Sodium Iodide → [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid ethyl ester

Participants

Reaction Conditions

Reaction Steps

A mixture of sodium iodide (0.05 mol equiv) in xylene (1.0 rel vol), acetic acid (1.0 rel vol) and acetic anhydride (1.2 mole equiv) was heated to 97-103° C. in vessel 1 with stirring. In vessel 2, acetic anhydride (1.3 mole equiv) was added to a stirred slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (1 mole equiv, limiting reagent) in xylene (1.0 rel vol) and acetic acid (1.0 rel vol) at 19-25° C. After stirring at this temperature for 2 h, this mixture was added to the solution in reaction vessel 1 over 2.5 h, maintaining the temperature at between 98 and 102° C. Vessel 2 was rinsed with a mixture of xylene (0.25 rel vol) and acetic acid (0.25 rel vol) which was added to vessel 1. The reaction was held at 98 to 102° C. for a further 1.5 h then cooled to 60° C. Xylene (0.9 rel vol) was added followed by a warm (60° C.) solution of sodium chloride (0.19 rel wt) in water (1.5 rel vol) and the temperature adjusted to 60° C. The aqueous layer was separated and discarded. A warm (60° C.) solution of sodium thiosulfate (0.1 mole equiv) in water (0.5 rel vol) was added and after mixing, the aqueous layer was separated and discarded. The product was precipitated by the is addition of heptanes (3 rel vol) to the organic layer, whilst maintaining the temperature at between 57 and 63° C. The resulting slurry was cooled to 20° C. over 1 h then the solid product was collected by centrifugation, washed with ethanol (3.0 rel vol) and dried to afford crude ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate as a solid in 77% yield; purity by UHPLC 97.4 area %.

Provenance & Evidence