Exploring a sustainable synthesis of artemisinin

Sharif, Nasiru (2022) Exploring a sustainable synthesis of artemisinin. PhD thesis, University of Nottingham.

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Abstract

Malaria causes many deaths per year, according to report released by WHO in November 2020, there were 229 million cases of malaria in 2019, with estimated number of deaths which stood at 409, 000. With the children under the age of 5 years being the most vulnerable, accounting for 67 % (274 000) of all malaria death worldwide. The World Health Organization has recommended Artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite P. falciparum.

Artemisinin is a sesquiterpene lactone compound known for its antimalarial properties. Artemisinin has been isolated for centuries from Artemisia annua plant, accounting for 0.6 – 1.0 % of the dried mass of the plant material. After the development of its synthetic route and subsequent commercialisation by Sanofi in 2013,1 efforts have been made to improve its yield, thereby reducing the cost of the final antimalarial drug.2, 3 This work shows how the use of a simple photo-reactor, the PhotoVap, can improve the yield of Artemisinin.4, 5

In Chapter 2 the semi-synthesis of Artemisinin from DHAA, through semi-continuous method in the PhotoVap reactor has been reported, employing two-step and one-pot strategies. Various conditions were optimised with the view to finding the best possible route to the improved industrial production of Artemisinin 1. Highest yield of 75 % Artemisinin 1 was obtained through one-pot approach using [Ru(bpy)3]Cl2 and TFA as photosensitiser and acid catalyst respectively, at -10 oC.

Chapter 3 involved the mechanistic consideration for the various steps involved in the synthesis of Artemisinin 1. With the aim of identifying most of the side products responsible for the reduction in the overall yield, selectivity, and productivity of Artemisinin 1. These side products include the aldehyde 32,  and lactones (33 and 37), deoxyartemisinin 35, polymers and unidentified oligomers. The synthesis, and isolation of δ-lactone 33 and its crystal information has been described. Its reactivity has been studied to explore the possibility of opening its ring back to enol intermediate, which can undergo thermal oxidation to Artemisinin 1.

Various esters and carbonates of DHAA 3 have been synthesized, which include methyl ester 8, ethyl ester 90, isopropyl ester 91, hexafluoro isopropyl ester 92, methyl carbonate 93, and ethyl carbonate 43. The esters and carbonates have been used for the synthesis of Artemisinin 1 through one-pot and two-step process, with the aim finding the possible method of blocking the formation of some of the lactone side-products, for improving the yield and productivity of Artemisinin 1.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: George, Michael W.
Poliakoff, Martyn
Keywords: Artemisinin, Synthesis
Subjects: Q Science > QD Chemistry > QD450 Physical and theoretical chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 68270
Depositing User: Sharif, Nasiru
Date Deposited: 17 Mar 2022 12:51
Last Modified: 17 Mar 2022 12:51
URI: http://eprints.nottingham.ac.uk/id/eprint/68270

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