Opioids are well-known pain relievers. However, their side effects, such as constipation, respiratory depression, and the development of tolerance, addiction liability and abuse, highlight the need for safer opioid prescribing practices. The development of new chemical probes will assist to further the understanding of opioid-receptor interactions. As a part of a collaborative UOIT-Purdue Pharma program, the synthesis of opioid derivatives for use as chemical probes was undertaken to better understand the structure of opioid receptors. The bromination of codeine affords an attractive platform for further functionalization and the synthesis of other opioid derivatives. Here we describe the development of a new methodology for the large-scale bromination of codeine under mild conditions, which was applied for the preparation of a broad range of codeine derivatives. The developed protocol is safer and has higher yield than the commonly employed procedure for the bromination of codeine, which involves toxic HBr gas and H<sub>2</sub>O<sub>2</sub>. In addition to the bromination protocol, we accomplished the first synthesis of natural product bismorphine A, a novel alkaloid extracted from opium in 2003. Biological activities of selected 1-bromocodeine derivatives and bismorphine A will be discussed.

Practical synthesis of 1-bromocodeine derivatives and the first synthesis of bismorphine A

2019 Fall National Meeting

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