Updating Levothyroxine Synthesis for the Modern Age

Author(s): Shashika Sevvandi Perera, Umayangani Kumari Wanninayake, Dhanushi Thathsara Welideniya, Adeesha Saseenda Jayathilaka, Anjana Delpe Acharige, Upamalika Samanthi, Shihan Shalinda Kaleel, Veranja Karunaratne, Gehan Amaratunga, Dinara Shashanka Gunasekera*

Journal Name: Current Organic Synthesis

Volume 18 , Issue 4 , 2021


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Abstract:

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.

Keywords: Levothyroxine, hyperthyroidism, triiodothyronine, L-tyrosine, Sandmeyer reaction, tetrazotisation.

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Article Details

VOLUME: 18
ISSUE: 4
Year: 2021
Published on: 30 December, 2020
Page: [371 - 376]
Pages: 6
DOI: 10.2174/1570179417666201231110306
Price: $65

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