Sri Lanka Institute of Nanotechnology, Nanotechnology and Science Park, Mahewatta, Pitipana, Homagama 10200, Sri Lanka.
Curr Org Synth. 2021;18(4):371-376. doi: 10.2174/1570179417666201231110306.
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.
左甲状腺素钠是甲状腺素的一种合成左旋异构体的钠盐，它的合成彻底改变了甲状腺功能减退症及相关症状的治疗方式。然而，这种活性药物成分（API）的主要合成路线已有 70 多年的历史，其中包括产率低的步骤和过时的试剂。该方法缺乏中间体的实验数据，使得实验室和大规模合成这种 API 既困难又耗时。在这里，我们描述了一种使用常见现代试剂改进的左甲状腺素合成方法。通过修改和替换 Chalmers 合成中产率低和/或非生产性的步骤，我们能够始终如一地实现更高的总收率（39-51%）。关键的改进包括选择性 N-乙酰化步骤的替代途径，该途径以纯且一致的方式得到 5。我们改进的方法，结合详细的实验数据，为现有方法提供了一种实用的替代方案，可以方便地在精细化工环境中合成左甲状腺素钠。
