18-Crown-6 → 4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepane-1-carboxylic acid tert-butyl ester

HRID 1689823Notes

Reaction equation

HRID 1689823 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:41][C:42]1[C:43]([C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[N:44][O:45][C:46]=1[CH:47]1[CH2:49][CH2:48]1>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH2:41][C:42]2[C:43]([C:50]3[C:51]([Cl:57])=[CH:52][CH:53]=[CH:54][C:55]=3[Cl:56])=[N:44][O:45][C:46]=2[CH:47]2[CH2:49][CH2:48]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 2855718-Crown-6HCID 22933363tert-Butyl 4-hydroxyazepane-1-carboxylateHCID 23665647Potassium tert-butoxideHCID 593693284-(Bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

Product 1

HCID 593693274-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepane-1-carboxylic acid tert-butyl esterYield 83.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 36.11 g (167.7 mmol) of 4-hydroxy-azepane-1-carboxylic acid tert-butyl ester in 300 mL of tetrahydrofuran at 0° C. (ice bath), 18-crown-6 (63.43 g, 237.58 mmol) and potassium tert-butoxide (28.06 g, 250.04 mmol) are added. The resulting mixture is stirred for 20 min at room temperature under nitrogen, followed by addition of a solution of 48.5 g (139.75 mmol) of 4-Bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole in 100 mL tetrahydrofuran over a 1 hour period. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 12 hours. Water (200 mL) is added to the reaction mixture and the solvent is removed under reduced pressure. The resulting brown oil is diluted with EtOAc (2×250 mL), and washed with brine (2×150 mL). The organic layer is dried (Na2SO4), filtered and concentrated to afford a crude which is purified on silica gel column chromatography (Eluting with Hexanes/EtOAc 8:2) to obtain 56 g of the title compound as a white/yellow oil. (83%). MS (m/e): 481 (M+1).

Workup

  1. stirringThe resulting mixture is stirred at room temperature under nitrogen atmosphere for 12 hours
  2. customthe solvent is removed under reduced pressure
  3. additionThe resulting brown oil is diluted with EtOAc (2×250 mL)
  4. washwashed with brine (2×150 mL)
  5. dry with materialThe organic layer is dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto afford a crude which
  9. customis purified on silica gel column chromatography (Eluting with Hexanes/EtOAc 8:2)

Sources & evidence

ORD record
ord-5e473ae68db14fa4a43b542ff6ecca18
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

Loading…