Hydrochloric Acid → 2-bromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide

Participants

Reaction Steps

A solution of 600 mg (1.6 mmol) of 2-bromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (lot was contaminated with 2,4-dibromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide) and 10 mL of 1M BBr3 /CH2Cl2 in 100 mL of CH2Cl2 was stirred for 2.5 hours, 100 mL of 1N HCl added, stirred well, and the CH2 Cl2 layer separated. After washing and drying (Na2SO4), the solvent was removed at reduced pressure. The residue was chromatographed on silica and eluted with a gradient (1% MeOH/CH2 Cl2 →4% MeOH/CH2Cl2) to give in the early fractions 2,4-dibromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (115 mg) and in the later fractions 2-bromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (115 mg). The material from the later fractions (100 mg, 0.28 mmol) was dissolved in 20 mL of DMSO, 20 mg of 60% NaH/mineral was added, and after 10 minutes, 0.1 mL of ethyl 4-bromobutyrate was added. After heating for 1.25 hours at 85° C., the mixture was diluted with water, extracted with EtOAc, and the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica (eluted with 1% MeOH/CH2Cl2 →3% MeOH/CH2Cl2) to give 80 mg of 4-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester as an oil. This material was dissolved in 20 mL of EtOH, 1 mL of 2N NaOH added, and the mixture stirred for 19 hours. After acidifying with 1N HCl, the mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was crystallized from EtOH/ether to give 80 mg of 4-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]-butanoic acid.

Provenance & Evidence