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

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Reaction Conditions

Reaction Steps

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.

Provenance & Evidence