Microcrystalline Cellulose Triacetate Research Articles

Bis[oxo/thioxothiazolinyl] Aromatic Compounds - Synthesis and Conformational Assignment

A series of bis(oxo/thioxothiazolinyl) aromatic atropisomers with two chiral C(aryl)-N(heterocycle) axes was synthesized. The separation of antiparallel, parallel diastereomers was achieved by chromatography on silica. Conformational assignment for the bis-thione atropisomers 1a,b-4a,b and bis-one atropisomers 9a,b-12a,b was based on polarimetric results in analytical chiral chromatography on microcrystalline cellulose triacetate. The relationship conformation-1H NMR chemical shifts, found for the bis-thiones and bis-ones was successfully applied for the conformational assignment of thione-one atropisomers not assigned by chiral liquid chromatography.

Enantiomer Preference of Trypodendron lineatum and Effect of Pheromone Dose and Trap Length on Response to Lineatin-baited Traps in Interior British Columbia

Both enantiomers of the aggregation pheromone lineatin were obtained in very high enantiomeric purity by preparative chiral liquid chromatography on microcrystalline cellulose triacetate. Catches of the striped ambrosia beetle, Trypodendron lineatum, in multiple-funnel traps baited with lineatin enatiomer ratios (plus/minus) of 100 : 0, 75 : 25, 50 : 50, 25 : 75, and 0 : 100, demonstrated that (+)-lineatin is the only active enantiomer in interior British Columbia, where two other Trypodendron species are sympatric. In additional experiments using (±)-lineatin, catches of both sexes increased significantly with trap length, either at a constant pheromone dose per trap, or a constant dose per four-funnel unit, up to 16 funnels per trap. When trap length was held constant at eight funnels, increasing the lineatin dose fourfold had no effect on trap catches.

Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.

Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.

Kinetic study of the mass transfer of S-Tröger’s base in the system cellulose triacetate and ethanol

A recent study of the mass transfer kinetics of (−)- or S-Tröger’s base (TB) between ethanol and microcrystalline cellulose triacetate (CTA) allows an analysis of the concentration dependence of the mass transfer rate coefficient ( k m). S-TB elutes before R-TB. The retention time of the both compounds decreases with increasing temperature. In this study, experimental data measured between 30 and 50°C were analyzed to provide information on the kinetics of several mass transfer processes which take place in the chromatographic column, i.e., axial and intraparticle dispersion, the fluid-to-particle mass transfer, and the kinetics of adsorption/desorption at the actual adsorption sites. Intraparticle diffusion has the dominant contribution to band broadening at high flow-rates. Both intraparticle diffusivity and the surface diffusion coefficient exhibit a small concentration dependence. The positive dependence of k m on the concentration of S-TB seems to result from the properties of the adsorption/desorption kinetics and can be interpreted by considering the phase equilibrium properties. A quantitative analysis of the activation energy of the mass transfer kinetics of S-TB in the CTA column was also attempted.

Separation of enantiomers of a chiral epoxide by simulated moving bed chromatography

The paper deals with chiral separation by simulated moving bed (SMB) chromatography. The separation of chiral epoxide enantiomers in microcrystalline cellulose triacetate using methanol as eluent is considered as illustrative example. The use of microcrystalline cellulose triacetate for the chromatographic separation of enantiomers is first reviewed and a methodology for obtaining basic data (adsorption equilibrium isotherms, axial dispersion and mass transfer coefficient) is discussed. A model for the prediction of the cyclic steady-state performance of the SMB, based on the analogy with the true moving bed, is developed assuming multicomponent adsorption equilibria, axial dispersion flow and linear driving force approximation to describe the intraparticle mass transfer rate. The simulation package is used to predict the effect of operating variables on the process performance and to define the regions for enantiomer separation. A simple optimization procedure is proposed for choosing the best SMB operating conditions. This procedure is extensively tested for the separation of chiral epoxide enantiomers. The experimental operation of a SMB pilot unit was carried out for this system. Purities and recoveries higher than 90% were obtained for both extract and raffinate, using a 420 ml inventory of stationary phase. The SMB pilot allows the continuous resolution of 52 g of racemic mixture per day and per liter of bed, with a solvent consumption of 0.4 l of mobile phase per gram of racemic mixture processed. The simulation package is also used to predict the steady-state internal concentration profiles for the SMB operation with reasonable agreement with experimental results.

Detailed study of the mass transfer kinetics of Tröger's base on cellulose triacetate

The adsorption isotherm of S-Tröger's base on microcrystalline cellulose triacetate was measured by frontal analysis at several flow-rates between 0.2 and 1.2 ml/min. Two chromatographic models were used in order to study the kinetics of mass transfer between the two phases and to derive plate height values, the equilibrium–dispersive model and the transport model of chromatography. The dependence of the plate height on the flow velocity and on the solute concentration was studied. A modified Van Deemter equation was used to separate the contributions due to slow mass transfer and to axial dispersion.

Enantioselective synthesis of tacrine–huperzine A hybrids. Preparative chiral MPLC separation of their racemic mixtures and absolute configuration assignments by X-ray diffraction analysis

A new synthesis of racemic 7-substituted bicyclo[3.3.1]non-6-en-3-ones, rac- 4, whose key-step involves the reaction of a vinyl triflate, rac- 7, with an organometallic reagent, has been developed. This procedure has been applied to the enantioselective synthesis of (+)- and (−)-7-ethylbicyclo[3.3.1]non-6-en-3-one, (+)- and (−)- 4b, from which both enantiomers of the cholinesterase inhibitor, tacrine–huperzine A hybrid, 9b, have been obtained. Rac- 9b and its related compounds rac- 9a and rac- 10a were separated into their enantiomers on a preparative scale by medium pressure liquid chromatography (MPLC) using microcrystalline cellulose triacetate as the chiral stationary phase. X-ray diffraction analysis of (−)- 10a as the o-iodobenzoic acid salt, allowed us to establish its absolute configuration and deduce those of other enantiopure tacrine–huperzine A hybrids.

Influence of Substituents on the Rotational Energy Barrier of Axially Chiral Biphenyls, II

AbstractThe influence of substituents on the rotational energy barrier of a series of 2,2′‐bis(trifluoromethyl)‐ and 2,2′‐diisopropylbiphenyl derivatives with various substitution patterns was investigated by dynamic gas chromatography (DGC) with selectively modified cyclodextrins and by high‐performance liquid chromatography (HPLC) on microcrystalline cellulose triacetate combined with polarimetry. Investigation of the steric effect of substituents was possible by gradually increasing the bulkiness of substituents in the ortho positions of 2,2′‐disubstituted biphenyls and determination of the corresponding energy barriers. The buttressing effect of alkyl groups adjacent to the ortho substituents is discussed. Comparison of the energy barriers of 2,2′‐bis(trifluoromethyl)biphenyl (1) with its derivatives possessing alkyl groups in positions 3 and 5, respectively, allows a discrimination between the electronic and steric contributions of the meta substituents and thus the determination of the influence on the energy barrier. The electronic effect on the rate of rotation, i.e. the rate of enantiomerization, of axially chiral biphenyls bearing substituents in the para positions depends on the aromatic system to which they are attached. Electron‐donating groups decrease the rotational energy barrier of 2,2′‐bis(trifluoromethyl)biphenyl derivatives but increase the barrier of 2,2′‐diisopropylbiphenyl derivatives. Electron‐accepting groups exhibit the opposite behavior. The unexpected effects in the case of para‐substituted 2,2′‐diisopropylbiphenyl derivatives are possibly related to C–H/π interactions.

Determination of competitive adsorption isotherms of enantiomers on a dual-site adsorbent

The competitive adsorption isotherms of praziquantel enantiomers on microcrystalline cellulose triacetate were determined by concentration pulse chromatography. A model comprising a non-selective linear term and a selective first order improved Langmuir term was found to fit the data excellently. It is postulated that this chiral stationary phase consists of two types of binding sites: one responsible for the chiral, selective interactions and one responsible for the achiral, non-selective interactions of the enantiomers with the stationary phase. The selective sites are easily saturated compared to the non-selective sites, accounting for the experimental observation of lower separation efficiency at higher enantiomer concentrations.

Recovery of (−)-praziquantel from racemic mixtures by continuous chromatography and crystallisation

Enantiomerically pure (−)-praziquantel, an anthelmintic drug, is resolved by coupling a continuous chromatographic process and a multi-stage crystallisation. The partial separation of praziquantel racemic mixture is first achieved by a simulated countercurrent chromatographic (SCC) process. The chiral stationary phase used is microcrystalline cellulose triacetate and the mobile phase is methanol. The SCC system consists of eight identical chromatographic columns (445 mm × 12.5 mm ID) connected in series. At steady state, the raffinate and extract streams contain 97.5% (−)-praziquantel and 85.0% (+)-praziquantel, respectively. The raffinate stream from the chromatographic process is concentrated and allowed to crystallise at −15°C. The crystallisation process is optimised with the aid of the solubility phase diagram determined in a previous study. The recovery of the (−)-praziquantel crystals is maximised by performing a four-stage crystallisation. By coupling these two processes, about 11.7 g of the enantiomerically pure (−)-praziquantel can be obtained per day at an overall recovery of about 80% with the present set-up.

Micro LC on cellulose triacetate (CTA): Influence of particle diameter and column temperature

AbstractFused silica columns (320 μm i.d.) were packed with 10 μm, 15–25 μm, and 25–40 μm microcrystalline cellulose triacetate (CTA) and the influence of the particle diameter on column efficiency was investigated. The dependence of retention, selectivity, resolution, and analysis time on column temperature was studied for the separation of several racemates on microcolumns packed with 15–25 μm CTA. © 1995 John Wiley & Sons, Inc.

Modelling of the competitive isotherms and the chromatographic separation of two enantiomers

Using frontal analysis, we measured the adsorption isotherms of each Tröger's base enantiomers on microcrystalline cellulose triacetate, with ethanol as solvent. The isotherm of the first eluted (−)- enantiomer can be described satisfactorily by the Langmuir equation. The isotherm of the (+)-enantiomer has an inflection point and can be modelled by a quadratic isotherm equation. As a consequence, both the retention time of the (+)-enantiomer and the resolution of a racemic mixture increase with increasing concentration in a certain range. Using the pure enantiomer isotherms and the equilibrium-dispersive model, we could calculate the elution profiles of racemic mixtures of the two enantiomers. At low sample sizes, the bands are well resolved, the competition between the two enentiomers can be neglected in the calculations, and satisfactory band profiles are obtained for the racemic mixture. At high concentrations, the ideal adsorbed solution (IAS) theory was applied to predict the competitive isotherms. Experimental data on the separation of racemic mixtures at high concentrations, including the individual band profiles, are well represented by the results of calculations made with these isotherms.

Asymmetric synthesis by reduction or by oxidation of prochiral substrates absorbed into chiral polymer supports

Prochiral ketones absorbed into chiral polymer supports were reduced with aqueous potassium borohydride. 2-Substituted naphthoquinones absorbed into chiral polymer supports were epoxidized using aqueous alkaline hydrogen peroxide. In both systems asymmetric synthesis was achieved. Best results were obtained with microcrystalline cellulose triacetate as the polymer support: 8.6% ee in a reduction, 4.5% ee in an epoxidation. Use of tetra- n-butylammonium bromide as a phase transfer catalyst tended to improve chemical yields and ees. The potential of this type of approach in asymmetric synthesis is discussed.

Study of band broadening in enantioselective separations using microcrystalline cellulose triacetate: II. Frontal analysis

Frontal analysis is classically used to measure adsorption isotherms, and in this work the isotherms of Tröger's base were determined on microcrystalline cellulose triacetate with ethanol as solvent at 30, 40 and 50°C for the (−)-enantiomer and at 30°C for the (+)-enantiomer. The isotherms of the first eluted (−)-enantiomer are described satisfactorily by the Langimuir equation at all temperatures. In contrast, the isotherm of the longer retained (+)-enantiomer possesses a pronounced inflection point and can be described by a quadratic isotherm equation. However, besides supplying information about the adsorption equilibrium, frontal analysis data can be used to determine kinetic parameters. Using the equilibrium-dispersive model of chromatography, the apparent axial dispersion coefficient was derived by fitting the breakthrough curve for each concentration step. The values are in general agreement with those obtained from the classical determination of the efficiency of elution profiles under linear conditions. However, the apparent dispersion coefficient determined from frontal analysis depends on the concentration.

Study of band broadening in enantioselective separations using microcrystalline cellulose triacetate: I. The linear case

Linear chromatographic data were obtained for the enantiomers of Tröger's base separated on microcrystalline cellulose triacetate with pure ethanol as the mobile phase. The efficiency was determined for flow-rates between 0.1 and 1.0 ml/min at temperatures of 303, 318, 333 and 348 K. The efficiency is poor (below 100 plates) at 303 K, but increases rapidly with increasing temperature. From studies of the effects of these two parameters, the band profile dispersion is attributed to flow anisotropy and adsorption-desorption kinetics. The experimental elution profiles are compared with calculated profiles as a check on the quality of the efficiency measurements.

Preparative resolution of praziquantel enantiomers by simulated counter-current chromatography

The continuous chromatographic separation of a racemic anthelmintic drug, praziquantel, was carried out using a simulated counter-current system. The system consists of four identical columns (445 mm × 12.5 mm I.D.) connected in series through solenoid valves. The chiral stationary phase used is microcrystalline cellulose triacetate and the eluent is methanol. Feed at 50 mg/ml was continuously introduced into the system at 0.3 ml/min and 429 mg/h of (+)-praziquantel and 404 mg/h of (−)-praziquantel were obtained from the extract and raffinate streams, respectively. The optical purity of the products was more than 90%. This method provides an extremely useful technique for preparative-scale enantioseparation. Compared with conventional batch preparative-scale processes, this system offers a higher solute to adsorbent mass ratio.

Thermodynamics of the adsorption of Tröger's base enantiomers from ethanol on cellulose triacetate

The adsorption isotherms of the (−)- and (+)-enantiomers of Tröger's base on microcrystalline cellulose triacetate with ethanol as solvent were measured at 30, 40, 50 and 60°C using frontal analysis. The isotherms of the first eluted (−)-enantiomer can be described satisfactorily with the Langmuir equation at all temperatures. By contrast, the isotherms of the longer retained (+)-enantiomer exhibit a pronounced inflection point in the lower temperature range. This point nearly vanishes at 60°C where the isotherm is almost linear in the concentration range investigated. All these isotherms can be satisfactorily described by a quadratic isotherm equation. The standard thermodynamic functions were derived from these equilibrium data. The enthalpies and the isosteric heats of adsorption are not constant in the temperature region studied. The adsorption enthalpies of both enantiomers increase with increasing temperature. At constant temperature, the isosteric heat of adsorption of the (−)-enantiomer depends only slightly on the stationary phase concentration whereas that of the (+)-enantiomer increases strongly with increasing concentration.

Separation of N‐arylthiazoline‐2‐(thi)‐one atropisomers on p‐methylbenzoyl cellulose beads: A factorial design approach

AbstractA two level full factorial design has been applied to quantify the effect of three selected structural parameters on the capacity factors and chiral separation of atropisomers in N‐arylthiazoline‐2‐(thi)‐ones derivatives on tris(p‐methylbenzoyl) cellulose beads. The behavior of the two enantiomers is influenced by different factors which might result from different retention sites within the same stationary phase. It appears that the two enantiomers behave independently on the CSP, the order of elution and separation being controlled by a minor steric modification in a very precise location in the molecule for one enantiomer. The methodology of the experimental design allows the comparison of equations generated from data issued from designed compounds. These equations afford much more information than the step by step comparison of individual molecules. In our case, the tris(p‐methylbenzoyl)cellulose beads and microcrystalline cellulose triacetate appear as complementary CSPs for the resolution of atropisomers of the series studied. © 1993 Wiley‐Liss, Inc.

Enantiomeric Separation of Ketamine Hydrochloride in Pharmaceutical Formulation and Human Serum by Chiral Liquid Chromatography

Abstract A commercially available microcrystalline cellulose triacetate (CA-1) chiral stationary phase was used for the enantiomeric resolution of ketamine [(±)-2-(2-chlorophenyf)-2-methylaminocyclohexanone]. A simple isocratic and direct liquid chromatographic resolution of racemic ketamine was accomplished without derivatization, using pure ethanol as eluent with flow rate of 1 ml/min and at 25°C. The enantiomeric elution order was determined by chromatographing the racemic ketamine and the separate enantiomers under the similar conditions. The capacity factor (k) for the first eluted peak was 2.2, stereochemical separation factor (α) and stereochemical resolution factor (R) were 2.32 and 3.38, respectively. This method has been applied to determine and identify ketamine enantiomers in human serum and a pharmaceutical dosage form.

Suitable chiral packing material for the high-performance liquid chromatographic separation of derivatives of 1′-hydroxyeugenol

Plants of the genus Coreopsis contain rare phenylpropanoids of the 1′-hydroxyeugenol (Eu) type. To investigate the biological activities of these compounds, 1′-hydroxyeugenol isobutyrate (Eu1) and its derivatives were synthesized. The aim was to separate racemic Eul by high-performance liquid chromatography into its enantiomers on a preparative scale, in order subsequently to synthesize the equivalent esters. To control the stereoselectivity of esterification of Eul, analytical systems investigated for Eu1Eu5 can be utilized. The best results were obtained on microcrystalline cellulose triacetate (CTA), Pirkle Convent phenylglycine and Chiracel OK columns. Racemic Eu1 could be separated on a preparative scale on CTA.