Abstract
Background: Synthetic processes reported for ivabradine hydrochloride (1), a heart rate lowering drug (an antianginal agent), are inefficient and uneconomical at an industrial scale due to their inability to control the formation of process related impurities. Generation of huge amount of solvent and solid waste due to repeated purifications and/or chromatographic purifications to eliminate impurities makes them industrially unsuitable hence requires the development of practical and greener process for 1.
Method: Based on the spectral analysis and synthetic route followed for 1, the structures for the impurities were identified and confirmed by their synthesis. Evaluated the genesis of these impurities based on the mechanistic understanding of the reaction pathways and established suitable strategies to eliminate/ minimize by optimizing the process parameters. The greenness and productivity of newly developed process were determined using process evaluation benchmarks such as process mass intensity (PMI), e-factor, atom economy, and volume time output (VTO).
Results: Established process delivered greener, productive and efficient method for 1 with an overall yield of around 62.0% and HPLC purity of >99.9%.
Conclusion: An efficient, economic and industrially feasible process for the synthesis of 1 is established which not only controls the formation of impurities but also minimizes the aqueous, organic and solid waste substantially to achieve the greener and productive process.
Keywords: Antianginal drug, benzazepin, finkelstein reaction, impurity profile, ivabradine, polonovski reaction.
Graphical Abstract
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