Water → 4-(4-Chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole

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Reaction Steps

A mixture of powdered KOH (7 mmol) in DMSO (12 mL) at room temperature (rt) under N2 was stirred for 0.5 h. 4-Chloro-1H-indole (Intermediate A1) (1.67 mmol) was added and the mixture was allowed to stir for 2 h at rt. The 4-chloromethyl-1-trityl-1H-imidazole (prepared according to the procedures in: James, L. K. et al; J. Med. Chem. 1997, 20, 721. and Cordi, A. A. et al Eur. J. Med. Chem. 1990, 25, 557, incorporated herein by reference) (Intermediate A2) (1.19 mmol) was added and the mixture was stirred at rt for 18 h. The solution was diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, dried over MgSO4, filtered and evaporated to give the crude product. The residue was purified by chromatography on SiO2 with 1-2% MeOH in CH2Cl2 to give 4-chloro-1-(1-trityl-1H-imidazol-4-ylmethyl)-1H-indole (Intermediate A3). The protected imidazole compound (Intermediate A3) was mixed with H2O (3 mL) and acetic acid (6 mL) and heated to reflux for 1 to 2 h. The mixture was cooled to rt and made basic with 2M NaOH. The aqueous layer was extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried over Na2SO4. This mixture was filtered, freed of solvent and purified by chromatography with 5% NH3:MeOH in CH2Cl2 to give 4-(4-chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole (Intermediate A4) (˜20% over two steps).

Provenance & Evidence