YI YANG
Chemical Development, Global Pharmaceutical R&D, Ferring Pharmaceuticals A/S, Kastrup, Denmark

Abstract

Conventional SPPS involves extensive use of protecting groups and large volumes of trifluoroacetic acid (TFA) for deprotection and cleavage, contributing to inefficiencies and environmental concerns. The need for sustainable practices in peptide synthesis has led to the development of innovative approaches such as minimal-protection solid-phase peptide synthesis (MP-SPPS) and minimal-rinsing SPPS (MR-SPPS). This study explores MP-SPPS, which employs unprotected side-chain amino acids, specifically Fmoc-Arg-OH, Fmoc-His-OH, and Fmoc-Tyr-OH, to streamline the synthesis process. By reducing the need for protecting groups and TFA, MP-SPPS not only diminishes chemical waste but also enhances productivity, achieving a 5.3-fold increase in efficiency compared to traditional methods. Additionally, the integration of MR-SPPS further minimizes solvent usage, highlighting the potential of these sustainable strategies to improve peptide synthesis while addressing environmental impact.

INTRODUCTION
The industrial manufacturing of peptides via Solid-Phase Peptide Synthesis (SPPS) faces several sustainability challenges. First, low productivity, which results from the complex, multi-step deprotection, coupling, and washing, limits large-scale production (1).

SPPS also involves high consumption of organic solvents like DMF and DCM, increasing costs and waste generation. The hazardous nature of these solvents further poses environmental risks and health concerns, as many are toxic and difficult to manage (2).

Furthermore, SPPS suffers from low Process Mass Intensity (PMI) due to excessive solvent and reagent use, inefficient reactions, and high byproduct generation (3). Improving PMI is critical to making SPPS more resource-efficient and environmentally friendly.

Conventional SPPS, which involves side-chain protection to prevent undesired modifications, significantly reduces atom economy and necessitates large volumes of TFA for deprotection and peptide cleavage. This inefficiency is particularly pronounced in large-scale peptide manufacturing, where the volumes of TFA and ...