Diisopropylethylamine → 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde

HRID 716015Notes

Reaction equation

HRID 716015 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.C(N(C(C)C)CC)(C)C.[CH3:24][C@H:25]1[O:30][C@@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:27]3[CH2:26][C@H:25]([CH3:24])[O:30][C@H:29]([CH3:31])[CH2:28]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 6415002,6-Dimethylmorpholine, cis-HCID 866581203-Chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde

Product 1

HCID 866581213-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
85 °C

Procedure

To an ice cooled solution of 3-chloro-6,7-difluoro-1,2-benzoxazole-5-carbaldehyde (prepared according to the procedure described in International Application Publication No. WO 2010/043893, 5.0 g, 23.0 mmol) in anhydrous acetonitrile (50 ml) was added diisopropylethylamine (5.9 g, 45.9 mmol) followed by cis-2,6-dimethylmorpholine (2.6 g, 23.0 mmol) and the mixture was heated at 85° C. for 12 hours in a sealed tube. The solution was cooled to room temperature and the volatiles were removed under vacuum. The residue was dissolved in Ethyl acetate, washed with water followed by brine and then dried over anhydrous Na2SO4. Removal of solvent under vacuum afforded the crude product, which was purified over silica gel column using a gradient of ethyl acetate in pet. ether to give title compound as solid. Yield: 6.0 g (84%). 1H NMR (400 MHz, DMSO-d6) δ: 1.0 (d, 6H), 2.9 (t, 2H), 3.1 (d, 2H), 3.8 (m, 2H), 7.7 (s, 1H), 10.2 (s, 1H). MS (ES) MH+: 313 for C14H14ClFN2O3.

Workup

  1. temperatureThe solution was cooled to room temperature
  2. customthe volatiles were removed under vacuum
  3. dissolutionThe residue was dissolved in Ethyl acetate
  4. washwashed with water
  5. dry with materialdried over anhydrous Na2SO4
  6. customRemoval of solvent under vacuum
  7. customafforded the crude product, which
  8. customwas purified over silica gel column

Sources & evidence

ORD record
ord-e36f2a6014f140ad9c23959a1fc19285
Source dataset
uspto-grants-2015_11
Patent number
US09187495B2

Reaction notes

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