Hydrochloric Acid → 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid

HRID 18564Notes

Reaction equation

HRID 18564 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][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=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][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=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>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=[C:11]2[C:14](=[O:25])[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)=[CH:29][CH:30]=1.[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][CH2:48][N:46]2[C:47]3[C:39]([C:37]([OH:38])=[O:36])=[CH:40][CH:41]=[CH:42][C:43]=3[N:44]=[C:45]2[C:57](=[O:68])[NH:58][CH:59]2[CH2:64][CH2:63][N:62]([CH:65]([CH3:66])[CH3:67])[CH2:61][CH2:60]2)=[CH:51][CH:52]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 68790202HCID 68790202, compoundHCID 68792229HCID 68792229, compound

Product 2

HCID 670123531-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acidHCID 67012577HCID 67012577, 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 989.1 mg (7.16 mmol) K2CO3 and 1.11 g (6.32 mmol) 1-chloro-4-(2-chloro-ethyl)-benzene were added and the resulting mixture was stirred for 24 h at 80° 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 and purified by flash chromatography using an ethyl acetate-methanol mixture as eluent to give 1.30 g of a 3:1-mixture of 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 3-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-4-carboxylic acid methyl ester. That mixture of isomers was dissolved in 100 mL MeOH. 16.2 mL (16.2 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 1 M HCl-solution and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave both isomers a) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and b) 3-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-4-carboxylic acid as white amorphous solids. Both isomers were isolated as their formiates.

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-57a669167cf349498e2ce73823be2372
Source dataset
uspto-grants-2010_06
Patent number
US07741341B2

Reaction notes

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