Methyl Isobutyl Ketone → [4-Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-4H-indol-1-yl]acetic acid

Participants

Reaction Conditions

Reaction Steps

To a stirred slurry of ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate (3.16 kg, 3.05 kg corrected for assay, 7.3 moles) in 1-propanol (15.3 L) was added aqueous NaOH (1M, 15.3 L). The mixture was then heated at 70° C. for 2 h, cooled to 40° C. then MIBK (30.5 L) was added and the mixture reheated to 80° C. Approximately 20% of the resulting biphasic mixture was removed from the reaction vessel to be processed separately. To the remainder, aqueous hydrochloric acid (1M, 13.4 L) was added to the solution over a period of 45 mins then the resulting slurry was cooled to 15° C. over 1 h and stirring continued at this temperature for a further 30 mins. The solid product was collected by filtration, washed with water (2×9.8 L) followed by EtOAc (7.3 L) then dried on the filter for 10 mins then in vacuo at 45° C. to give the title compound as a solid; 2.15 kg; assay by 1H NMR: 99.4% w/w; 2.14 kg corrected for assay (94%); purity: 99.5 area % by HPLC; m/z: 389 (MH+); 1H NMR: 1.86 (3H, s), 2.34 (3H, s), 5.11 (2H, s), 6.97-7.00 (2H, d), 7.08-7.11 (1H, m), 7.27-7.30 (3H, m), 7.47-7.50 (1H, d), 9.50 (1H, br s).

Provenance & Evidence