Development of a Commercial Manufacturing Route to 2-Fluoroadenine, The Key Unnatural Nucleobase of Islatravir

Abstract

We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and pre-exposure prophylaxis (PrEP) against HIV infection. The fragment, the unnatural nucleobase 2-fluoroadenine, is incorporated into MK-8591 via a biocatalytic aldolglycosylation cascade, which imposes stringent requirements for its synthesis and isolation. Presented herein is the development work leading to a practical, scalable route from guanine, featuring a dual fluorination approach to a novel 9-THP-2,6-difluoropurine intermediate that enables a mild, highly selective, direct amination. This one-pot fluorination/amination sequence utilizes a direct isolation to deliver high purity 9-THP-2-fluoroadenine, which features ideal properties with respect to reactivity, solubility, and crystallinity. An acid-catalyzed liberation of 2-fluoroadenine in aqueous buffer delivers the appropriate purity profile to facilitate the enzymatic cascade to access MK-8591.

Tetramethylammonium Fluoride Tetrahydrate for SNAr Fluorination of 4-Chlorothiazoles at a Production Scale

“…We propose that this is due to instability of TBAF (anh) at the elevated temperature required for thiazole S N Ar fluorination. This reagent can undergo competing Hofmann elimination with the very basic fluoride anion in its anhydrous form, leading to the formation of bifluoride (HF 2 ), which is significantly less nucleophilic than fluoride …”

“…Having established that TMAF (anh) could lead to full conversion of the starting material at the lab scale, we turned our attention to large-scale production. It became quickly evident that TMAF (anh) could not be procured in bulk . To obtain large quantities of TMAF (anh), we began to investigate methods to prepare it in situ.…”

“…This reagent is more stable than other anhydrous tetraalkylammonium salts . Unlike TBAF (anh), it cannot undergo problematic Hofmann elimination as it lacks the β-protons required for E2 elimination . For this reason, TMAF (anh) is commercially available and can be stored in its anhydrous form under ambient conditions.…”

Synthesis of Isotopically Labeled Anti-HIV Nucleoside Islatravir through a One-Pot Biocatalytic Cascade Reaction

“…[ 14 C]­Islatravir was first synthesized to support drug metabolism and pharmacokinetics (DMPK) studies in the early stage of the drug development process in 2015, and multiple syntheses of unlabeled islatravir have been reported in recent years. ,, On the basis of the structure of islatravir, labeling either the sugar or the 2-fluoroadenine (2-FA, 11 ) should be acceptable from a metabolic stability perspective. Our process chemistry team recently reported the development of a commercial manufacturing route to the unnatural nucleobase 2-FA that nicely summarized the challenges of the synthesis . Since the 2-FA fragment was not readily amenable to 14 C introduction, we sought instead to modify the sugar moiety.…”

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

“…THP-2-fluoroadenine synthesis scheme . Adapted with permission from ref . Copyright 2021 American Chemical Society.…”