2,6-Lutidine → HCID 44517635, compound

HRID 1818737Notes

Reaction equation

HRID 1818737 reaction equation
[CH3:1][S:2]([CH2:5][C@H:6]([NH:8][C:9]([C:11]1[C:12](OC2C=CC(F)=CC=2F)=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[N:15][CH:16]=1)=O)[CH3:7])(=[O:4])=[O:3].N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OC(C)(C)C)(=O)[NH:57][NH2:58]>ClCCl>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[N:13]=[C:12]2[NH:57][N:58]=[C:9]([NH:8][C@H:6]([CH3:7])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]2=[CH:16][N:15]=1

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 9845Trifluoroacetic anhydrideHCID 70091tert-Butyl carbazateHCID 57886817HCID 57886817, compound

Product 1

HCID 44517635HCID 44517635, compoundYield 64.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

2,4-Bis-(2,4-difluoro-phenoxy)-pyrimidine-5-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amide (61.16 g, 122.5 mmol) was added to 600 mL dry dichloromethane, and the mixture was stirred under nitrogen. 2,6-lutidine (43.0 mL, 184 mmol) was added, and the mixture was cooled to 0° C. in an ice bath for 30 minutes with stirring. Trifluoroacetic anhydride (31.0 mL, 184 mmol) was added dropwise over five minutes, and the reaction mixture was stirred for 10 minutes at 0 ° C. The ice bath was removed and the reaction mixture was stirred for 3.5 hours. The reaction mixture was then cooled to 0 ° C. in an ice bath for 30 minutes, and tert-butyl carbazate (24.36 g, 184 mmol) was added in portions over five minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was again cooled to 0° C. in an ice bath for 30 minutes, and trifluoroacetic acid (200 mL) was added in portions over 15 minutes. The reaction mixture was stirred for another 15 minutes, then the ice bath was removed and stirring was continued for two hours. The reaction mixture was concentrated under reduced pressure, and 500 mL dichloromethane was added to the residue. The mixture was cooled in an ice bath for 15 minutes, and 1.5 L of saturated aqueous sodium bicarbonate was slowly added in portions with stirring, resulting in an aqueous solution of pH=8 and the formation of a precipitate. The precipitate was collected by filtration and rinsed with water, followed by dichloromethane, and dried under vacuum at 80° C. to give 30.15 g (60%) of [6-(2,4-Difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-((R)-2-methanesulfonyl-1-methyl-ethyl)-amine. Mp=177.7-178.8° C., MS(M+H)=384.

Workup

  1. stirringwith stirring
  2. stirringthe reaction mixture was stirred for 10 minutes at 0 ° C
  3. customThe ice bath was removed
  4. stirringthe reaction mixture was stirred for 3.5 hours
  5. temperatureThe reaction mixture was then cooled to 0 ° C. in an ice bath for 30 minutes
  6. customThe ice bath was removed
  7. stirringthe reaction mixture was stirred at room temperature for 12 hours
  8. temperatureThe reaction mixture was again cooled to 0° C. in an ice bath for 30 minutes
  9. additiontrifluoroacetic acid (200 mL) was added in portions over 15 minutes
  10. stirringThe reaction mixture was stirred for another 15 minutes
  11. customthe ice bath was removed
  12. stirringstirring
  13. concentrationThe reaction mixture was concentrated under reduced pressure, and 500 mL dichloromethane
  14. additionwas added to the residue
  15. temperatureThe mixture was cooled in an ice bath for 15 minutes
  16. addition1.5 L of saturated aqueous sodium bicarbonate was slowly added in portions
  17. stirringwith stirring
  18. customresulting in an aqueous solution of pH=8
  19. filtrationThe precipitate was collected by filtration
  20. washrinsed with water
  21. customdried under vacuum at 80° C.

Sources & evidence

ORD record
ord-df332f929c67447aa137808379cb5f78
Source dataset
uspto-grants-2009_10
Patent number
US07601726B2

Reaction notes

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