Hydrochloric Acid → 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid

HRID 44530Notes

Reaction equation

HRID 44530 reaction equation
[Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:16]=[C:17]([C:18]([O:20]C)=[O:19])[C:12]=3[N:11]=[C:10]2[C:28]([F:31])([F:30])[F:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.O1CCCC1.CS(C)=O>[Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=3[N:11]=[C:10]2[C:28]([F:31])([F:29])[F:30])[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 56960264methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate

Product 1

HCID 569604001-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

A suspension of methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 49 (1.09 g, 2.330 mmol) in Methanol (12 mL) and Tetrahydrofuran (THF) (4 mL) was treated with 1 M aq. sodium hydroxide (12 mL, 12.00 mmol) and stirred at 70° C. for 1.5 h (mixture turned homogeneous). The reaction was cooled to room temperature, the volume reduced to half and the residue was acidified (pH 4) by the addition of 1 N HCl. The precipitate was collected, washed with water and dried to give crude desired product (918.6 mg, 2.024 mmol, 87% yield) as a yellow solid. A portion of it (140 mg) was suspended in 3.5 mL of DMSO. After sonication and heating, the solid went into solution but it crashed out. The precipitate was collected and washed with DMSO, but it still showed impurities by LC/MS. Another aliquot (132 mg) was dissolved with heating in 5 mL of DMSO and purified by reverse phase-HPLC (15 to 95% AcCN in water plus 0.1% TFA). The desired product was isolated by evaporation of the organic solvent: the precipitate was collected by filtration, washed with water and dried in a vacuum oven to afford pure desired product (89 mg, 0.192 mmol, 8.25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 7.63 (d, J=2.27 Hz, 1H), 7.36 (d, J=7.83 Hz, 1H), 7.30 (d, J=2.27 Hz, 1H), 7.05 (t, J=7.96 Hz, 1H), 5.98 (d, J=7.58 Hz, 1H), 5.70 (s, 2H), 3.66-3.83 (m, 4H), 3.08-3.24 (m, 4H), 2.47 (s, 3H). MS (ES+) m/e 453.9 [M+H]+.

Workup

  1. customprepared
  2. temperatureThe reaction was cooled to room temperature
  3. customThe precipitate was collected
  4. washwashed with water
  5. customdried
  6. customto give crude desired product (918.6 mg, 2.024 mmol, 87% yield) as a yellow solid
  7. customAfter sonication
  8. temperatureheating
  9. customThe precipitate was collected
  10. washwashed with DMSO, but it still showed impurities by LC/MS
  11. dissolutionAnother aliquot (132 mg) was dissolved
  12. temperaturewith heating in 5 mL of DMSO
  13. custompurified by reverse phase-HPLC (15 to 95% AcCN in water plus 0.1% TFA)

Sources & evidence

ORD record
ord-35aa8d8a333f4037a2fb53c9219c75cc
Source dataset
uspto-grants-2013_09
Patent number
US08541411B2

Reaction notes

Loading…