Imidazole → Sitaxentan

Participants

Reaction Steps

1,1′-carbonyldiimidazole (600 mg) was added to a solution of 3-[(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxylic acid (900 mg, 2.79 mmol) in anhydrous tetrahydrofuran (20 mL). The mixture was stirred at ambient temperature for about 15 minutes and then sequentially treated with imidazole (380 mg, 5.58 mmol) and N,O-dimethylhydroxylamine hydrochloride (420 mg, 4.3 mmol). Under continuous stirring, the mixture was maintained at ambient temperature for about 4 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and 1 N hydrochloric acid (30 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was treated with toluene and re-concentrated. The resulting red oil was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to about 0° C., and then treated with a Grignard reagent prepared from 5-chloromethyl-6-methyl-benzo[1,3]dioxole (800 mg, 4.36 mmol) and magnesium turnings (826 mg, 34.4 mmol) in tetrahydrofuran (50 mL). Under continuous stirring, the mixture was maintained at about 0° C. for about 1 hour and then at ambient temperature for about 2 hours. At about 0° C., the reaction mixture was quenched with a mixture of concentrated hydrochloric acid (20 mL) and methanol (50 mL). The mixture was stirred at about 0° C. for about 10 minutes, and then concentrated in vacuo. The aqueous residue was partitioned between ethyl acetate (100 mL) and 1 N hydrochloric acid (30 mL). The crude product was isolated using standard extractive work up and purified by prep-TLC (eluted with CH2Cl2:MeOH=7:1) to give 2-[2-(6-methyl-benzo[1,3]dioxol-5-yl)-acetyl]-thiophene-3-sulfonic acid (4-chloro-3-methyl-isoxazol-5-yl) amide (150 mg, 30%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.77 (d, J=5.1 Hz, 1H), 7.40 (d, J=5.1 Hz, 1H), 6.74 (d, J=4.2 Hz, 2H), 5.94 (s, 3H), 4.76 (s, 2H), 2.04 (s, 3H), 1.99 (s, 3H); ESI-MS: m/z=455 (MH)+; HPLC purity: 95%.

Provenance & Evidence