Enantioseparation of (±)-trans-β-lactam Ureas by Supercritical Fluid Chromatography

In this study the enantioseparation of (±)-trans-β-lactam ureas 1a–g by supercritical fluid chromatography (SFC) was examined using different polysaccharide based chiral stationary phases (CSPs), and CO2/alcohol (70:30, V/V) as the mobile phase. The influence of CSP type (coated or immobilized), modifiers (alcohols), additive (isopropylamine), temperature and backpressure on enantioseparation were examined. From five tested columns, only the column filled with tris-(4-methylphenylcarbamoyl) cellulose selector proved superior in terms of broad range substrate acceptability and selectivity. This work is licensed under a Creative Commons Attribution 4.0 International License

Recent Achievements in Simulated Moving Bed (SMB) Technology. Part I.

Tehnologija simuliranog pokretnog ležaja poznata je više od pola stoljeća na području kontinuirane kromatografske separacije binarnih smjesa. Otkrivena i razvijena u petrokemijskoj i industriji šećera, ova tehnologija je prepoznata od strane organskih kemičara u farmaceutskoj industriji kao moćno oruđe za separaciju racemičnih smjesa. Niz godina razvijana je kao standardna laboratorijska metoda, zatim kao postupak za pilotna postrojenja, i konačno kao industrijska metoda za dobivanje kiralnih spojeva u optički čistom obliku. Konačni produkti ove tehnologije su enantiomerno čisti lijekovi te drugi biološki aktivni spojevi i njihovi intermedijari. U prvom dijelu ovog pregleda prikazani su osnovni principi i odabrani primjeri nedavne primjene tehnologije SMB.Simulated moving bed (SMB) technology is over half a century known in continuous chromatographic separation of binary mixtures. Invented and developed in the petrochemical and sugar industries, it was recognized by organic chemists in the pharmaceutical industry as a powerful tool in separation of racemic mixtures. Over the years, it was developed into a standard laboratory, then pilot-plant and finally large-scale method for production of chiral compounds in the optically pure form. Final products of this technology are enantiopure drugs, other biologically active compounds and their intermediates. In Part I of this review, the basic principles and selected examples of recent SMB technology applications are presented

Study of Chromatographic Enantioseparation of the Esters of N-Dinitrobenzoyl (N-DNB) and N-Benzoyl (N-B) α-Amino Acids on Novel Chiral Stationary Phases Containing Structurally Matching N-DNB and N-B-α-AA Amides in the Chiral Selector

Enantioseparation ability and enantiopreference of chiral stationary phases CSP 1–CSP 3, containing a terminal N-3,5-dinitrobenzoyl (N-DNB) unit, and CSP 4, containing a terminal N-benzoyl (N-B) unit, are studied. Separation factors (α) for the two sets of test racemates (TR) that structurally match the chiral selector of these CSPs have been determined. The first set consists of seven N-DNB α-amino acid isopropylesters (TR 1A–TR 7A), and the second one of their N-B analogues (TR 1–TR 7). The best enantioseparation (αaverage 1.27) is obtained when π-acceptor DNB unit is present in both TR and CSP. One π-acceptor unit, either in the analyte or in CSP, suffices for efficient enantioseparation (αaverage 1.19). Interaction between π-neutral units in the CSP and test racemate does not afford effective enantioseparation (αaverage 1.03). Using (S)-enantiomers of all TRs as standards, CD detection has revealed regular preference of the CSPs for the enantiomers containing amino acid amide of the same absolute configuration. The possible origin of such enantiopreference is discussed

Study of Chromatographic Enantioseparation of the Esters of N-Dinitrobenzoyl (N-DNB) and N-Benzoyl (N-B) α-Amino Acids on Novel Chiral Stationary Phases Containing Structurally Matching N-DNB and N-B-α-AA Amides in the Chiral Selector

Enantioseparation ability and enantiopreference of chiral stationary phases CSP 1–CSP 3, containing a terminal N-3,5-dinitrobenzoyl (N-DNB) unit, and CSP 4, containing a terminal N-benzoyl (N-B) unit, are studied. Separation factors (α) for the two sets of test racemates (TR) that structurally match the chiral selector of these CSPs have been determined. The first set consists of seven N-DNB α-amino acid isopropylesters (TR 1A–TR 7A), and the second one of their N-B analogues (TR 1–TR 7). The best enantioseparation (αaverage 1.27) is obtained when π-acceptor DNB unit is present in both TR and CSP. One π-acceptor unit, either in the analyte or in CSP, suffices for efficient enantioseparation (αaverage 1.19). Interaction between π-neutral units in the CSP and test racemate does not afford effective enantioseparation (αaverage 1.03). Using (S)-enantiomers of all TRs as standards, CD detection has revealed regular preference of the CSPs for the enantiomers containing amino acid amide of the same absolute configuration. The possible origin of such enantiopreference is discussed

Experiments and Models in Enantiorecognition by Chiral Pirkle-type Stationary Phases Containing Aromatic π-Acid Branching Units

An overview of the projects in the authors\u27 laboratory aimed at developing novel chiral stationary phases (CSPs) is presented. Emphasis is put on the origin of the concept of using 2,4,5,6-tetrachloro-1,3-dicyanobenzene (TCDCB) and 4-chloro-3,5-dinitrobenzoic acid (CDNB) as the branching units in the Pirkle-type (brush-type) CSPs. Preparations of nearly a hundred novel CSPs, requiring synthesis of almost three hundred new compounds as intermediates or model structures, are described. Specific recognition properties and enantioselection efficacy of individual CSPs is demonstrated for various sets of test racemates (TR). Correlation between the structure and conformational properties of chiral selectors and racemic analytes is discussed. Specific properties of some CSPs, such as enhancement of their capacity by introducing the tweezer unit in the chiral selector, and catalysis of the enantiomerization process of configurationally unstable analyte are discussed. The mechanism of enantiorecognition of some TRs by structurally related CSPs is suggested

Enantioseparation of syn- and anti-3,5-Disubstituted Hydantoins by HPLC and SFC on Immobilized Polysaccharides-Based Chiral Stationary Phases

The enantioseparation of syn- and anti-3, 5-disubstituted hydantoins 5a–i was investigated on three immobilized polysaccharide-based columns (CHIRAL ART Amylose-SA, CHIRAL ART Cellulose-SB, CHIRAL ART Cellulose-SC) by high performance liquid chromatography (HPLC) using n-hexane/2-PrOH (90/10, v/v) or 100% dimethyl carbonate (DMC) as mobile phases, respectively, and by supercritical fluid chromatography (SFC) using CO2/alcohol (MeOH, EtOH, 2-PrOH ; 80/20, v/v) as a mobile phase. The chromatographic parameters, such as separation and resolution factors, have indicated that Amylose-SA is more suitable for enantioseparation of the most analyzed syn- and anti- 3, 5-disubstituted hydantoins than Celullose- SB and Cellulose-SC in both HPLC and SFC modalities. All three tested columns showed better enantiorecognition ability toward anti- hydantoins compared to syn-hydantoins, both in HPLC and SFC modes. We have demonstrated that environmentally friendly solvent DMC can be efficiently used as the mobile phase in HPLC mode for enantioseparation of hydantoins on the immobilized polysaccharide- based chiral stationary phases

HPLC and SFC Enantioseparation of (±)-<i>Trans</i>-β-Lactam Ureas on Immobilized Polysaccharide-Based Chiral Stationary Phases—The Introduction of Dimethyl Carbonate as an Organic Modifier in SFC

A series of nine racemic trans-β-lactam ureas were analyzed for enantiomer separation by high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC). The separations were performed on three immobilized polysaccharide-based chiral analytical columns (CHIRAL ART Amylose-SA, CHIRAL ART Cellulose-SB and CHIRAL ART Cellulose-SC). In HPLC mode, a normal-phase consisting of n-hexane/2-PrOH (90/10, v/v), a polar organic mobile phase consisting of 100% MeOH or 100% EtOH, and a non-standard mobile phase consisting of 100% dimethyl carbonate (DMC) were investigated. In SFC mode, the mobile phases CO2/alcohol (80/20, v/v) and CO2/DMC/alcohol (MeOH or EtOH; 70/24/6, v/v/v or 60/32/8, v/v/v) were investigated. The best achieved enantioseparation of trans-β-lactam ureas was obtained with an Amylose-SA column. We have shown that the green solvent dimethyl carbonate (DMC) can be efficiently used as a mobile phase in HPLC mode as well as in SFC mode along with the addition of polar organic modifiers (MeOH or EtOH)

Antimicrobial assesment of aroylhydrazone derivatives in vitro

Aroylhydrazones 1–13 were screened for antimicrobial and antibiofilm activities in vitro. N′-(2-hydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (2), N′-(5-chloro-2-hydroxyphenyl-methylidene)-3-pyridinecarbohydrazide (10), N′-(3,5-chloro-2-hydroxyphenylmethylidene)-3-pyridinecarbohydrazide (11), and N′-(2-hydroxy-5-nitrophenylmethylidene)-3-pyridinecarbohydrazide (12) showed antibacterial activity against Escherichia coli, with MIC values (in µmol mL−1) of 0.18–0.23, 0.11–0.20, 0.16–0.17 and 0.35–0.37, resp. Compounds 11 and 12, as well as N′-(2-hydroxy-3-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (6) and N′-(2-hydroxy-5- methoxyphenylmethylidene)-3-pyridinecarbohydrazide (8) showed antibacterial activity against Staphylococcus aureus, with the lowest MIC values of 0.005–0.2, 0.05–0.12, 0.06–0.48 and 0.17–0.99 µmol mL−1. N′-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (7) showed antifungal activity against both fluconazole resistant and susceptible C. albicans strains with IC90 range of 0.18–0.1 µmol mL−1. Only compound 11 showed activity against C. albicans ATCC 10231 comparable to the activity of nystatin (the lowest MIC 4.0 ×10−2vs. 1.7 × 10−2 µmol mL−1). Good activity regarding multi-resistant clinical strains was observed for compound 12 against MRSA strain (MIC 0.02 µmol mL−1) and compounds 2, 6 and 12 against ESBL+ E. coli MFBF 12794, with the lowest MIC for compound 12 (IC50 0.16 µmol mL−1). Anti-biofilm activity was found for compounds 2 (MBFIC 0.015–0.02 µmol mL−1 against MRSA) and 12 (MBFIC 0.013 µmol mL−1 against EBSL+ E. coli). In the case of compound 2 against MRSA biofilm formation, MBFIC values were comparable to those of gentamicin sulphate, whereas in the case of compound 12 and EBSL+ E. coli even more favourable activity compared to gentamicin was observed

Antimicrobial assesment of aroylhydrazone derivatives in vitro

Aroylhydrazones 1–13 were screened for antimicrobial and antibiofilm activities in vitro. N-(2-hydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (2), N-(5-chloro-2-hydroxyphenyl-methylidene)-3-pyridinecarbohydrazide (10), N-(3,5-chloro-2-hydroxyphenylmethylidene)-3-pyridinecarbohydrazide (11), and N-(2-hydroxy-5-nitrophenylmethylidene)-3-pyridinecarbohydrazide (12) showed antibacterial activity against Escherichia coli, with MIC values (in µmol mL–1) of 0.18–0.23, 0.11–0.20, 0.16–0.17 and 0.35–0.37, resp. Compounds 11 and 12, as well as N-(2-hydroxy-3-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (6) and N-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (8) showed antibacterial activity against Staphylococcus aureus, with the lowest MIC values of 0.005–0.2, 0.05–0.12, 0.06–0.48 and 0.17–0.99 µmol mL–1. N-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (7) showed antifungal activity against both fluconazole resistant and susceptible C. albicans strains with IC90 range of 0.18–0.1 µmol mL–1. Only compound 11 showed activity against C. albicans ATCC 10231 comparable to the activity of nystatin (the lowest MIC 4.0 ×10–2 vs. 1.7 × 10–2 µmol mL–1). Good activity regarding multi-resistant clinical strains was observed for compound 12 against MRSA strain (MIC 0.02 µmol mL–1) and compounds 2, 6 and 12 against ESBL+ E. coli MFBF 12794, with the lowest MIC for compound 12 (IC50 0.16 µmol mL–1). Anti-biofilm activity was found for compounds 2 (MBFIC 0.015–0.02 µmol mL–1 against MRSA) and 12 (MBFIC 0.013 µmol mL–1 against EBSL+ E. coli). In the case of compound 2 against MRSA biofilm formation, MBFIC values were comparable to those of gentamicin sulphate, whereas in the case of compound 12 and EBSL+ E. coli even more favourable activity compared to gentamicin was observed