Synthesis of 4-hydroxy-2-methyl-2H-1,2 benzothiazine-3-[N-(2-pyridyl) carboxamide]-1,1-dioxide and its reaction mechanism

Abstract

Innovative synthesis of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridyl) carboxamide-1,1-dioxide(piroxicam), non-steroidal antiinflammatory agent, was carried out. Starting from alkyl benzoisothiazoline-2-acetate-1,1-dioxide, a new bifunctional (i.e. half-acid and half-ester) N-methylated benzenesulfonamide ester derivative was synthesized and the compound was then subjected to amidation with 2-aminopyridine and subsequent cyclization to obtain piroxicam in respectable yields. During the course of such synthesis, formation of the bifunctional compound occurred via acidhydrolysis of the N-methylated benzenesulfonamide diester derivative. A possible mechanism of this reaction was postulated. Furthermore, it has been observed that methyl benzoisothiazoline-2-acetate-1,1-dioxide underwent interesting transformation by alkoxide into the N-methylated sulfonamide diester derivative in the absence of methylating reagent in methanol medium. Mechanism of such a reaction was clarified in detail.