Greener solvents for solid-phase organic synthesis

Abstract

Solid-phase organic synthesis is an essential method for the rapid synthesis of complex biological structures and libraries of small organic molecules. However, it is often associated with the use of large quantities of problematic solvents for the removal of excess reagents and reaction by-products. Given that solvent will often be the biggest contributor to waste generated in the average pharmaceutical/fine-chemical process, its exchange for a more desirable alternative often presents the biggest gains in terms of reducing environmental impact. This review aims to explore recent approaches to performing solid-phase organic synthesis, and associated solid-phase peptide synthesis, in neoteric solvents and reaction media that present greener alternatives.

Resin Swelling in Mixed Solvents Analysed using Hansen Solubility Parameter Space

“…These three parameters can then be used as the axes of three‐dimensional scatter plots to show the position of solvents in HSP space and the points can be colour coded according to how well they swell a resin. This approach was applied to 27 solvents used in our previous work (see the Supporting Information, Figure S2 for structures and Table S1 for their HSPs) and the results for Merrifield and HypoGel 200 resins are shown in Figures and respectively.…”

Cyclopentyl Methyl Ether (CPME): A Versatile Eco‐Friendly Solvent for Applications in Biotechnology and Biorefineries

“…[83] As they are highly specific in the interaction with their in vivo targets while causing few negative side effects, their role in the future of drug discoveryi sf oreseen to be even higher. [85,86] Thus, reprotoxic polar aprotic solvents, such as dimethylformamide (DMF), dimethylacetamide (DMA), and N-methyl pyrrolidone (NMP), are commonly used, although all of them are classified as substances of very high concern( SVHCs) under Registration, Evaluation, Authorization and restrictiono fC hemicals (REACH), indicating that their use will be restricted in the near future. In economic terms, the overall peptidic drugs market in 2015 was estimated to be around US$ 14.1 billion, and was predicted to grow up to aroundUS$ 25.4 billion by 2018.…”

“…[84] In fact, as recentlyr eported by Lawreson et al, [85] there are presently more than 60 peptide-based drugs that have been approved for use by the US Food & Drug Administration, around1 40 peptided rugs currentlyi n clinicalt rials and over 500 in preclinical trials. [86] Needless to say,D CM and Et 2 Ou sed for synthetic workupsa re also problematic. [83b] Unfortunately,t raditional peptides ynthesis cannot be regarded ass ustainable, since many auxiliary reagents are requireda sp rotecting or activating groups, and generally toxic solvents such as DMF or DMF/DCM mixtures are used.…”

“…This scenario becomes more challenging when considering solid-phase peptide synthesis (SPSS), which requires large amountso fs olvents for multiple washings of resins between procedures to remove excessr eagents and byproducts. [85,86] Thus, reprotoxic polar aprotic solvents, such as dimethylformamide (DMF), dimethylacetamide (DMA), and N-methyl pyrrolidone (NMP), are commonly used, although all of them are classified as substances of very high concern( SVHCs) under Registration, Evaluation, Authorization and restrictiono fC hemicals (REACH), indicating that their use will be restricted in the near future. [86] Needless to say,D CM and Et 2 Ou sed for synthetic workupsa re also problematic.…”

Investigation of Parameters that Affect Resin Swelling in Green Solvents

“…[7] However, SPOS is traditionally very dependent on the highly toxic polar aprotic and chlorinated solvents as the resins typically used in SPOS swell in these solvents. [8,9,10] This was apparent in our previous work where propylene carbonate (S1) was used instead of conventional solvents in SPPS. [11] It totally failed to swell cross-linked polystyrene based resins such as the widely used Merrifield resin (cross-linked chloromethyl polystyrene), so its use in SPPS was restricted to the considerably more expensive polyethylene glycol (PEG) based ChemMatrix resin.…”