Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

Self Cite

The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic understanding of the cyclization step in the presence of guanidine was established by performing isotopic labeling experiments and identification of impurities. Guided by the mechanistic understanding, further attempts to modify the cyclization reaction by employing additives to reduce the triazine (9) formation and guanidine loading will also be presented. This newly developed method delivered compound 1 in 88−94% yield on a commercial scale and addressed the shortcomings of the early synthetic route including high PMI, low atom economy, long cycle-time, and multiple purifications to achieve the desired quality.

Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 3: Development of a One-Pot Formylation–Cyclization Sequence to the Diaminopyrimidine Core

Basu

Lehnherr

Martin

et al. 2020

Self Cite

“…Benzofuran is the core structure of GSK852A (96) During the development of a green and sustainable manufacturing process for gefapixant citrate (118), 132 an antagonist of the purinergic receptor P2X3 for the treatment of chronic cough, 133 Peng et al at Merck developed a scalable and effective synthesis for a key intermediate, phenol 113, for the synthesis of 118 (Scheme 37). 134 The previously reported synthesis started from mequinol (111) via a 4-step sequence of acetylation, Fries rearrangement, Grignard, and hydrogenation. This route, although successfully delivering the target phenol in a 45% overall yield, was not desirable for large-scale practice because of its large process mass intensity (PMI) of 127 and potential safety risks associated with the handling of triflic acid (TfOH) at high temperatures.…”

Section: Applications In Route Design Process Development and Scale-u...mentioning

confidence: 99%

“…138 The discovery route (Campaign 1 Route) involved an Ullmann coupling of 131 and 132 in the presence of Cu 2 O in DMF at 150 °C, which afforded the desired product 133 in a moderate yield of 51%. This route was used to deliver 270 g of AZD7545 (134) and provided easy access to a variety of different analogs with functionalization on the left side of the molecule. However, the Ullmann coupling of 131 and 132 required a stoichiometric amount of Cu 2 O, a high reaction temperature, and a long reaction time to afford only a moderate yield after difficult and diluted workup.…”

Section: Applications In Route Design Process Development and Scale-u...mentioning

confidence: 99%

Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

Yang

Zhao

2022

128

100

Cu-mediated Ullmann-type cross-coupling has experienced significant advances over the last century since the seminal publication by Ullmann in 1901. These advances have significantly expanded the scope of the original classical Ullmann coupling of aryl halides for formation of diaryl compounds to include the formation of carbon−heteroatom and other carbon− carbon bonds. The introduction of bidentate ligands drastically improved the performance of this class of transformations to enable milder reaction conditions that can tolerate a wide range of sensitive functional groups. Recent development of more powerful second-generation bidentate ligands has further allowed the coupling of less reactive aryl chlorides to proceed smoothly and realized low catalyst and ligand loadings for a broad scope of Ullmann-type cross-coupling reactions. As a result of these breakthrough advances in the past decades, Cu-mediated Ullmann-type cross-coupling reactions have been frequently implemented in academic research and have found ubiquitous industrial applications including the preparation of pharmaceutical and agrochemical products. This review provides an overview of selected general Cu-mediated Ullmann-type transformations for the formation of carbon− carbon and carbon−heteroatom (C−N, C−O, C−S, and C−P) bonds and their applications in route design, process development, and scale-up of pharmaceutical and agrochemical processes.

“…A Merck process team has applied a Cu-catalyzed C−O coupling to the synthesis of a key phenol fragment for the preparation of Gefapixant (Scheme 3). 10 Early development work evaluated a ligand-less coupling of NaOMe and an aryl bromide in DMF, but dehalogenation and phenol-dimer formation were prevalent (even with exclusion of oxygen). As a result, a THP protecting group was integrated into the substrate which suppressed the dimer impurity to less than 0.1% and provided the desired methoxyphenol in 96% yield.…”

mentioning

confidence: 99%

Recent Advances in Nonprecious Metal Catalysis

Singer

Monfette

Bernhardson

et al. 2021

Nonprecious metal catalysts are cost-effective and sustainable alternatives to other commonly used, expensive transition metals. Therefore, process chemists across various industries have invested in this technology, harnessing iron, cobalt, nickel, copper, as well as other metals to catalyze well-studied and novel transformations. This review continues a series highlighting industry-relevant literature published in the field of nonprecious metal catalysis between November 2020 and February 2021.