Lithium Hydroxide → HCID 16062171, compound

HRID 1160799Notes

Reaction equation

HRID 1160799 reaction equation
C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.OS([O-])=O.[Na+].[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH2:35])[CH:29]=2)=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21].[Li+].[OH-]>CC(N(C)C)=O.CCOC(C)=O.O>[CH2:18]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]3[N:34]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][CH:6]=4)[NH:35][C:30]=3[CH:29]=2)=[CH:26][CH:27]=1)[CH2:19][CH2:20][CH3:21]

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 15294Methyl 4-FormylbenzoateHCID 23665763Sodium BisulfiteHCID 59518023HCID 59518023, compound

Product 1

HCID 16062171HCID 16062171, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent2×

Conditions

Temperature
140 °C

Procedure

A hot (140° C.) mixture of 4-formyl-benzoic acid methyl ester (21.0 mg, 0.129 mmol) and NaHSO3 (20.1 mg, 0.193 mmol, 1.5 eq.) in DMA (250 μL) is treated with the dropwise addition of 4′-butyl-biphenyl-3,4-diamine (31 mg, 0.129 mmol) in DMA (100 μL) over 10 minutes. The resulting mixture is stirred for 1 hour at 140° C. and is then treated with H2O (1 ml) and stirred an additional hour. The reaction is diluted with EtOAc and the phases separated. The organic phase is dried over MgSO4, filtered, and concentrated. The crude benzimidazole product is diluted with 95% Ethanol (0.5 ml) and THF (1 ml) and transferred into a Smith-Process Vial containing LiOH (15.4 mg, 0.645 mmol, 5 eq.). The reaction vessel is heated to 165° C. under microwave irradiation for 5 minutes. After concentration, the crude product is purified by preparative RP LC-MS to give 4-[6-(4-butyl-phenyl)-1H-benzoimidazol-2-yl]-benzoic acid: 1H NMR (400 MHz, CD3OD) δ 9.00 (d, J=8.2 Hz, 1H), 8.91 (d, J=8.1 Hz, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 8.31 (d, J=7.6 Hz, 2H), 8.23 (d, J=8.3 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 3.38 (dd, J=7.8, 7.7 Hz, 1H), 2.69 (dd, J=7.8, 7.6 Hz, 1H), 2.35 (m, 1H), 2.09 (m, 1H), 1.66 (dd, J=7.4, 7.3 Hz, 3H), 1.41 (m, 1H), 0.97 (dd, J=7.3, 6.9 Hz, 2H); ESMS m/z 371.2 (M+H+).

Workup

  1. stirringstirred an additional hour
  2. customthe phases separated
  3. dry with materialThe organic phase is dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. additionThe crude benzimidazole product is diluted with 95% Ethanol (0.5 ml) and THF (1 ml)
  7. temperatureThe reaction vessel is heated to 165° C. under microwave irradiation for 5 minutes
  8. concentrationAfter concentration
  9. customthe crude product is purified by preparative RP LC-MS

Sources & evidence

ORD record
ord-49bd2353e7c84aec832b684b1d4be3bd
Source dataset
uspto-grants-2010_10
Patent number
US07816542B2

Reaction notes

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