1,1'-Carbonyldiimidazole → 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide

HRID 1792999Notes

Reaction equation

HRID 1792999 reaction equation
[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:39][O:40][CH2:41][CH2:42][OH:43]>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:14])=[C:5]([F:21])[CH:4]=1)[CH3:2]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 3014186Ethanol, 2-(aminooxy)-HCID 3386966ImidazolateHCID 220256532-[(4-Ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid

Product 1

HCID 101936532-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamideYield 65%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

The title compound was prepared from the reaction of the product of Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (93 mg, 0.32 mmol) dissolved in dry THF (5 mL), and carbonyldiimidazole (CDI) (102 mg, 0.63 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (97 mg, 1.26 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (50 mL) and EtOAc (50 mL). The EtOAc layer was then washed with water (50 mL) and saturated NaCl solution (50 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a cream solid (65%); m.p. (EtOAc/hexanes) 134–138° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.76 (br s, 1 H), 7.43–7.37 (m, 1 H), 7.14–7.02 (m, 2 H), 6.90 (dd, J=8.3, 1.5 Hz, 1 H), 6.83. (td, J=8.6, 4.4 Hz, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.54 (q, J=7.6 Hz, 2 H), 1.15 (t, J=7.6 Hz, 3 H).

Workup

  1. customa bright yellow solution was obtained
  2. customThe reaction solvent was removed under reduced pressure
  3. customthe residue partitioned between 1 M HCl (50 mL) and EtOAc (50 mL)
  4. washThe EtOAc layer was then washed with water (50 mL) and saturated NaCl solution (50 mL)
  5. dry with materialdried (Na2SO4)
  6. customthe solvent removed under reduced pressure
  7. customto afford an oil which
  8. customwas purified by flash column chromatography on silica gel (50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-4ecc0f5765204fb38ea527400b4d8bc4
Source dataset
uspto-grants-2006_07
Patent number
US07078438B2

Reaction notes

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