18-Crown-6 → Tert-butyl 3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 1748154Notes

Reaction equation

HRID 1748154 reaction equation
[CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:42][C:43]1[C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[O:57][C:58]([F:61])([F:60])[F:59])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>O1CCCC1>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[O:57][C:58]([F:61])([F:60])[F:59])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:49][CH2:50]1

Participants

6

Reactant 4

HCID 2855718-Crown-6HCID 21187725tert-Butyl 3-hydroxy-8-azabicyclo(3.2.1)octane-8-carboxylateHCID 23665647Potassium tert-butoxideHCID 669060924-(Bromomethyl)-5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]isoxazole

Product 1

HCID 67983217Tert-butyl 3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A 250-mL flask was purged with nitrogen and then charged with N-Boc-nortropine (2.9 g, 12.8 mmol), 18-Crown-6 (3.4 g, 12.8 mmol), and anhydrous tetrahydrofuran (80 mL). Potassium tert-butoxide (2.9 g, 25.6 mmol) was added in small portions, and the mixture was stirred vigorously under nitrogen fo(1 h. 4-(bromomethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)-phenyl)isoxazole (4.18 g, 11.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and added dropwise, and the reaction mixture was stirred overnight under a positive nitrogen pressure. The solvent was removed in vacuo and the mixture diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried with anhydrous MgSO4, and evaporated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate/hexanes to yield the desired product as yellow oil. MS m/z 509.2 (M+1).

Workup

  1. customA 250-mL flask was purged with nitrogen
  2. custom1 h
  3. additionadded dropwise
  4. stirringthe reaction mixture was stirred overnight under a positive nitrogen pressure
  5. customThe solvent was removed in vacuo
  6. additionthe mixture diluted with water (100 mL) and ethyl acetate (100 mL)
  7. customThe organic layer was separated
  8. dry with materialdried with anhydrous MgSO4
  9. customevaporated in vacuo
  10. customThe crude residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-dc15b7ebd1cf4ad388f859f113845528
Source dataset
uspto-grants-2015_10
Patent number
US09150568B2

Reaction notes

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