Theoretical and Experimental Synthesis of β-Fluorinated Morphine Derivative for Selective Binding in Inflamed Tissue

Over the past two decades, the United States has experienced a substantial rise in opioid overdoses and related fatalities. Morphine is a frequent prescription for pain management following traumatic procedures and contributes to potential tolerance and dependency with prolonged use. By reconstructing the structure of morphine, adverse side effects may be eliminated. Previous studies have identified several morphine derivatives that, in theory, could result in fewer side effects. This was determined by a decreased pKₐ of the biochemically active amine group to promote the selective binding in peripheral opioid receptors within inflamed tissue (pH=6-6.5). This activation provides analgesia while central receptors within the brain remain inactive, thus preventing undesired side effects associated with opioids. The study aims to experimentally synthesize the novel opioid derivative Fluoromorphine β-C2 from a theoretical synthesis plan assisted by computational resources. A SmilesCode generator created a single-line string of symbols to illustrate a 3-dimensional molecular compound. These symbols were inputted into IBM RXN for Chemistry, an AI synthesis program, to determine a theoretical synthesis plan starting from the compound 2-chloro-3-fluoromethoxypyridine. The resulting information was cross-referenced with peer-reviewed articles and experts in the field. The first synthesis step was a palladium-catalyzed dechlorination and hydrogenation, which used palladium on carbon in methanol. Stoichiometric ratios of reagents were used to calculate the corresponding masses and volumes of Pd/C, methanol, and the starting reagent. The first step was completed in vivo, and H1 NMR concluded no desired product was synthesized. According to IBM RXN, the reaction step has high confidence (0.965), indicating additional attempts with procedural adjustments could be fruitful. This would mark a significant achievement toward the synthesis of a morphine derivative less capable of the dangerous side effects associated with narcotics.