Biocatalytic oxidations have the potential to address many synthetic chemistry challenges, enabling the selective synthesis of chiral intermediates such as carbonyl compounds, alcohols, or amines. The use of oxygen-dependent enzymes can dramatically reduce the environmental footprint of redox transformations at manufacturing scale. Here, as part of the biocatalytic cascade to an anti-HIV investigational drug islatravir 1, we describe the development of an aerobic oxidation process delivering (R)-ethynylglyceraldehyde 3-phosphate 3 using an evolved galactose oxidase enzyme. Integrated enzyme and reaction engineering were critical for achieving a robust, high-yielding oxidation performed at pilot plant scale (&gt;20 kg, 90% yield). 

Development of a Biocatalytic Aerobic Oxidation for the Manufacturing Route to Islatravir

MSD’s Process Safety Scale-Up Methodology for Pilot Plant Scale and Beyond

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

/pdf/development-of-an-efficient-route-to-2-ethynylglycerol-for-pxio4ha0ag.pdf

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

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