Brivudine, or (E)-5-(2-bromovinyl)-2′-deoxyuridine, stands as a potent antiviral agent for treating herpes zoster virus (HZV) and herpes simplex virus type 1 (HSV-1) infections. Historically, its synthesis relied on costly iodouridine as a starting material and expensive palladium catalysts in Heck reactions, driving the production cost to around ¥60,000 per kilogram. This high expense hampered large-scale industrial adoption, limiting broader therapeutic applications. The need for economical, scalable manufacturing methods has spurred significant research, culminating in a breakthrough new synthesis approach.

The novel process, revealed through cutting-edge chemical research, replaces iodouridine with affordable β-thymidine and bypasses palladium catalysts entirely. It unfolds in three straightforward, controlled steps. First, in Step S1, β-thymidine reacts with DMF-DMA (N,N-dimethylformamide dimethyl acetal) in a formylation reaction at temperatures between 110–130°C for 4–10 hours. Optimized parameters like β-thymidine to DMF mass-volume ratios of 1:8–12 and mole ratios of 1:2–4 for DMF-DMA ensure high yields of intermediate I, a brownish-yellow oil, achieved through controlled addition and extraction. This step minimizes residual reactants to below 5%, as confirmed by HPLC monitoring. Next, in Step S2, intermediate I undergoes cyclization with acetic acid at 60–115°C for 1–5 hours. Ratios such as 4–10:1 for acetic acid to β-thymidine lead to intermediate II, a light-yellow solid purified through recrystallization in 80–85% methanol solutions. Crucially, stepwise temperature control (e.g., 65–80°C) prevents side reactions, boosting purity. Finally, in Step S3, intermediate II reacts with hydrogen bromide and ammonium bromide in DMF at 50–90°C for 2–6 hours, using mass-volume ratios of 1:5–8 for DMF and mole ratios of 1:1.1–1.6:1.1–1.5 for reactants. The resulting brivudine, >99% pure, crystallizes in 45–55% methanol.

This streamlined triphasic pathway offers tangible economic benefits, slashing raw material costs by 30–50%. Traditional methods averaged ¥60,000/kg due to iodouridine and palladium catalysts. In contrast, β-thymidine’s lower price and the catalyst-free design reduce expenses to ¥30,000–40,000/kg, as demonstrated in multiple laboratory trials. For instance, Exemplar Experiment 1 reported a 65% yield with 99.5% purity after recrystallization. Here, 0.1 mol β-thymidine processed through stepwise conditions delivered 10.8 g of brivudine. Similarly, Exemplar Experiments 2 and 3 showed 63% and 66% yields with purities exceeding 99.2%, underscoring reproducibility. Analytical confirmation solidifies product integrity. Nuclear magnetic resonance (NMR) spectroscopy, as seen in 1H NMR tests (400 MHz, DMSO-d6), matches expected signals like 11.57 ppm for N-H protons. Liquid chromatography-mass spectrometry (LC-MS) further verifies identity, producing m/z 331 peaks ([M-H]-), and HPLC confirms impurities below 5%. This robust validation pipeline ensures consistent quality without patented identifiers.

Beyond cost efficiency, the method excels in operational simplicity and industrial viability. Milder thermal conditions (e.g., 50–115°C versus higher thresholds) and solvent recycling (e.g., using acetic acid in excess) reduce energy consumption and waste, aligning with green chemistry principles. Recrystallization steps employ standardized methanol concentrations (80–85% and 45–55%) for high-purity outputs, while avoiding volatile organometallics enhances workplace safety and compliance. Such innovations address key R&D challenges in drug synthesis, potentially accelerating global access to this vital antiviral. Future adaptations could explore broader nucleoside applications or scale-up optimizations, cementing this as a landmark in pharmaceutical engineering.