Tetrabutylammonium Fluoride → 3-{[5-(biphenyl-4-yl)-6-chloro-1H-benzimidazol-2-yl]oxy}cyclopentane carboxylic acid

HRID 340780Notes

Reaction equation

HRID 340780 reaction equation
[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:34]([Cl:35])=[CH:33][C:10]3[N:11](COCC[Si](C)(C)C)[C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:34]([Cl:35])=[CH:33][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 71074041Ethyl 3-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclopentanecarboxylate

Product 1

HCID 533721183-{[5-(biphenyl-4-yl)-6-chloro-1H-benzimidazol-2-yl]oxy}cyclopentane carboxylic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of ethyl 3-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclopentanecarboxylate (80 mg, 0.135 mmol) in 2.7 mL of THF was added TBAF (0.700 mL, 0.700 mmol) dropwise via syringe. The reaction was heated at 80° C. for 1.5 h. After heating for 4 h, the reaction was concentrated and the residue was re-dissolved in 4 mL of MeOH and treated with 1 mL of 2.5 N NaOH. The reaction was maintained at ambient temperature overnight. Then the solvent was removed and the resulting residue was dissolved in H2O and acidified to pH 1 with 2 N HCl. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with 2 N HCl, H2O, and brine. The combined organic layers were then dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by reverse phase Gilson™ HPLC (30-100% MeCN/H2O) afforded a 1:1 cis/trans mixture of the title compound as a white solid. LCMS: calculated for C25H21ClN2O3 432.89, observed m/e 432.93 M+ (Rt 2.13/4 min). 1H NMR (500 MHz, CD3OD): δ7.7.72-7.63 (m, 8H), 7.58-7.55 (m, 2H), 7.49 (d, 4H), 7.47-7.42 (m, 4H), 7.42-7.38 (m, 2H), 7.37-7.32 (m, 2H), 5.54-5.47 (m, 1H), 5.46-5.40 (m, 1H), 3.16-3.05 (m, 1H), 3.05-2.95 (m, 1H), 2.54-2.43 (m, 1H), 2.42-2.31 (m, 3H), 2.31-1.95 (m, 8H).

Workup

  1. temperatureAfter heating for 4 h
  2. concentrationthe reaction was concentrated
  3. dissolutionthe residue was re-dissolved in 4 mL of MeOH
  4. additiontreated with 1 mL of 2.5 N NaOH
  5. temperatureThe reaction was maintained at ambient temperature overnight
  6. customThen the solvent was removed
  7. dissolutionthe resulting residue was dissolved in H2O
  8. customThe aqueous layer was separated
  9. extractionextracted with EtOAc
  10. washThe combined organic layers were washed with 2 N HCl, H2O, and brine
  11. dry with materialThe combined organic layers were then dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customPurification of the resulting residue by reverse phase Gilson™ HPLC (30-100% MeCN/H2O)
  15. customafforded

Sources & evidence

ORD record
ord-37c1793184bc4da597c70aa6f3586046
Source dataset
uspto-grants-2014_11
Patent number
US08895596B2

Reaction notes

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