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Current Organic Synthesis

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ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

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Letter Article

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 and Dinara Shashanka Gunasekera*

Volume 18, Issue 4, 2021

Published on: 31 December, 2020

Page: [371 - 376] Pages: 6

DOI: 10.2174/1570179417666201231110306

Price: $65

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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