Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment

Siler, David A.; Çalimsiz, Selçuk; Doxsee, Ian J.; Kwong, Bernard; Ng, Jeffrey D.; Sarma, Keshab; Shen, Jinyu; Curl, Jonah W.; Davy, Jason A.; Garber, Jeffrey A. O.; Ha, Sura; Lapina, Olga B.; Lee, Jisung; Lin, Lennie; Park, Sangsun; Rosario, Mary; St-Jean, Olivier; Yu, Guojun

doi:10.1021/acs.oprd.1c00026

Cited by 4 publications

(9 citation statements)

References 25 publications

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“…Iodine was of ACS reagent grade containing ≤0.005% each of chlorine and bromine. Starting materials 3 and 5 were prepared according to the procedures described in the associated publications. , …”

Section: Methodsmentioning

confidence: 99%

“…Starting materials 3 and 5 were prepared according to the procedures described in the associated publications. 12,13 Instrumentation. HPLC analyses were performed on a Waters ACQUITY H-Class UPLC system equipped with a quaternary pump, refrigerated sample chamber, flow-through needle autosampler/injector operating in partial loop needle overfill mode, column heater, and photodiode array detector.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…NMR analyses were carried out using either a Varian 400 MHz INOVA spectrometer equipped with a 5 mm ASW broadband probe or a Bruker 400 MHz AVANCE spectrometer equipped with a 5 mm BBO broadband probe. Chemical shifts for 1 H and 13 C spectra are reported in ppm relative to tetramethylsilane and were referenced to the solvent residual signal from the deuterated NMR solvent.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Purification of crude 1 by silica gel chromatography and subsequent crystallization as the citrate salt then yielded the desired API 1a . The synthesis and impurity control strategies of the starting materials 3 and 5 are addressed in the later parts of this series. , …”

Section: Introductionmentioning

confidence: 99%

“…The synthesis and impurity control strategies of the starting materials 3 and 5 are addressed in the later parts of this series. 12,13 It was seen early in the development of this route that protection of the adenine NH 2 was required prior to the iodoetherification reaction in order to suppress the competing iodoamination reaction. Additionally, the protected adenine moiety is significantly less prone to formation of the N-oxide at N-1 when treated with Oxone compared to the corresponding, unprotected adenine.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Rovafovir Etalafenamide (Part I): Active Pharmaceutical Ingredient Process Development, Scale-Up, and Impurity Control Strategy

Standley

Bringley

Çalimsiz³

et al. 2021

Org. Process Res. Dev.

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This manuscript describes the chemical process development and multi-kilogram synthesis of rovafovir etalafenamide (GS-9131), a phosphonamidate prodrug nucleotide reverse transcriptase inhibitor under investigation for the treatment of HIV-1 infection. Rovafovir etalafenamide is assembled in a four-step sequence beginning from the nucleoside core and an elaborated phosphonamidate alcohol. The assembly starts with a decarboxylative elimination of a β-hydroxyacid to yield the corresponding cyclic enol ether, which is subsequently coupled to a functionalized phosphonamidate alcohol in an iodoetherification reaction. Oxidative syn elimination then installs the required fluoroalkene, after which a final deprotection reaction yields the active pharmaceutical ingredient (API). Understanding the genesis, fate, and purge of the des-fluoro analog of the API, a mitochondrial toxin, proved to be a central driver in the development of the manufacturing route and impurity control strategy. Initial control strategies revolved around the use of silica gel chromatography or simulated moving bed chromatography to purge the des-fluoro impurity to an acceptable level, but ultimately a chromatography-free approach to mitigate the formation of this impurity was devised that expanded manufacturing flexibility. Design of experiments was used to improve the iodoetherification fragment coupling reaction and to reduce the level of the des-fluoro impurity formed in this step. Furthermore, several new crystalline intermediate forms were discovered and implemented as isolation points to bolster the overall impurity control strategy for standard, diastereomeric, and potentially mutagenic impurities as well as for the des-fluoro impurity. These processes were executed on multikilogram scale to produce API for clinical studies.

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Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Rovafovir Etalafenamide (Part I): Active Pharmaceutical Ingredient Process Development, Scale-Up, and Impurity Control Strategy

Standley

Bringley

Çalimsiz³

et al. 2021

Org. Process Res. Dev.

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The Discovery and Development of MK-1454, a Therapeutic Cyclic Dinucleotide STING Agonist

Marzijarani¹,

Phillips²

2024

Comprehensive Chirality

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Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454

et al. 2022

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As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.

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Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment

Cited by 4 publications

References 25 publications

Synthesis of Rovafovir Etalafenamide (Part I): Active Pharmaceutical Ingredient Process Development, Scale-Up, and Impurity Control Strategy

Synthesis of Rovafovir Etalafenamide (Part I): Active Pharmaceutical Ingredient Process Development, Scale-Up, and Impurity Control Strategy

The Discovery and Development of MK-1454, a Therapeutic Cyclic Dinucleotide STING Agonist

Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454

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