Updating Levothyroxine Synthesis for the Modern Age

Synthesis of levothyroxine sodium, the sodium salt of a synthetic levoisomer of thyroxine, revolutionized the management of hypothyroidism and related symptoms. However, the primary synthetic route to this active pharmaceutical ingredient (API) is more than 70+ years old with low-yielding steps and obsolete reagents. It lacks experimental data on intermediates, making laboratory and large-scale synthesis of this API difficult and time-consuming. Here, we describe an improved synthesis of levothyroxine using commonly available modern reagents. By modifying and replacing low yielding and/or unproductive steps of Chalmers synthesis, we were able to achieve higher overall yields (39-51%) consistently. Key modifications include an alternative path to the selective N-acetylation step that yielded 5 in a pure and consistent fashion. Our improved methodology, coupled with detailed experimental data, provides a practical alternative to existing methods that can be conveniently implemented to synthesize Levothyroxine sodium in fine chemical settings.

Automated summary

The synthesis of levothyroxine sodium revolutionized the treatment of hypothyroidism, but the traditional synthetic route is outdated and lacks experimental data on intermediates, making laboratory and large-scale synthesis challenging. By modifying the synthesis steps and using modern reagents, higher overall yields were consistently achieved, providing a practical alternative method to synthesize levothyroxine sodium.