1,2-Dimethoxyethane → 1H-Indole-2-propanoic acid, 3-[(1,1-dimethylethyl)thio]-1-[[4-(6-ethoxy-3-pyridinyl)phenyl]methyl]-5-hydroxy-alpha,alpha-dimethyl-, ethyl ester

Participants

Reaction Conditions

Reaction Steps

To a stirring mixture of dimethoxyethane (16.5 L) and water (6.6 L) in a 50 L reaction flask under nitrogen was added 3-{3-tert-butylsulfanyl-5-hydroxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (1652.19 g), 5-bromo-2-ethoxypyridine (650.30 g), and potassium carbonate (605.03 g). The mixture was sparged with nitrogen for 30 minutes to remove dissolved oxygen gas, and then tetrakis(triphenylphosphine)palladium(0) (59.15 g) was added, and the reaction mixture was heated to 65-85° C. over 2 hours and stirred at 65-85° C. under nitrogen for 19 hours. Once no starting material was seen by tlc analysis, the reaction was cooled to 40° C. and water (6.6 L) was added. Ethyl acetate (6.6 L) was added, and the mixture was agitated for 20 minutes and then allowed to separate over 1.5 hours. The aqueous layer was separated, and additional water (6.6 L) was added to the organic layer. The mixture was agitated for 2 minutes and then allowed to separate over 1 hour, with additional ethyl acetate (1.4 L) added to facilitate phase separation. The aqueous layer was separated, and the two aqueous layers were combined. Ethyl acetate (5.0 L) was added to the combined aqueous layer, and the mixture was agitated for 3 minutes and allowed to separate over 2 minutes. The aqueous layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (446.43 g). The mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2″ pad of Celite. The reaction flask was rinsed twice with ethyl acetate (1.25 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material. Methyl tert-butyl ether (8.2 L) was added to the solids, and the mixture was agitated for 1.5 hours and filtered. The flask was rinsed with methyl tert-butyl ether (1 L) three times and then filtered through the filter cake. The isolated solids were dried in a drying oven at 25° C. under vacuum for 3 days to give the desired product (1314 g).

Provenance & Evidence