Resolution of (+/-)-ibuprofen using (-)-brucine as a chiral selector by thin layer chromatography

The enantiomeric resolution of (+/-)-ibuprofen into its enantiomers was achieved by TLC on silica gel plate using optically pure (-)-brucine as a chiral selector and acetonitrile-methanol (5:1, v/v) as the solvent system. Spots were located in an iodine chamber. The detection limit was 4.9 microg. The effect of concentration of the chiral selector, temperature and pH on resolution has been studied.     

Direct enantiomeric TLC resolution of dl-penicillamine using (R)-mandelic acid and l-tartaric acid as chiral impregnating reagents and as chiral mobile phase additive

DL-Penicillamine has been resolved into its enantiomers by normal-phase TLC using L-tartaric acid as chiral impregnating reagent as well as chiral mobile phase additive, while (R)-mandelic acid has been found to be successful as a chiral impregnating reagent. The solvent system acetonitrile-methanol-water (5:1:1, v/v) was found to be successful when L-tartaric acid was used as impregnating agent while the solvent combination acetonitrile-methanol-(0.5% l-tartaric acid in water, pH 5)-glacial acetic acid (7:1:1.1:0.7, v/v) was successful as mobile phase as it contained L-tartaric acid as the chiral additive. (R)-mandelic acid was successful as chiral impregnating reagent with ethyl acetate-methanol-water (3:1:1, v/v), as the mobile phase. The effects of concentration of chiral selectors, temperature and pH were examined on enantiomeric resolution. The spots were detected with iodine vapors and the detection limits were found to be 0.12 microg for each enantiomer of penicillamine with L-tartaric acid, under both the conditions, and 0.11 microg with (R)-mandelic acid.     

Direct TLC resolution of atenolol and propranolol into their enantiomers using three different chiral selectors as impregnating reagents

Direct resolution of racemic atenolol and propranolol into their enantiomers was achieved by normal phase TLC on silica gel plates impregnated with optically pure L-tartaric acid, (R)-mandelic acid and (-)-erythromycin as chiral selectors. Different solvent systems were worked out to resolve the enantiomers. Spots were detected using iodine vapour. The TLC method was validated for linearity, limit of detection and limit of quantification. The influence of pH, temperature and concentration of chiral selector was studied.     

Resolution and isolation of enantiomers of (±)‐isoxsuprine using thin silica gel layers impregnated with l‐glutamic acid,comparison of separation of its diastereomers prepared with chiral derivatizing reagents having l‐amino acids as chiral auxiliaries

Thin silica gel layers impregnated with optically pure l ‐glutamic acid were used for direct resolution of enantiomers of (±)‐isoxsuprine in their native form. Three chiral derivatizing reagents, based on DFDNB moiety, were synthesized having l ‐alanine, l ‐valine and S‐benzyl‐l ‐cysteine as chiral auxiliaries. These were used to prepare diastereomers under microwave irradiation and conventional heating. The diastereomers were separated by reversed‐phase high‐performance liquid chromatography on a C₁₈ column with detection at 340 nm using gradient elution with mobile phase containing aqueous trifluoroacetic acid and acetonitrile in different compositions and by thin‐layer chromatography (TLC) on reversed phase (RP) C₁₈ plates. Diastereomers prepared with enantiomerically pure (+)‐isoxsuprine were used as standards for the determination of the elution order of diastereomers of (±)‐isoxsuprine. The elution order in the experimental study of RP‐TLC and RP‐HPLC supported the developed optimized structures of diastereomers based on density functional theory. The limit of detection was 0.1–0.09 µg/mL in TLC while it was in the range of 22–23 pg/mL in HPLC and 11–13 ng/mL in RP‐TLC for each enantiomer. The conditions of derivatization and chromatographic separation were optimized. The method was validated for accuracy, precision, limit of detection and limit of quantification. Copyright © 2014 John Wiley & Sons, Ltd.     

Thin layer chromatographic resolution of some 2-arylpropionic acid enantiomers using L-(-)-serine,L-(-)-threonine and a mixture of L-(-)-serine and L-(-)-threonine-impregnated silica gel as stationary phases

Impregnated silica TLC plates with L-(-)-serine and L-(-)-threonine and a mixture of L-(-)-serine and L-(-)-threonine (1:1) as chiral selectors were prepared to use as chiral stationary phases (CSPs) in thin layer chromatography. The resolution of the enantiomers of 2-arylpropionic drugs, including ibuprofen, ibuproxam, ketoprofen, pranoprofen, benoxaprofen, flurbiprofen and tiaprofenic acid was investigated on these CSPs. A mobile phase system of acetonitrile-methanol-water (16:4:0.5, v/v/v) was used. The spots were detected with iodine vapours and the detection limits were found to range between 0.25 and 0.5 micro g/mL for all racemic compounds investigated. The effect of temperature, pH and concentration of the impregnating chiral selectors on resolution has been studied.     

Chiral separation of N-methyl-dl-aspartic acid in rat brain tissue as N-ethoxycarbonylated (S)-(+)-2-octyl ester derivatives by GC-MS

A selective and sensitive analytical method was developed for enantiomeric separation and determination of N‐methyl‐DL‐aspartic acid (NMA). The method involved the conversion of each enantiomer into N‐ethoxycarbonylated (S)‐(+)‐2‐octyl ester derivative for the direct separation by gas chromatography–mass spectrometry (GC‐MS). The diastereomeric derivatives showed characteristic mass spectral properties for analysis by selected ion monitoring mode (SIM) and enabling enantioseparation on an achiral capillary column. Two enantiomers were baseline separated, and the detection limits for N‐methyl‐L‐aspartic acid (NMLA) and N‐methyl‐D‐aspartic acid (NMDA) were 0.07 and 0.03 ng/g, respectively. When applied to rat brain tissues for absolute configuration of NMA, only NMDA was determined, while NMLA was monitored as lower than the limit of detection. Copyright © 2012 John Wiley & Sons, Ltd.     

Direct chiral resolution of tartaric acid by ion-pair capillary electrophoresis using an aqueous background electrolyte with (1R,2R)-(-)-1,2-diaminocyclohexane as a chiral counterion

Chiral resolution of native DL-tartaric acid was achieved by ion-pair capillary electrophoresis (CE) using an aqueous-ethanol background electrolyte with (1R,2R)-(-)-1,2-diaminocyclohexane (R-DACH) as a chiral counterion. Factors affecting chiral resolution and migration time of tartaric acid were studied. By increasing the viscosity of the background electrolyte and the ion-pair formation, using organic solvents with a lower relative dielectric constant, resulted in a longer migration time. The optimum conditions for both high resolution and short migration time of tartaric acid were found to be a mixture of 65% v/v ethanol and 35% v/v aqueous solution containing 30 mM R-DACH and 75 mM phosphoric acid (pH 5.1) with an applied voltage of -30 kV at 25 degrees C, using direct detection at 200 nm. By using this system, the resolution (Rs) of racemic tartaric acid was approximately 1. The electrophoretic patterns of tartaric and malic acids suggest that two carboxyl groups and two hydroxyl groups of tartaric acid are associated with the enantioseparation of tartaric acid by the proposed CE method.     

Preparation and application of a chiral stationary phase based on (+)-(1 8-crown-6)-2,3,11,12-tetracarboxylic acid without extra free aminopropyl groups on silica surface

A crown ether-based chiral stationary phase (CSP) without extra aminopropyl groups on the surface of silica gel was newly prepared by bonding (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid to silica gel. The new CSP was applied to the resolution of various racemic alpha-amino acids, amines, and amino alcohols. The chiral recognition efficiency of the new CSP was generally superior to that of the original CSP containing unreacted residual aminopropyl groups on the surface of silica gel in terms of the separation (alpha) and the resolution factors (Rs). The retention behaviors of analytes on the new CSP with the variation of the content of organic and acidic modifiers in aqueous mobile phase were consistent with those on the original CSP in the resolution of alpha-amino acids, but somewhat different in the resolution of racemic amines and amino alcohols from those on the original CSP and the difference was rationalized by the lipophilicity difference of the two CSPs. The effect of the column temperature on the chromatographic resolution behaviors on the new CSP was consistent with that on the original CSP.     

(RS)‐Propranolol: enantioseparation by HPLC using newly synthesized (S)‐levofloxacin‐based reagent,absolute configuration of diastereomers and recovery of native enantiomers by detagging

Diastereomers of (RS)‐propranolol were synthesized using (S)‐levofloxacin‐based new chiral derivatizing reagents (CDRs). Levofloxacin was chosen as the pure (S)‐enantiomer for its high molar absorptivity (ε_o ～ 24000) and availability at a low price. Its ‐COOH group had N‐hydroxysuccinimide and N‐hydroxybenzotriazole, which acted as good leaving groups during nucleophilic substitution by the amino group of the racemic (RS)‐propranolol; the CDRs were characterized by UV, IR, ¹H‐NMR, high resolution mass spectrometry (HRMS) and carbon, hydrogen, nitrogen, and sulphur fundamental elemental components analyser (CHNS). Diastereomers were separated quantitatively using open column chromatography; absolute configuration of the diastereomers was established and the reagent moiety was detagged under microwave‐assisted acidic conditions. (S)‐ and (R)‐propranolol as pure enantiomers and (S)‐levofloxacin were separated, isolated and characterized. Optimized lowest‐energy structures of the diastereomers were developed using Gaussian 09 Rev. A.02 program and hybrid density functional B3LYP with 6‐31G* basis set (based on density functional theory) for explanation of elution order and configuration. In addition, RP HPLC conditions for separation of diastereomers were optimized with respect to pH, concentration of buffer, flow rate of mobile phase and nature of organic modifier. HPLC separation method was validated as per International Conference on Harmonization guidelines. With the systematic application of various analytical techniques, absolute configuration of the diastereomers (and the native enantiomers) of (RS)‐propranolol was established. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis of Deuterium Labeled (±)‐2,5‐Dimethoxyamphetamine (DMA), (±)‐4‐Bromo‐2,5‐Dimethoxyamphetamine (DOB), and (±)‐4‐Methoxyamphetamine (PMA) as Internal Standards for Quantitative Analyses by GC‐MS

DMA, DOB and PMA are increasingly abused central nervous system stimulants with neurotoxic properties. In recent years, many controlled substance analogs (designer drugs) with a large variety of structures have reached the illegal market, making their identification difficult. Therefore, this work studies the synthesis of DOB‐d₆, DMA‐d₆ and PMA‐d₃ as internal standards for use in gas chromatography‐mass spectrometry (GC‐MS) to identify controlled substances.     

Synthesis of arotinoid acid and temarotene using mixed (Z)-1,2-bis(organylchalcogene)-1-alkene as precursor

An efficient and novel total synthesis of the two bioactive retinoids temarotene and arotinoid acid (TTNPB) is described. The key steps in this process include the regio and stereoselective hydrotelluration of thioacetylene 9 and Te/Li transmetalation of mixed (Z)-1,2-bis(organylchalcogene)-1-alkene (Z)-3. The subsequent reaction involving the β-phenylthio vinyl lithiated intermediate 10 with dimethyl sulfate gave the (E)-vinyl sulfide 11. The Ni⁺² cross-coupling of 11 with the corresponding phenylzinc bromide and p-oxazoline phenylzinc bromide 12 afforded the respective temarotene 2 and retinoid-oxazoline substituted 13. Finally, compound 13 was deprotected with HCl to furnish arotinoid acid (TTNPB) 1.     

Enantiomeric separation of D,L-tryptophan and D,L-kynurenine by HPLC using pre-column fluorescence derivatization with R(-)-DBD-PyNCS

The enantiomeric separation of d ,l ‐tryptophan (Trp) and d ,l ‐kynurenine (KYN) was investigated by high‐performance liquid chromatography using pre‐column fluorescence derivatization with a chiral fluorescent labeling reagent, R(−)‐4‐(3‐isothiocyanatopyrrolidin‐1‐yl)‐7‐ (N,N‐dimethylaminosulfonyl)‐2,1,3‐benzoxadiazole [R(−)‐DBD‐PyNCS]. Using an octadecylsilica column, namely, an Inertsil ODS‐3 column (250 × 2.0 mm; i.d., 3 µm), four fluorescence peaks of D‐ and l ‐Trp as well as d ‐ and l ‐KYN derivatized with R(−)‐DBD‐PyNCS were clearly observed, and their chemical structures were confirmed by HPLC–time‐of‐flight–mass spectrometry. Simultaneous separation was achieved under the mobile phase condition of 1.5% acetic acid in H₂O–CH₃CN (60:40), and the separation factors of d ,l ‐Trp and d ,l ‐KYN derivatized with R(−)‐DBD‐PyNCS were 1.22 and 1.19, respectively. Fluorescence detection was carried out by setting the emission wavelength at 565 nm, and the excitation wavelength at 440 nm, and the detection limits were approximately 0.3–0.5 pmol (signal‐to‐noise ratio of 3). Copyright © 2010 John Wiley & Sons, Ltd.     

Kinetic resolution of heterocyclic amines by reaction with optically active acid chlorides. The effect of reaction conditions on the diastereoselectivity of acylation of (±)-3-methyl-2,3-dihydro-4H-1,4-benzoxazine

The influence of the reaction conditions (solvent, base) on the diastereoselectivity of acylation of (±)-3-methyl-2,3-dihydro-4H-1,4-benzoxazine with (S)-naproxen and N-tosyl-(S)-proline chlorides was studied. The highest diastereoselectivity was observed for the reaction carried out in benzene in the presence of aliphatic tertiary amines.     

Direct patterning of poly(amic acid) and low‐temperature imidization using a crosslinker,a photoacid generator,and a thermobase generator

A positive‐type photosensitive polyimide (PSPI) based on poly(amic acid) (PAA), a crosslinker 1,1,1‐tris{4‐[2‐(vinyloxy)ethoxy]phenyl}ethane (TVPE), a photoacid generator (PAG) (5‐propylsulfonyloxyimino‐5H‐thiophen‐2‐ylidene)‐2‐(methylphenyl)acetonitrile (PTMA), and a thermobase generator (TBG) t‐butyl 2,6‐dimethylpiperidine‐1‐carboxylate (BDPC) has been developed as a promising material in microelectronics. The PAA was prepared from 3,3′,4,4′‐biphenyltetracarboxylic dianhydride (BPDA) and 4,4′‐oxydianiline (ODA) in dimethyl sulfoxide (DMSO). The PSPI, consisting of PAA (69 wt %), TPVE (21 wt %), PTMA (3 wt %), and BDPC (7 wt %), showed high sensitivity of 21 mJ/cm² and a high contrast of 6.8 when it was exposed to a 436‐nm line (g‐line), postbaked at 90 °C for 5 min, and developed with 1.69 wt % TMAHaq. A clear positive image of 8 μm line and space pattern was printed on film, which was exposed to 50 mJ/cm² of g‐line by a contact printing mode and fully converted to the corresponding polyimide (PI) pattern on heating at 200 °C, confirmed by FTIR spectroscopy. Thus, this system will be a good candidate for next generation PSPIs. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3362–3369, 2009     

Different approaches of impregnation for resolution of enantiomers of atenolol,propranolol and salbutamol using Cu(II)-l-amino acid complexes for ligand exchange on commercial thin layer chromatographic plates

Atenolol and propranolol (the β-blocking agents) and salbutamol (broncho- and vasodilator) were resolved into their enantiomers by adopting different modes of loading/impregnating the Cu(II) complexes of l-proline (l-Pro), l-phenylalanine (l-Phe), l-histidine (l-His), N,N-dimethyl-l-phenylalanine (N,N-Me₂-l-Phe), and l-tryptophan (l-Trp) on commercial precoated normal phase plates. The three different approaches were (A) using the Cu(II)-l-amino acid complex as chiral mobile phase additive, (B) ascending development of plain commercial plates in the solutions of Cu complex, and (C) using a solution of Cu(II) acetate as mobile phase additive for the commercial TLC plates impregnated with ascending development of plates in the solutions of amino acid. Spots were located using iodine vapour. The results obtained for the three methods have been compared for their efficiency and the issue of involvement of the Cu(II) cation for the best performance of the three methods has been discussed with respect to the same mobile phase. The detection limit is 0.18 μg for each enantiomer.     

Formation of chiral 21-helical columnar host system with phenylacetylene unit by using (1R,2S)-2-amino-1,2-diphenylethanol

A tunable supramolecular phenylacetylene host system with a chiral channel-like cavity is developed by using (1R,2S)-2-amino-1,2-diphenylethanol. This host system possesses a chiral 2₁-helical columnar structure; chiral cavities are constructed by the self-assembly of the 2₁-helical column, and guest molecules are included by varying the packing of this column.     

Self-assembly of diorganotin(IV) 2-{[(E)-1-(2-oxyaryl)alkylidene]amino}acetates: An investigation of structures by X-ray diffraction, solution and solid-state tin NMR, and electrospray ionization MS

The diorganotin(IV) compounds, [Me₂SnL²(OH₂)]₂ (1), [ⁿBu₂SnL²(OH₂)]₂ (2), [ⁿBu₂SnL¹]₃ · 0.5C₃H₆O (3), [ⁿBu₂SnL³]₃ · 0.5C₆H₆ (4) and [Ph₂SnL³]_n · 0.5C₆H₆ (5) (L = carboxylic acid residue, i.e., 2-{[(E)-1-(2-oxyaryl)alkylidene]amino}acetate), were synthesized by treating the appropriate diorganotin(IV) dichloride with the potassium salt of the ligand in anhydrous methanol.The reaction of Ph₂SnL² (L = 2-{[(E)-1-(2-oxyphenyl)ethylidene]amino}acetate) with 1,10-phenanthroline (Phen) yielded a 1:1 adduct of composition, [Ph₂SnL²(Phen)] (6).The crystal structures of 1-6 were determined.The crystal of 1 is composed of centrosymmetric dimers of the basic Me₂SnL²(OH₂) moiety, where the two Sn-centres are linked by two asymmetric Sn-O?Sn bridges involving the carboxylic acid O atom of the ligand and a long Sn?O distance of 3.174(2) Å.The dimers are further linked into columns by hydrogen bonds.The coordination geometry about the Sn atom is a distorted pentagonal bipyramid with the two methyl groups in axial positions.The structure of 2 is similar.The same Sn atom coordination geometry is observed in compound 3, which is a cyclic trinuclear[ⁿBu₂SnL¹]₃ compound. Each Sn atom is coordinated by the phenoxide O atom, one carboxylate O atom and the imino N atom from one ligand and both the exo- and endo-carboxylate O atoms (mean Sn-O(exo): 2.35 Å; Sn-O(endo): 2.96 Å) from an adjacent ligand to form the equatorial plane, while the two butyl groups occupy axial positions. Compound 4 was found to crystallize in two polymorphic forms. The Sn-complex in both forms has a trinuclear [ⁿBu₂SnL³]₃ structural motif similar to that found in 3. In compound 5, distorted trigonal bipyramidal Ph₂SnL³ units are linked into polymeric cis-bridged chains by a weak Sn?O interaction (3.491(2) Å) involving the exocyclic O atom of the tridentate ligand of a neighboring Sn-complex unit. This interaction completes a highly distorted octahedron about the Sn atom, where the weakly coordinated exocyclic O atom and one phenyl group are trans to one another. In contrast, a monomeric distorted pentagonal bipyramidal geometry is found for adduct 6 where the Sn-phenyl groups occupy the axial positions. The solution and solid-state structures are compared by using ¹¹⁹Sn NMR chemical shift data. Compounds 1-6 were also studied using ESI-MS and their positive- and negative-ions mass fragmentation patterns are discussed.     

Dibutyltin(IV) complexes of the 5-[(E)-2-(Aryl)-1-diazenyl]-2-hydroxybenzoic acid ligand: an investigation of structures by X-ray diffraction, solution and solid state tin NMR, electrospray ionisation MS and assessment of in vitro cytotoxicity

A series of dibutylbis{5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoato}tin(IV) complexes, Bu₂Sn(LH)₂, have been prepared and characterized by ¹H, ¹³C, ¹¹⁹Sn NMR and ESI mass spectrometry in solution. The structures of the complexes Bu₂Sn(L¹H)₂ (1), Bu₂Sn(L³H)₂ (3), Bu₂Sn(L⁴H)₂ (4), and Bu₂Sn(L⁶H)₂ (6) (L = 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoate: aryl = phenyl (L¹H), 3-methylphenyl (L³H), 4-methylphenyl (L⁴H) and 4-bromophenyl (L⁶H)) were determined by X-ray crystallography and ¹¹⁷Sn CP-MAS NMR spectroscopy in the solid state. In general, the complexes were found to adopt a skew-trapezoidal bipyramidal arrangement around the tin atom. In addition, there are weak bridging intermolecular Sn?O contacts in complexes 1 and 3, but not in 4 and 6, where one of the hydroxy oxygen atoms from a neighboring molecule coordinates weakly with the Sn atom, thereby completing a seventh coordination site in the extended Sn coordination sphere. The Sn?O distance is 3.080(2) and 3.439(2) Å in 1 and 3, respectively, which are significantly shorter than the sum of the van der Waals radii of the Sn and O atoms (∼3.8 Å). In 1, this Sn?O interaction links the molecules into polymeric chains. In 3, these interactions link pairs of molecules into head-to-head dimeric units. The in vitro cytotoxicity of compound 2 indicates better results than cisplatin and etoposide against seven well characterized human tumor cell lines.     

Di-n-octyltin(IV) complexes with 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoic acid: Syntheses and assessment of solid state structures by Sn Mössbauer and X-ray diffraction and further insight into the solution structures using electrospray ionization MS, Sn NMR and variable temperature NMR spectroscopy

Reactions of 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoic acids (LHH′, where the aryl group is an R-substituted phenyl ring such that for L¹HH′: X = H; L²HH′: X=2′-OCH₃; L³HH′: X = 3′-CH₃; L⁴HH′: X = 4′-CH₃; L⁵HH′:X = 4′-Cl) with ⁿOct₂SnO in 2:1 and 1:1 molar ratios have been investigated. Two types of complexes, ⁿOct₂Sn(LH)₂ and {[ⁿOct₂Sn(LH)]₂O}₂, were isolated and they have been characterized by ¹H, ¹³C, ¹¹⁹Sn NMR, ESI-MS, IR and ^119mSn Mössbauer spectroscopic techniques in combination with elemental analyses. The crystal structures of ⁿOct₂Sn(L¹H)₂ (1), {[ⁿOct₂Sn(L²H)]₂O}₂ (3) and {[ⁿOct₂Sn(L³H)]₂O}₂(4) were determined. The mononuclear complex 1 was found to adopt a skew-trapezoidal bipyramidal arrangement around the tin atom while 3 and 4 are centrosymmetric tetranuclear bis(dicarboxylatotetrabutyldistannoxane) complexes containing a planar Sn₄O₂ core in which two μ₃-oxo O-atoms connect an Sn₂O₂ ring to two exocyclic Sn-atoms. The solution structures were confirmed by ¹¹⁹Sn NMR spectroscopy by observing one tin resonance in compound 1 and two tin resonances in {[ⁿOct₂Sn(L⁵H)]₂O}₂ (5). {[ⁿOct₂Sn(L²H)]₂O}₂ (3) and {[ⁿOct₂Sn(L³H)]₂O}₂ (4) undergo very complex exchange processes in deuteriochloroform solution, which has been confirmed by variable temperature ¹H NMR spectroscopy. The cleavage of the most labile bond in the molecule was studied by ESI mass spectrometry.