Sodium Hydroxide → 1-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-ylmethyl}1H-indole-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A solution of 1-butyl-3-indolecarboxylic acid (20.0 g, 0.092 mol), prepared as Example 13, in 450 mL of THF was cooled to -40° C. under argon. n-Butyllithium (2.5 M in hexane, 73.7 mL, 0.184 mol) was added at a rate such that the reaction temperature remained below -25° C. and then the mixture was allowed to warm to 0° C. The mixture was let stand for 30 minutes, cooled to -40° C. and then zinc chloride (1 M in diethyl ether, 220 mL, 0.219 mol), tetrakis(triphenylphosphine)palladium(0) (2.03 g, 0.0018 mol) and 4-bromomethyl-2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl (38.01 g, 0.0878 mol), prepared as in Example 12, were sequencially added. The mixture was allowed to warm to room temperature and then 200 mL of ethyl acetate and 200 mL of 1 N sodium hydroxide were added. The aqueous layer was separated and extracted with 50 mL of ethyl acetate. The combined ethyl acetate layers were washed with 200 mL of 1 M hydrochloric acid and then brine and dried (sodium sulfate). The mixture was filtered and the solvent was removed. The residue was redissolved in 200 mL of ethyl acetate and 200 mL of methanol was slowly added to the solution giving a crystalline product which was isolated by filtration. The filtrate was concentrated and the residue was dissolved in 50 mL of ethyl acetate and proceeding similarly additional crystalline product was obtained. Drying and combining the products from each crystallization gave 1-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-ylmethyl}1H-indole-3-carboxylic acid (45.5 g, 0.08 mol), m.p. 146'-148° C.

Provenance & Evidence