Amidation by reactive extrusion for the synthesis of active pharmaceutical ingredients teriflunomide and moclobemide

Abstract

The solventless synthesis of an amide, starting from a carboxylic acid and an amine, was performed in a twin-screw extruder in the presence of a coupling agent, providing a high...

Batch and continuous flow mechanochemical synthesis of organic compounds including APIs

“…23 The authors have described a simple-to-operate procedure requiring an ester, amine, and stoichiometric KO t Bu to synthesize a broad library of 78 amides derivatives with good to excellent yield. The methyl or ethyl ester (77) reacted with primary or secondary amine (78) and stoichiometric KO t Bu for 1 h to give amide compound (79) in a vibratory ball mill, giving 52-98% yield, as shown in Scheme 19.…”

“…Some of these include mechanochemistry for carrying out the impossible reactions, 69 green metrics in mechanochemistry, 70 and mechanochemical rearrangement for organic synthesis with eco-friendly approach, especially for active pharmaceutical and complex natural products. 71 Recent reports on direct continuous mechanochemical solvent-free amidation 76,77 cover an important step toward solvent-free manufacturing.…”

Supramolecular intermediates in thermo-mechanochemical direct amidations

“…[21][22][23] Solvent-free or minimum-solvent mechanochemical reaction environment is known to have tremendous sustainability benefits 24 and is known to be effective in the synthesis of amides. [25][26][27][28][29][30][31][32][33][34][35] Here, we present a conceptually different approach that involves the thermo-mechanochemical 36 treatment of carboxylic acids and amines for the quantitative conversion to amides without additives. Moreover, we observed and structurally characterised multicomponent crystalline solids as stable reaction intermediates preceding the amide bond formation.…”

“…3a), marketed in more than 50 countries worldwide. 41 Mechanosynthesis of moclobemide had previously been reported by ball milling 33 and by extrusion, 35 although in both cases, activated substrates (esters) 33 or coupling reagents 35 were needed for the amide bond formation to occur. After milling an equimolar mixture of 6 and 7 for 1 h at room temperature, we observed the formation of a new crystalline product 8 , as confirmed by PXRD analysis (ESI,† Fig.…”

Direct amidation of acids in a screw reactor for the continuous flow synthesis of amides

“…21 Very recently, Lavayssiere and Lamaty have shown amidation by a twin screw reactor starting from a carboxylic acid and amines. 22 They have further extended this approach for the synthesis of teriflunomide and moclobemide.…”