References of "Toupy, Thomas"
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See detailAccelerated Microfluidic Native Chemical Ligation at Difficult Amino Acids Towards Cyclic Peptides
Toupy, Thomas ULiege; Ollivier, Nathalie; Melnyk, Oleg et al

Poster (2019, February 26)

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Three types of peptides, namely POL (10 residues), RTD-1 (18 residues ... [more ▼]

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Three types of peptides, namely POL (10 residues), RTD-1 (18 residues) and F2-K1 (28 residues) as well as specific difficult junctions were chosen as the main targets of this research. The microfluidic setup for the intramolecular SEA ligation formally telescoped two process steps. In the first microreactor, the reversible N,S-acyl shift reaction leading to a super reactive SEA thioester species (3) proceeded in ~90% conversion for all studied peptide sequences. Extremely fast cyclative ligations (< 5 min) at difficult junctions that are notoriously time-consuming were achieved accordingly in a second, telescoped microfluidic module. Efficient ligations at difficult (valine, threonine or isoleucine) and even intractable junctions (such as proline) were achieved with extremely short ligation times down to 2 min (vs 48 h under conventional conditions). Excellent conversions (60 to 96%) and overall isolated yields were obtained for the cyclization of POL and analogs (64 min total production time) and for RTD-1 and analogs (75 min total) [less ▲]

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See detailExpedient Prepararation of Active Pharmaceutical Ingredient Ketamine under Sustainable Continuous Flow Conditions
Kassin, Victor-Emmanuel ULiege; Gerardy, Romaric ULiege; Toupy, Thomas ULiege et al

Poster (2019, February 26)

According to the World Health Organization, depression has become one of the most challenging health issue. With most current antidepressant medications, weeks, if not months, are typically required for ... [more ▼]

According to the World Health Organization, depression has become one of the most challenging health issue. With most current antidepressant medications, weeks, if not months, are typically required for improving patient conditions. By contrast, ketamine (1a), is effective within the first intake. Recent Phase III clinical studies demonstrated the ability of ketamine to rapidly reduce the most severe symptoms of depression. However, current synthetic routes for the preparation of 1a require the use of toxic reagents, FDA class 1-2 solvents and are low atom economy processes. In this work, we describe an effective continuous flow procedure for the expedient and sustainable preparation of 1a and analogs. This procedure involves commercially available low-toxicity chemicals and a FDA class 3 solvent (ethanol). The continuous flow procedure (Figure 1) features 3 steps, including a unique hydroxylation step with molecular oxygen, an iminiation relying on triisopropyl borate and a thermal rearrangement catalyzed by Montmorillonite K10. Each continuousflow step can be performed individually or can be concatenated, thus providing a compact yet robust process for the manufacture of ketamine and analogs (1a-c). The scalability of the critical hydroxylation step was assessed in a commercial pilot continuous-flow reactor. [less ▲]

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See detailExpedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions
Kassin, Victor-Emmanuel ULiege; Gerardy, Romaric ULiege; Toupy, Thomas ULiege et al

in Green Chemistry (2019)

A robust three-step continuous flow procedure is presented for the efficient and sustainable preparation of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous ... [more ▼]

A robust three-step continuous flow procedure is presented for the efficient and sustainable preparation of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous flow processing, starts from commercially available chemicals, utilizes low toxicity reagents and a FDA class 3 solvent under intensified conditions. The procedure features a unique hydroxylation step with molecular oxygen, a fast imination relying on triisopropyl borate and a thermolysis employing Montmorillonite K10 as a heterogeneous catalyst, all three steps being performed in ethanol. The three individual steps can be run independently or can be concatenated, thus providing a compact yet efficient setup for the production of ketamine. The scalability of the critical hydroxylation step was assessed in a commercial pilot continuous flow reactor. The process can also be adapted for the preparation of ketamine analogs. A thorough computational study on the backbone rearrangement of the cyclopentylphenylketone scaffold under thermal stress rationalizes the experimental selectivity and the various experimental observations reported herein. [less ▲]

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See detailAccelerated Microfluidic Native Chemical Ligation at Difficult Amino Acids Toward Cyclic Peptides
Toupy, Thomas ULiege; Ollivier, Nathalie; Melnyk, Oleg et al

Conference (2018, December 07)

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Three types of peptides, namely POL (10 residues), RTD-1 (18 residues ... [more ▼]

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Three types of peptides, namely POL (10 residues), RTD-1 (18 residues) and F2-K1 (28 residues) as well as specific difficult junctions were chosen as the main targets of this research. The microfluidic setup for the intramolecular SEA ligation formally telescoped two process steps. In the first microreactor, the reversible N,S-acyl shift reaction leading to a super reactive SEA thioester species (3) proceeded in ~90% conversion for all studied peptide sequences. Extremely fast cyclative ligations (< 5 min) at difficult junctions that are notoriously time-consuming were achieved accordingly in a second, telescoped microfluidic module. Efficient ligations at difficult (valine, threonine or isoleucine) and even intractable junctions (such as proline) were achieved with extremely short ligation times down to 2 min (vs 48 h under conventional conditions). Excellent conversions (60 to 96%) and overall isolated yields were obtained for the cyclization of POL and analogs (64 min total production time) and for RTD-1 and analogs (75 min total production time) [less ▲]

Detailed reference viewed: 18 (2 ULiège)
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See detailAccelerated Microfluidic Native Chemical Ligation at Difficult Amino Acids Towards Cyclic Peptides
Toupy, Thomas ULiege; Ollivier, Nathalie; Melnyk, Oleg et al

Poster (2018, December 06)

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Three types of peptides, namely POL (10 residues), RTD-1 (18 residues ... [more ▼]

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Three types of peptides, namely POL (10 residues), RTD-1 (18 residues) and F2-K1 (28 residues) as well as specific difficult junctions were chosen as the main targets of this research. The microfluidic setup for the intramolecular SEA ligation formally telescoped two process steps. In the first microreactor, the reversible N,S-acyl shift reaction leading to a super reactive SEA thioester species (3) proceeded in ~90% conversion for all studied peptide sequences. Extremely fast cyclative ligations (< 5 min) at difficult junctions that are notoriously time-consuming were achieved accordingly in a second, telescoped microfluidic module. Efficient ligations at difficult (valine, threonine or isoleucine) and even intractable junctions (such as proline) were achieved with extremely short ligation times down to 2 min (vs 48 h under conventional conditions). Excellent conversions (60 to 96%) and overall isolated yields were obtained for the cyclization of POL and analogs (64 min total production time) and for RTD-1 and analogs (75 min total production time) [less ▲]

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See detailAccelerated microfluidic native chemical ligation at difficult amino acids toward cyclic peptides
Ollivier, Nathalie; Toupy, Thomas ULiege; Hartkoorn, Ruben et al

in Nature Communications (2018), 9

Cyclic peptide-based therapeutics have a promising growth forecast that justifies the development of microfluidic systems dedicated to their production, in phase with the actual transitioning toward ... [more ▼]

Cyclic peptide-based therapeutics have a promising growth forecast that justifies the development of microfluidic systems dedicated to their production, in phase with the actual transitioning toward continuous flow and microfluidic technologies for pharmaceutical production. The application of the most popular method for peptide cyclization in water, i.e., native chemical ligation, under microfluidic conditions is still unexplored. Herein, we report a general strategy for fast and efficient peptide cyclization using native chemical ligation under homogeneous microfluidic conditions. The strategy relies on a multistep sequence that concatenates the formation of highly reactive S-(2-((2-sulfanylethyl)amino)ethyl) peptidyl thioesters from stable peptide amide precursors with an intramolecular ligation step. With very fast ligation rates (<5 min), even for the most difficult junctions (including threonine, valine, isoleucine, or proline), this technology opens the door toward the scale-independent, expedient preparation of bioactive macrocyclic peptides. [less ▲]

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See detailContinuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges
Gerardy, Romaric ULiege; Emmanuel, Noémie ULiege; Toupy, Thomas ULiege et al

in European Journal of Organic Chemistry (2018)

This review intends to provide the reader with a clear and concise overview of how preparative continuous flow organic chemistry could potentially impact on current important societal challenges. These ... [more ▼]

This review intends to provide the reader with a clear and concise overview of how preparative continuous flow organic chemistry could potentially impact on current important societal challenges. These societal challenges include health/well-being and sustainable development. Continuous flow chemistry has enabled significant advances for the manufacturing of pharmaceuticals, as well as for biomass valorization toward a biosourced chemical industry. Examples related to pharmaceutical production are herein focused on (a) the implementation of flow chemistry to reduce the occurrence of drug shortages, (b) continuous flow manufacturing of orphan drugs, (c) continuous flow preparation of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufacturing of peptide-based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform molecules. Besides positive impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technology within the actual context of terrorism and drug abuse. [less ▲]

Detailed reference viewed: 91 (39 ULiège)
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See detailSEA Ligation Assisted Preparation of Cyclic Peptides Under microfluidic Conditions
Toupy, Thomas ULiege; Ollivier, Nathalie; Melnyk, Oleg et al

Poster (2017, December 08)

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Two type of pep- tides, namely POL (10 residues) and RTD-1 (18 residues ... [more ▼]

The intramolecular SEA ligation for the preparation of cyclic peptides of various sizes was studied under microfluidic conditions. Two type of pep- tides, namely POL (10 residues) and RTD-1 (18 residues) as well as difficult junctions (e.g. valine, isoleucine, and threonine) were chosen as the main targets of this research. The microfluidic setup for the intramolecular SEA ligation formally telescoped two process steps. In the first microreactor, the reversible N,S-acyl shift reaction lead to the reactive SEA thioester species in ~90% conversion for all studied peptides. The telescoping of the first step and the use of the reactive SEA thioester species in the capture step of the N- terminal cysteine mediated by an exogenous arylthiol catalyst produced a cyclic thioester intermediate which upon irreversible S,N-acyl shift gave the final cyclic product. This fully telescoped process of 64 (POL and analogs) to 75 min (RTD-1 and analogs) total residence time gave the associated de- sired cyclic product with conversions ranging from 60 to 96% depending on the peptide sequence and the ligation site. [less ▲]

Detailed reference viewed: 17 (5 ULiège)