3.2. Synthesis

In a 250 mL reaction flask, (R,S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (28) (18.0 g, 77.48 mmol), i-PrOH (61 mL), and water (36 mL) were added and stirred until dissolved, then heated to 45 °C. A solution of l-(–)-dibenzoyl tartaric acid (29) (14 g, 39.07 mmol) in i-PrOH (61 mL) was slowly added to the reaction mixture, resulting in the precipitation of a white solid. The mixture was stirred at 45 °C for 2 h and then cooled in an ice bath. After stirring at 0–10 °C for 10 h, the mixture was filtered, and the filter cake was washed with i-PrOH to obtain a white solid. The white solid was transferred to a 250 mL reaction flask, and EA (54 mL) and water (54 mL) were added. The pH of the mixture was slowly adjusted to 12.0–14.0 using a 20% NaOH solution at 35 °C, followed by liquid–liquid extraction. The organic phase was successively washed with 0.1 mol/L NaOH solution (75 mL) and water (72 mL). The organic layer was concentrated under reduced pressure to a viscous state, heated to 70 °C, and stirred to dissolve the solid. The mixture was then stirred in an ice bath for 10 h to induce crystallization. After filtration, the solid was washed with cold EA to obtain crude intermediate 5. Purification: The crude intermediate 5 was transferred to a 100 mL reaction flask, and EA (23 mL) was added. The mixture was heated to 56 °C to dissolve the solid, then cooled in an ice bath. After stirring at 0–10 °C for 12 h, the mixture was filtered, washed with 3 mL of cold EA, and dried under vacuum at 50 °C for 6 h to obtain a white crystalline solid, namely, (2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (5) (5.3 g, 59% (calculated based on (2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide 9 g)), with a purity of 99.98% (HPLC peak area normalization method: Welch C18 column (150 mm × 3.9 mm × 5.0 μm); mobile phase A: MeCN, mobile phase B: 0.02 mol/L phosphate buffer (sodium phosphate buffer, pH = 8.0); 60 min (A:B = 25:75); column temperature 35 °C; flow rate 1.0 mL/min; detection wavelength 210 nm; injection volume 20 µL; sample concentration 0.2 mg/mL; retention time 10.783 min). m.p. 129~130 °C; ESI-MS m/z: 233.0 [M+H]⁺; ¹H NMR (CDCl₃, 300 MHz) δ 8.24 (1H, s, CONH), 7.12–7.03 (3H, m, Ar-H), 3.42 (1H, dd, J = 9.9, 3.4 Hz, 2-CH), 3.12 (1H, dt, J = 12.3, 3.8 Hz, 6-CH), 2.86–2.70 (1H, m, NH), 2.22 (6H, s, Ar-CH₃), 2.09 (1H, dd, J = 12.0, 3.5 Hz, 3-CH), 1.87–1.43 (6H, m, 3-CH, 4-CH₂, 5-CH₂, 6-CH); ¹³C NMR (101 MHz, DMSO-d₆) δ 172.38, 135.71, 135.52, 128.02, 126.71, 60.26, 45.67, 30.52, 26.35, 24.48, 18.56; Anal. Calcd for C₁₄H₂₀N₂O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.43; H, 8.53; N, 11.86 (Figures S1–S4).

In a 100 mL reaction flask, EtOH (26 mL), intermediate 5 (5.31 g, 22.83 mmol), bromobutane (4.50 g, 34.25 mmol), and Na₂CO₃ (2.90 g, 27.30 mmol) were added sequentially. The mixture was stirred to disperse and heated to 75 °C. The reaction was carried out for 5 h with TLC monitoring of the reaction. Water (78 mL) was added to the reaction mixture, precipitating a significant amount of light yellow solid. After cooling in an ice bath and stirring at 0–10 °C for 12 h, the mixture was filtered, washed with 56 mL of water, and then subjected to vacuum drying at 50 °C for 6 h. This yielded a light yellow solid, which was (2S)-1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (Levobupivacaine, 6) (6.14 g, 93%) with a purity of 99.12% (HPLC peak area normalization method: Welch C18 column (150 mm × 3.9 mm × 5.0 μm); mobile phase A: MeCN, mobile phase B: phosphate buffer (prepared by dissolving 4.9 g of KH₂PO₄ and 3.0 g of NaH₂PO₄ in water and adjusting the pH to 7.0); 30 min (A:B = 35:65); column temperature 33 °C; flow rate 1.0 mL/min; detection wavelength 210 nm; injection volume 20 µL; sample concentration 1.0 mg/mL; retention time 9.757 min). m.p. 136~137 °C; ESI-MS m/z: 289.0 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ 8.15 (1H, s, CONH), 7.16–7.01 (3H, m, Ar-H), 3.21 (1H, dtd, J = 11.8, 3.8, 1.3 Hz, 2-CH), 2.88 (1H, dd, J = 10.4, 3.6 Hz, 6-CH), 2.87–2.77 (1H, m, 7-CH), 2.32–2.21 (1H, m, 3-CH), 2.25 (6H, s, Ar-CH₃), 2.17–2.06 (1H, m, 7-CH, 7-CH), 2.03 (1H, dd, J = 11.6, 2.8 Hz, 6-CH), 1.84–1.21 (9H, m, 3-CH, 4-CH₂, 5-CH₂, 8-CH₂, 9-CH₂), 0.92 (3H, t, J = 7.3 Hz, 10-CH₃); ¹³C NMR (101 MHz, DMSO-d₆) δ 172.35, 135.81, 135.59, 128.14, 126.82, 67.99, 56.39, 51.54, 30.65, 28.77, 25.38, 23.60, 20.73, 18.61, 14.45; Anal. Calcd for C₁₈H₂₈N₂O: C, 74.96; H, 9.79; N, 9.71. Found: C, 74.48; H, 9.66; N, 9.45 (Figures S5–S8).

In a 100 mL reaction flask, levobupivacaine (6) (6.14 g) and EA (31 mL) were added, and the mixture was heated to 45 °C. The solid gradually dissolved, and 2.45 g of hydrochloric acid was slowly added to adjust the pH to 2.5–3.5. The mixture was stirred for an additional 2 h. It was then placed in an ice bath, and stirring was continued for 12 h. The mixture was filtered, and the filter cake was washed with 8 mL of EA. The resulting material was vacuum-dried at 50 °C for 6 h to obtain crude levobupivacaine hydrochloride (21). Purification: In a 100 mL reaction flask, the crude product and i-PrOH (30 mL) were added, and the mixture was heated to 70 °C with stirring to dissolve the solid. The hot reaction mixture was filtered, and the filtrate was heated again to 70 °C to redissolve any remaining solid. The mixture was then cooled in an ice bath and stirred at 0–10 °C for 12 h. It was filtered, and the filter cake was washed with 5 mL of cold i-PrOH. The resulting white solid was levobupivacaine hydrochloride (21) (5.63 g, 82%), with a chemical purity of 99.90% (HPLC peak area normalization method: Welch C18 column (150 mm × 3.9 mm × 5.0 μm); mobile phase A: MeCN, mobile phase B: phosphate buffer (prepared by dissolving 4.9 g of KH₂PO₄ and 3.0 g of NaH₂PO₄ in water to a total volume of 1000 mL, adjusting the pH to 6.9); 40 min (A:B = 33:67); column temperature 33 °C; flow rate 1.0 mL/min; detection wavelength 210 nm; injection volume 20 µL; sample concentration 1.0 mg/mL; retention time 10.423 min), and an ee value of 99.30% (HPLC peak area normalization method: DAICE CHIRALPAK IG-3 column (250 mm × 4.6 mm × 3 μm); mobile phase A: MeCN, mobile phase B: phosphate buffer (10 mmol/L KH₂PO₄-10 mmol/L NaH₂PO₄, mixed in a 1:1 ratio, and the pH was adjusted to 7.0 using phosphoric acid or ammonia); 20 min (A:B = 70:30); column temperature 25 °C; flow rate 0.5 mL/min; detection wavelength 210 nm; injection volume 10 µL; sample concentration 0.5 mg/mL; retention time 15.087 min). m.p. 254~256 °C; ESI-MS m/z: 289.2 [M-Cl]⁺; ¹H NMR (Deuterium Oxide, 400 MHz) δ 7.28–7.14 (3H, m, Ar-CH), 4.23–4.07 (1H, m, 2-CH), 3.71 (1H, d, J = 12.5 Hz, 6-CH), 3.14 (3H, tt, J = 13.4, 8.3 Hz, 6-CH, 7-CH₂), 2.41 (1H, d, J = 14.1 Hz, 3-CH), 2.17 (6H, s, Ar-CH₃), 1.97 (3H, d, J = 12.1 Hz, 3-CH, 5-CH₂), 1.87–1.61 (4H, m, 4-CH₂, 8-CH₂), 1.36 (2H, h, J = 7.4 Hz, 9-CH₂), 0.90 (3H, t, J = 7.4 Hz, 10-CH₃); ¹³C NMR (Deuterium Oxide, 101 MHz) δ 168.37, 135.72, 131.95, 128.56, 128.36, 65.81, 56.15, 52.14, 28.99, 25.14, 22.35, 20.91, 19.35, 17.33, 12.74; Anal. Calcd for C₁₈H₂₉ClN₂O: C, 65.51; H, 8.90; N, 8.12. Found: C, 65.33; H, 9.10; N, 8.23 (Figures S9–S13).