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

HRID 1689807Notes

Reaction equation

HRID 1689807 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.[Cl-].[Na+].O.C(OCC)(=O)C.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

9

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-carboxylate

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

Cool a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (352 g, 1.75 mol) and 18-crown-6 (463 g, 1.75 mol) in THF to between 0° C. and 5° C. Add potassium tert-butoxide (268 g, 2.39 mol) while maintaining the temperature between 0° C. and 10° C. Cool the resulting mixture to −10° C. to −5° C. Add a 40 wt % solution of 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole in THF (1.38 kg, 1.59 mol) while maintaining the temperature between −5° C. and 0° C. Allow the mixture to warm to 15° C. to 25° C. and stir for 2 h. Cool to 0° C. to 5° C., and add water dropwise while maintaining the temperature between 0° C. and 10° C. Add ethyl acetate (3.5 L) and brine (5.5 L). Separate the phases and extract the aqueous phase with ethyl acetate (2×2.5 L). Wash the combined organic phases with brine (3×5.5 L). Concentrate the organic phase under vacuum to approximately 1.5 L total volume to afford a solution of crude 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester. Add additional ethyl acetate (3.0 L). Cool the solution to 0° C. to 5° C. Add HCl (gaseous) (319 g, 8.75 mol) while maintaining the temperature between 0° C. and 5° C. Allow to warm to 15° C. to 25° C. and stir for 4 h. Concentrate the mixture under vacuum to approximately 1.2 L total volume. Filter the resulting solid and wash with cold ethyl acetate (2×0.6 L). Dry to afford 506 g (79%) of the title compound as an off-white solid. mp 200-202° C. (by differential scanning calorimetry).

Workup

  1. temperatureCool the resulting mixture to −10° C. to −5° C
  2. temperaturewhile maintaining the temperature between −5° C. and 0° C
  3. temperatureAllow the mixture to warm to 15° C. to 25° C.
  4. temperatureCool to 0° C. to 5° C.
  5. temperaturewhile maintaining the temperature between 0° C. and 10° C
  6. customSeparate the phases
  7. extractionextract the aqueous phase with ethyl acetate (2×2.5 L)
  8. washWash the combined organic phases with brine (3×5.5 L)
  9. concentrationConcentrate the organic phase under vacuum to approximately 1.5 L total volume

Sources & evidence

ORD record
ord-f8e2d9777c7b453fbdffb8148e5abc66
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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