Synthesis of 2‐Oxo‐2H‐[1,2,4]oxadiazolo‐[2,3‐c]pyrimidine‐5‐carbamates

Abstract

The 2-oxo-2H-[ 1,2,4]oxadiazolo [2,3-a]pyrimidine-7-carbamate 3 belongs to a new class of potent peripheral vasodilators. This compound was shown to exert a strong and long-lasting antihypertensive effect in experimental animals as well as in humans [l]. Its synthesis was previously reported [2], the last step being a highly regioselective cyclization of the pyrimidine-N-oxide dicarbamate 2 (Scheme 1). Subsequently, we examined this reaction in more detail and found that thermal ring closure of 2 led to a 95 : 5 mixture of the regioisomers 3 and 4. The structure of the major isomer 3 has been unequivocally established before by an X-ray crystallographic analysis [2 b]. The minor component, isolated from the mother liquor by high pressure liquid chromatography, was identified as 4 on the basis of its spectroscopic properties.

A New Route to the Synthesis of 2‐Amino‐6‐(methoxycarbonyl)amino‐4‐(tetrahydropyridyl)pyrimidine 1‐Oxide

“…In a series of reports, we recently described the synthesis of new 2-0x0-2H-[ 1, 2,4]oxadiazolo [2,3-a]pyrimidine-7-carbamates 1 [ 11 [2] and the synthesis of the regioisomers 2-0x0-2 H-[ 1, 2,4]oxadiazolo [2,3-c]pyrimidine-5-carbamates 2 [3], which both possess interesting cardiovascular properties. As a result of these investigations, l a (Ro 12-4713), a potent antihypertensive agent was chosen to undergo clinical trials.…”

“…To secure 3 in quantities sufficient for its biological evaluation and for its further transformation into 2, it was necessary to develop an alternative to the previously reported routes [l] [3].…”