2-Methylbenzenesulfonamide → 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide

Participants

Reaction Steps

To a solution of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (125.9 g) in tetrahydrofuran (3.0 l, distilled from sodium benzophenone ketyl) (prepared by heating at 50° C. until dissolution was complete, followed by cooling to room temperature with an ice-water bath) was added 4-dimethylaminopyridine (56.6 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102.4 g), and the mixture was stirred one hour. To the mixture was added 2-methylbenzene-sulfonamide (67.1 g), and the reaction mixture was stirred about 3 days (for convenience). The reaction mixture was diluted with ethyl acetate (2.0 l) and washed with 1N hydrochloric acid (twice) and brine (3 times, until neutral), and the aqueous extracts were back washed with ethyl acetate. The combined ethyl acetate solution was dried (MgSO4), and partially evaporated to give a slurry of solid in ethyl acetate (about 0.5 l) which was refrigerated overnight. Collection of the solid afforded the crude product (158.5 g, 88%, essentially pure by TlC) as a light pink solid. Recrystallization by dissolution in hot tetrahydrofuran (1.5 l), filtration while hot, dilution with ethyl acetate (2.0 l), and boiling down to a final volume of about 2.5 l afforded a first crop of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (105.5 g, 59%) as a white solid; mp 211°-213° C.; NMR (250 MHz, DMSO-d6): 2.60 (s, 3H, ArCH3), 3.76 (s, 3H, NCH3), 3.82 (s, 3H, CO2CH3), 3.92 (s, 3H, ArOCH3), 4.04 (s, 2H, ArCH2Ar'), 7.15 (d, 1H), 7.22 (s, 1H), 7.38-7.58 (m, 6H), 7.75 (dd, 1H), 8.03 (dd, 1H), 8.17 (d, 1H). (Two additional crops (35.5 g, 20%) and crude product (39.5 g) from concentration of the mother liquors were also obtained.)

Provenance & Evidence