Hydrochloric Acid → trans-2-({4'-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid

HRID 9622

Reaction equation

HRID 9622 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[NH:30][C:29]2[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:28]=2[N:27]=1.Cl.[OH-].[Na+]>C(O)CCC.O1CCCC1>[F:36][C:32]1[C:33]([F:35])=[CH:34][C:28]2[NH:27][C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][C@H:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:30][C:29]=2[CH:31]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 4694162-chloro-5,6-difluoro-1H-benzimidazoleHCID 21985670Methyl 2-[(4'-aminobiphenyl-4-yl)carbonyl]cyclopentanecarboxylate

Product 1

HCID 11374616trans-2-({4'-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acidYield 98.6%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

Methyl 2-[(4′-aminobiphenyl-4-yl)carbonyl]cyclopentanecarboxylate (264 mg, 0.02 mmol) was dissolved in n-butanol (8 mL), 2-chloro-5,6-difluoro-1H-benzimidazole (185 mg, 0.98 mmol) and 4 N HCl (0.2 mL) were then added, and the resulting mixture was heated at 90° C. for 5 h. The mixture was then cooled to rt, and solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and then treated with 1 N aqueous sodium hydroxide (2.45 mL, 2.45 mmol). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford trans-2-({4′-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (9.1 mg, 3%). LC-MS m/z 462.3 (MH+), ret. time 3.23 min; 1H NMR (300 MHz, DMSO-d6) δ 1.69–1.81 (m, 4H), 1.98–2.18 (m, 2H), 3.14–3.22 (m, 1H), 4.04–4.09 (m, 1H), 7.38 (t, 2H), 7.77–7.84 (m, 6H), 8.05 (d, 2H).

Workup

  1. temperatureThe mixture was then cooled to rt
  2. customsolvent was removed under reduced pressure
  3. dissolutionThe residue was dissolved in methanol (5 mL)
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA)

Sources & evidence

ORD record
ord-2221d47fa7cf42b4b8a49b4187fa1ea1
Source dataset
uspto-grants-2006_08
Patent number
US07091228B2

Linked notes

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