The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride
In this study, we not only optimized and improved the synthesis process of levobupivacaine hydrochloride (<b>21</b>) but also conducted a comprehensive exploration of critical industrial-scale production details, and a novel high-performance liquid chromatography (HPLC) analysis method w...
| Main Authors: | , , , , , |
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/22/7482 |
| _version_ | 1797458225471160320 |
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| author | Qiuming Yan Houjun Gan Chunzheng Li Gang Gui Jianbo Wang Xiaoming Zha |
| author_facet | Qiuming Yan Houjun Gan Chunzheng Li Gang Gui Jianbo Wang Xiaoming Zha |
| author_sort | Qiuming Yan |
| collection | DOAJ |
| description | In this study, we not only optimized and improved the synthesis process of levobupivacaine hydrochloride (<b>21</b>) but also conducted a comprehensive exploration of critical industrial-scale production details, and a novel high-performance liquid chromatography (HPLC) analysis method was developed. Starting with the readily available and cost-effective (<i>R</i>,<i>S</i>)-<i>N</i>-(2,6-dimethylphenyl)piperidine-2-carboxamide (<b>28</b>) as the initial material and utilizing <span style="font-variant: small-caps;">l</span>-(–)-dibenzoyl tartaric acid (<b>29</b>) for chiral separation, and then through substitution and a salting reaction, levobupivacaine hydrochloride (<b>21</b>) was obtained with high purity (chemical purity of 99.90% and enantiomeric excess (<i>ee</i>) values of 99.30%). The total yield of the three steps was 45%. Structures of intermediates and the final product were confirmed using nuclear magnetic resonance (NMR) (<sup>1</sup>H NMR, <sup>13</sup>C NMR), mass spectrometry (MS), and elemental analysis. The crystal structure of the final product was determined through differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). Furthermore, we evaluated the risk of the substitution reaction using a reaction calorimeter and accelerating rate calorimetry (ARC). This process offers the advantages of simple operation, greenness, safety, controllable quality, and cost-effectiveness. It provides reliable technical support for the industrial-scale production of levobupivacaine hydrochloride (<b>21</b>), which is of significant importance in meeting clinical demands. Pilot-scale production has already been successfully completed by China National Medicines Guorui Pharmaceutical Co., Ltd., with a production scale of 20 kg. |
| first_indexed | 2024-03-09T16:34:02Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T16:34:02Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-28fd2437215a42618e6c1b50a6d1d0082023-11-24T14:57:53ZengMDPI AGMolecules1420-30492023-11-012822748210.3390/molecules28227482The Optimization of the Synthesis Process and the Identification of Levobupivacaine HydrochlorideQiuming Yan0Houjun Gan1Chunzheng Li2Gang Gui3Jianbo Wang4Xiaoming Zha5School of Engineering, China Pharmaceutical University, Nanjing 211198, ChinaChina National Medicines Guorui Pharmaceutical Co., Ltd., Huainan 232008, ChinaSchool of Engineering, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Engineering, China Pharmaceutical University, Nanjing 211198, ChinaChina National Medicines Co., Ltd., Beijing 100077, ChinaSchool of Engineering, China Pharmaceutical University, Nanjing 211198, ChinaIn this study, we not only optimized and improved the synthesis process of levobupivacaine hydrochloride (<b>21</b>) but also conducted a comprehensive exploration of critical industrial-scale production details, and a novel high-performance liquid chromatography (HPLC) analysis method was developed. Starting with the readily available and cost-effective (<i>R</i>,<i>S</i>)-<i>N</i>-(2,6-dimethylphenyl)piperidine-2-carboxamide (<b>28</b>) as the initial material and utilizing <span style="font-variant: small-caps;">l</span>-(–)-dibenzoyl tartaric acid (<b>29</b>) for chiral separation, and then through substitution and a salting reaction, levobupivacaine hydrochloride (<b>21</b>) was obtained with high purity (chemical purity of 99.90% and enantiomeric excess (<i>ee</i>) values of 99.30%). The total yield of the three steps was 45%. Structures of intermediates and the final product were confirmed using nuclear magnetic resonance (NMR) (<sup>1</sup>H NMR, <sup>13</sup>C NMR), mass spectrometry (MS), and elemental analysis. The crystal structure of the final product was determined through differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). Furthermore, we evaluated the risk of the substitution reaction using a reaction calorimeter and accelerating rate calorimetry (ARC). This process offers the advantages of simple operation, greenness, safety, controllable quality, and cost-effectiveness. It provides reliable technical support for the industrial-scale production of levobupivacaine hydrochloride (<b>21</b>), which is of significant importance in meeting clinical demands. Pilot-scale production has already been successfully completed by China National Medicines Guorui Pharmaceutical Co., Ltd., with a production scale of 20 kg.https://www.mdpi.com/1420-3049/28/22/7482levobupivacaine hydrochloridelocal anestheticsynthesischiral separationcrystal structureprocess improvement |
| spellingShingle | Qiuming Yan Houjun Gan Chunzheng Li Gang Gui Jianbo Wang Xiaoming Zha The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride Molecules levobupivacaine hydrochloride local anesthetic synthesis chiral separation crystal structure process improvement |
| title | The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride |
| title_full | The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride |
| title_fullStr | The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride |
| title_full_unstemmed | The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride |
| title_short | The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride |
| title_sort | optimization of the synthesis process and the identification of levobupivacaine hydrochloride |
| topic | levobupivacaine hydrochloride local anesthetic synthesis chiral separation crystal structure process improvement |
| url | https://www.mdpi.com/1420-3049/28/22/7482 |
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