Risks and benefits of opioids
The alkaloids are chemically modified to increase their potency and make them more easily absorbable. In the case of producing oxycodone, thebaine undergoes a series of chemical reactions to produce the final product; it is prepared in two-steps by the oxidation of the diene moiety (a specific group of atoms within a molecule that is responsible for characteristic chemical reactions of that molecule) with a peroxyacid to an alkenone with successive hydrogenation. The key step in this process involves
selectively oxidizing the C6-C7 double bond in thebaine to form the 6-keto group, which is reduced and further rearranged to yield oxycodone. It is important to note that the abundance of available thebaine limits the quantity of production of this drug, highlighting an issue for chemists in the production of semi-synthetic opioids, however the genetic modification of poppies can produce higher yields of the alkaloids necessary to the production of semi- synthetic opioids. It is interesting to note the similarities between the molecules of thebaine and oxycodone (pictured left), highlighting how the drug is derived from the naturally occurring alkaloid thebaine.
Figure 2: Oxycodone molecule diagram. (Source: Wikipedia, 2024: online)
By contrast, total synthesis involves constructing the opioid molecule entirely from simpler organic compounds, without the use of substances extracted from an opium poppy plant as a starting material. I have decided to cover the synthesis of fentanyl (1-phenethyl-4-N-propinoylanilinopiperidine), a highly potent opioid (the risks of which I will cover later), generally used in the pain management of
cancer patients. It was first synthesized by Janssen Pharmaceutica in four steps; firstly, condensation with analine gave N-benzoyl-4-piperidone, which was then reduced with LAH (lithium aluminium hydride, a common reducing agent used in organic chemistry). These simple organic molecules are chosen for their ability to be easily transformed into the core structure of fentanyl. Then the resulting product underwent acylation with propionic anhydride, where a propionyl group is introduced, a step essential for providing the pain-relieving properties of the drug, followed by the 1-benzyl group being deprotected through hydrogenation at 1 atmosphere. Finally, the Finkelstein reaction, a process in which an alkyl halide is converted into a different alkyl halide via nucleophilic substitution (SN2), was performed. The total synthesis of fentanyl (pictured right) requires careful control over reaction conditions to ensure the correct stereochemistry of the product, avoiding by-products and ensuring the precise placement of functional groups in order to maintain the opioid’s high potency.
Figure 3: Fentanyl molecule diagram. (Source: EUDA, 2024: online)
It is also important to note the latest developments in the synthesis of opioids, namely biosynthesis. Recent advancements in biotechnology have enabled this process through the use of genetically engineered microorganisms. This process resolves various issues that come with the production of opiates and semi-synthetic opioids. To meet the demand, 100,000 hectares of optimum poppies are cultivated every year, and the farming process is difficult due to weather, climate change, and pests, which can all decrease the crop yield. In some cases, yeast is genetically engineered to produce thebaine and hydrocodone, starting from sugar, a process combining enzyme discovery, engineering, and pathway and strain optimization in order to fully biosynthesize the opioid in yeast. Despite this process being beneficial, in order to scale up, more hurdles must first be overcome, meaning plenty more research must be done into the biosynthesis of opioids.
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