ABSTRACT

Polar aprotic solvents such as N,N-Dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N,N’-dimethylacetamide (DMAc) and chlorinated solvent such dichloromethane (DCM) are the most widely used solvents for Fmoc solid-phase peptide synthesis (SPPS). These solvents are considered hazardous chemicals but are normally used in large amounts for washing, deprotection, and coupling steps during SPPS. DMF, DMAc and NMP are classified as toxic for reproduction in accordance with Article 57(c) of REACH (Registration, Evaluation Authorization and Restriction of CHemicals) and were identified as SVHC (Substance Very High Concern). The aim of this study was to find a greener solvent alternative which could replace DMF in SPPS manufacturing processes at Ipsen. Greener solvents which demonstrated efficient resin swelling and solubility were selected as candidates for SPPS trials for the small-scale synthesis of commercial and developmental peptides.

摘要

极性非质子传递溶剂，例如N，N-二甲基甲酰胺（DMF），N-甲基-2-吡咯烷酮（NMP），N，N'-二甲基乙酰胺（DMAc）和氯化溶剂（例如二氯甲烷）是Fmoc固相肽合成（SPPS）的最广泛使用的溶剂。这些溶剂被认为是危险化学品，但通常在SPPS期间大量用于清洗，脱保护和偶联步骤。根据REACH（化学品的注册，评估授权和限制）第57（c）条，DMF，DMAc和NMP被归类为有毒生殖物质，并被确定为SVHC（高度关注物质）。这项研究的目的是找到一种更绿色的溶剂替代品，该替代品可以在Ipsen的SPPS制造工艺中替代DMF。选择具有较高树脂溶胀性和溶解性的绿色溶剂作为SPPS试验的候选物，用于商业和开发肽的小规模合成。