In recent years, there has been a growing interest in therapeutic peptides within the pharmaceutical industry with more than 50 peptide drugs on the market, approximately 170 in clinical trials, and ...>200 in preclinical development. However, the current state of the art in peptide synthesis involves primarily legacy technologies with use of large amounts of highly hazardous reagents and solvents and little focus on green chemistry and engineering. In 2016, the ACS Green Chemistry Institute Pharmaceutical Roundtable identified development of greener processes for peptide API as a critical unmet need, and as a result, a new Roundtable team formed to address this important area. The initial focus of this new team is to highlight best practices in peptide synthesis and encourage much needed innovations. In this Perspective, we aim to summarize the current challenges of peptide synthesis and purification in terms of sustainability, highlight possible solutions, and encourage synergies between academia, the pharmaceutical industry, and contract research organizations/contract manufacturing organizations.
With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ...ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation. In 2016, the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) identified the development of greener processes for oligonucleotide Active Pharmaceutical Ingredients (APIs) as a critical unmet need. As a result, the Roundtable formed a focus team with the remit of identifying green chemistry and engineering improvements that would make oligonucleotide production more sustainable. In this Perspective, we summarize the present challenges in oligonucleotide synthesis, purification, and isolation; highlight potential solutions; and encourage synergies between academia; contract research, development and manufacturing organizations; and the pharmaceutical industry. A critical part of our assessment includes Process Mass Intensity (PMI) data from multiple companies to provide preliminary baseline metrics for current oligonucleotide manufacturing processes.
The medicinal chemistry subgroup of the American Chemical Society’s Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally ...sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.
Abstract The peptide coupling reaction is one of the most critical steps in the solid phase synthesis of therapeutic peptides/proteins. Improper reaction conditions can result in several common ...impurities such as single amino acid deletions, additions, N‐terminus modifications, and D‐isomers, all while potentially impacting the active pharmaceutical ingredient critical quality attributes. In this work, we developed a first‐principle mechanistic reaction kinetics model for the solid‐phase peptide/protein coupling reaction based on well‐established reaction mechanisms and experimental data from literature. Utilizing the reaction kinetics model, we present a systematic, quality by design approach for the coupling reaction control strategy. Critical process parameters are identified via univariate analysis and the design space is designated via multivariate risk assessment. The presented approach provides a novel solution for designing solid‐phase peptide/protein synthesis control strategies and identifying normal operating ranges for each process parameter, as well as the associated design space.
Peptides are steadily gaining importance as pharmaceutical targets, and efficient, green methods for their preparation are critically needed. A key deficiency in the synthetic toolbox is the lack of ...an industrially viable peptide desulfurization method. Without this tool, the powerful native chemical ligation reaction typically used to assemble polypeptides and proteins remains out of reach for industrial preparation of drug targets. Current desulfurization methods require very large excesses of phosphine reagents and thiol additives or low-abundance metal catalysts. Here, we report a phosphine-only photodesulfurization (POP) using near-UV light that is clean, high-yielding, and requires as little as 1.2 equiv phosphine. The user-friendly reaction gives complete control to the chemist, allowing solvent and reagent selection based on starting material and phosphine solubility. It can be conducted in a range of solvents, including water or buffers, on protected or unprotected peptides, in low or high dilution and on gram scale. Oxidation-prone amino acids, π-bonds, aromatic rings, thio-aminal linkages, thioesters, and glycans are all stable to the POP reaction. We highlight the utility of this approach for desulfurization of industrially relevant targets including cyclic peptides and glucagon-like peptide 1 (GLP-1(7-36)). The method is also compatible with NCL buffer, and we highlight the robustness of the approach through the one-pot disulfide reduction/multidesulfurization of linaclotide, aprotinin, and wheat protein.
Phosphines and phosphites are critical tools for non-metal desulfurative methodologies due to the strength of the P=S bond. An overarching premise in these methods has been that stoichiometric (or ...excess) P(iii) reagent is required for reactivity. Despite decades of research, a desulfurative process that is catalytic in phosphine/phosphite has not been reported. Here, we report the successful merging of two thermal radical processes: the desulfurization of unactivated and activated alkyl thiols and the reduction of P(v) = S to P(iii) by reaction with a silyl radical species. We employ catalytic trimethyl phosphite, catalytic azo-bis(cyclohexyl)nitrile, and two equivalents of tris(trimethylsilyl)silane as the stoichiometric reductant and sulfur atom scavenger. This method is tolerant of common organic functional groups and affords products in good to excellent yields.
The large and steadily growing demand for medicines combined with their inherent resource-intensive manufacturing necessitates a relentless push for their sustainable production. Pharmaceutical ...companies are constantly seeking to perform reliable life cycle assessments of their medicinal products and assess the true value of their sustainable development achievements; however, they find themselves impeded by the lack of a universal metric system that allows for objective quantification of the underlying core denominators. Guided by the unambivalent purpose of the United Nations Sustainable Development Goal 12, which aims at substantially reducing production waste by 2030, and driven by a vision to catalyze greener active pharmaceutical ingredient (API) manufacturing around the globe, the authors set out to overcome current obstacles by defining an improved model for the metric named innovation green aspiration level, iGAL 2.0. We propose yield and convergence as new key sustainability indicators and include a new formula for convergence with potential applicability in computer assisted synthesis planning (CASP) algorithms. The improved statistical model of iGAL 2.0 represents a valuable extension to the common API process waste metrics, process mass intensity (PMI) and complete E factor (cEF), by putting those measures into perspective: iGAL 2.0 enables determination of relative process greenness (RPG) to identify potentially underperforming and environmentally concerning processes early and thereby deliver environmental value. At the same time, iGAL 2.0 generates economic value since reduced waste correlates to lower API production costs. The metric is complemented by its scorecard companion to highlight the impact of innovation on reductions of API manufacturing waste, enabling scientists to readily communicate the value of their work to their peers, managers, and the general public. We believe that iGAL 2.0 can readily be adopted by pharmaceutical firms around the globe and thereby empower and inspire their scientists to make meaningful and significant contributions to global sustainability.
Phosphines and phosphites are critical tools for non-metal desulfurative methodologies due to the strength of the P&z.dbd;S bond. An overarching premise in these methods has been that stoichiometric ...(or excess) P(
iii
) reagent is required for reactivity. Despite decades of research, a desulfurative process that is catalytic in phosphine/phosphite has not been reported. Here, we report the successful merging of two thermal radical processes: the desulfurization of unactivated and activated alkyl thiols and the reduction of P(
v
) = S to P(
iii
) by reaction with a silyl radical species. We employ catalytic trimethyl phosphite, catalytic azo-bis(cyclohexyl)nitrile, and two equivalents of tris(trimethylsilyl)silane as the stoichiometric reductant and sulfur atom scavenger. This method is tolerant of common organic functional groups and affords products in good to excellent yields.
Catalytic phosphite radical desulfurization: trimethyl phosphite serves as a sulfur trapping agent in thermal radical desulfurization, using TTMSS as the terminal reductant. The conversion of P(
v
) = S to P(
iii
) proceeds through a tetravalent phosphoryl radical intermediate.
We establish herein conditions for the cyclization of unprotected N-acyl urea-linked peptides to form macrocyclic peptides mediated by N-terminal cysteine. We report a detailed investigation of the ...parameters of the reaction, including variation of the reaction conditions, the C-terminal residue, and the macrocycle size. C-Terminal epimerization was not observed. The synthesis of macrocyclic targets ranging from tetrapeptides to the disulfide-linked 14-mer, sunflower trypsin inhibitor 1 are demonstrated. For most substrates, hydrolysis and head-to-tail dimer formation are avoided.
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