C
  26. temperatureThe suspension was cooled down to room temperature before the suspension
  27. filtrationwas filtered
  28. filtrationover filter cloth
  29. filtrationagain filtered
  30. filtrationover filter cloth
  31. customdried at 40° C. in vacuo (200 mbar) for several days

Sources & evidence

ORD record
ord-2a52eb2a457545149d25ef6aa9099ef1
Source dataset
uspto-grants-2009_03
Patent number
US07501513B2

Reaction notes

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