Development of a Kilogram-Scale Synthesis of a Key Ulevostinag Subunit Part I: Accessing a Keto-Nucleoside Intermediate from Guanosine

Abstract

A kilogram-scale synthesis of a key fragment of Ulevostinag (MK-1454), a cyclic dinucleotide agonist of the stimulator of interferon genes (STING), is described. Ulevostinag comprises two non-natural nucleoside derivatives linked together via two P-chiral phosphorothioate groups. The strategy utilized to prepare one of these nucleosides, namely, 3′-deoxy-3′-α-fluoroguanosine (3′-FG), hinges on a diastereoselective α-fluorination of a key keto-nucleoside derivative, followed by substrate-directed reduction of the ketone. Herein, we describe the development of a robust and scalable synthesis of this intermediate, a 3′-deoxy-2′keto-guanosine derivative, from guanosine. Salient features of the approach include activation of the 2′ and 3′-alcohol groups of guanosine as a bis-tosylate, which enables regioselective E2 elimination to simultaneously deoxygenate the 3′-position and generate the 2′-ketone.

The First GMP Synthesis of MK-2118, a Small Molecule Agonist for Stimulator of Interferon Genes

“…Our company and others have observed promising clinical results with this class of molecules (Figure ). Our efforts in this field led to the discovery of MK-1454, and significant efforts were undertaken to develop an elegant manufacturing route for this potential therapeutic. − In addition to CDNs, screening campaigns revealed small molecule benzothiophene agonists as promising alternatives to the more complex structures. An internal medicinal chemistry effort ultimately identified MK-2118 as a highly potent agonist for STING.…”

Development of a Kilogram-Scale Synthesis of a Key Ulevostinag Subunit Part II: An Electrophilic Approach to Fluorinated Nucleosides

“…Herein, we describe the challenges and ultimate solutions that enabled the kg-scale implementation of the electrophilic fluorination/reduction sequence from 3 to 1 , delivering materials of suitable quality to complete the synthesis of Ulevostinag for parenteral delivery in clinical studies. The development of an efficient process to 2′-keto-nucleoside intermediate 3 is the subject of an adjoining report …”

“…The development of an efficient process to 2′-keto-nucleoside intermediate 3 is the subject of an adjoining report. 16 ■ RESULTS AND DISCUSSION Development of the Organocatalytic Fluorination Process. As our protecting group strategy was undefined at the early stages of process development, initial studies were conducted on bis-pivaloyl-protected ketone Piv-3, which was both readily accessible, and any findings were expected to translate to closely related analogues.…”