Sodium Carbonate → 5-(2-amino-4-methoxycarbonylphenyl)-2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile

HRID 574009Notes

Reaction equation

HRID 574009 reaction equation
C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([C:24]1[N:25]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:26](I)=[C:27]([C:29]#[N:30])[N:28]=1)[CH2:21][CH2:22][CH3:23].Cl.[NH2:38][C:39]1[CH:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][C:40]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:38][C:39]1[CH:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][C:40]=1[C:26]1[N:25]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:24]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:28][C:27]=1[C:29]#[N:30]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 11776Triphenylphosphine2×HCID 16427083[2-Amino-4-(methoxycarbonyl)phenyl]boronic acid--hydrogen chloride (1/1)HCID 867279612-butyl-1-(2-hydroxy-2-methylpropyl)-5-iodo-1H-imidazole-4-carbonitrile

Product 1

HCID 867279605-(2-amino-4-methoxycarbonylphenyl)-2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 equiv) and PPh3 (26.2 mg, 0.1 mmol, 0.1 equiv) in DME (4 mL) were sequentially added 2-butyl-1-(2-hydroxy-2-methylpropyl)-5-iodo-1H-imidazole-4-carbonitrile S5 (347 mg, 1 mmol, 1 equiv), 2-amino-4-methoxycarbonylphenylboronic acid hydrochloride salt (347 mg, 1.5 mmol, 1.5 equiv) and 1.5 M aqueous Na2CO3 (2.0 mL, 3 mmol, 3 equiv) at 25° C. The reaction was heated at 100° C. for 6 h. TLC and MS analysis indicated the presence of S5; consequently, additional Pd(OAc)2 (5 mg) and PPh3 (13 mg) were added and the reaction was heated further at 100° C. for 15 h. The reaction was then cooled down to 25° C. and partitioned between EtOAc (50 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers was washed with saturated aqueous NaCl (20 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (118 mg, ˜90% pure, 32%) as light yellow foam, which was used in the next step without further purification.

Workup

  1. customat 25° C
  2. temperaturethe reaction was heated further at 100° C. for 15 h
  3. temperatureThe reaction was then cooled down to 25° C.
  4. custompartitioned between EtOAc (50 mL) and H2O (10 mL)
  5. extractionThe aqueous layer was extracted with EtOAc (3×15 mL)
  6. washThe combined organic layers was washed with saturated aqueous NaCl (20 mL)
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated in vacuo
  9. customPurification by flash column chromatography on silica gel (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient)

Sources & evidence

ORD record
ord-c29ae60a5991422d80dd4d219c9163a2
Source dataset
uspto-grants-2015_05
Patent number
US09034336B2

Reaction notes

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