G. Kumaraswamy, A. Das, N. Jena
Dec 1, 2003
Citations
0
Influential Citations
7
Citations
Journal
Organic Preparations and Procedures International
Abstract
(*) Doxazosin mesylate (6*mesylate), an important drug of the quinazoline family in current use €or the treatment of hypertension has also been proven effective for the treatment of benign prostatic hyperplasia (BPH). Doxazosin mesylate displays high binding affinity for a,-adrenoceptor, with no significant activity at q-sites. This mode of action provides appropriate therapy which is being increasingly employed in order to ameliorate hemodynamic derangements without affecting n o d physiological functions.' The advantages and limitations of the original method2 are discussed herein and we report an alternative route of preparation for the intermediate (*) ethyl 2,3-dihydrobenzo[ 1,4]dioxin-2-carboxylate (3) and a simple work-up procedure for the separation of the bis-amide impurity as well as optimum conditions for the synthesis of intermediate (*) N-(2,3-dihydro[l f-dioxin-2-carbony1)pipermine (4). Several routes have been described for the synthesis of (*) doxazosin (6). The most studied method2 shown in Scheme I, involves crucial intermediates (*) ethyl 2,3-dihydrobenzo[ 1,4]dioxin-2-carboxylate (3) and (*) N-(2,3-dihydro[ 1,4]dioxin-2-carbonyl)piperazine (4). After our initial efforts toward the synthesis of these intermediates, we made the following observations. The purity and crystalline nature of (*) doxazosin mesylate (6amesylate) depends on the purity of doxazosin which, in turn, depends on the purity of (*) N-(2,3dihydro-[ 1,4]dioxin-2-carbonyl)piperazine (4). The product obtained by condensation of (i) ethyl 2,3-di-hydrobenzo[ 1,4]dioxin-2-carboxylate (3) with piperazine contained substantial amounts of the bis-amide [from the reaction of piperazine with two molecules of (*) 31 as impurity and further purification of the doxazosin proved to be very difficult due to its polymorphic nature.'