A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladium-catalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity.

Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis

Yasunori Aoyama*^† , Toshikazu Hakogi^‡, Yuki Fukui^†, Daisuke Yamada^†, Takao Ooyama^§, Yutaka Nishino^‡, Shoji Shinomoto^†, Masahiko Nagai^§, Naoki Miyake^‡, Yoshiyuki Taoda^§, Hiroshi Yoshida^§, and Tatsuro Yasukata^† 

^† API R&D Laboratory, CMC R&D Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan

^‡ Production Technology Department, Manufacturing Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan

^§ Shionogi Pharmaceutical Research Center, Shionogi and Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00409

Publication Date (Web): March 1, 2019

Copyright © 2019 American Chemical Society

*E-mail: yasunori.aoyama@shionogi.co.jp.

This article is part of the Japanese Society for Process Chemistry special issue.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00409

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