Streamlined Green Synthesis and Process Optimization for Tetrazole Derivatives Via Metal-Free Reactions

Abstract

Introduction: This work presents a pioneering approach to in situ tetrazole formation for active ingredients, achieving high yields and eco-friendly outcomes. This innovation is significant for sartan drugs, essential in hypertension treatment. The study addresses synthetic challenges, functionalization, and applications of poly-nitrogen heterocyclic compounds, revealing novel conditions for tetrazole synthesis utilizing versatile catalytic systems and advanced techniques. With a focus on green synthesis, the research steers towards impactful areas in tetrazole chemistry. The [3+2] cycloaddition of sodium azide to nitriles, efficiently catalyzed by a Copper (II) complex, yields 5-substituted 1H-tetrazoles. This method reduces risks associated with spark discharge and nitrogen gas explosions, with structural characterization confirming its effectiveness. Consistent results across various derivatives underscore the method’s potential for developing new active pharmaceutical ingredients (APIs). The active compound was characterized using IR, PMR, CMR, and mass spectrometry, highlighting the necessity for continuous innovation in this field.

Objectives: The objective of this research is to develop an innovative, eco-friendly method for in situ tetrazole formation, enhancing the synthesis of sartan drug APIs through optimized [3+2] cycloaddition of sodium azide to nitriles catalysed by a Copper (II) complex, with a focus on high yield, safety, and novel pharmaceutical applications.

Methods: In this research, focused on developing a sustainable method for synthesizing tetrazoles, key compounds in drug development. Using a [3+2] cycloaddition reaction between sodium azide and nitriles, we employed a Copper (II) catalyst to achieve high yields under safer, greener conditions. This approach not only minimizes environmental risks like spark discharge and nitrogen gas explosions but also enhances the efficiency of the process. We used advanced techniques such as IR, PMR, CMR, and Mass Spectrometry to carefully analyse and confirm the structure and quality of the tetrazoles produced, ensuring their suitability for pharmaceutical applications.

Results: This study presents an efficient, eco-friendly method for synthesizing 5-substituted 1H-tetrazoles using copper sulfate pentahydrate as a catalyst in a one-pot process with DMSO. The method improves yields, avoids toxic reagents, and streamlines API production, offering a versatile, scalable solution for pharmaceutical synthesis.

Conclusions: In conclusion, this study presents a novel and efficient synthesis route for 1H-tetrazoles, utilizing a copper (II) complex with a tetradentate ligand under mild conditions. Employing green solvents and non-toxic reagents, the method adheres to sustainable chemistry principles, offering improved efficiency and scalability for API development. These findings underscore the potential of innovative, eco-conscious synthetic pathways in advancing pharmaceutical manufacturing.