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<p>Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, is widely prescribed for the management of hypertension and heart failure. The cost and efficiency of its production are strongly influenced by the synthesis of a key intermediate, 3-bromo-4,5-dihydro-1<i>H</i>-benzo<i>[b]</i>azepin-2(3<i>H</i>)-one. Conventional synthetic routes often involve multiple steps, high raw material consumption and extensive solvent use, which limit scalability and compromise environmental sustainability. To develop a streamlined, cost-effective and greener synthesis of Bromo-benzo[b]azepinone Intermediate for Benazepril that improves scalability, reduces costs and delivers high product quality with minimal environmental impact. The optimized process combines electrophilic bromination of <i>α</i>-tetralone with subsequent oxime formation in a telescoped sequence, reducing solvent usage and operational steps. The oxime undergoes C–N aryl migration via a Beckmann rearrangement using Eaton’s reagent-a greener, more efficient alternative to polyphosphoric acid-enhancing reaction control and product quality. Reaction conditions, purification strategy and solvent recovery were systematically refined to maximize efficiency and sustainability. The developed process yielded the target intermediate in 78% yield with &gt; 95% purity, while improving operational efficiency and minimizing waste. Telescoping the bromination and oxime formation steps reduced by-product formation and simplified work-up, resulting in a cleaner product. Replacing polyphosphoric acid with Eaton’s reagent improved reaction efficiency, eased handling and lowered environmental impact. Together, these innovations reduced raw material costs substantially and delivered a robust, scalable process. The developed process demonstrates the benefits of step telescoping and the use of Eaton’s reagent for Beckmann rearrangement, providing improved reaction control, easier handling and enhanced selectivity compared with conventional polyphosphoric acid systems. The strategy reduces operational steps and purification requirements, improving process efficiency and lowering waste generation. These improvements enhance the overall sustainability and economic feasibility of the process, making it suitable for scalable industrial production. This optimized synthetic route for 3-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one is efficient, scalable, and environmentally sustainable. By integrating step telescoping with greener reagents, the process meets industrial pharmaceutical manufacturing goals, offering both economic advantages and environmental benefits in Benazepril production.</p>

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Cost effective industrial scale synthesis of bromo-benzo[b]azepinone: an intermediate for benazepril

  • 期刊论文

  • 发表日期：

    2026年5月1日

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  • Anjan Kumar Nayak,
  • Divya Bajpai Tripathy,
  • Dhananjay Pendharkar,
  • Gaurav Sharma

摘要

Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, is widely prescribed for the management of hypertension and heart failure. The cost and efficiency of its production are strongly influenced by the synthesis of a key intermediate, 3-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one. Conventional synthetic routes often involve multiple steps, high raw material consumption and extensive solvent use, which limit scalability and compromise environmental sustainability. To develop a streamlined, cost-effective and greener synthesis of Bromo-benzo[b]azepinone Intermediate for Benazepril that improves scalability, reduces costs and delivers high product quality with minimal environmental impact. The optimized process combines electrophilic bromination of α-tetralone with subsequent oxime formation in a telescoped sequence, reducing solvent usage and operational steps. The oxime undergoes C–N aryl migration via a Beckmann rearrangement using Eaton’s reagent-a greener, more efficient alternative to polyphosphoric acid-enhancing reaction control and product quality. Reaction conditions, purification strategy and solvent recovery were systematically refined to maximize efficiency and sustainability. The developed process yielded the target intermediate in 78% yield with > 95% purity, while improving operational efficiency and minimizing waste. Telescoping the bromination and oxime formation steps reduced by-product formation and simplified work-up, resulting in a cleaner product. Replacing polyphosphoric acid with Eaton’s reagent improved reaction efficiency, eased handling and lowered environmental impact. Together, these innovations reduced raw material costs substantially and delivered a robust, scalable process. The developed process demonstrates the benefits of step telescoping and the use of Eaton’s reagent for Beckmann rearrangement, providing improved reaction control, easier handling and enhanced selectivity compared with conventional polyphosphoric acid systems. The strategy reduces operational steps and purification requirements, improving process efficiency and lowering waste generation. These improvements enhance the overall sustainability and economic feasibility of the process, making it suitable for scalable industrial production. This optimized synthetic route for 3-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one is efficient, scalable, and environmentally sustainable. By integrating step telescoping with greener reagents, the process meets industrial pharmaceutical manufacturing goals, offering both economic advantages and environmental benefits in Benazepril production.