Journal
CURRENT ORGANIC SYNTHESIS
Volume 18, Issue 4, Pages 371-376Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1570179417666201231110306
Keywords
Levothyroxine; hyperthyroidism; triiodothyronine; L-tyrosine; Sandmeyer reaction; tetrazotisation
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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of levothyroxine sodium revolutionized the treatment of hypothyroidism, but the traditional synthetic route is outdated and lacks experimental data on intermediates, making laboratory and large-scale synthesis challenging.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.
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.
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