From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected Meropenem
Meropenem is currently the most common carbapenem in clinical applications. Industrially, the final synthetic step is characterized by a heterogeneous catalytic hydrogenation in batch mode with hydrogen and Pd/C. The required high-quality standard is very difficult to meet and specific conditions ar...
| Asıl Yazarlar: | , , , , , |
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| Materyal Türü: | Makale |
| Dil: | English |
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MDPI AG
2023-04-01
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| Seri Bilgileri: | Pharmaceutics |
| Konular: | |
| Online Erişim: | https://www.mdpi.com/1999-4923/15/5/1322 |
| _version_ | 1827740374148317184 |
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| author | Marziale Comito Riccardo Monguzzi Silvia Tagliapietra Angelo Maspero Giovanni Palmisano Giancarlo Cravotto |
| author_facet | Marziale Comito Riccardo Monguzzi Silvia Tagliapietra Angelo Maspero Giovanni Palmisano Giancarlo Cravotto |
| author_sort | Marziale Comito |
| collection | DOAJ |
| description | Meropenem is currently the most common carbapenem in clinical applications. Industrially, the final synthetic step is characterized by a heterogeneous catalytic hydrogenation in batch mode with hydrogen and Pd/C. The required high-quality standard is very difficult to meet and specific conditions are required to remove both protecting groups [i.e., <i>p</i>-nitrobenzyl (pNB) and <i>p</i>-nitrobenzyloxycarbonyl (pNZ)] simultaneously. The three-phase gas–liquid–solid system makes this step difficult and unsafe. The introduction of new technologies for small-molecule synthesis in recent years has opened up new landscapes in process chemistry. In this context, we have investigated meropenem hydrogenolysis using microwave (MW)-assisted flow chemistry for use as a new technology with industrial prospects. The reaction parameters (catalyst amount, T, P, residence time, flow rate) in the move from the batch process to semi-continuous flow were investigated under mild conditions to determine their influence on the reaction rate. The optimization of the residence time (840 s) and the number of cycles (4) allowed us to develop a novel protocol that halves the reaction time compared to batch production (14 min vs. 30 min) while maintaining the same product quality. The increase in productivity using this semi-continuous flow technique compensates for the slightly lower yield (70% vs. 74%) obtained in batch mode. |
| first_indexed | 2024-03-11T03:24:02Z |
| format | Article |
| id | doaj.art-0db9febc863d4877bbc35f3d8abd08f8 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T03:24:02Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-0db9febc863d4877bbc35f3d8abd08f82023-11-18T02:49:53ZengMDPI AGPharmaceutics1999-49232023-04-01155132210.3390/pharmaceutics15051322From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected MeropenemMarziale Comito0Riccardo Monguzzi1Silvia Tagliapietra2Angelo Maspero3Giovanni Palmisano4Giancarlo Cravotto5Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125 Turin, ItalyResearch and Development, ACS Dobfar SpA, Via Paullo 9, 20067 Tribiano, ItalyDipartimento di Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125 Turin, ItalyDipartimento di Scienza e Alta Tecnologia, University of Insubria, Via Valleggio 9, 22100 Como, ItalyDipartimento di Scienza e Alta Tecnologia, University of Insubria, Via Valleggio 9, 22100 Como, ItalyDipartimento di Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125 Turin, ItalyMeropenem is currently the most common carbapenem in clinical applications. Industrially, the final synthetic step is characterized by a heterogeneous catalytic hydrogenation in batch mode with hydrogen and Pd/C. The required high-quality standard is very difficult to meet and specific conditions are required to remove both protecting groups [i.e., <i>p</i>-nitrobenzyl (pNB) and <i>p</i>-nitrobenzyloxycarbonyl (pNZ)] simultaneously. The three-phase gas–liquid–solid system makes this step difficult and unsafe. The introduction of new technologies for small-molecule synthesis in recent years has opened up new landscapes in process chemistry. In this context, we have investigated meropenem hydrogenolysis using microwave (MW)-assisted flow chemistry for use as a new technology with industrial prospects. The reaction parameters (catalyst amount, T, P, residence time, flow rate) in the move from the batch process to semi-continuous flow were investigated under mild conditions to determine their influence on the reaction rate. The optimization of the residence time (840 s) and the number of cycles (4) allowed us to develop a novel protocol that halves the reaction time compared to batch production (14 min vs. 30 min) while maintaining the same product quality. The increase in productivity using this semi-continuous flow technique compensates for the slightly lower yield (70% vs. 74%) obtained in batch mode.https://www.mdpi.com/1999-4923/15/5/1322flow chemistrymicrowave-assistedsemi-continuous synthesismeropenemhydrogenationdrug synthesis |
| spellingShingle | Marziale Comito Riccardo Monguzzi Silvia Tagliapietra Angelo Maspero Giovanni Palmisano Giancarlo Cravotto From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected Meropenem Pharmaceutics flow chemistry microwave-assisted semi-continuous synthesis meropenem hydrogenation drug synthesis |
| title | From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected Meropenem |
| title_full | From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected Meropenem |
| title_fullStr | From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected Meropenem |
| title_full_unstemmed | From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected Meropenem |
| title_short | From Batch to the Semi-Continuous Flow Hydrogenation of <i>p</i>NB, <i>p</i>NZ-Protected Meropenem |
| title_sort | from batch to the semi continuous flow hydrogenation of i p i nb i p i nz protected meropenem |
| topic | flow chemistry microwave-assisted semi-continuous synthesis meropenem hydrogenation drug synthesis |
| url | https://www.mdpi.com/1999-4923/15/5/1322 |
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