Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP) DOI
Jan Pawlas,

Tharwat Mohy El‐Dine,

Katharina von Bargen

и другие.

Organic Process Research & Development, Год журнала: 2024, Номер 28(8), С. 3347 - 3367

Опубликована: Июль 25, 2024

While numerous studies aimed at producing peptides in a sustainable manner have recently been reported, the impact of quality starting materials on sustainability peptide synthesis has less investigated. Here we report that NBP, greener dipolar aprotic solvent suitable for use SPPS, readily undergoes air oxidation to corresponding hydroperoxide (NBP-OOH), which adversely affects oxidation-sensitive amino acids and peptides. Air, light, elevated temperatures, common reagents such as DIC accelerated rate NBP oxidation. LC-HRMS analyses revealed air-induced degradation proceeds via different mechanism than previously elucidated closely related NMP while GC–MS containing NBP-OOH showed standard GC-based analytical methods are unsuitable detection, warranting implementation improved analyses. Assessment NBP-OOH-induced Met, Trp, Cys, Tyr breakdown not only degrades all these oxidation-prone substrates, but it was also discovered DITU, reported suppress N-oxyl radical-induced breakdown, constitutes an efficient suppressant hydroperoxide-induced degradation. Studies aerial additional solvents DMSO DMPU former is stable does cause oxidation, latter oxidized extensively upon exposure substrates significant extent. On other hand, bubbling DMSO, proved unexpected positive effect stability α-amino-bound Fmoc group, finding may be leveraged minimize premature loss during synthesis. Overall, our understanding mitigating formation illustrate importance thorough assessment development synthetic methods.

Язык: Английский

N,N‐Dimethyl Formamide European Restriction Demands Solvent Substitution in Research and Development DOI Creative Commons
James Sherwood, Fernando Alberício, Beatriz G. de la Torre

и другие.

ChemSusChem, Год журнала: 2024, Номер 17(8)

Опубликована: Янв. 10, 2024

Abstract As of December 2023, the use common solvent N , ‐dimethyl formamide (DMF) will be restricted in European Union because its reproductive health hazard. Industrial facilities must comply with stricter exposure limits, and researchers are recommended to find alternative solvents. Here we explain restrictions on DMF, which disciplines affected, how substitute DMF keep research development commercially relevant.

Язык: Английский

Процитировано

25
Optimization of peptide synthesis time and sustainability using novel eco‐friendly binary solvent systems with induction heating on an automated peptide synthesizer DOI Creative Commons
Lorenzo Pacini, Manoj Kumar Muthyala, Luísa Aguiar

и другие.

Journal of Peptide Science, Год журнала: 2024, Номер 30(9)

Опубликована: Апрель 25, 2024

On December 12th, 2023, the European Commission took regulatory action to amend Annex XVII of REACH, imposing restrictions on use N , ‐dimethylformamide (DMF) within EU market owing its high toxicity. Historically, DMF has been widely considered gold standard for solid‐phase peptide synthesis (SPPS). Being urgent propose alternative solvents, we tested suitability non‐hazardous neat and mixed solvents. Notably, binary solvent mixtures containing dimethyl sulfoxide as one partners demonstrated efficacy in solubilizing reagents while maintaining desired swelling characteristics common resins. A series were automated SPPS, both at room temperature temperature, employing PurePep® Chorus synthesizer, which enabled controlled induction heating between 25 90°C with oscillation mixing. The performances assessed challenging sequences, i.e., ACP (65–74), longer aggregating sequences like SARS‐CoV‐2 RBM (436–507) β‐amyloid (1–42). Furthermore, part proposed sustainable approach minimize utilization hazardous coupled novel PurePep EasyClean catch‐and‐release purification technology. This work, addressing compliance, emphasizes crucial role green chemistry advancing safer more environmentally friendly practices SPPS.

Язык: Английский

Процитировано

9
Scalable and sustainable DMF-free solid-phase synthesis of liraglutideby 1-tert-butyl-3-ethylcarbodiimide-mediated couplings and catch-and-release acylation and purification strategies DOI Creative Commons
Lorenzo Pacini, Manoj Kumar Muthyala, Robert Zitterbart

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Abstract The growing need for sustainable practices in pharmaceutical manufacturing has stimulated advancements peptide synthesis. This study focuses on applying green chemistry principles to the synthesis of Glucagon-Like Peptide-1 analog liraglutide, using novel and solid-phase synthetic strategies. By adopting safer coupling reagent 1-tert-butyl-3-ethylcarbodiimide (T-Bec®) combination with eco-friendly binary solvents like dimethyl sulfoxide butyl acetate, we demonstrated that it is possible significantly reduce environmental impact while maintaining high efficiency quality T-Bec® minimizes hazardous byproducts, such as hydrogen cyanide, enhances solvent compatibility, achieving crude purities yields comparable conventional syntheses. Two strategies were developed liraglutide production. first strategy based a “direct synthesis”, incorporating lipidated lysine building block into sequence, 86% HPLC purity after catch-and-release purification. second “catch-lipidation-and-release” approach, allowed obtain precursor without lipid moiety, which was later linked during controlled lipidation step. latter yielded exceeding 90% reduced reliance preparative HPLC. These findings highlight effectiveness systems optimize scalable SPPS processes. methods improve resource impact, allow viable pathway produce therapeutic ingredients liraglutide. work underscores potential align innovation responsibility.

Язык: Английский

Процитировано

0
Scalable and Sustainable DMF-Free Solid-Phase Synthesis of Liraglutide by 1-Tert-Butyl-3-Ethylcarbodiimide-Mediated Couplings and Catch-and-Release Acylation and Purification Strategies DOI Creative Commons
Lorenzo Pacini, Manoj Kumar Muthyala, Robert Zitterbart

и другие.

International Journal of Peptide Research and Therapeutics, Год журнала: 2025, Номер 31(3)

Опубликована: Фев. 22, 2025

Язык: Английский

Процитировано

0
Expanding the Reach of Sustainable Solid-Phase Peptide Synthesis: One-Pot, Metal-Free Alloc Removal–Peptide Coupling DOI
Jan Pawlas,

A. Lindgren

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

While the allyloxycarbonyl (Alloc) protecting group has played a key role in solid-phase peptide synthesis (SPPS), providing access to wide range of peptides, its removal suffered from relying on air-sensitive Pd(0) complexes hazardous solvents. We report metal-free, on-resin Alloc using readily available iodine/water environmentally sensible PolarClean (PC)/ethyl acetate (EtOAc) carried out one-pot manner with racemization-free couplings employing both 9-fluorenylmethoxycarbonyl (Fmoc) and amino acids (AAs). SPPS been demonstrated by performing consecutive removals–peptide couplings, whereas compatibility long peptides proven carrying an removal–coupling 39 AA resin. Upscaling 10 g was combined TFA-free resin cleavage, opening up opportunities for Alloc-AAs as synthons sustainable manufacturing.

Язык: Английский

Процитировано

0
Sustainable Approaches in Solid-phase Peptide Synthesis (SPPS) DOI
Jan Pawlas,

Jon H. Rasmussen

Royal Society of Chemistry eBooks, Год журнала: 2024, Номер unknown, С. 50 - 84

Опубликована: Окт. 18, 2024

Solid-phase peptide synthesis (SPPS) is a ubiquitous methodology for making peptides from R&D to manufacturing plant, not least in the context of using and peptidometics as pharmaceuticals. Nevertheless, SPPS has long been plagued by its reliance on large amounts hazardous materials such dimethylformamide solvent trifluoroacetic acid cleavage reagent. Consequently, with methods producing sustainable manner being high demand, numerous reports covering various aspects greening have appeared recent years. In this chapter, an integrated overview state-of-the-art field presented, highlighting advances within entire workflow starting amino coupling cycle cleaving off polymer support. Greener assembly complex waste minimization tactics are also delineated, together discussion adoption practice, scale-up, procurement, costs intellectual property key considerations attaining truly SPPS. Finally, perspective future directions towards elevating versatile, platform provided.

Язык: Английский

Процитировано

2
Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP) DOI
Jan Pawlas,

Tharwat Mohy El‐Dine,

Katharina von Bargen

и другие.

Organic Process Research & Development, Год журнала: 2024, Номер 28(8), С. 3347 - 3367

Опубликована: Июль 25, 2024

While numerous studies aimed at producing peptides in a sustainable manner have recently been reported, the impact of quality starting materials on sustainability peptide synthesis has less investigated. Here we report that NBP, greener dipolar aprotic solvent suitable for use SPPS, readily undergoes air oxidation to corresponding hydroperoxide (NBP-OOH), which adversely affects oxidation-sensitive amino acids and peptides. Air, light, elevated temperatures, common reagents such as DIC accelerated rate NBP oxidation. LC-HRMS analyses revealed air-induced degradation proceeds via different mechanism than previously elucidated closely related NMP while GC–MS containing NBP-OOH showed standard GC-based analytical methods are unsuitable detection, warranting implementation improved analyses. Assessment NBP-OOH-induced Met, Trp, Cys, Tyr breakdown not only degrades all these oxidation-prone substrates, but it was also discovered DITU, reported suppress N-oxyl radical-induced breakdown, constitutes an efficient suppressant hydroperoxide-induced degradation. Studies aerial additional solvents DMSO DMPU former is stable does cause oxidation, latter oxidized extensively upon exposure substrates significant extent. On other hand, bubbling DMSO, proved unexpected positive effect stability α-amino-bound Fmoc group, finding may be leveraged minimize premature loss during synthesis. Overall, our understanding mitigating formation illustrate importance thorough assessment development synthetic methods.

Язык: Английский

Процитировано

0