Water → 4-Amino-5-chloro-2-[(3-chlorophenyl)methoxy]benzoic acid

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Reaction Steps

A cooled (0° C.) suspension of 60% sodium hydride/oil dispersion (7.2 g, 180 mmol) in anhydrous N,N-dimethylformamide (200 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid, methyl ester (30.24 g, 150 mmol) so as to keep the pot temperature below 20° C. After one hour at 40° C., the mixture was treated with 3-chlorobenzyl bromide (37.0 g, 180 mmol) and heated to 100°±5° C. for one hour, then cooled to room temperature and added to water (600 mL). A solid precipitate soon formed, which was collected, washed with water, partially air dried, and dissolved in methylene chloride. The solution was filtered through alumina (eluted with methylene chloride) and the filtrate was concentrated in vacuo. The residue was taken up in a mixture of 50% sodium hydroxide (50 mL), water (50 mL), and ethanol (100 mL), and refluxed for one hour. Most of the ethanol was removed in vacuo and water (400 mL) was added to dissolve all solid. The aqueous solution was extracted with ether (100 mL), then with petroleum ethers (30°-60° C., 100 mL), cooled (0° C.), and acidified to pH 3 with concentrated hydrochloric acid (about 90 mL). The resultant precipitate was collected and the solid was washed with water, dried, and recrystallized (2 crops) from ethanol to afford 28.36 g (61%) of pale tan solid; mp 182.5°-184.0° C.

Provenance & Evidence