18-Crown-6 → Tert-butyl 4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidine-1-carboxylate

HRID 1689805Notes

Reaction equation

HRID 1689805 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:40][C:41]1[C:42]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[N:43][O:44][C:45]=1[CH:46]1[CH2:48][CH2:47]1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:40][C:41]2[C:42]([C:49]3[C:50]([Cl:56])=[CH:51][CH:52]=[CH:53][C:54]=3[Cl:55])=[N:43][O:44][C:45]=2[CH:46]2[CH2:48][CH2:47]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 2855718-Crown-6HCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 23665647Potassium tert-butoxideHCID 593693284-(Bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

Product 1

HCID 59369325Tert-butyl 4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidine-1-carboxylateYield 79.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 13.05 g (64.83 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in THF (120 mL) is added at 0° C. (ice bath) 18-crown-6 (19.6 g, 73.48 mmol) and potassium tertiary butoxide (8.68 g, 73.48 mmol). The resulting mixture is stirred for 20 min at room temperature, and added dropwise to a solution of 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (15 g, 43.22 mmol) in 75 mL of THF. The resulting mixture was stirred at room temperature for 14 h. To the reaction mixture is added water (500 mL), and it is extracted with EtOAc (3×200 mL). The organics are washed with brine (2×250 mL), dried (Na2SO4), filtered and concentrated to afford a crude which is purified by flash chromatography eluting with Hexanes/EtOAc 8:2, to obtain the title compound as a pale yellow oil (16 g (79%)). MS (m/e): 467 (M+1)

Workup

  1. stirringThe resulting mixture was stirred at room temperature for 14 h
  2. extractionis extracted with EtOAc (3×200 mL)
  3. washThe organics are washed with brine (2×250 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto afford a crude which
  8. customis purified by flash chromatography
  9. washeluting with Hexanes/EtOAc 8:2

Sources & evidence

ORD record
ord-dc505d8eb5f444fea4fb5f426055a4c2
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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