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

HRID 1689773Notes

Reaction equation

HRID 1689773 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.[K].Br[CH2:36][C:37]1[C:38]([C:45]2[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:52])=[N:39][O:40][C:41]=1[CH:42]1[CH2:44][CH2:43]1>C1COCC1.O.C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH2:36][C:37]2[C:38]([C:45]3[C:46]([Cl:52])=[CH:47][CH:48]=[CH:49][C:50]=3[Cl:51])=[N:39][O:40][C:41]=2[CH:42]2[CH2:44][CH2:43]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 4

HCID 2855718-Crown-6HCID 5462222PotassiumHCID 22933363tert-Butyl 4-hydroxyazepane-1-carboxylateHCID 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 17%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6386tert-ButanolSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-hydroxy-azepane-1-carboxylic acid tert-butyl ester (1.88 g, 8.73 mmol) in anhydrous THF (15 mL) at 0° C. is added 18-crown-6 (2.3 g, 8.70 mmol) and tert-butyl alcohol, potassium derivative (8.8 mL, 1.0 M, 8.80 mmol). The mixture is stirred at room temperature for 20 minutes following which 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (1.8 g, 5.19 mmol) in THF is added over 2 minutes. The mixture is stirred for 2 h and water (10 mL) is added. The mixture is concentrated under reduced pressure and extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), concentrated, and purified via flash chromatography (120 g silica) eluting with a gradient of ethyl acetate in heptane (0 to 60%) to provide the title compound (420 mg, 17%).

Workup

  1. additionis added over 2 minutes
  2. stirringThe mixture is stirred for 2 h
  3. concentrationThe mixture is concentrated under reduced pressure
  4. extractionextracted with ethyl acetate (3×)
  5. dry with materialThe combined ethyl acetate layers are dried (MgSO4)
  6. concentrationconcentrated
  7. custompurified via flash chromatography (120 g silica)
  8. washeluting with a gradient of ethyl acetate in heptane (0 to 60%)

Sources & evidence

ORD record
ord-69143933efac44b3a752dc535cc7f8af
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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