Thiazolidines have been described as a valuable scaffold for the synthesis of pharmacologically active molecules, [1, 2], as a tool in peptide synthesis for b-turn induction, [3] as well as an easily convertible intermediates in the synthesis of more complex molecules [4]. This is why a large number of thiazolidines derivatives is present in the catalogues of the major world chemical suppliers. The synthesis of thiazolidines is based on the reaction of 2-aminoethanethiols and their esters with aldehydes under heating conditions. Despite high yields and easy work up procedures, long reaction time are necessary especially when sterically hindered aldehydes are used. Instability of certain aldehydes further limits batchwise approach to thiazolidines. Therefore, we decided to investigatewhether continuous-flow synthesis could be used in this context in order to shorten reaction times and increase reaction yields. Thus the experimental set up showed in scheme 1 was designed. The Weinreb amide was reduced by lithium aluminium hydride. In-line quenching and separation of the resulting aluminium salts resulted in high putity aldehydes. The aldehydes was then mixed with an equimolar solution of cysteine ethyl ester to gain the final thiazolidine. A DoE-assisted optimization of the experimental setup allowed the selection of the most suitable parameters for synthesizing thiazolidines in excellent yields (80-100%) and purities (>95%). Optimized continuous flow setup allows high-throughput synthesis (6 compounds/hour) and is scalable to gram-scale

Continuous-flow synthesis of thiazolidine libraries: one-pot two steps protocol optimization

OSTACOLO, CARMINE;Alessia Bertamino;MUSELLA, SIMONA;NOVELLINO, ETTORE;
2015-01-01

Abstract

Thiazolidines have been described as a valuable scaffold for the synthesis of pharmacologically active molecules, [1, 2], as a tool in peptide synthesis for b-turn induction, [3] as well as an easily convertible intermediates in the synthesis of more complex molecules [4]. This is why a large number of thiazolidines derivatives is present in the catalogues of the major world chemical suppliers. The synthesis of thiazolidines is based on the reaction of 2-aminoethanethiols and their esters with aldehydes under heating conditions. Despite high yields and easy work up procedures, long reaction time are necessary especially when sterically hindered aldehydes are used. Instability of certain aldehydes further limits batchwise approach to thiazolidines. Therefore, we decided to investigatewhether continuous-flow synthesis could be used in this context in order to shorten reaction times and increase reaction yields. Thus the experimental set up showed in scheme 1 was designed. The Weinreb amide was reduced by lithium aluminium hydride. In-line quenching and separation of the resulting aluminium salts resulted in high putity aldehydes. The aldehydes was then mixed with an equimolar solution of cysteine ethyl ester to gain the final thiazolidine. A DoE-assisted optimization of the experimental setup allowed the selection of the most suitable parameters for synthesizing thiazolidines in excellent yields (80-100%) and purities (>95%). Optimized continuous flow setup allows high-throughput synthesis (6 compounds/hour) and is scalable to gram-scale
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4812107
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