## 1 Introduction  
Peptides play an important role in the fields of drug discovery and delivery, immunology, diagnostics, and biomaterials. Pharmaceutical industries are paying more and more attention to therapeutic peptides. In fact, there are currently more than 50 peptide drugs on the market and about 400 in the testing phase [1]. This relevance is attributed to their potential as drugs with high efficacy and minimal side effects [2]. SPPS is the preferred technique for the synthesis of therapeutic peptides, as it allows the synthesis of long-chain peptides, including those containing difficult sequence and cyclic peptides. Additionally, SPPS can be automated and is industrially scalable [3]. In recent years, the pressure to use less dangerous and more \"benign\" substances is growing, thanks to the work carried out by the ACS Green Chemistry Institute, which has drawn attention to greener processes development for the synthesis of biologically active peptides and to encourage much needed innovations [1]. In this context, the individual steps of the SPPS cannot be considered green due to the low atom economy (the presence of protecting groups) and mainly to a large amount of waste generated [2]. In fact, the main disadvantage of SPPS concerns the environmental pollution caused by a large number of toxic reagents and solvents used for all phases of peptide synthesis, particularly during the washing steps. The solvents most used in the SPPS are DMF, 1-Methyl-2-pyrrolidone (NMP), and dichloromethane (DCM), which are substances that are not very safe for the environment, and humans and will soon need to be replaced [4]. Recently, researchers have identified more eco-sustainable solvents, such as 2-methyletrahydrofuran (2-MeTHF) [5], tetrahydrofuran (THF) [6], cyclopentyl methyl ether (CPME) [7], \(\gamma\)-valerolactone (GVL) [8], N-formylmorpholine (NFM) [9], propylene carbonate (PC) [10], 1,3-Dimethyl-2-imidazolinone (DMI) [11], N-butyl pyrrolone (NBP) [12], 4-methyletrahydropyran [13], dimethyl carbonate (DMC) [14], and cyclopentanone [15]. The most used coupling agents in SPPS are benzotriazole derivatives, which are considered dangerous and explosive. However, according to literature data, Oxyma-Pure and COMU are safer reagents [4]. Unfortunately, green peptide chemistry is still a relatively small research field, and many of these advances take a long time to be applied to peptide manufacturing [1]. Taking this into consideration, in this work, we tested a new well-known green solvent, DMM [3], for all steps of the SPPS. DMM is a non-toxic solvent that is safe for the environment and humans and was first evaluated in terms of solubility, resin swelling, couplings, deprotections, and washing processes. After obtaining favorable results, the synthesis of a dipeptide was reported. Then, the best protocols were selected for the synthesis of two difficult sequences, such as Aib-enkephalin 5-mer and Aib-ACP 10-mer.  
Various strategies have been suggested to tackle the cost challenges associated with eco-friendly SPPS solvents, including the increase in demand to lower costs and recycling. However, the high volume and low cost of conventional solvents pose obstacles to the widespread adoption of eco-friendly SPPS methods. As part of a green chemistry program focused on peptides, a more environmentally conscious approach to peptide circular chemistry, called \"ReGreen SPPS\", has been proposed. This approach would use more-affordable and eco-friendly solvents and enable the easy recycling of reagents and solvents from SPPS waste [16].