Development of an Efficient Route to 2-Ethynylglycerol for the Synthesis of Islatravir

Abstract

The unnatural, alkyne-containing nucleoside analog islatravir (MK-8591) is synthetically accessed through a biocatalytic cascade starting from 2-ethynylglycerol as a building block. Herein, we describe the development of an efficient synthesis of this building block including the initial route, route scouting and final process development. Key challenges that have been overcome are the development of an efficient and safe acetylenic nucleophile addition to an appropriate ketone, and the identification of a 2-ethynylpropane-1,2,3-triol derivative with favorable physical properties. An acid-catalyzed cracking of commercially available 1,3-dihydroxyacetone dimer and subsequent 1,2-addition of an acetylenic nucleophile has been discovered and optimized into the manufacturing process

Cocrystal Synthesis through Crystal Structure Prediction

“…Two triol-DABCO multicomponent crystals were previously reported: a hemi-DABCO (2:1 stoichiometry) cocrystal and a mono-DABCO (4:4 stoichiometry) cocrystal (Figure S6; Table ). Both cocrystals exhibit an improved melting property and deliquescence behavior over the free acid (see Figures and ). Earlier cocrystallization attempts of triol with benzoic acid, caffeine, saccharin, Tris, and urea did not yield any cocrystal hit and only the individual components were observed.…”

“…The preparation and synthesis of both the hemi-DABCO and mono-DABCO cocrystals have been described elsewhere . Both cocrystals were formed from THF at ambient temperature.…”

“…Triol or 2-ethynylglycerol (Figure b) is a key building block in the biocatalytic cascade for the commercial synthesis of islatravir (MK-8591) . Triol itself is crystalline; however, it has a low melting point of ca.…”

“…43 °C and deliquesces at ambient conditions, which makes it very unattractive as a solid precursor in terms of storage and shipment as it does not provide sufficient flexibility within the supply chain. Alternative solid forms were identified, including a sodium salt and two 1,4-diazabicyclo[2.2.2]­octane (DABCO) cocrystals with triola hemi-DABCO cocrystal and a mono-DABCO cocrystal . Both cocrystals had solids with enhanced melting points and hygroscopicity behaviors.…”