Dichloromethane → 4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide

HRID 1874909

Reaction equation

HRID 1874909 reaction equation
[OH-].[K+].[CH3:3]N(N=O)C(N)=O.[Cl:10][C:11]1[N:12]=[CH:13][N:14]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:15]=1[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][C:28]2[CH:33]=[C:32]([CH:34]=[CH2:35])[CH:31]=[C:30]([C:36]#[N:37])[CH:29]=2)[C:21]=1[F:38])=[O:17].C(Cl)Cl>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:10][C:11]1[N:12]=[CH:13][N:14]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:15]=1[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][C:28]2[CH:33]=[C:32]([CH:34]3[CH2:3][CH2:35]3)[CH:31]=[C:30]([C:36]#[N:37])[CH:29]=2)[C:21]=1[F:38])=[O:17]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 12699N-Methyl-N-nitrosoureaHCID 14797Potassium HydroxideHCID 684870564-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide

Product 1

HCID 684876074-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
0 °C

Procedure

To a mixture of 30% aqueous KOH (30 mL) and diethyl ether (30 mL) was added N-methyl-N-nitrosourea (0.264 g, 2.56 mmol) in one potion with stirring and cooling at 0° C. and the reaction mixture was maintained at this temperature for 20 min. The organic phase was isolated, dried over KOH pellets and added dropwise to a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.144 g, 0.256 mmol) and palladium(II) acetate (5.8 mg, 0.026 mmol) in diethyl ether (30.0 mL) with stirring and cooling at 0° C. DCM (20 mL) was added to the reaction mixture to achieve complete solution and the reaction mixture was stirred at 0° C. for 1 h at which time LC-MS indicated complete conversion to desired product. Water and a small amount of acetic acid were added to the reaction mixture and stirred vigorously at room temperature for 1 h. The organic phase was isolated, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 60% EtOAc/hexanes to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.132 g, 0.230 mmol, 90% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (t, J=5.68 Hz, 1H), 8.00 (s, 1H), 7.36-7.54 (m, 2H), 7.28 (s, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 5.51 (s, 2H), 4.50 (d, J=5.68 Hz, 2H), 3.40 (t, J=8.10 Hz, 2H), 1.92-2.05 (m, 1H), 0.95-1.05 (m, 2H), 0.71-0.82 (m, 4H), −0.07 (s, 9H). LC-MS (ES−) m/z 575.13, 575.05 [M−1]. LC-MS (ES+) m/z 575.11, 577.12 [M+H].

Workup

  1. temperaturethe reaction mixture was maintained at this temperature for 20 min
  2. customThe organic phase was isolated
  3. dry with materialdried over KOH pellets
  4. stirringwith stirring
  5. temperaturecooling at 0° C
  6. stirringthe reaction mixture was stirred at 0° C. for 1 h at which time LC-MS

Sources & evidence

ORD record
ord-1e3a592c0ff44c908855241d62169de0
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Linked notes

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