Synthesis of 4-Hydroxy-N--2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-Dioxide and oxoacetic Acid. Major Metabolites of Isoxicam

Article abstract of DOI:10.1021/jo00350a056

4-Hydroxy-N-<5-(hydroxymethyl)-3-isoxazolyl>-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (2), the major oxidative human metabolite of isoxicam (1), and <(5-methyl-3-isoxazolyl)amino>oxoacetic acid (3), the major rat metabolite of isoxicam (1), were synthesized. 2 was synthesized by condensation of the known benzothiazine ester 8 with the isoxazolamine 9b. 9b was synthesized via a nine-step sequence starting with 5-methyl-3-isoxazolecarboxylic acid (14).NBS bromination of 14 gave 5-(bromomethyl)-3-isoxazolecarboxylic acid, which was coverted to the carbamate ester via a Curtius rearrangement of the acid azide.Displacement of bromine with silver acetate gave the acetoxy compound 21.Hydrolysis of 21 gave the unstable 3-isoxazolamine derivative 9a, which was converted to the OSiMe3 derivative 9b.The compound 3 was synthesized by reaction of ethyl oxalyl chloride with 5-methyl-3-isoxazolamine followed by base hydrolysis.