Propylphosphonic Anhydride (T3P®) as Coupling Reagent for Solid‐Phase Peptide Synthesis

Abstract

Amidation is the predominant reaction within the pharmaceutical setting, and it is attracting greater attention due to the increased demand for therapeutic peptides. The high therapeutic efficacy and safety profile of peptides have placed these molecules in prime position within the pharmaceutical arena, which is reflected by these molecules receiving several approvals from various regulatory agencies each year. In this context, the demand for developing efficient strategies for peptide synthesis has also risen. Although propylphosphonic anhydride (T3P®), which has been recently proposed as a green coupling reagent, has shown good performance in solution, it has never been applied to solid‐phase peptide synthesis (SPPS). Here we test the use of T3P® for SPPS. Satisfactory yields were achieved with a mild activation protocol. Various green solvents were tested and proved to be compatible with this coupling reagent. Several commonly used reagents cause allergic reactions or are susceptible to explosion under certain conditions. To overcome these issues, we propose T3P® as a potential alternative coupling reagent in SPPS.

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

“…135 Moreover, its related by-product after activation is water-soluble. Albericio's group 136 investigated the use of T3P® in SPPS (Table 3, entry 48). The results did not look promising because the reaction required large excesses of OxymaPure® and diisopropyl ethyl amine (DIPEA), and the most efficient reactions were performed using T3P® as an alternative to carbodiimides.…”

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

“…15,29 Furthermore, for SPPS in greener solvents, 30 needed due to risks related to the standard SPPS solvent DMF, 31 DIC/ Oxyma is used essentially exclusively, 32 with only a few suitable alternatives currently available. 33 With regards to DIC/Oxyma, it ought to be noted that McFarland these reagents as such or during amino acid (AA) activation leads to the formation of small amounts of the highly toxic prussic acid (H-CN), for which safety aspects of using DIC/ Oxyma should always be considered, in particular on industrial manufacturing scales. 34 Importantly, prompted by this study, efficient means of suppressing the H−CN formation by reaction engineering 35 H−CN scavenging and/or solvent engineering 36 as well as by replacing DIC with TBEC 37,38 have been developed.…”

From green innovations in oligopeptide to oligonucleotide sustainable synthesis: differences and synergies in TIDES chemistry

“…In fact, due to the necessity to replace piperidine with bases displaying a better environmental, health and safety (EHS) profile, other bases are usually combined with green solvents and applied in some cases at lower concentrations to ensure efficient deprotection. In particular, 10% piperazine in DMF/EtOH, 49 50% morpholine in 2-MeTHF 47 or An, 43 0.5% 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in 2-MeTHF, 47 0.2 M NaOH in 2-MeTHF/MeOH 47 or An/EtOH, 43 5% 4-(Me)piperidine in NBP/EtOAc 45 or EtOAc/DMSO, 46 20% 4-(Me)piperidine in ACN, 50 2.5% 4-(Me)piperidine in DMF, 51 30% tetrabutylamine (TBA) in DMF 52 or NOP, 53 20% pyrrolidine in EtOAc/DMSO, 54 5% 3-diethylaminopropylamine (DEAPA) in NOP or NOP/DMC, 46 and 5% DBU in An 43 have been recently used for this purpose.…”