Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam
In an effort to strengthen the resiliency of supply chains for active pharmaceutical ingredients (API), continuous manufacturing processes may be optimized with respect to improved chemoselectivity, production rate, yield, and/or process intensity. We report an efficient two-step continuous flow syn...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Chemical Engineering |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fceng.2022.877498/full |
| _version_ | 1811334475857002496 |
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| author | Robert J. Nicholas Michael A. McGuire Seok-Hee Hyun Madeline N. Cullison David H. Thompson |
| author_facet | Robert J. Nicholas Michael A. McGuire Seok-Hee Hyun Madeline N. Cullison David H. Thompson |
| author_sort | Robert J. Nicholas |
| collection | DOAJ |
| description | In an effort to strengthen the resiliency of supply chains for active pharmaceutical ingredients (API), continuous manufacturing processes may be optimized with respect to improved chemoselectivity, production rate, yield, and/or process intensity. We report an efficient two-step continuous flow synthesis of diazepam, an agent on the World Health Organization’s (WHO) list of essential medicines. Different conditions were rapidly screened in microfluidic chip reactors by varying residence times, temperatures, solvents, and ammonia sources to identify the best telescoped reaction conditions. We report a telescoped flow synthesis that uses two microreactors in series set to 0°C and 60°C, respectively, to produce a 96% yield of 91% pure diazepam within 15 min using an NH4Br/NH4OH solution in the second step. Diazepam of >98% purity was obtained after a single recrystallization. |
| first_indexed | 2024-04-13T17:08:29Z |
| format | Article |
| id | doaj.art-dfd3fdb93a664897b31d9fddfe983f0d |
| institution | Directory Open Access Journal |
| issn | 2673-2718 |
| language | English |
| last_indexed | 2024-04-13T17:08:29Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemical Engineering |
| spelling | doaj.art-dfd3fdb93a664897b31d9fddfe983f0d2022-12-22T02:38:23ZengFrontiers Media S.A.Frontiers in Chemical Engineering2673-27182022-06-01410.3389/fceng.2022.877498877498Development of an Efficient, High Purity Continuous Flow Synthesis of DiazepamRobert J. Nicholas0Michael A. McGuire1Seok-Hee Hyun2Madeline N. Cullison3David H. Thompson4Department of Chemistry, Purdue University, West Lafayette, IN, United StatesContinuity Pharma LLC, West Lafayette, IN, United StatesContinuity Pharma LLC, West Lafayette, IN, United StatesDepartment of Chemistry, Purdue University, West Lafayette, IN, United StatesDepartment of Chemistry, Purdue University, West Lafayette, IN, United StatesIn an effort to strengthen the resiliency of supply chains for active pharmaceutical ingredients (API), continuous manufacturing processes may be optimized with respect to improved chemoselectivity, production rate, yield, and/or process intensity. We report an efficient two-step continuous flow synthesis of diazepam, an agent on the World Health Organization’s (WHO) list of essential medicines. Different conditions were rapidly screened in microfluidic chip reactors by varying residence times, temperatures, solvents, and ammonia sources to identify the best telescoped reaction conditions. We report a telescoped flow synthesis that uses two microreactors in series set to 0°C and 60°C, respectively, to produce a 96% yield of 91% pure diazepam within 15 min using an NH4Br/NH4OH solution in the second step. Diazepam of >98% purity was obtained after a single recrystallization.https://www.frontiersin.org/articles/10.3389/fceng.2022.877498/fulldiazepambenzodiazepinecontinuous synthesesreaction scale-upcommon ion effectprocess optimization |
| spellingShingle | Robert J. Nicholas Michael A. McGuire Seok-Hee Hyun Madeline N. Cullison David H. Thompson Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam Frontiers in Chemical Engineering diazepam benzodiazepine continuous syntheses reaction scale-up common ion effect process optimization |
| title | Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam |
| title_full | Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam |
| title_fullStr | Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam |
| title_full_unstemmed | Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam |
| title_short | Development of an Efficient, High Purity Continuous Flow Synthesis of Diazepam |
| title_sort | development of an efficient high purity continuous flow synthesis of diazepam |
| topic | diazepam benzodiazepine continuous syntheses reaction scale-up common ion effect process optimization |
| url | https://www.frontiersin.org/articles/10.3389/fceng.2022.877498/full |
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