Abstract

In this study, known chemical syntheses of MK-8527 (alimatravir) were examined and new synthetic routes proposed.

The baseline route to alimatravir was described in the 2015 Merck patent (WO2015148746A1). It involves a chemical synthesis of MK-8527 (no biocatalysis). Because of its similarities to islatravir (MK-8591), there has been a considerable amount of synthetic work related to this nucleoside structure. This synthetic chemistry is also briefly summarized.

Three synthetic routes are proposed with the aim of lowering the cost and improving the accessibility of MK-8527. In Proposed Route 1, the single enantiomer furanose intermediate (Cpd 31) is prepared from ozonolysis of a chiral cyclopentene substrate (Cpd 30). Further synthetic elaboration provides MK-8527 in a total of 11 steps with an estimated overall yield around 10%.

In Proposed Route 2, (D)-glucose (Cpd 36) is used to prepare the single enantiomer ribofuranose derivative (Cpd 41) in a seven-step synthetic sequence. This synthesis has been used in the preparation of islatravir (Org. Lett. 2015, 17, 828) and it could potentially give MK-8527 in three subsequent steps. From (D)-glucose, this route leads to MK-8527 in 11 proposed synthetic steps with an estimated overall yield of around 40%.

In Proposed Route 3, the chemistry utilizes a synthetic approach from 2-deoxy-D-ribose. A large-scale synthesis of (2R,4S)-4-allyl-2-phenyl-1,3-dioxan-5-one has been reported by Merck (Org. Lett. 2020, 22, 2167) and this intermediate provides the acetylide addition product in good yield and stereoselectivity. Further synthetic steps are proposed to give the deoxyribose intermediate (Cpd 51) and nucleoside product (Cpd 52). p-Tolyl esters are used to protect the hydroxyl groups – with the goal of producing crystalline intermediates. Global deprotection and SNAr substitution then provides MK-8527. From 2-deoxy-D-ribose, this route leads to MK-8527 in 11 steps with an estimated overall yield of 8%.

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This work is licensed under a Creative Commons Attribution 4.0 License.

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