Diisopropylethylamine → 3-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde

HRID 245532Notes

Reaction equation

HRID 245532 reaction equation
[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9](F)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[CH3:15][C@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:18]3[CH2:17][C@@H:16]([CH3:15])[O:21][C@H:20]([CH3:22])[CH2:19]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 11137133trans-2,6-DimethylmorpholineHCID 866581203-Chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde2×

Product 1

HCID 866581223-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of 3-chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 532, 3.32 g, 10.6 mmol), (2R,6R)-2,6-dimethylmorpholine (Purchased from BASF®, 2.64 g, 22.9 mmol) and DIEA (4 ml, 22.9 mmol) in acetonitrile (20 ml) was heated at reflux for 3 hours. The mixture was cooled to room temperature before being partitioned between EtOAc and 1N HCl. The EtOAc was separated and washed with brine. The combined aqueous layers were extracted with EtOAc, which was washed with brine. The combined EtOAc was dried (MgSO4) and concentrated to give an oil that was chromatographed on silica gel (50% hexanes in CH2Cl2 followed by gradient elution to 100% CH2Cl2 followed by gradient elution to 5% EtOAc in CH2Cl2) to give 2 materials in order of elution: the first material (265 mg) is consistent with starting material and the second (3.33 g) with desired product.

Workup

  1. temperatureat reflux for 3 hours
  2. custombefore being partitioned between EtOAc and 1N HCl
  3. customThe EtOAc was separated
  4. washwashed with brine
  5. extractionThe combined aqueous layers were extracted with EtOAc, which
  6. washwas washed with brine
  7. dry with materialThe combined EtOAc was dried (MgSO4)
  8. concentrationconcentrated
  9. customto give an oil that
  10. customwas chromatographed on silica gel (50% hexanes in CH2Cl2 followed by gradient elution to 100% CH2Cl2 followed by gradient elution to 5% EtOAc in CH2Cl2)
  11. customto give 2 materials
  12. washin order of elution

Sources & evidence

ORD record
ord-6c22e4b57a434ecf9d99efc5b31bc65e
Source dataset
uspto-grants-2014_02
Patent number
US08658641B2

Reaction notes

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