Journal of Molecular Pharmaceutics & Organic Process Research
Open Access

Mechanochemistry; Amidation; Solvent-free synthesis; Green chemistry; Ball milling; Process intensification; Pharmaceutical intermediates; Sustainable synthesis; Amide bond formation; API manufacturing

Introduction

Amide bonds are ubiquitous in active pharmaceutical ingredients (APIs), natural products, and peptides. Over 25% of marketed drugs contain at least one amide moiety [1]. Conventional methods for amide bond formation typically involve the activation of carboxylic acids using coupling agents such as DCC, EDC, or HATU in organic solvents like DMF, DCM, or THF [2]. While efficient, these protocols generate significant waste and raise environmental and safety issues, particularly at industrial scale.

Mechanochemistry, defined as chemical transformation initiated by mechanical energy, has gained traction as a solvent-free, energy-efficient alternative to traditional solution-phase synthesis [3]. Ball milling, a key mechanochemical technique, facilitates intimate mixing of reagents under dry conditions and can often enable reactions without catalysts or excess reagents [4]. Despite growing interest, application of mechanochemistry to amide bond formation for API intermediates remains underexplored in industrial settings.

This work presents a comprehensive study of solvent-free, mechanochemical amidation using various coupling agents under ball milling conditions. Optimization, scope, and scale-up of the process are demonstrated with a focus on green chemistry metrics relevant to process research and development.

Materials and Methods

Reagents including benzoic acid, benzylamine, EDC·HCl, CDI, triphosgene, and others were purchased from Sigma-Aldrich. Mechanochemical reactions were conducted in a Retsch MM400 ball mill with 10 mL stainless steel jars and 5 mm steel balls.

In a typical experiment, 1 mmol of carboxylic acid, 1.2 mmol of amine, and the coupling agent (1.2–1.5 mmol) were added to the jar. Reactions were milled at 25 Hz for 30–60 min at ambient temperature. No solvents or external heating were used. Reactions were monitored by TLC and confirmed by ^1H NMR and LC-MS. Product isolation involved minimal work-up: washing with aqueous bicarbonate and extraction with ethyl acetate. Yield was calculated after drying and purification.

To test scalability, reactions were performed at 10 g scale using a 250 mL planetary ball mill. Various carboxylic acids (aromatic, aliphatic) and amines (primary, secondary) were screened to assess reaction scope.

Results

Initial optimization using benzoic acid and benzylamine with EDC·HCl gave a 92% yield after 40 min of milling. CDI offered similar efficiency (89%), while triphosgene resulted in slightly lower yields (81%) but faster reactions (30 min). Reactions were reproducible and clean, with minimal by-product formation. No liquid additives (liquid-assisted grinding) were required [5].

Mechanochemical amidation was extended to various substrates including:

• Acetic acid + benzylamine → N-benzylacetamide (90%)
• 4-nitrobenzoic acid + morpholine → amide (87%)
• Fmoc-protected glycine + isopropylamine → Fmoc-amide intermediate (84%)

These reactions were completed within 30–50 min of milling. Scale-up to 10 g batches gave comparable yields (±2%) and product purity. Reaction monitoring by in situ Raman spectroscopy showed that product formation occurred progressively with continuous milling [6].

Green chemistry metrics were favorable: E-factor values were reduced by 80–90% compared to conventional methods [7]. Energy consumption per gram of product was also significantly lower. Minimal workup eliminated the need for column chromatography in most cases [8].

Discussion

This study confirms that mechanochemistry provides a robust platform for efficient, solvent-free amidation suitable for pharmaceutical intermediate synthesis. EDC and CDI proved to be the most effective coupling agents under mechanochemical conditions, enabling rapid product formation with high selectivity and minimal by-products.

Mechanochemical methods benefit from enhanced mass transfer and intimate reagent contact, making them ideal for coupling reactions [9]. The solid-state nature of the reactions allows for easy scalability, with planetary ball mills offering straightforward pathways for gram to kilogram scale-up.

Importantly, this process aligns with green chemistry principles: no solvents, low waste, energy efficiency, and simplified purification. It circumvents the challenges associated with solvent disposal, flammability, and worker safety in large-scale manufacturing. In addition, mechanochemistry may offer regulatory advantages due to simplified batch documentation and reduced hazardous emissions.

Future work will explore the integration of mechanochemical amidation into continuous manufacturing platforms using twin-screw extrusion and reactive milling reactors [10].

Conclusion

We report an efficient, scalable, solvent-free mechanochemical method for amide bond formation using ball milling. The process eliminates the need for hazardous solvents, reduces waste, and maintains high yields and purity across a range of pharmaceutical intermediates. This method represents a green, industrially relevant alternative to conventional amidation and holds promise for sustainable API manufacturing.

Conflicts of Interest

None