Water → 7-[4-Nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane

HRID 335394Notes

Reaction equation

HRID 335394 reaction equation
CC1CCC[O:3]1.[CH:7]12[N:13]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=3)[CH:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8]2.O=C1C2C(=CC=CC=2C(F)(F)F)NC=C1C(O)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1.[OH2:67]>>[N+:18]([C:17]1[CH:19]=[CH:20][C:14]([N:13]2[CH:10]3[CH2:9][CH2:8][CH:7]2[CH2:12][CH2:11]3)=[CH:15][C:16]=1[C:21]([F:24])([F:22])[F:23])([O-:3])=[O:67]

Participants

7

Reactant 6

HCID 962WaterHCID 1049PyridineHCID 73012-Methyltetrahydrofuran4×HCID 111923Propylphosphonic anhydrideHCID 156185574-Oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acidHCID 529133904-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline

Product 1

HCID 575168437-[4-Nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane

Conditions

Temperature
45 °C

Procedure

2-Methyltetrahydrofuran (1 vol) was charged into a 30 L jacketed reactor vessel followed by the addition of the hydrochloride salt of 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (3-HCl) (1.2 eq) and 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (2) (573 g, 2.228 mol). Additional 2-methyltetrahydrofuran (9 vol) was charged into the vessel and stirring commenced. T3P in 2-methyltetrahydrofuran (2 eq) was added to the reaction mixture over a period of 15 min. Pyridine (3 eq) was added rapidly in a dropwise fashion using an addition funnel. Under stirring, the mixture was then heated to 45° C. over a period of about 30 min and this temperature was maintained for about 5 h. The mixture was cooled to room temperature. 2-methyltetrahydrofuran (4 vol) was added followed by the slow addition of water (6.9 vol), and the temperature of the reaction was kept below 30° C. The water layer was removed and the organic layer was washed twice with NaHCO3 saturated aqueous solution. The organic layer was then carefully washed with 10% w/w citric acid (5 vol) and washed with water (7 vol), and polished filtered and transferred into another dry vessel. 2-methyltetrahydrofuran (10 vol) was added and stirring commenced. Heptane (10 vol) was rapidly added in a dropwise fashion with stirring. The mixture was stirred for a period of about 12 h, and then vacuum filtered. The solid filter cake was introduced into another vessel. Water (15 vol) was charged into the vessel and the suspension was stirred vigorously for 48 h, then filtered. The solid cake was washed with water (5 vol) and dried at 45° C. to constant weight to produce Compound 1 Form B.

Workup

  1. stirringUnder stirring
  2. temperaturethis temperature was maintained for about 5 h
  3. temperatureThe mixture was cooled to room temperature
  4. customwas kept below 30° C
  5. customThe water layer was removed
  6. washthe organic layer was washed twice with NaHCO3 saturated aqueous solution
  7. washThe organic layer was then carefully washed with 10% w/w citric acid (5 vol)
  8. washwashed with water (7 vol)
  9. filtrationpolished filtered
  10. customtransferred into another dry vessel
  11. addition2-methyltetrahydrofuran (10 vol) was added
  12. stirringstirring commenced
  13. additionHeptane (10 vol) was rapidly added in a dropwise fashion
  14. stirringwith stirring
  15. stirringThe mixture was stirred for a period of about 12 h
  16. filtrationvacuum filtered
  17. filtrationThe solid filter cake
  18. additionwas introduced into another vessel
  19. additionWater (15 vol) was charged into the vessel
  20. stirringthe suspension was stirred vigorously for 48 h
  21. filtrationfiltered
  22. washThe solid cake was washed with water (5 vol)
  23. customdried at 45° C. to constant weight

Sources & evidence

ORD record
ord-ecfe594eaa1a4edd9513a9633353bede
Source dataset
uspto-grants-2014_11
Patent number
US08884018B2

Reaction notes

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