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

HRID 1748207Notes

Reaction equation

HRID 1748207 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+].Cl[CH2:42][C:43]1[C:44]([C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[C:57]([F:60])([F:59])[F:58])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>C1COCC1.O>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C@@H:51]3[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]3[C:57]([F:59])([F:60])[F:58])[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)[CH2:50][CH2:49]1

Participants

7

Reactant 4

HCID 2855718-Crown-6HCID 21187725tert-Butyl 3-hydroxy-8-azabicyclo(3.2.1)octane-8-carboxylateHCID 23665647Potassium tert-butoxideHCID 867043964-(Chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazole

Product 1

HCID 86704411Tert-butyl 3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-Boc-nortropine (579 mg, 2.55 mmol) and 18-crown-6 (808 mg, 3.06 mmol) in THF (8.5 mL) was treated with potassium tert-butoxide (343 mg, 3.06 mmol) and stirred for 10 minutes. A solution of 4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazole (784 mg, 2.55 mmol) in THF was added. The resulting mixture was stirred at rt for 2 hours and then poured into water and extracted with EtOAc. Organics were collected, dried (MgSO4), filtered, concentrated and chromatographed (SiO2, linear gradient, 0-60% EtOAc in Hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 4.28 (m, 2H), 4.19 (m, 1H), 4.11 (m, 1H), 3.66 (dd, J=4.8, 4.7 Hz, 1H), 3.47 (dd, J=7.6, 3.7 Hz, 1H), 2.42 (m, 1H), 2.19 (ddd, J=25.2, 12.5, 3.4 Hz, 1H), 2.00-1.77 (m, 13H), 1.69 (m, 1H), 1.52 (m, 1H), 1.46 (s, 9H), 1.35 (m, 1H), 1.12 (m, 2H), 1.03 (m, 2H)4; MS m/z 443.2 (M-tBu+1).

Workup

  1. stirringThe resulting mixture was stirred at rt for 2 hours
  2. extractionextracted with EtOAc
  3. customOrganics were collected
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customchromatographed (SiO2, linear gradient, 0-60% EtOAc in Hexanes)

Sources & evidence

ORD record
ord-f4b26a48baa145869d8be049643b3749
Source dataset
uspto-grants-2015_10
Patent number
US09150568B2

Reaction notes

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