Greening SPPS with Bachem

Bachem, the world’s largest peptides manufacturer, has announced some results of two studies it carried out with Novo Nordisk, seeking to make solid-phase peptide synthesis (SPPS) greener.

SPPS requires large volumes of solvents and the current gold standards, because of their excellent solubilisation and stability properties for reagents and resin swelling capabilities, are N-dimethylformamide (DMF), dichloromethane and N-methyl-2-pyrrolidone. All now face restrictions under REACH because of their hazardous nature.

Bachem and Novo Nordisk first investigated the properties of 19 solvents with an acceptable REACH profile that could be used neat or in mixtures. They found that binary mixtures with similar polarity and viscosity profiles to DMF, such as dimethyl sulfoxide with ethyl acetate, 1,3-dioxolane and 2-methyl tetrahydrofuran “are viable, less toxic solvent alternatives”.

The second study focused on how such mixtures influence Fmoc-removal, peptide coupling and common side reactions in SPPS and used them to synthesise “a range of challenging model peptides and peptide therapeutics on meaningful scale”, proving them to be viable green alternatives to DMF. The polarity and viscosity profile of a binary solvent mixture can be used to predict its usability in SPPS.

In addition, it was established that varying the composition of the mixture during synthesis “represents a novel and simple tool to mitigate certain side reactions in SPPS”, for example an Arg-lactamisation in the synthesis of Bivalirudin at 7.5 mmol scale. “These results underline that green binary solvent mixtures not only can replace DMF in SPPS, but also provide novel solutions for mitigating common side-reactions in SPPS,” they concluded.