Potassium Carbonate → 3-{1-(4-Bromobenzyl)-6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1H-benzimidazol-2-yl}-2,2-dimethylpropanoic acid

HRID 1848734Notes

Reaction equation

HRID 1848734 reaction equation
[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:4][CH:3]=1.Cl[CH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C.C1COCC1.CO>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:29][C:30]4[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 4239233-(Chloromethyl)-1-methyl-1H-pyrazoleHCID 90411063Ethyl 3-(1-(4-bromobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate

Product 1

HCID 862674493-{1-(4-Bromobenzyl)-6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1H-benzimidazol-2-yl}-2,2-dimethylpropanoic acidYield 19%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of ethyl 3-(1-(4-bromobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (322 mg, 0.75 mmol), 3-(chloromethyl)-1-methyl-1H-pyrazole (97.5 mg, 0.75 mmol) and K2CO3 (310 mg, 2.25 mmol) in DMF (20 mL) was stirred at 50° Celsius for 18 h. The resulting residue was dissolved in THF (9 mL), MeOH (9 mL) and NaOH (2 mL, 5%). The mixture was stirred at 40° Celsius. After 16 h the reaction was concentrated to dryness and the residue was dissolved in water (30 mL), washed with EtOAc (20 mL). The aqueous layer was separated and acidified to pH ˜6 with HCl (6 N) then extracted with DCM (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness and purified by reverse phase HPLC to give the title compound (63 mg, 19%). MS (ESI): mass calcd. for C24H25BrN4O3, 496.11; m/z found, 497.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J=2.4, 1H), 7.76 (d, J=9.0, 1H), 7.54 (d, J=8.5, 2H), 7.32 (dd, J=9.0, 2.3, 1H), 7.27 (d, J=2.1, 1H), 7.16 (d, J=8.4, 2H), 6.49 (d, J=2.4, 1H), 5.83 (s, 2H), 5.21 (s, 2H), 3.98 (s, 3H), 3.51 (s, 2H), 1.41 (s, 6H).

Workup

  1. stirringThe mixture was stirred at 40° Celsius
  2. concentrationAfter 16 h the reaction was concentrated to dryness
  3. dissolutionthe residue was dissolved in water (30 mL)
  4. washwashed with EtOAc (20 mL)
  5. customThe aqueous layer was separated
  6. extractionthen extracted with DCM (2×30 mL)
  7. dry with materialThe combined organic layers were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to dryness
  10. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-a7e47f21d992486fa441089485f593b5
Source dataset
uspto-grants-2015_02
Patent number
US08952177B2

Reaction notes

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