Triethylamine → 1,1-Dimethylethyl 3-[5-(5-{3-chloro-4-[(difluoromethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate

HRID 2192502Notes

Reaction equation

HRID 2192502 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13])[C:5](Cl)=[O:6].O[NH:16][C:17](=[NH:37])[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[C:23]2[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:16]=[C:17]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:37]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 581499223-Chloro-4-[(difluoromethyl)oxy]benzoyl chlorideHCID 178450938HCID 178450938, compound

Product 1

HCID 581499271,1-Dimethylethyl 3-[5-(5-{3-chloro-4-[(difluoromethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoateYield 28.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

A solution of 3-chloro-4-[(difluoromethyl)oxy]benzoyl chloride (D18; 69.5 mg, 0.289 mmol) in dry DMF (1 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 70 mg, 0.222 mmol) and triethylamine (0.046 ml, 0.333 mmol) in dry DMF (2 ml) at 0° under nitrogen and stirring was continued at room temperature for 50 min, then heated at 100° for 5 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown gum. The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (32 mg).

Workup

  1. temperatureheated at 100° for 5 h
  2. customThe cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml)
  3. washthe organic layer was washed with 50:50 brine
  4. dry with materialwater and brine, dried (MgSO4)
  5. customevaporated in vacuo
  6. customto give a brown gum
  7. customThe crude product was purified by flash chromatography on silica gel
  8. washeluting with 0-30% ethyl acetate-cyclohexane
  9. customevaporated in vacuo

Sources & evidence

ORD record
ord-0be584187f3141d9aefc8c9002db4dd7
Source dataset
uspto-grants-2012_12
Patent number
US08329730B2

Reaction notes

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