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 main synthetic route to this active pharmaceutical ingredient (API) is more than 70+ years old with low-yielding steps, obsolete reagents, and lacks experimental data on intermediates, which makes 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.