Development and Implementation of an Aluminum-Promoted Phosphorylation in the Uprifosbuvir Manufacturing Route

Abstract

A novel application of the synthesis of pronucleotide (ProTide) 5′-phosphoramidate monoesters promoted by aluminum-based Lewis acids is described. In the multikilogram synthesis of uprifosbuvir (MK-3682, 1), a clinical candidate for the treatment of hepatitis C, this methodology provided >100:1 diastereoselectivity at the phosphorus stereocenter and >100:1 selectivity for the 5′-mono phosphorylation over undesired bisphosphorylation side products. The high diastereoselectivity and mono/bis ratio achieved enabled elimination of the tedious workup associated with the tert-butyl magnesium chloride protocol commonly used to install this functionality in similar nucleotide prodrugs, achieving a near doubling of the isolated yield from 45% to 81%. The process development and purity control strategy of MK-3682, as well as handling of the pyrophoric reagent on scale, will also be discussed.

Palladium-Catalyzed N-Alkenylation of N-Aryl Phosphoramidates with Alkenes

“…Multi-functionalized phosphoramidates represent a promising class of phosphorous compounds and have fascinating applications in the pharmaceutical industry, as flame retardants, and in asymmetric catalysis [1,2]. In medicinal chemistry, the late-stage modification of phosphoramidates skeletons led to the discovery of plentiful FDA-approved drugs [3,4], such as Tenofovir Alafenamide (for HBV), Sofosbuvir (a blockbuster drug for HCV) and Thymectacin (for cancer therapy). Recently established, Redesivir is a new broad-spectrum antiviral drug developed by Gilead, which has been effectively used to treat COVID-19 [5].…”

“…(2) There is a large steric hindrance between the adjacent phosphoryl and aniline, which would weaken the N-H activation of N-aryl phosphoramidates with transition-metal catalysts. (3) The good affinity between phosphoramidates and the transition-metal centre would reduce the catalyst's Lewis acidity [15,16], thus inhibiting the activation of alkenes. According to the theory of soft and hard acid-base, we envisioned that excessive soft ligands could occupy the coordination space of transition metal ions, thus reducing the chance of chelating phosphoramidate with the transition metal.…”

Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at P(V): Improved Generality, Efficiency and Modularity

“…Thirdly, chiral, yet racemic at P(V) electrophiles bearing a single leaving group (and often possessing a chiral sidechain) can be coupled diastereoselectively to enantiopure nucleophiles employing chiral catalysts (Scheme 1B, iii). [55][56][57][58][59][60][61][62][63][64] A subsequent approach involves the direct functionalization of secondary phosphine oxides (SPO) by means of a metal catalyst bearing chiral ligands to obtain tertiary phosphine oxides. To date, however, this approach has been limited to the synthesis of all carbon substituted phosphine oxides (Scheme 1B, iv).…”

Manufacturing Process Development for Uprifosbuvir (MK-3682): A Green and Sustainable Process for Preparing Penultimate 2′-Deoxy-α-2′-Chloro-β-2′-Methyluridine

“…Uprifosbuvir (MK-3682) has recently been introduced as a ProTide (pronucleotide) for the treatment of hepatitis C (HCV), , Chlorouridine 1 was established as a key precursor to the manufacture of Uprifosbuvir, rendering development of an efficient and cost-effective process to deliver metric-ton quantities of good quality 1 critical. The supply route used readily available glucose as the starting material, which suffered from the inefficiencies of an unwieldy 10-step sequence to generate 1 in a mere 0.5–4% overall yield. To identify a more direct and high-yielding synthesis of 1 , we envisioned uridine as an ideal starting material, requiring only the installation of the methyl and chloro substituents at the 2′-position to produce the desired intermediate 1 (Scheme ).…”