Grant: Idea to Innovation

The proposed project is concerned with the conversion of thebaine to oripavine, and oripavine to hydromorphone, an important analgesic agent used for pain control. The annual demand for hydromorphone in Canada has steadily increased to about 1,600 kg/year, with global production estimated at 6.1 tons and global (legal) consumption at 3.4 tons.All opiate analgesics and antagonists, including hydromorphone, are manufactured by semi-synthesis from alkaloids derived from the opium poppy, including morphine, codeine, and thebaine, with global production at 440, 381, and 145 tons, respectively, with opium poppies produced primarily in Afghanistan, India, Turkey,and Tasmania. Although at present there is no commercial de novo synthesis of any opiate-derived medicinal agent, it would be prudent to consider alternatives for production of these medicinal agents should the supply diminish because of future climate or political instabilities.As thebaine (and oripavine) are ideal feedstocks for the synthesis of oxycodone, oxymorphone, naltrexone, and naloxone, it is essential to develop efficient methods for O- and N-demethylation of these compounds. Tasmanian Alkaloids has developed an opium poppy that produces thebaine at the expense of morphine and codeine. Thus, with a more abundant supply of thebaine, new protocols for the synthesis of analgesics and antagonists can be developed that do not rely only on morphine or codeine as starting materials.We propose solutions that will ensure a continuous commercial supply of these important compounds: (A) improvement of our previously established chemical conversion of thebaine to oripavine and hydromorphone and (B) streamlining a de novo synthesis of hydromorphone and related medicinal agents. We also will provide results for (C) optimizing the enzymatic production of specific morphine alkaloids and derivatives such as oripavine and nororipavine, ideal precursors to opiate antagonists such as naloxone and naltrexone, important compounds for treatment of overdoses or opiate addictions.