ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

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

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, and Sanjay S. Gaikwad

Department of Chemistry, MES Abasaheb Garware College, Pune, India

E-mail: sanjchem99@gmail.com

Received: 30 November 2025  Accepted: 4 February 2026

Abstract:

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

Keywords: Continuous-flow chemistry; Nucleophilic substitution; Clotrimazole; Process intensification; Green chemistry; E-Factor

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-026-04717-5

Chemical Papers 80 (5) 5383–5394 (2026)