Investigating Scale-Up and Further Applications of DABAL-Me₃ Promoted Amide Synthesis

Abstract

Methods for the batch scale up of DABAL-Me 3 promoted direct ester to amide synthesis have been demonstrated at 10−100 g scales using a tert-amide model compound. Procedures for 20 g scale couplings in standard laboratory glassware and up to 0.1 kg in industry-standard jacketed glass reactors in near quantitative yields are given. A derivative of the anticancer agent Imatinib (Gleevec) has been synthesized on a 26 g scale (98% yield, >98% purity) establishing DABAL-Me 3 as a potential alternative for the synthesis of amides in API scale preparations. Continuous flow methodology provides a method for larger scales (productivities of >50 g h −1 ). In addition, nitriles were coupled to primary amines and hydrazines with DABAL-Me 3 , resulting in the clean formation of free amidines (16 examples) and amidrazones.

Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold

“…[12] To quickly diversify the scaffolds, we utilized eleven commercially available primary amine subunits enriched in heteroatoms and aromatic rings, chemotypes that are known to be important for selective RNA recognition. [13] Subunit addition to the three dinitrile scaffolds 3 was achieved by optimizing previously reported copper [14] - or aluminum [15] -assisted coupling reactions for diamidine formation to afford three sublibraries ( p , m , and o ) with eleven identical subunits on each scaffold ( DPF-R ). This final one-step coupling, which had not been applied to the synthesis of DPF-based small molecules, was found to increase efficiency relative to a reported two-step procedure that involves an imidate ester intermediate.…”

Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans

“…The synthetic scheme for ligands in this work can be found in Supplementary Scheme S1 . DPFp20 was synthesized using toluene as solvent due to reported side product formation of tetrahydrofuran with aniline subunits ( 41 ). All compounds were purified through silica column chromatography using a dichloromethane/methanol/28% ammonium hydroxide gradient (95:4:1 to 90:8:2), with the exception of DPFp12 , which was additionally purified using a 1:1 mixture of ethyl acetate:(acetonitrile:methanol:water).…”

A Continuous Flow Strategy for the Facile Synthesis and Elaboration of Semi‐Saturated Heterobicyclic Fragments

“…Its use has been described for both batch and microwave methodologies, however elevated temperature and pressure are generally required for the ester conversion into an amide, and this is a limitation for possible scale‐up. Lee and co‐workers have reported one of the few examples of this transformation in continuous flow as a validated strategy to scale‐up amide synthesis . Based on these results, we were interested in derivatizing 18 and 30 in small scale, with the intention of exploring the utility of the approach.…”