3-Hydroxypyridine is a critical chemical intermediate widely used in pharmaceuticals, pesticides, and dyes, such as serving as a precursor for benidipine hydrochloride. However, conventional industrial synthesis methods face significant drawbacks. For example, the sulfonation-pyrolysis route requires high temperatures and mercury catalysts, generating substantial waste and high energy consumption. Other approaches, like halogen-based oxidation with chlorine or bromine, pose severe safety risks due to toxicity, while electrochemical or photochemical methods demand specialized equipment, making them impractical for large-scale production. Even peroxide-based oxidation under acidic conditions achieves low yields due to extraction issues and explosion hazards, hindering efficiency and sustainability.

To address these limitations, a new synthesis process has been developed. This innovative method features a streamlined four-step sequence using easily accessible raw materials. First, peracetic acid is generated by mixing acetic anhydride with hydrogen peroxide, heated gently at 30–50°C to ensure safe formation. Then, furfurylamine is added to this solution at 0–25°C for oxidation, producing a crude 3-hydroxypyridine mixture. Crucially, the next step involves acetylation using additional acetic anhydride (at 25–100°C), converting the mixture into stable 3-acetoxypyridine for easier handling. Finally, hydrolysis is performed by dissolving this intermediate in a solvent like methanol and reacting it with an alkaline solution (e.g., sodium hydroxide) at 0–100°C, yielding pure 3-hydroxypyridine. Optional recrystallization with solvents such as ethyl acetate enhances purity for applications requiring high standards.

Key reaction parameters optimize outcomes and safety. The mole ratio is critical: furfurylamine to acetic anhydride is maintained at 1:8–16, and furfurylamine to hydrogen peroxide at 1:2.0–4.0 with peroxide concentrations of 25–35%. For acetylation, acetic anhydride is used at 4–10 times the mole ratio of furfurylamine to ensure complete conversion. Hydrolysis employs alkaline solutions in alcohol solvents at controlled temperatures to minimize side reactions. This approach avoids hazardous reagents and extreme conditions, using standard equipment to make it highly accessible for factories. By reducing waste and toxicity, it supports greener chemistry principles and cuts operational risks without compromising yield or quality.

This process offers compelling advantages over existing techniques. It utilizes low-cost starting materials like acetic anhydride and furfurylamine, which are readily available, keeping material expenses minimal. Reaction conditions are mild, with temperatures typically below 100°C and atmospheric pressure, lowering energy demands. Safety is significantly enhanced as no toxic chemicals are involved, and risks of overheating or explosions are mitigated. Environmental benefits include minimal waste production for reduced disposal costs, and recoverable solvents enable recycling for eco-friendly operations. Overall yields exceed 70% with purity levels above 99% in optimal trials, outperforming many alternatives that struggle to achieve 30–50% yields and high costs.

Experimental validation confirms the efficiency and reliability of this method. In a series of tests, optimized conditions resulted in consistent high-yield production. For instance, when mixing furfurylamine with appropriate ratios of ingredients and processing through acetylation and hydrolysis, the final product demonstrated excellent purity via analytical techniques. Nuclear magnetic resonance (NMR) and mass spectrometry analyses showed clear matches to 3-hydroxypyridine, validating structural integrity and molecular weight. Such results indicate that this process is scalable for industrial implementation, offering a robust solution to the shortcomings of older methods. As demand grows for intermediates like this, innovations like this synthesis pathway will play a vital role in advancing sustainable and cost-effective chemical manufacturing globally.