Application of Crystallization Inhibitors to Chiral Separations. 1. Design of Additives to Discriminate between the Racemic Compound and the Pure Enantiomer of Mandelic Acid (original) (raw)
Related papers
Chiral co-crystallization for enantiomer separation
2010
This report concentrates on the possibility of separating a mixture of enantiomers by cocrystallization. To discover this area in a systematic way, two main tracks are followed: solubility prediction of organic compounds and experimental co-crystallization. The determination of the pure component solubility is one of the key steps in co-crystal screening: the region in the phase diagram in which the co-crystal is formed, depends on the solubility of the pure components. It turned out that the prediction of the solubility is not accurate enough to play an important role in designing co-crystals. UNIFAC can be used for preliminary estimations of the solubility, PC-SAFT looks more promising, but this method needs at least five solubility points to be able to calculate the solubility. Experimental co-crystallization is devided into two sub-topics: atenolol and amino acids. RSatenolol forms a solid solution and DL-amino acids form a racemic compound or a conglomerate. A couple of co-formers were tested. RS-atenolol and L-MA form a salt, which is very stable in ethanol at low concentration of L-MA. Atenolol with dibenzoyl-L-tartaric acid forms two liquid phases in ethanol: a liquid and a viscous oil phase. No crystals could be obtained from this combination, even not at long storing at room temperature. Only hydrophobic amino acids formed co-crystals during cooling crystallization. Due to steric hindrance, only D-L combinations of amino acids can be co-crystallized, this leads to separation of enantiomers. Separations were performed for DL-Val with L-Phe and for DL-Phe with L-Phe and L-Leu. Both DL-Phe and DL-Val are racemic compounds. The separation of DL-Val with L-Phe was the easiest one, for the crystal growth of Land DL-Val is prevented by L-Phe. Only the co-crystal was obtained as solid phase. The L/D ratio for the separation of Val is 0.75. The stability of DL-Phe was larger than DL-Val, thus the separation of enantiomers was only possible at a L/D ratio of max.
A hybrid process for chiral separation of compound-forming systems
Chirality, 2010
The resolution of chiral compound-forming systems using hybrid processes was discussed recently. The concept is of large relevance as these systems form the majority of chiral substances. In this study, a novel hybrid process is presented, which combines pertraction and subsequent preferential crystallization and is applicable for the resolution of such systems. A supported liquid membrane applied in a pertraction process provides enantiomeric enrichment. This membrane contains a solution of a chiral compound acting as a selective carrier for one of the enantiomers. Screening of a large number of liquid membranes and potential carriers using the conductor-like screening model for realistic solvation method led to the identification of several promising carriers, which were tested experimentally in several pertraction runs aiming to yield enriched (1)-(S)-mandelic acid (MA) solutions from racemic feed solutions. The most promising system consisted of tetrahydronaphthalene as liquid membrane and hydroquinine-4-methyl-2-quinolylether (HMQ) as chiral carrier achieving enantiomeric excesses of 15% in average. The successful production of (1)-(S)-MA with a purity above 96% from enriched solutions by subsequent preferential crystallization proved the applicability of the hybrid process.
Chiral separation by combining pertraction and preferential crystallization
Chemical Engineering and Processing, 2013
This work describes the application of a hybrid two-step enantioselective separation process. As a first step, pertraction using supported liquid membranes provides an initial enrichment, while the following preferential crystallization delivers the enantiopure crystals as final product. Mandelic acid in water was studied as a model system. Using a suitable chiral selector, pertraction provides enrichments exceeding 10% and reaching up to 20% in the permeate phase, which was sufficient to allow for subsequent selective preferential crystallization. Based on the individual performances of pertraction and crystallization, overall yields and productivities are estimated. The calculated productivities are compared with values achievable in alternatively applicable chromatographic separation processes using chiral stationary phases. The realized hybrid pertraction-crystallization process is in its present state for the example considered still inferior to preparative chromatography. Strategies for further improvement are suggested.
Crystal Growth & Design, 2010
Resolution of mandelic acid (MA), a racemic compound, is presented in this article using direct crystallization from enantiomeric enriched water solutions. Final crystals with enantiomeric excess (ee) of (R)-MA higher than 96.4% were obtained. Because of the presence of the opposite enantiomer ((S)-MA), it was reported that nucleation and growth of (R)-MA was inhibited at the initial stage of the experiment (Perlberg, et al. Ind. Eng. Chem. Res. 2005, 44, 1012-1020. In order to understand the nucleation and growth kinetics of (R)-MA in the presence of (S)-MA, batch crystallization experiments were performed for controlled linear cooling mode with various operating conditions. Nucleation and growth parameters were then estimated by nonlinear fitting the measured liquid concentrations obtained from the signals of in situ attenuated total reflectance infrared (ATR-IR) spectroscopy and online polarimetry with model predictions. The effects of supersaturation, seed amount, cooling rate, and the presence of opposite enantiomer on the growth and nucleation rate of (R)-MA were discussed.
Simultaneous Chiral Resolution of Two Racemic Compounds by Preferential Cocrystallization
2021
We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization.We highlight how the two racemic compounds RS-mandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN:R-ETI and S-Man:S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98%) and mandelic acid (ee~95%) enantiomers
The Separation of Racemic Crystals into Enantiomers by Chiral Block Copolymers
Chemistry - A European Journal, 2002
A series of chiral double hydrophilic block copolymers (DHBCs) was synthesized and employed as additives in the crystallization of calcium tartrate tetrahydrate (CaT). We found that appropriate polymers can slow down the formation of the thermodynamically most stable racemic crystals as well as the formation of one of the pure enantiomeric crystals so that chiral separation by crystallization occurs even when racemic crystals can be formed. In addition, the presence of DHBCs results in major modifications of crystal morphology, creating unusual morphologies of higher complexity. Our study demonstrates the potential application of chiral DHBCs in the control of chirality throughout crystallization, in particular for racemic crystal systems, and also shows that enantiomeric excess of one enantiomer can be maximized by the kinetic control of crystallization.
Chirality, 1997
New chiral host molecules 1 and 2 involving a bulky terpenoid unit and aromatic ethyne spacer groups were synthesized using Pd-catalyzed cross-coupling reactions of (+)-2␣-ethynyl-2-hydroxybornane (4) or (+)-2␣-ethynyl-2-hydroxyfenchane (5) with 9,10-dibromoanthracene. Host compounds 1 and 2 form crystalline inclusions with 1-methoxy-2-propanol (3) in 1:1 and 1:2 stoichiometry, respectively. In the case of 1, complete enantiomer resolution (ee > 99%) of 3 is effected in one cocrystallization step. However, constitutional isomer 2 failed in the enantiomer separation of 3, which might be explained due to the different crystal lattice buildup of these cocrystals.
Organic Communications
This study consists of two parts. In the first part of the study; a Pirkle-type chiral stationary phase was prepared by synthesizing an aromatic amine derivative of (R)-2-amino-1-butanol as a chiral selector and binding to L-tyrosine-modified cyanogen bromide (CNBr)-activated Sepharose 4B and then, packed into the separation column. The chromatographic performance of the separation column was evaluated with racemic mandelic acid and 2-phenylpropionic acid by using phosphate buffers at three different pHs as mobile phase. In the resolution processes, the prepared solutions were loaded onto the separation column at two different concentrations and at three different pHs for each racemic organic acid, separately. Enantiomeric excess (ee%) of the eluates was determined on CHIRALPAK AD-H chiral analytical column by HPLC. The maximum ee% for mandelic acid and 2-phenylpropionic acid was determined to be 60.84 and 27.4, respectively. Separation factors (k 1 ' , k 2 ' , α, and Rs) were calculated for each acid. The structures of the obtained compounds were characterized using the spectroscopic methods (NMR, and elemental analysis). In the second part of the study; enantioselective interactions between the prepared CSP and the analytes have been widely studied by docking, molecular dynamics simulation and quantum mechanical computation methods. The reason of column eluation of rac-2-phenylpropionic acid with lower enantiomeric yield was explained by these techniques.