The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride

Abstract

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.

Keywords: chiral separation; crystal structure; levobupivacaine hydrochloride; local anesthetic; process improvement; synthesis.

Scheme 1

The synthesis of levobupivacaine (6) via route 1.

Scheme 2

The synthesis of levobupivacaine (6) via route 2.

Scheme 3

The synthesis of levobupivacaine hydrochloride (21) via route 3.

Scheme 4

The synthesis of levobupivacaine (6) via route 4.

Scheme 5

The synthesis of levobupivacaine (6) via route 5.

Scheme 6

The new synthetic route of levobupivacaine hydrochloride (21) (overall yield 45%).

Figure 1

(a) Reaction calorimetry of the new reaction; (b) reaction calorimetry of the original reaction; (c) ARC of the new reaction; (d) ARC of the original reaction.

Figure 2

Crystal structure of levobupivacaine hydrochloride (21).

Figure 3

(a) DSC of levobupivacaine hydrochloride (21); (b) TGA of levobupivacaine hydrochloride (21); (c) XRPD of levobupivacaine hydrochloride (21).