A groundbreaking synthesis method for sodium creatine phosphate has been developed, promising higher efficiency and lower toxicity in producing this critical compound widely used in treating heart conditions such as myocardial infarction. Sodium creatine phosphate, marketed under brand names like Neoton, functions as a vital energy source for cells and is essential in cardioprotective therapies, particularly in metabolic myocardial protection. This innovation addresses long-standing challenges in traditional processes, offering a scalable solution for the growing demand in heart disease management and pharmaceutical manufacturing.

Historically, multiple pathways have been explored for sodium creatine phosphate synthesis. These include reactions using creatine and phosphorus oxychloride in alkaline conditions, techniques involving creatine and triethyl phosphite, and biological enzyme-based approaches. However, these methods are plagued by issues such as high toxicity from reagents like carbon tetrachloride, difficult separation of by-products, low yields, and significant waste generation, which hinder industrial feasibility and environmental sustainability.

To overcome these drawbacks, the new process employs a three-step mechanism. First, creatine monohydrate and phosphoric acid react in an ethanol solution at specific mass ratios (e.g., ethanol:phosphoric acid:creatine monohydrate at 16:10:9) for 2.5 to 3.5 hours. This yields a white solid intermediate after filtration and drying. Next, this solid undergoes phosphocreatine formation in ethyl acetate, using 4-dimethylaminopyridine (DMAP) as a catalyst and dicyclohexylcarbodiimide (DCC) as a dehydrating agent, with ratios such as DMAP:DCC:creatine monohydrate at 0.05:3:5. The reaction runs under reflux for 2.5–3.5 hours, producing a light yellow solid. Finally, alkali hydrolysis with sodium hydroxide for 1.5–2.5 hours, followed by ethanol precipitation, yields pure sodium creatine phosphate. This method ensures high atom economy and minimal by-product contamination.

The advantages of this synthesis are multifaceted. Yields exceeding 75% based on creatine input were demonstrated in controlled examples, with one trial achieving 78.5%. This represents a significant improvement over existing methods, which often suffer from sub-optimal outputs. Furthermore, the process uses inexpensive, readily available reagents, reduces toxicity by avoiding harmful chemicals, and minimizes wastewater through solvent recycling. Dehydrating agents like DCC convert into easily removable solids (e.g., 1,3-dicyclohexylurea), simplifying purification and enabling high-purity products as confirmed by purity analyses above 99% via chromatographic testing.

In practical applications, this synthesis paves the way for cost-effective production of sodium creatine phosphate, crucial for cardiac drugs that protect myocardium or enhance athletic endurance. Its scalability and eco-friendly profile make it ideal for global pharmaceutical industries, particularly in regions with high incidences of cardiovascular diseases. Future implementations could extend to other amino acid derivatives, reinforcing its role in advancing synthetic chemistry and therapeutic innovations.