In this study, we not only optimized and improved the synthesis process of levobupivacaine hydrochloride (21) 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 (R,S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (28) as the initial material and utilizing l-(–)-dibenzoyl tartaric acid (29) for chiral separation, and then through substitution and a salting reaction, levobupivacaine hydrochloride (21) was obtained with high purity (chemical purity of 99.90% and enantiomeric excess (ee) 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) (1H NMR, 13C 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 (21), 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.

中文翻译：

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盐酸左布比卡因的合成工艺优化及鉴定

在本研究中，我们不仅优化和改进了盐酸左布比卡因（21）的合成工艺，而且对工业规模生产的关键细节进行了全面探索，开发了一种新型的高效液相色谱（HPLC）分析方法。以易于获得且具有成本效益的 (R,S)-N-(2,6-二甲基苯基)哌啶-2-甲酰胺 (28) 作为初始材料，并利用 L-(–)-二苯甲酰酒石酸 (29)进行手性分离，再经取代和成盐反应，得到高纯度的盐酸左布比卡因(21)(化学纯度99.90%，对映体过量(ee)值99.30%)。三步总收率为45%。使用核磁共振（NMR）（1H NMR、13C NMR）、质谱（MS）和元素分析确认中间体和最终产物的结构。通过差示扫描量热法（DSC）、热重分析（TGA）和X射线衍射（XRD）确定最终产物的晶体结构。此外，我们使用反应量热计和加速量热法（ARC）评估了取代反应的风险。该工艺具有操作简单、绿色、安全、质量可控、成本效益高等优点。为盐酸左布比卡因(21)的工业化生产提供了可靠的技术支撑，对满足临床需求具有重要意义。国药国瑞药业有限公司已顺利完成中试生产，生产规模为20公斤。