Morpholine → 3-Fluoro-4-morpholinobenzoic acid

HRID 1500242Notes

Reaction equation

HRID 1500242 reaction equation
[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1F)[C:11]([OH:13])=[O:12]>>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:11]([OH:13])=[O:12]

Participants

3

Reactant 2

HCID 8083MorpholineHCID 991663,4-Difluorobenzoic acid

Product 1

HCID 121095953-Fluoro-4-morpholinobenzoic acid

Procedure

A 2 L 3-neck round bottom flask fitted with mechanical stirrer and reflux condenser was charged with morpholine (700 g, 700 ml, 8 mol) and to the stirring solution was added 3,4-difluorobenzoic acid (158 g, 1 mol) (AmplaChem, Inc). The clear solution was heated at reflux and after 29 hours a ca. 0.5 ml aliquot was removed from the light yellow reaction solution, acidified with 6 N HCl and the precipitate was analyzed by 1H NMR (DMSO-d6) showing that the reaction was complete by the absence of the aromatic peaks at δ7.78-7.92 present in the starting material. The reaction was allowed to cool to below 100° C. and was carefully acidified (pH 1 to 2) with 6 N hydrochloric acid with rapid stirring (initial addition of 6N HCl was dropwise but then as a slow stream with cooling). The product starts to precipitate as the pH falls below 6. The precipitate was collected by filtration and washed thoroughly with hot (80° C.) water (2 L) to ensure the removal of morpholine hydrochloride (that appears as two triplets just above the morpholine peaks for (14) in the NMR) The white precipitate was dried at 110° C. under house vacuum and recrystallized by dissolving in ethanol (4.5 L) and concentration to 1.5 L with stirring. Crystals started to form in the refluxing solution when the volume had been reduced to ca. 3.5 L. The crystals were cooled to room temp with stirring, cooled in an ice bath for 1 hour with stirring, collected by filtration and dried in vacuo at 80° C. (172.5 g, 77%). 1H NMR spectrum identical with that for the product described in the previous paragraph.

Workup

  1. customA 2 L 3-neck round bottom flask fitted with mechanical stirrer
  2. temperaturereflux condenser
  3. temperatureThe clear solution was heated
  4. temperatureat reflux and after 29 hours a ca. 0.5 ml
  5. customaliquot was removed from the light yellow reaction solution
  6. temperatureto cool to below 100° C.
  7. additionaddition of 6N HCl
  8. temperatureas a slow stream with cooling)
  9. customto precipitate as the pH
  10. filtrationThe precipitate was collected by filtration
  11. washwashed thoroughly with hot (80° C.) water (2 L)
  12. customthe removal of morpholine hydrochloride (that
  13. customwas dried at 110° C. under house vacuum
  14. customrecrystallized
  15. dissolutionby dissolving in ethanol (4.5 L)
  16. concentrationconcentration to 1.5 L
  17. stirringwith stirring
  18. customto form in the refluxing solution when the volume
  19. stirringwith stirring
  20. temperaturecooled in an ice bath for 1 hour
  21. stirringwith stirring
  22. filtrationcollected by filtration
  23. customdried in vacuo at 80° C. (172.5 g, 77%)

Sources & evidence

ORD record
ord-e7106543ee5f4643ac76c6edb59069b2
Source dataset
uspto-grants-2015_12
Patent number
US09206141B2

Reaction notes

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