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<p>Continuous-flow synthesis of clotrimazole via nucleophilic substitution between α-chlorotrityl chloride <b>1</b> and <i>1&#xa0;H</i>-imidazole <b>2</b> demonstrates substantial process intensification relative to conventional batch methodologies. Systematic optimization was performed across three continuous-flow reactor platforms at a reaction scale (23.94 mmol). Among these, the Proto-1 system (10 mL reactor volume, DMF as solvent, 100&#xa0;°C, 5&#xa0;min residence time) delivered the highest isolated yield of 89.8%, significantly exceeding the batch process average yield (78%) by nearly 11.8%. The continuous-flow approach affords marked advantages, including a 37% reduction in E-factor, a 72% decrease in reaction holdup time, and a 15% improvement in effective atom economy. Key process design parameters were identified, notably an optimal residence time of 5&#xa0;min., the superior performance of DMF compared with ACN, DCM solvent systems, and enhanced mass transfer efficiency at elevated flow rates. Overall, this study establishes a quantitatively validated and scalable continuous-flow platform for the manufacture of Clotrimazole an antifungal active pharmaceutical ingredient, supported by a rigorous batch to flow comparison that demonstrates improved yield, reproducibility, higher productivity, and reduced environmental impact.</p> Graphical abstract <p></p>

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Continuous-flow nucleophilic substitution for efficient clotrimazole synthesis: process intensification

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Onkar G. Kachi,
  • Saloni Shinde,
  • Makarand Pimplapure,
  • Nitin V. Ganjave,
  • Nitin H. Kolhe,
  • Vijay M. Kasture,
  • Narayan P. Firke,
  • Amardeep R. Jadhao,
  • Hari R. Pawar,
  • Sanjay S. Gaikwad

摘要

Continuous-flow synthesis of clotrimazole via nucleophilic substitution between α-chlorotrityl chloride 1 and 1 H-imidazole 2 demonstrates substantial process intensification relative to conventional batch methodologies. Systematic optimization was performed across three continuous-flow reactor platforms at a reaction scale (23.94 mmol). Among these, the Proto-1 system (10 mL reactor volume, DMF as solvent, 100 °C, 5 min residence time) delivered the highest isolated yield of 89.8%, significantly exceeding the batch process average yield (78%) by nearly 11.8%. The continuous-flow approach affords marked advantages, including a 37% reduction in E-factor, a 72% decrease in reaction holdup time, and a 15% improvement in effective atom economy. Key process design parameters were identified, notably an optimal residence time of 5 min., the superior performance of DMF compared with ACN, DCM solvent systems, and enhanced mass transfer efficiency at elevated flow rates. Overall, this study establishes a quantitatively validated and scalable continuous-flow platform for the manufacture of Clotrimazole an antifungal active pharmaceutical ingredient, supported by a rigorous batch to flow comparison that demonstrates improved yield, reproducibility, higher productivity, and reduced environmental impact.

Graphical abstract