1,2-Dichloroethane → 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide

HRID 1874924Notes

Reaction equation

HRID 1874924 reaction equation
[NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:19][CH:20]=[CH2:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH2:19][CH:20]=[CH2:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 684835313-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrileHCID 684855334-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid2×

Product 1

HCID 684834184-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamideYield 42.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
25 °C

Procedure

3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrile (0.113 g, 0.358 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.099 g, 0.358 mmol), and DIEA (0.125 mL, 0.715 mmol) were combined in THF (4 mL) and stirred at 25° C. overnight. Additional 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.049 g, 0.179 mmol), EDC (0.069 g, 0.358 mmol) and THF (4.00 mL) were added to the reaction mixture and stirred at 50° C. overnight. The reaction mixture was concentrated to dryness and partitioned between DCM and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 70% EtOAc/hexanes to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.088 g, 0.153 mmol, 42.7% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (t, J=5.81 Hz, 1H), 8.00 (s, 1H), 7.36-7.52 (m, 3H), 7.20 (s, 1H), 7.17 (s, 1H), 5.86-6.01 (m, 1H), 5.51 (s, 2H), 5.10 (d, J=5.49 Hz, 1H), 5.07 (s, 1H), 4.50 (d, J=5.77 Hz, 2H), 3.40 (m, 4H), 0.77 (t, J=8.10 Hz, 2H), −0.07 (s, 9 H). LC-MS (ES−) m/z 573.22, 575.17 [M−1]. LC-MS (ES+) m/z 575.15, 577.16 [M+H].

Workup

  1. stirringstirred at 50° C. overnight
  2. concentrationThe reaction mixture was concentrated to dryness
  3. custompartitioned between DCM and saturated aqueous NaHCO3
  4. customThe organic phase was isolated
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe residue was purified on 40 g silica gel
  9. washeluted with 20 to 70% EtOAc/hexanes

Sources & evidence

ORD record
ord-f46603cff0ca4592b41b15b4b43bbaf0
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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