Synthesis Method of Optically Pure Enantiomers of 5-Aryl Substituted3-Methyl‑7- Nitro‑1,2-Dihydro‑3h‑1,4-Benzodiazepin‑2-Ones

Abstract

The aim of this work is to develop a simple, fast and efficient method for the synthesis of optically pure enantiomers of some 5-aryl-substituted 3-methyl‑7-nitro‑1,2-dihydro‑3H‑1,4-benzodiazepin‑2-ones using simple reagents. In the course of the study, we found that the interaction of 2-amino‑5-nitrobenzophenone or 2-amino‑2’-chloro‑5-nitrobenzophenone with optically active L- or D‑α-alanine N‑carboxyanhydrides in the presence of two equivalents of trifluoroacetic acid does not leads to the formation of the corresponding reaction intermediates (2-amino-N-(2-benzoylphenyl)propanamide), even when refluxed for 24 hours in xylene. Acylation of 5-nitro‑2-aminobenzophenones with hydrochlorides of L- or D‑α-alanine acid chlorides, followed by cyclization under mild conditions, leads to target 3-methyl‑7-nitro‑1,2-dihydro‑3H‑1,4-benzodiazepin‑2-ones characterized by high optical purity. It is noteworthy that these reactions allow the coupling of acid chlorides derived from stereospecific α-alanines with weakly reactive 5-nitro derivatives of 2-aminobenzophenone without racemization. It is important to note that the acid chloride hydrochlorides of optically active α-alanines, which are chemically unstable and extremely sensitive to moisture, are used as building blocks in the work. In this case, acid chlorides of individual antipodes of L- or D‑α-alanine were synthesized in absolute chloroform using phosphorus pentachloride and the products were isolated by simple filtration of precipitates, without applying additional purification to them. The structure of the title compound was confirmed by spectroscopy 1H and 13C NMR, and FAB mass spectrometry methods, purity was controlled by HPLC. To analyze the optical purity of the1,2-dihydro‑3H‑1,4-benzodiazepines synthesized in this work, HPLC was applied using stationary chiral phase CiraDex®. This simple preparation method is of potential practical importance for the design and synthesis of optically pure enantiomers of various 3-alkyl derivatives of 1,2-dihydro‑3H‑1,4-benzodiazepin‑2-ones with a wide spectrum of biological activity.