The use of synthetic opiate impurities as reference materials has become vital to the pharmaceutical industry. To this end, brominated oxymorphone impurities 1-bromooxymorphone (1) and 2-bromooxymorphone (2) were synthesized using desirable short, direct, and regioselective methods. Using a combination of 1H, 13C and 2-D NMR spectra, unequivocal evidence for the electrophilic aromatic substitution of bromine at the 1- and 2-positions of the aromatic ring of oxymorphone has been demonstrated. HO Br Br HO
Impurities in drugs and drug substances (APIs) are a major concern for the pharmaceutical industry. These impurities can be unreacted starting materials, intermediates, or by-products from the manufacturing process and can affect the safety and efficacy of the drug. Identification and monitoring of these impurities is critical to this industry. Therefore there is a growing need for these impurities as high purity reference materials, applicable to process development and validation of compounds as APIs or routine impurity analysis in the pharmaceutical industry.
Opiates are an extremely important class of compounds for use in pain management. Chlorinated and brominated opiates, substituted on the aromatic ring, have been reported in the literature as manufacturing impurities and degradants in opiates used as active pharmaceutical ingredients.1 Interestingly, whereas the regioselective bromination of related opiates such as oxycodone (3)2,3 and hydromorphone (4)3 have been studied; to date no details of the bromination of oxymorphone can be found in the literature. As a consequence, we sought to synthesize the mono-brominated species, 1-bromooxymorphone (1) and 2- bromooxymorphone (2). Utilizing divergent methods we were able to regioselectively synthesize and isolate both products in high purity.
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• Based on literature precedence for similar compounds2,3, it was expected that electrophilic aromatic substitution could be used to install a bromine at the 1 position of oxymorphone. Synthesis of 1-bromooxymorphone (1) was therefore initially attempted by direct bromination of oxymorphone using bromine under acidic conditions. However, to our surprise, we isolated exclusively 2-bromooxymorphone (2) in 6% yield and 97% chromatographic purity, along with overbromination impurities. Unfortunately, this was not discovered for several months and was not evident from the 1H NMR, thus requiring extensive 2D NMR for structural confirmation. • Alternate methods were therefore sought to synthesize the corresponding 1-bromo derivative. Direct bromination of oxymorphone via NBS resulted in a complex mixture of unreacted starting material and degradation products. It was found that only by first brominating oxycodone followed by O-demethylation could 1- bromooxymorphone (1) be successfully synthesized in 16% yield and 98% chromatographic purity. • HPLC, HPLC/MS and 1H, 13C, HMBC, COSY, and HSQC NMR techniques were used to determine the purity and to confirm the identity of 1- and 2- bromooxymorphone.