2-Methyltetrahydrofuran → 4-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline

HRID 1943047Notes

Reaction equation

HRID 1943047 reaction equation
Cl.[CH:2]12[N:8]([C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[N+](C1C=CC(N2C3CCC2CC3)=CC=1C(F)(F)F)([O-])=O.CC1CCCO1>[Pd]>[CH:5]12[N:8]([C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([C:16]([F:19])([F:17])[F:18])[CH:10]=3)[CH:2]([CH2:3][CH2:4]1)[CH2:7][CH2:6]2

Participants

5

Reactant 3

HCID 73012-MethyltetrahydrofuranHCID 575168437-[4-Nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptaneHCID 670026364-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline hydrochloride

Product 1

HCID 529133904-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline

Reagents, catalysts & solvents 1

HCID 23938PalladiumCatalyst

Procedure

Preparation 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2 -(trifluoromethyl)aniline hydrochloride (11B), method 1. Palladium on carbon (150 g, 5% w/w) was charged into a Büchi Hydrogenator (20 L capacity) under a nitrogen atmosphere, followed by the addition of 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (10A, 1500 g), as prepared in Example 2A (method 2) above, and 2-methyltetrahydrofuran (10.5 L, 7 vol). The hydrogenator was then purged with Hydrogen gas and then continuously charged to the mixture at a pressure of 0.5 bar above atmospheric pressure. The mixture was then stirred at a temperature between 18° C. and 23° C. by cooling the vessel jacket. A vacuum was applied to the vessel when no more hydrogen gas was consumed and when there was no further exotherm. Nitrogen gas was then charged into the vessel at 0.5 bar and a vacuum was reapplied, followed by a second charge of 0.5 bar nitrogen gas. When the HPLC of a filtered aliquot showed that none of 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (10A) remained (e.g., ≦0.5%), the reaction mixture was transferred to a receiving flask under nitrogen atmosphere via a filter funnel using a Celite filter. The Celite filter cake was washed with 2-methyltetrahydrofuran (3 L, 2 vol). The washings and filtrate were charged into a vessel equipped with stirring, temperature control, and a nitrogen atmosphere. 4M HCl in 1,4-dioxane (1 vol) was added continuously over 1 h into the vessel at 20° C. The mixture was stirred for at least an additional 10 h, filtered, and washed with 2-methyltetrahydrofuran (2 vol) and dried to generate 1519 g of the hydrochloride salt of 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (11B) as a white crystalline solid.

Workup

  1. customThe hydrogenator was then purged with Hydrogen gas
  2. additioncontinuously charged to the mixture at a pressure of 0.5 bar above atmospheric pressure
  3. temperatureby cooling the vessel jacket
  4. customwas consumed
  5. additionNitrogen gas was then charged into the vessel at 0.5 bar
  6. additiona second charge of 0.5 bar nitrogen gas
  7. customthe reaction mixture was transferred to a receiving flask under nitrogen atmosphere via a filter funnel
  8. filtrationfilter
  9. filtrationThe Celite filter cake
  10. washwas washed with 2-methyltetrahydrofuran (3 L, 2 vol)
  11. additionThe washings and filtrate were charged into a vessel
  12. customequipped
  13. stirringwith stirring
  14. addition4M HCl in 1,4-dioxane (1 vol) was added continuously over 1 h into the vessel at 20° C
  15. stirringThe mixture was stirred for at least an additional 10 h
  16. filtrationfiltered
  17. washwashed with 2-methyltetrahydrofuran (2 vol)
  18. customdried

Sources & evidence

ORD record
ord-4254ff77733d416bb3806ce63d059a43
Source dataset
uspto-grants-2013_03
Patent number
US08389727B2

Reaction notes

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