Synthesis of the antimalarial API artemether in a flow reactor

Yaseneva, Polina; Plaza, Dorota; Fan, Xiaolei; Loponov, Konstantin N.; Lapkin, Alexei

doi:10.1016/j.cattod.2014.04.014

Cited by 19 publications

(18 citation statements)

References 11 publications

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“…Artemether ( 3 ) is obtained by reduction of artemisinin ( 1 ) to dihydroartemisinin ( 2 ) followed by methylation ( Scheme 34 ) [ 150 , 151 ]. This synthesis can be performed in flow reactor [ 152 , 153 ].…”

Section: 124-trioxanesmentioning

confidence: 99%

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions

et al. 2017

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The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity, which is still being given insufficient attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in detail earlier. The review is mainly concerned with the development of methods for the synthesis of biologically active natural peroxides, as well as its isolation from natural sources and the modification of natural peroxides. In addition, much attention is paid to the substantially cheaper biologically active synthetic peroxides. The present review summarizes 217 publications mainly from 2000 onwards.

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Section: 124-trioxanesmentioning

confidence: 99%

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions

et al. 2017

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“…Since the reagent is applied in high excess and the substrate is the limiting species, the reaction can be assumed to follow pseudo‐first order kinetics . Consequently, the total reaction rate is described in Equation , and the application of

t = 0

and

C_{substrate} = C_{substrate}^{0}

boundary conditions gives Equation .

true r = - r_{substrate} = - \frac{{d C}_{substrate}}{d t} = k^{^{'}} C_{substrate}

true \ln C_{substrate} = - k^{^{'}} t + \ln C_{substrate}^{0}

…”

Section: Resultsmentioning

confidence: 99%

“…From another perspective, solvents account for 80–90 % of the overall mass during the manufacturing processes in pharmaceutical industries . Continuous‐flow reactors can only be truly sustainable if solvent recovery is employed –. Solvent waste has a large carbon footprint and consequently it is detrimental to the sustainability of the process.…”

Section: Introductionmentioning

confidence: 99%

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

et al. 2017

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Solvent usage in the pharmaceutical sector accounts for as much as 90 % of the overall mass during manufacturing processes. Consequently, solvent consumption poses significant costs and environmental burdens. Continuous processing, in particular continuous‐flow reactors, have great potential for the sustainable production of pharmaceuticals but subsequent downstream processing remains challenging. Separation processes for concentrating and purifying chemicals can account for as much as 80 % of the total manufacturing costs. In this work, a nanofiltration unit was coupled to a continuous‐flow rector for in situ solvent and reagent recycling. The nanofiltration unit is straightforward to implement and simple to control during continuous operation. The hybrid process operated continuously over six weeks, recycling about 90 % of the solvent and reagent. Consequently, the E‐factor and the carbon footprint were reduced by 91 % and 19 %, respectively. Moreover, the nanofiltration unit led to a solution of the product eleven times more concentrated than the reaction mixture and increased the purity from 52.4 % to 91.5 %. The boundaries for process conditions were investigated to facilitate implementation of the methodology by the pharmaceutical sector.

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“…However, these syntheses described in the scientific literature are not suitable for an industrial large-scale process because they require very low temperature, highly expensive or toxic reagents and solvents or provide only moderate yields. Recently, some continuous flow protocols for the preparation of 2 and 3 were published [26–28]. Flow protocols have some technical advantages over batch protocols.…”

Section: Introductionmentioning

confidence: 99%

A simplified and scalable synthesis of artesunate

2016

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An efficient and economically viable approach for the large-scale conversion of artemisinin into the antimalarial frontline drug artesunate was developed. This advanced synthesis includes an NaBH4-induced reduction, followed by an esterification with succinic anhydride under basic conditions. The entire conversion follows the principles of green chemistry, i.e., application of reusable solvents.Graphical abstract

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Synthesis of the antimalarial API artemether in a flow reactor

Cited by 19 publications

References 11 publications

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

A simplified and scalable synthesis of artesunate

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