Volume 3 Issue 3 | 2026 | View PDF
Paper Id: IJMSM-V3I3P106
doi: 10.71141/30485037/V3I3P106

Optimization and Process Scale-up for the Synthesis of Pharmaceutical-Grade N-Acetyl-DL-Leucine from L-Leucine

Mai Van Phong, Pham Nguyen Vu, Vu Duc Thanh

Citation:
Mai Van Phong, Pham Nguyen Vu, Vu Duc Thanh, "Optimization and Process Scale-up for the Synthesis of Pharmaceutical-Grade N-Acetyl-DL-Leucine from L-Leucine" International Journal of Multidisciplinary on Science and Management, Vol. 3, No. 3, pp. 76-85, 2026.

Abstract:
N-Acetyl-DL-leucine is a well-established active pharmaceutical ingredient widely prescribed for the symptomatic treatment of vestibular vertigo. However, its industrial supply in developing markets still relies heavily on imports due to a lack of optimized, large-scale domestic manufacturing processes. Herein, we report an eco-friendly, highly reproducible, and cost-effective synthetic process for pharmaceutical-grade N-acetyl-DL-leucine from readily available L-leucine, scaled up to 1 kg/batch. The procedure comprises two main steps: N-acylation of L-leucine with acetic anhydride (Ac_2 O) in an aqueous sodium hydroxide solution, followed by catalytic thermal racemization. Key operational parameters were systematically investigated to optimize the overall process. The ideal acylation conditions were achieved at 20"--" 45^∘ "C" with a molar ratio of Ac_2 O:"L-leucine"=2.1:1, and product isolation was optimal by acidification to pH = 3. Subsequent racemization in an aqueous environment proceeded completely at 90^∘ "C" for 5 hours using a 1:1 molar ratio of Ac_2 O to N-acetyl-L-leucine. Scale-up trials executed at 100 g/batch and 1 kg/batch demonstrated remarkable consistency, delivering an overall yield of 87.28% with a chemical assay purity of 98.1% at the 1 kg/batch level, as determined by HPLC and acid-base titration. The chemical structure of the synthesized compound was unambiguously validated by IR, ESI-MS, (_^1)"H-NMR" , and (_^13)"C-NMR" spectroscopies. Complete racemization was confirmed by an optical rotation value of [α]_D^20=0^∘. Overall, this robust, water-based synthetic route avoids hazardous organic solvents and offers a practical, industrial-ready solution for domestic N-acetyl-DL-leucine production.

Keywords: Acylation, API synthesis, L-Leucine, N-Acetyl-DL-leucine, Process Scale-up, Racemization.

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