Progress towards the flow synthesis of antibiotics vital to the treatment of tuberculosis in South Africa

Abstract

The burden of tuberculosis (TB) on the world has been explored in recent literature and described as a major source of human suffering. More specifically, the socio-economic implications of TB on South Africa were described and key problems identified, chief of which was the financial complexities of providing treatment to those suffering from this disease, especially in remote and impoverished communities. Uncertainty in regard to the availability of active pharmaceutical ingredients (APIs) to countries such as South Africa were in part attributed to the reliance on foreign imports for obtaining crucial medicines needed for the treatment of TB, MDR-TB, and XDR-TB. The local production of APIs for the treatment of TB is worth pursuing to ensure a constant supply of drugs and timely delivery of lifesaving medicines in a financially sound manner, especially in scenarios where global supply chains are disrupted to such a degree that reliance on foreign suppliers is no longer an option (as seen with the SARS-CoV-2 pandemic). The core drug regimen for treating TB usually includes isozianid and ethambutol (together with rifampin and pyrazinamide), while resistant TB are treated with second-line TB drugs like the fluoroquinolones and thioamides. Thus, three of the most common TB medications were chosen to demonstrate the potential for translation to flow syntheses, namely ethionamide, ethambutol, and isoniazid. For the attempted total synthesis of ethionamide, only the first step could be successfully completed, albeit delivering the enolated form of the expected product. It was shown that this step still offers a unique way to access a ring system featuring a nitrogen adjacent to a carbonyl group. Steps 1 and 2 of the three-step ethambutol synthesis were successfully reproduced in batch and translated into flow. The use of methanol-stabilised formalin as a substitute for gaseous formaldehyde in the first step proved to be successful, eliminating the need for more complicated methods relying on specialised flow equipment when handling gases in flow. The highest yield obtained for 1-nitrobutanol was 59 %, 30 % higher than its batch equivalent. Furthermore, it was 2 demonstrated that hydrotalcite, a reusable solid catalyst, was an effective substitute for the liquid base triethylamine. Step 2 of the ethambutol synthesis in flow using Raney-Nickel delivered high yields, plateauing at 85 %, 53 % higher than its batch equivalent. The dangers of using hydrazine, however, were clear after a column reactor burst during a reduction reaction. Initial attempts at using gaseous hydrogen instead showed some promise, but only trace yields were recovered by the end of the experimental phase of this project. The final step of the ethambutol synthesis was unsuccessful, and requires further study. Special attention will be given to fully elucidating the reaction mechanism, as this might provide alternative strategies to obtaining the final product. For the planned synthesis of isoniazid, only the first of the two steps could be replicated in flow and batch. The flow synthesis reaction in step 1 delivered a superior yield at 73 %, 26 % above that of the batch method. The hydrazinolysis of isonicotinamide, however, proved unsuccessful and requires further study. In summary, the goal of translating each of the three target APIs onto a flow platform was partially accomplished. Those steps that proved viable in flow serve to demonstrate that the local production of valuable intermediates is indeed feasible using steady-state chemistry. South Africa currently has almost no batch manufacturing plants for pharmaceuticals, and thus adopting flow production with the safer, cleaner, and more reliable processes associated with this burgeoning field can solve the many difficulties associated with the importation of APIs.