Hydrochloric Acid → 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-4-carboxylic acid

HRID 18563Notes

Reaction equation

HRID 18563 reaction equation
C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C[O:36][C:37]([C:39]1[C:47]2[N:46]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[CH:50]=3)[C:45]([C:57](=[O:68])[NH:58][CH:59]3[CH2:64][CH2:63][N:62]([CH:65]([CH3:67])[CH3:66])[CH2:61][CH2:60]3)=[N:44][C:43]=2[CH:42]=[CH:41][CH:40]=1)=[O:38].[Li+].[OH-].Cl>CO>[CH:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:14]([C:11]2[N:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[O:25])[CH2:21][CH2:20]1)([CH3:24])[CH3:23].[CH:65]([N:62]1[CH2:63][CH2:64][CH:59]([NH:58][C:57]([C:45]2[N:46]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[CH:50]=3)[C:47]3[C:39]([C:37]([OH:38])=[O:36])=[CH:40][CH:41]=[CH:42][C:43]=3[N:44]=2)=[O:68])[CH2:60][CH2:61]1)([CH3:67])[CH3:66]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 68789983HCID 68789983, compoundHCID 68792474HCID 68792474, compound

Product 2

HCID 670118282-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-4-carboxylic acidHCID 67012518HCID 67012518, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

1.45 g (4.21 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 45 mL DMF. Subsequently 698.2 mg (5.05 mmol) K2CO3 and 888.8 mg (4.42 mmol) 1-bromomethyl-3-methoxy-benzene were added and the resulting mixture was stirred for 2 h at 60° C. The solvent was distilled off. The residue was taken up in 300 mL ethyl acetate and washed once with a saturated NaHCO3-solution and with brine. The organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica gel using an ethyl acetate-methanol mixture as eluent to give 1.19 g of a 4:1-mixture of 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benzyl)-3H-benzoimidazole-4-carboxylic acid methyl ester. That mixture of isomers was dissolved in 100 mL MeOH. 12.8 mL (12.8 mmol) of a 1 M aqueous LiOH-solution were added and the resulting suspension was stirred for 3 h at 60° C. The mixture was acidified by the addition of a 1M HCl-solution and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave both isomers a) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benyl)-1H-benzoimidazole-4-carboxylic acid and b) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benzyl)-3H-benzoimidazole-4-carboxylic acid as white amorphous solids. Both isomers were transformed to the corresponding dihydrochlorides.

Workup

  1. additionThat mixture of isomers
  2. concentrationconcentrated under reduced pressure
  3. customFinal purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid)

Sources & evidence

ORD record
ord-c3f4fc83c6854f22a2ea52134ac92fa8
Source dataset
uspto-grants-2010_06
Patent number
US07741341B2

Reaction notes

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