Degradation studies under neutral and basic conditions on ciprofibrate, an orally active hypolipidemic agent containing a (4-alkoxyaryl)-1,1-dichlorocyclopropane unit

Abstract

The major product of degradation of ciprofibrate (1), 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid, in aqueous sodium hydroxide under reflux is 2-[4-(3-hydroxypropynyl)-phenoxy]-2-methylpropanoic acid (11). A further product, 2-(4-ethynylphenoxy)-2-methylpropanoic acid (12) is derived from 11 under the reaction conditions. A third degradant is identified as 2-[4-(2-carboxyethyl)phenoxy]-2-methylpropanoic acid (13). Under similar conditions, but at pH 7, the products of degradation were found to be 2-[4-(2-chloro-1-hydroxyprop-2-en-1-yl)phenoxy]-2-methylpropanoic acid (9) and (Z)-2-[4-(2-chloro-1-hydroxyprop-2-en-3-yl)-phenoxy]-2-methylpropanoic acid (10). Treatment of 10 with aqueous sodium hydroxide under reflux afforded a mixture of products in which 11 and 12 predominated, whereas similar treatment of 9 led to compound 13 among other products. A labelling study indicates that the acid 21 derived from base treatment of 17 is labelled only at C-2 of the propanoic acid side chain; the same labelling pattern is observed in the acid 21 derived by base treatment of the labelled allylic alcohol 18. Mechanisms are suggested which may explain these observations.