Large‐scale production of peptides using the solid‐phase continuous flow method. Preparative synthesis of the novel tachykinin antagonist MEN 10627

Abstract

The large-scale solid-phase continuous flow synthesis of the bicyclic peptide MEN 10627, a new potent Neurokinin A receptor antagonist, is described using the Fmoc-polyamide method on both macrosorb 125 and Macrosorb 250 resin. A new synthesizer designed in-house was realized by assembling Whitey valves and Waters pump in order to allow small-scale (0.0001 mol; 1 x 10 cm Omnifit columns) synthetic studies which were strongly predictive of the conditions required for large-scale (0.01-0.10 mol; 3.6 or 5.9 x 46 cm Büchi columns) production, performed on the same apparatus.

Scale-Up of the Synthesis of a Pyrimidine Derivative Directly on Solid Support

“…As pointed out by Raillard, the use of reactors employed for scaling up solid-phase peptide synthesis is advantageous. These consist essentially of stirred suction filters with different volumes (if not, continuous flow reactors are employed) . As peptide coupling and deprotection reactions are highly optimised, they usually run at room temperature; therefore, these suction filters do not have heating/cooling jackets.…”

Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production

“…100 The accomplishments, including ultrarapid synthesis of complex proteins 101 and full system automation, 102 have reinvigorated a field of investigation that started the following decade after Merrifield's SPPS concept took root in research laboratories 103,104 and focused on online feedback, reduction of material usage, and automation. 105 Until now, there have been very few reports of scalable SPPS in flow, 106,107 although attempts are being made to rectify this using a continuous band approach, feeding through sequential specifically designed reactor units. 108 The Journal of Organic Chemistry LPPS in flow has also been investigated to enable the swift synthesis of small peptide fragments in a fast, efficient and low waste manner.…”

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

“…The recent rebirth in flow‐based SPPS protocols took advantage from the implementation of packed‐bed flow SPPS and full system automation [93–96] . A limited number of reports, however, is available for scalable continuous‐flow SPPS [97,98] . More efforts have been performed in the context of fast, safer, and more sustainable small peptide motifs, also involving the use of N ‐carboxyanhydrides and derivatives as an efficient alternative for amino acid activation [98,99] .…”

“…[ 93 , 94 , 95 , 96 ] A limited number of reports, however, is available for scalable continuous‐flow SPPS. [ 97 , 98 ] More efforts have been performed in the context of fast, safer, and more sustainable small peptide motifs, also involving the use of N ‐carboxyanhydrides and derivatives as an efficient alternative for amino acid activation. [ 98 , 99 ] This field, nevertheless, clearly still needs substantial optimization efforts in order to provide robust alternative approaches and technologies that could ultimately lead to overall benefits in terms of efficiency and reduction of the environmental impact for peptide synthesis and production.…”