Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine

Kincaid, Joseph R. A.; Kavthe, Rahul D.; Caravez, Juan C.; Takale, Balaram S.; Thakore, Ruchita R.; Lipshutz, Bruce H.

doi:10.1021/acs.orglett.2c00944

Cited by 11 publications

(11 citation statements)

References 28 publications

(27 reference statements)

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“…and epimerization, and allows for facile removal of the (odorless) 2-mercaptopyridine by-product via an in-flask extraction with limited amounts of aqueous hydroxide. In contrast to the by-products of conventional amide bond coupling reagents, as used in the Pfizer route 18 and which are known to be genotoxic, 19 , 20 , 31 , 32 benign 2-mercaptopyridine formed can be easily recovered for recycling to DPDTC (see SI, section 4). Both intermediate thioesters 3 and 7 are stable, isolable species constituting activated carboxylic acids, potentially simplifying their large-scale manufacture and distribution compared to other activated acid derivatives.…”

Section: Resultsmentioning

confidence: 99%

“…Computational studies are included in Supplementary Data 1. 1 H, 13 C, and 19 F NMR spectra are presented in Supplementary Data 2.…”

Section: Data Availabilitymentioning

confidence: 99%

“…In continuing our group efforts to develop scalable routes to APIs under cost effective and environmentally friendly conditions [19][20][21] , and in an ongoing partnership with the Bill and Melinda Gates Foundation initially formed for purposes of preparing APIs for the treatment of malaria (e.g., pyronaridine) 19 , we have developed a route to nirmatrelvir that simultaneously addresses these issues while maximizing both time and pot economies (Fig. 1) 22,23 .…”

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confidence: 99%

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A sustainable synthesis of the SARS-CoV-2 Mpro inhibitor nirmatrelvir, the active ingredient in Paxlovid

et al. 2022

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Pfizer’s drug for the treatment of patients infected with COVID-19, Paxlovid, contains most notably nirmatrelvir, along with ritonavir. Worldwide demand is projected to be in the hundreds of metric tons per year, to be produced by several generic drug manufacturers. Here we show a 7-step, 3-pot synthesis of the antiviral nirmatrelvir, arriving at the targeted drug in 70% overall yield. Critical amide bond-forming steps utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. DFT calculations for various conformers of nirmatrelvir predict that two rotamers about the tertiary amide would be present with an unusually high rotational barrier. Direct comparisons with the original literature procedures highlight both the anticipated decrease in cost and environmental footprint associated with this route, potentially expanding the availability of this important drug worldwide.

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Section: Resultsmentioning

confidence: 99%

“…Computational studies are included in Supplementary Data 1. 1 H, 13 C, and 19 F NMR spectra are presented in Supplementary Data 2.…”

Section: Data Availabilitymentioning

confidence: 99%

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confidence: 99%

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A sustainable synthesis of the SARS-CoV-2 Mpro inhibitor nirmatrelvir, the active ingredient in Paxlovid

et al. 2022

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“…The overall sequence involved four individual reaction steps performed in three pots. The overall yield was 87% [ 131 ].…”

Section: Multistep One-pot Reactionsmentioning

confidence: 99%

Cascade Processes with Micellar Reaction Media: Recent Advances and Future Directions

Tang

McInnes

2022

Molecules

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Reducing the use of solvents is an important aim of green chemistry. Using micelles self-assembled from amphiphilic molecules dispersed in water (considered a green solvent) has facilitated reactions of organic compounds. When performing reactions in micelles, the hydrophobic effect can considerably accelerate apparent reaction rates, as well as enhance selectivity. Here, we review micellar reaction media and their potential role in sustainable chemical production. The focus of this review is applications of engineered amphiphilic systems for reactions (surface-active ionic liquids, designer surfactants, and block copolymers) as reaction media. Micelles are a versatile platform for performing a large array of organic chemistries using water as the bulk solvent. Building on this foundation, synthetic sequences combining several reaction steps in one pot have been developed. Telescoping multiple reactions can reduce solvent waste by limiting the volume of solvents, as well as eliminating purification processes. Thus, in particular, we review recent advances in “one-pot” multistep reactions achieved using micellar reaction media with potential applications in medicinal chemistry and agrochemistry. Photocatalyzed reactions in micellar reaction media are also discussed. In addition to the use of micelles, we emphasize the process (steps to isolate the product and reuse the catalyst).

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“…In continuation of our group efforts to develop scalable routes to active pharmaceutical ingredients under cost-effective and environmentally friendly conditions, − and in an ongoing collaboration with the Bill and Melinda Gates Foundation focused to date on pyronaridine (an antimalarial drug) and nirmatrelvir (the key ingredient in Pfizer’s Paxlovid for treatment of COVID-19), we now describe an environmentally responsible route to tafenoquine that simultaneously addresses these issues while maximizing both time and pot economies (Scheme ). , This has been accomplished by taking advantage of neat reactions following the Sheldon philosophy that “the best solvent is no solvent...”, − and multistep, one-pot processes using environmentally preferred solvents. , …”

Section: Introductionmentioning

confidence: 99%

An Efficient and Sustainable Synthesis of the Antimalarial Drug Tafenoquine

Kavthe

Kincaid

Lipshutz

2022

ACS Sustainable Chem. Eng.

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An 11-step, 8-pot synthesis of the antimalarial drug tafenoquine succinate was achieved in 42% overall yield using commercially available starting materials. Compared to the previous manufacturing processes that utilize environmentally egregious organic solvents and toxic reagents, the current route features a far greener (as measured by Sheldon’s E Factors) and likely more economically attractive sequence, potentially expanding the availability of this important drug worldwide.

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Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine

Cited by 11 publications

References 28 publications

A sustainable synthesis of the SARS-CoV-2 Mpro inhibitor nirmatrelvir, the active ingredient in Paxlovid

A sustainable synthesis of the SARS-CoV-2 Mpro inhibitor nirmatrelvir, the active ingredient in Paxlovid

Cascade Processes with Micellar Reaction Media: Recent Advances and Future Directions

An Efficient and Sustainable Synthesis of the Antimalarial Drug Tafenoquine

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