Abstract
A selective transformation of clopidogrel hydrogen sulfate (CLP) by reactive halogen species (HOX) generated from peroxymonosulfate (PMS) and sodium halide (NaX) is described. Other sustainable oxidants as well as different solvents have also been investigated. As result of this study, for each sodium salt the reaction conditions were optimized, and four different degradation products were formed. Three products were halogenated at C-2 on the thiophene ring and have concomitant functional transformation, such as N-oxide in the piperidine group. A halogenated endo-iminium product was also observed. With this condition, a fast preparation of known endo-iminium clopidogrel impurity (new counterion) was reported as well. The progress of the reaction was monitored using nuclear magnetic resonance spectroscopy as an analytical tool and all the products were characterized by 1D-, 2D-NMR and HRMS.
Highlights
The direct insertion of halogens inaromatic drugs, in a selective way, has been the object of much interest by the synthetic community [1]
The treatment of clopidogrel hydrogen sulfate (CLP) with H2O2 or tert-butyl hydroperoxide (TBHP) in the presence of NaCl did not lead to the formation of products after 24 h at room temperature (Table 1, Entries 1 and 2)
Using PMS in D2O, we observed the complete consumption of CLP and the formation of various degradation products after one minute
Summary
The direct insertion of halogens in (hetero)aromatic drugs, in a selective way, has been the object of much interest by the synthetic community [1]. Several methods of direct activation of halogens in organic compounds have been reported using safe halogen sources such as HX, NH4X and NaX (X = Cl, Br and I) To sustainably transform these halides into more reactive species, the use of oxidizing agents that conform to the principles of Green Chemistry is essential [1]. To the best of our knowledge, detection, characterization, and selective preparation of the products in this oxidative method are first reported
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