Dichloromethane → N-(2-bromophenyl)-2,2-dimethylpropanamide

HRID 1513326Notes

Reaction equation

HRID 1513326 reaction equation
C(Cl)Cl.[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CCN(CC)CC>[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 119922-BromoanilineHCID 62493Pivaloyl chloride

Product 1

HCID 357675N-(2-bromophenyl)-2,2-dimethylpropanamide

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Procedure

DCM (670 Kg) and Et3N (76.4 Kg) were added to a 1000 L glass-lined reactor at 0° C. Then, 2-bromoaniline (3a) (100 Kg, 581 moles, 1.0 equiv.) was added with stirring. The resulting mixture was cooled to 0˜10° C. and pivaloyl chloride (77.1 kg, 640 moles, 1.1 equiv.) was added dropwise (5 kg/h) while maintaining the same temperature. The mixture was stirred at this temperature for 1 h 25 min and reaction progress monitored by HPLC. When it was deemed complete, the reaction was quenched by addition of a 5% aqueous solution of Na2CO3 (120 kg) at a rate of 2 kg/min. After addition, the mixture was stirred for 1.5 h and the pH value tested to be between 7 and 8. The reaction was allowed to stand for 20-30 min and the organic phase was separated out. The aqueous layer was extracted with DCM twice (60×2 kg). During each extraction, the bi-phasic mixture was stirred for 15-20 min and then held for 15˜20° C. to allow for layer separation. All the organic layers were combined and a 3% aqueous solution of HCl (251.8 kg) was added to adjust the pH value between 5 and 6. Then the aqueous layer was separated and the organic layer was washed with saturated NaHCO3 (150 L). During the washing, the bi-phasic mixture was stirred for 30 min and held for 30 min. The organic phase was separated and dried over NaSO4 (50 kg) with stirring for 13 h. The resulting slurry was filtered under vacuum using a 50 L vacuum filter. The filtration cake was washed with DCM twice (25 kg×2). The filtrate was concentrated by evaporation at T<50° C. under atmospheric pressure until no solvent distilled out. Then it was additionally concentrated by evaporation under vacuum (P≦MPa) at 65˜70° C. After concentration, the mixture was cooled to 55˜60° C. and THF was added (993 kg). Then the mixture was concentrated by evaporation again under the same conditions as above. The content of DCM was monitored by GC using method F until <0.1%. The mixture was cooled to 20˜30° C. under N2 and then filtered though silica gel (8 kg) under vacuum in order to dry it. The silica plug was washed twice with THF (20 kg×2) to give a solution of crude (3b) which was transferred into 200 L drums for the following step. Typical retention time for starting material (3a) is 8.0 min and for product (3b) is 8.9 min.

Workup

  1. temperatureThe resulting mixture was cooled to 0˜10° C.
  2. temperaturewhile maintaining the same temperature
  3. stirringThe mixture was stirred at this temperature for 1 h 25 min
  4. customreaction progress
  5. customthe reaction was quenched by addition of a 5% aqueous solution of Na2CO3 (120 kg) at a rate of 2 kg/min
  6. additionAfter addition
  7. stirringthe mixture was stirred for 1.5 h
  8. customthe organic phase was separated out
  9. extractionThe aqueous layer was extracted with DCM twice (60×2 kg)
  10. extractionDuring each extraction
  11. stirringthe bi-phasic mixture was stirred for 15-20 min
  12. customheld for 15˜20° C.
  13. customto allow for layer separation
  14. additiona 3% aqueous solution of HCl (251.8 kg) was added
  15. customThen the aqueous layer was separated
  16. washthe organic layer was washed with saturated NaHCO3 (150 L)
  17. stirringDuring the washing, the bi-phasic mixture was stirred for 30 min
  18. waitheld for 30 min
  19. customThe organic phase was separated
  20. dry with materialdried over NaSO4 (50 kg)
  21. stirringwith stirring for 13 h
  22. filtrationThe resulting slurry was filtered under vacuum
  23. filtrationfilter
  24. washThe filtration cake was washed with DCM twice (25 kg×2)
  25. concentrationThe filtrate was concentrated by evaporation at T<50° C. under atmospheric pressure until no solvent
  26. distillationdistilled out
  27. concentrationThen it was additionally concentrated by evaporation under vacuum (P≦MPa) at 65˜70° C
  28. concentrationAfter concentration
  29. temperaturethe mixture was cooled to 55˜60° C.
  30. additionTHF was added (993 kg)
  31. concentrationThen the mixture was concentrated by evaporation again under the same conditions as above
  32. temperatureThe mixture was cooled to 20˜30° C. under N2
  33. filtrationfiltered though silica gel (8 kg) under vacuum in order
  34. customto dry it
  35. washThe silica plug was washed twice with THF (20 kg×2)

Sources & evidence

ORD record
ord-beca251b37e0476282900e14a5f79947
Source dataset
uspto-grants-2012_07
Patent number
US08217172B2

Reaction notes

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