Liquid chromatographic resolution of 3‐amino‐1,4‐benzodiazepin‐2‐ones on crown ether‐based chiral stationary phases

Abstract

3-Amino-5-phenyl (or 5-methyl)-1,4-benzodiazepin-2-ones, which are chiral precursors of anti-respiratory syncytial virus active agents, were resolved on three different chiral stationary phases (CSPs) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid or (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. Among the three CSPs, the CSP that is based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 and containing residual silanol group-protecting n-octyl groups on the silica surface was found to be most effective with the use of 80% ethanol in water containing perchloric acid (10 mM) and ammonium acetate (1.0 mM) as a mobile phase. The separation factors (α) and resolutions (R(S) ) were in the range of 1.90-3.21 and 2.79-5.96, respectively. From the relationship between the analyte structure and the chromatographic resolution behavior, the chiral recognition mechanism on the CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was proposed to be different from that on the CSP based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. In addition, the chromatographic resolution behavior of the most effective CSP was investigated as a function of the composition of aqueous mobile phase containing organic and acidic modifier and ammonium acetate.

Development of HPLC Chiral Stationary Phases Based on (+)‐(18‐Crown‐6)‐2,3,11,12‐tetracarboxylic Acid and Their Applications

“…) was not resolved at all. From these results, the N‐H hydrogen at the 1‐position of analytes was proposed to play an important role in the chiral recognition for the resolution of 3‐amino‐5‐phenyl (or 5‐methyl)‐1,4‐benzodiazepin‐2‐ones on CSP 1 …”

“…CSP 1 was also successfully applied to the resolution of 3‐amino‐5‐phenyl (or 5‐methyl)‐1,4‐benzodiazepin‐2‐ones (Fig. ), which are chiral precursors of antirespiratory syncytial virus (RSV) active agents . Among eight analytes resolved on CSP 1 , seven analytes were resolved quite well with separation factors (α) of 1.42–1.58 and resolutions (R S ) of 1.97–2.75, but one analyte containing a methyl group instead of N‐H hydrogen at the 1‐position (see the structure of 3‐amino‐5‐phenyl‐1,4‐benzodiazepin‐2‐one in Fig.…”

“…After that, other CSPs based on (3,3’‐diphenyl‐1,1’‐binaphthyl)‐20‐crown‐6 dynamically coated on octadecyl silica gel or covalently bonded to silica gel were developed and reported to be successful in the resolution of racemic compounds containing a primary amino group. For example, α‐amino acids, β‐amino acids, primary amino alcohols, chiral primary amines, and various chiral drugs such as fluoroquinolone antibaterials, cathinone (central nervous system stimulant), tocainide (antiarrhythmic agent), 3‐amino‐5‐phenyl‐1,4‐benzodiazepin‐2‐ones, mexiletine (antiarrhythmic agent), and valacyclovir (a prodrug for the treatment of patients with herpes simplex and herpes zoster) were resolved well on the CSPs based on (3,3’‐diphenyl‐1,1’‐binaphthyl)‐20‐crown‐6 covalently bonded to silica gel.…”

Synthesis and Enantiomeric Recognition Studies of Novel C2-Symmetrical Chiral Tetra-Amide Compounds

“…Since the pioneering research on the application of chiral recognition reported by Cram and coworkers, great number of chiral macrocyclic and complex structured ligands have been synthesized and studied for enantiomeric recognition of racemic compounds (Nakashima et al, 2000;Lu et al, 2010;Lee et al, 2010;Deniz et al, 2011;Park et al, 2012;Sipos et al, 2012;Bako et al, 2012;Howard et al, 2013;Yi et al, 2013;Tsioupi et al, 2013;Paik et al, 2013;Guo et al, 2013;Liu et al, 2014;Şeker et al, 2014) However, in recent years non-cyclic ligands have begun to be used in enantiomeric recognition studies (Peri et al, 1998;Liu et al, 2001;Wang et al, 2007;Ballistreri et al, 2010;Aral et al, 2013;Kormos et al, 2013;Ulatowski and Jurczak, 2014;Pal et al, 2015;Forte et al, 2015;Pal et al, 2016). Still there are limited papers have been reported on the using non-cyclic ligands as chiral receptor for enantiomeric recognition of the racemic compounds.…”