N-Butylpyrrolidinone as Alternative Solvent for Solid-Phase Peptide Synthesis

Abstract

By means of a systematic approach, several green solvent candidates were tested for their feasibility to replace the reprotoxic dimethylformamide (DMF) as a solvent used in solid-phase peptide synthesis (SPPS). According to the results presented in this paper, it is clear that N-butylpyrrolidinone (NBP) is the best green solvent candidate to replace DMF in SPPS.

Making Solid‐Phase Peptide Synthesis Greener: A Review of the Literature

“…In contrast, the amide bond formation is faster in nonpolar aprotic solvents. From an industrial point of view though, the use of a mixture of solvents makes the recycling process more expensive and arduous and the regulations that a manufacturing company has to implement are more complicated …”

“…When it comes to ag reeners olvent for peptides yntheses, all research data seem to suggest that ad ual solvent system might be ideal forS PPS. [51] Deprotection of the Fmoc group seems to be more favorable in polar aprotic solvents. In contrast, the amide bond formation is faster in nonpolara protic solvents.…”

“…From an industrial point of view though, the use of a mixture of solvents makes the recycling process more expensive and arduous and the regulations that am anufacturing company has to implement are more complicated. [51] The most important changes that need to be adopteda re the use of third-generation couplingr eagents, such as COMU, which are provent ob es afer and result in excellent yields with low racemization, and the use of green solvents, such as GVL, PC, andN BP.N one of the methodsm entioneda bove have been used for longers equences (except for Albericio's synthesis mentioned above using GVL) and sequences prone to aggregation. Nevertheless, PC providedg ood resultsi na ll steps of the synthesis (from resin swelling to purity of the final crude product) of an onapeptide.…”

“…Interestingly though, the authors report that the piperidine cocktail needs to be freshly prepared, but no data on the stability of piperidine in PC are given. The most recent report on the greening of peptide synthesis comes from Novartis Pharmaceutical . Scientists at Novartis screened a series of solvents and provided in‐depth information regarding all challenging steps of the synthesis.…”

“…[50] Interestingly though, the authors report that the piperidine cocktail needs to be freshly prepared, but no data on the stability of piperidine in PC are given.T he most recent report on the greening of peptide synthesis comes from Novartis Pharmaceutical. [51] Scientists at Novartis screened as eries of solvents and provided in-depthi nformationr egarding all challenging steps of the synthesis. Out of the 34 solvents that were screened, NBP (N-butylpyrrolidinone) was found to have optimal performance for all steps and was successfully used both for the synthesis of the linear precursor of the cyclic peptide octeotride, which is manufactured by the company and is currently used in the treatment of gigantism [52] (Figure 4).…”