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

Participants

Reaction Conditions

Reaction Steps

3-{3-tert-Butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-hydroxy-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (1313.2 g) was dissolved in acetonitrile (20.0 L) in a 50 L reaction flask under nitrogen, and the mixture was stirred and heated to 30-40° C. Cesium carbonate (2118.67 g) was added, followed by 2-chloro-5-methylpyridine hydrochloride (497.17 g), and the temperature was increased to 70-80° C. over 2 hours. After heating at 70-80° C. for 4 hours, no starting material was seen by tlc analysis, and the mixture was cooled to 55° C. and concentrated. The residue was dissolved in dichloromethane (2 L) and water (2 L) and transferred to a flask containing dichloromethane (4 L) and water (4 L). The original flask was rinsed twice with dichloromethane (2 L) and water (2 L), and the combined material was then diluted with an additional 3 L of dichloromethane and 6 L water to a total volume of 13 L of dichloromethane and 16 L of water. The mixture was agitated for 10 minutes and allowed to separate over 10 minutes. The organic layer was separated, and additional dichloromethane (9 L) was added to the aqueous layer. The mixture was agitated for 6 minutes and allowed to separate over 5 minutes. The organic layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (433.07 g) and silica gel, thiol derivatized (91.17 g). The mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2″ pad of Celite. The flask was rinsed with dichloromethane (2.6 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material. Ethanol (9.2 L) was added to the solids, and the mixture was stirred slowly for 17 hours and filtered. The isolated solids were dried in a drying oven at 45° C. under vacuum for 2 days to give the desired product (1459.4 g).

Provenance & Evidence