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Paper | Regular issue | Vol 104, No. 3, 2022, pp.524-540
Published online, 4th January, 2022
DOI: 10.3987/COM-21-14599
Development of a Scalable Synthesis of SIRT1 Modulator Macrocycles

János Tatai, Márk Molnár, Maud Villeneuve, Laure Haberkorn, and Miklós Nyerges*

*Servier Research Institute of Medicinal Chemistry, 7 Záhony utca, 1031, Budapest, Hungary

Abstract

An improved multigram route to key intermediate 26 for macrocyclic SIRT1 modulators has been developed. The increasing demand for this key intermediate caused the rerouting of the initial discovery route resulted in increase of overall yield to 8.3% over 8 steps, with the elimination of some tedious chromatographic purifications, and the substitution of critical reaction steps, which hindered a feasible scale-up. The key modification was the introduction of the microwave assisted intramolecular Suzuki reaction for the macrocyclization step, which provided in a reliable and reproducible manner of the targeted product 40. This newly developed synthetic access to this first described macrocyclic ring system was capable of ensuring the supply of our medicinal chemistry program.