8-ethoxy-8-oxooctanoic acid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-(5-chloro-2-hydroxyanilino)-8-oxooctanoic acid was prepared as follows. A suspension of 2-amino-4-chlorophenol (17.88 g, 124.5 mmol), 8-ethoxy-8-oxooctanoic acid (25.19 g, 124.5 mmol), boric acid (0.385 g, 6.23 mmol) in 150 mL of dried toluene was heated at reflux (110° C.) under nitrogen for 4 hours during which water (2.5 mL) produced in the reaction was removed by azeotropic distillation in a Dean-Stark separation unit. The reaction was observed by thin layer chromatography on silica gel (Eluant: ethylacetate:heptane 1:1). The reaction mixture was cooled in a water bath to room temperature. 2N aqueous solution of sodium hydroxide (125 mL, 250 mmol) was added to the mixture. The mixture was heated at reflux for 4 hours. The reaction mixture was cooled in a water bath to room temperature. The mixture was then diluted with ethyl acetate (300 mL) and water (150 mL). The aqueous layer was washed with two portions of ethyl acetate (250 mL). After careful separation, the aqueous layer was chilled and acidified with a 10% (by weight) solution of hydrochloric acid (86.20 mL, 250 mmol) to yield a solid which was filtered, washed with hexane, and dried under vacuum. Trituration with dichloromethane yielded the desired acid (21.75 g, 57%) as an off-white solid. HPLC (Column: Higgins Kromasil 100 C18, water/acetonitile/acetic acid: 950/50/1, 3 mL/min, 220 nm) showed one single peak. Rt was 5.38 minutes. was heated produced in the reaction was removed by azeotropic distillation in a Dean-Stark separation unit The mixture was heated at reflux for 4 hours The reaction mixture was cooled in a water bath to room temperature The aqueous layer was washed with two portions of ethyl acetate (250 mL) After careful separation the aqueous layer was chilled to yield a solid which was filtered washed with hexane dried under vacuum

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-(5-chloro-2-hydroxyanilino)-8-oxooctanoic acid was prepared as follows. A suspension of 2 amino-4-chlorophenol (17.88 g, 124.5 mmol), 8-ethoxy-8-oxo-octanoic acid (25.19 g, 124.5 mmol), boric acid (0.385 g, 6.23 mmol), and 2-amino-5-picoline (0.675 g, 6.23 mmol) in 160 mL of dried toluene was heated at reflux (110° C.) under nitrogen for 4 hours during which water (2.5 mL) produced in the reaction was removed by azeotropic distillation in a Dean-Stark separation unit. Thin layer chromatography on silica gel with an eluant of ethylacetate and heptane at a molar ratio of 1:1 indicated the completion of the reaction. The mixture was cooled and a 2N aqueous solution of sodium hydroxide (125 mL, 250 mmol) was added. The mixture was heated at reflux (about 85° C.) for 4 hours and cooled. The cooled mixture was diluted with ethyl acetate (300 mL) and water (150 mL). The aqueous layer was washed with two portions of ethyl acetate (250 mL). After careful separation, the aqueous layer was chilled and acidified with a 10% (by weight) solution of hydrochloric acid (86.20 mL, 250 mmol) to yield a solid. The solid was filtered, washed with hexane, and dried under vacuum. Trituration with dichloromethane yielded the 8-(5-chloro-2-hydroxyanilino)-8-oxooctanoic acid (22.39 g, 60%) as an off-white solid. HPLC (Column: Higgins Kromasil 100 C18, water/acetonitile/acetic acid: 950/50/1, 3 mL/min, 220 nm) Rt 5.38 min.; melting point 123-124° C.; 1H NMR(DMSO d6, 300 MHz)δ: 1.28(m, 4H), 1.51 (m, 4H), 2.19 (t, 2H), 2.39 (t, 2H),6.83 (d, 1H), 6.93 (dd, 1H), 7.95 (d, 1H), 9.20 (s, 1H), 10.10 (s, 1H), 12.00 (br s, 1H); 13C NMR (DMSO d6, 75 MHz) δ: 24.29, 24.90, 28.20, 33.58, 35.90, 116.50, 121.02, 122.20, 123.41, 127.74, 148.23, 171.93, 174.26. MS m/z 300 (M+1)+. Anal. Calcd for C14H18ClNO4: C, 56.10; H, 6.05; Cl, 11.83, N, 4.67. Found: C, 56.07, H, 6.11, 11.98, N, 4.64. 8-(5-chloro-2-hydroxyanilino)-8-oxooctanoic acid was prepared was heated produced in the reaction was removed by azeotropic distillation in a Dean-Stark separation unit the completion of the reaction The mixture was cooled The mixture was heated cooled The aqueous layer was washed with two portions of ethyl acetate (250 mL) After careful separation the aqueous layer was chilled to yield a solid The solid was filtered washed with hexane dried under vacuum