Synthetic Development and Scale-Up of the Aminoindazole Fragment of Lenacapavir

We describe herein the development and scale-up of the aminoindazole fragment of lenacapavir, a drug recently approved for long-acting treatment of HIV (Sunlenca) and pre-exposure prophylaxis (as Yeztugo and Yeytuo). This five-step route to fragment 1 was developed from the initial “fit-for-purpose” large-scale synthesis to a commercially viable process. Key improvements include an alternative condition to hydroxylamine-O-sulfonic acid-mediated nitrile formation and a significant overhaul of the key Miyaura borylation process. The culmination of all development efforts improved the final product quality and process safety, resulting in a more efficient and higher-yielding process.