Crystallization Of Diastereomeric Salts Research Articles

Resolution by diastereomeric salts: Access to both enantiomers of racemic acid using the same enantiomer of resolving base.

Racemic carboxylic acid, a Diels-Alder cycloadduct derived from 5-bromo-3-phenyl-α-pyrone and acrylate dienophile, was resolved into enantiomers by diastereomeric salt crystallization. Quinidine was used as a sole resolving base. The salt of (+)-acid crystallized from aqueous acetonitrile solution. Once this salt was separated by filtration, quinidine salt with (-)-acid crystallized from mother liquor. As a result, both enantiomers of Diels-Alder cycloadduct were isolated in high enantiomeric purity.

Population Balance Modeling of Diastereomeric Salt Resolution

Diastereomeric salt crystallization is a classical, widely applicable chiral resolution technique, which enables the separation of the enantiomers of both racemate and conglomerate-forming compounds. A resolution method for racemic pregabalin with l-tartaric acid was developed to obtain pure (S)-pregabalin l-tartrate monohydrate crystals with the yield ranging from 43 to 50%. A series of designed resolution experiments were executed at different cooling rates and temperature end points to estimate the crystallization kinetics using population balance modeling. Inline ATR-FTIR measurements of these experiments were used to calculate concentrations in the crystallization phase and to collect solid–liquid equilibrium data by the solubility trace method after product sampling. Since diastereomeric salts are dissociable ionic compounds, solubility product expressions were used in the model to express the relative supersaturation as the driving force of crystallization. As a result, a population balance model with secondary nucleation, growth, and agglomeration mechanisms was identified, and the simulated supersaturation profiles and product size distributions well reproduced the measured data.

Possibilities of Exploiting Kinetic Control in the Continuous Fractional Crystallization of Diastereomeric Mixtures

For rapid and kinetic control-influenced resolutions, it is advisable to choose a resolving agent with the highest possible eutectic composition (eeEuResAg). It may also be advantageous to add the crystalline resolving agent directly to the solution of the racemic compound. In addition, the use of a quasi-racemic resolving agent or amphoteric resolving agent can provide kinetic resolution. In some cases, the continuous fractional crystallization of diastereomeric salts requires the salt of the resolving agent (Ca2+, Na+, etc.) or other achiral additives (thiourea) that cause rapid crystallization and provide high diastereomeric purity. A further advantage may be the sequential use of the same resolving agent that is capable of forming crystalline diastereomers with both enantiomers when using kinetic control (tandem resolution).

Diastereomeric salt crystallization of chiral molecules via sequential coupled‐Batch operation

A novel process, sequential coupled‐batch diastereomeric crystallization is presented for the resolution of racemic mixtures. This strategy utilized a preferential crystallization of diastereomeric salt followed by sequential coupled diastereomeric salt resolution of racemic ibuprofen with the resolving agent (S)‐lysine utilizing a novel small scale pneumatic liquid exchange design to couple two batch crystallizers. Results were compared to conventional sequential resolution via seeded isothermal batch crystallization. Diastereomeric salt resolution was developed using the ternary phase diagram of the isolated (R)‐ibuprofen‐(S)‐lysine and (S)‐ibuprofen‐(S)‐lysine salts and optimized empirically with the aid of process analytical technology. Sequential coupled‐batch crystallization was found to be capable of increasing the yield of both salts while maintaining purity. This gave an increase in both the productivity and yield (20.5% for (S)‐ibuprofen‐(S)‐lysine) compared to the equivalent sequential batch (17.7% for (S)‐ibuprofen‐(S)‐lysine) crystallization methodology. Single crystals of the (S)‐ibuprofen‐(S)‐lysine were isolated, and its single crystal structure determined. © 2018 American Institute of Chemical Engineers AIChE J, 65: 604–616, 2019

Biocatalytic Approaches to the Synthesis of Enantiomerically Pure Chiral Amines

Enantiomerically pure chiral amines are valuable building blocks for the synthesis of pharmaceutical drugs and agrochemicals. Indeed it is estimated that currently 40 % of pharmaceuticals contain a chiral amine component in their structure. Chiral amines are also widely used as resolving agents for diastereomeric salt crystallization. One of the challenges of preparing chiral amines in enantiomerically pure form is the development of cost-effective and sustainable catalytic methods that are able to address the requirement for the entire range of primary, secondary and tertiary amines. In this review we highlight various biocatalytic strategies that have been developed, particularly those based upon asymmetric synthesis or their equivalent therefore (i.e. dynamic kinetic resolution, deracemisation) in which yields and enantiomeric excesses approaching 100 % can be attained. Particular attention is given to the use of monoamine oxidase (MAO-N) from Aspergillus niger which has been engineered by directed evolution to provide a tool-box of variants which can generate enantiomerically pure primary, secondary and tertiary amines. These MAO-N variants are combined with non-selective chemical reducing agents in deracemisation processes.

A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor Antagonist

An efficient and alternative synthesis of enantiomerically pure (+)-(S)-4-(4-((4-chlorophenyl)(pyrid-2-yl)methoxy]piperidin-1-yl)butanoic acid, bepotastine (1) is described. The key resolution of (R/S)-bepotastine l-menthyl ester (3) is achived via diastereomeric salt crystallization using N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA) as the resolving agent to provide (S)-bepotastine l-menthyl ester (S)-3. Hydrolysis of (S)-bepotastine l-menthyl ester (S)-3 afforded the desired bepotastine (1) with good yields and enantiopurity (> 99%). Finally, bepotastine besilate (4) and bepotastine calcium (5) are achived by salt formation of bepotastine (1) with benzene sulfonic acid and calcium salt respectively. The reaction conditions were optimized to make suitable for commercial scale production.

Solid solutions of quasi-isomorphous diastereomeric salts – kinetics versus thermodynamics

Attempts of racemic resolution by a fractional crystallization of diastereomeric salts of enantiopure resolving agent very often leads to precipitation of solid solutions with different ratios of both diastereomeric salts. Structural investigations of solid solutions can be helpful for a better understanding of the chiral discrimination mechanism which is useful for the rationalization of optical resolution. Based on the crystal structures of a few related solid solutions of brucinium diastereomeric salts and the corresponding diastereomeric salts factors influencing the kinetics and thermodynamics on the molecular recognition leading to the solid solution formation are proposed.

Why Is the Resolution of Certain Racemic Modifications Inefficient? Formation of Diastereomeric Double Salts of Brucinium

Fractional crystallization of diastereomeric salts remains the most frequently used method for a separation of racemic compounds, and yet it has been performed by trial and error. For a better understanding of the chiral discrimination mechanism that is useful for the rationalization of optical resolution and help in choosing the crucial experimental parameters, structural investigations of products of both successful and unsuccessful racemic resolution are important. The former and the latter typically involve diastereomeric salts precipitating fractionally and the formation of solid solutions of diastereomeric salts or diastereomeric double salts, respectively. In this contribution, a mechanism of recognition leading to formation of the diastereomeric double salts is proposed based on crystal structures of three brucinium double salts (bis(brucinium) N-(3,5-dinitrobenzoyl)-dl-alaninate methanol 3-solvate, bis(brucinium) N-(3,5-dinitrobenzoyl)-dl-alaninate 5.75-hydrate, and bis(brucinium) N-(3,5-dinitrobenzoyl)-dl-serinate 0.10-hydrate) as well as of some relevant diastereomeric salts (containing the d- or l-enantiomer of the alanine or the serine derivative).

ジアステレオマー塩法による光学分割の効率化を目指して

In order to overcome trial-and-error situation in the enantioseparation by the diastereomeric salt formation, we carried out systematic studies on the enantioseparation of racemic 1-arylethylamines with/without a substituent on the aryl group by using enantiopure arylglycolic acids. The studies revealed that there are three factors for the growth and stabilization of less-soluble diastereomeric salt crystals; 1)infinite hydrogen bonding interaction to form a 21-column, which enables a crystal to grow in one dimension, 2)effective van der Waals interaction between the columns to make the crystal growable in a three-dimensional manner, and 3)sufficient CH-π interaction in/between the columns, which also play an important role for three-dimensional crystal growth. On the basis of the observations, we propose molecular length rule and aromatic ring rule, which realize efficient van der Waals interaction and CH-π interaction, respectively.Keeping in mind of these requirements for the molecular structure of a resolving agent, we industrialized an elegant process for the enantioseparation of racemic 1-phenylethylamine into the (R)-form, which is one of the most valuable chiral auxiliaries in the synthesis of drugs/drug intermediates in industrial scales, with (R)-mandelic acid upon optimizing conditions such as solvent, molar ratio, concentration, temperature, and additive, as well as the recycling process of (R)-mandelic acid and the racemizing process of (S)-1-phenylethylamine remained.

Rational Screening Approach for Classical Chiral Resolution under Thermodynamic Equilibrium: A Case Study of Diphenyl-Substituted N-Methyl-Piperazine

Separation of racemic mixtures by the formation and crystallization of diastereomeric salts (classical resolution) is an important process in the pharmaceutical industry. We have developed and implemented a high-throughput screening workflow to effectively guide the development and optimization of a thermodynamically favored resolution process. A case study is presented for optical resolution of a diphenyl-substituted N-methyl-piperazine derivative, a racemic compound with a eutectic point of 60% ee. Through a rational screening approach, the effect of equilibrium solubility on resolution efficiency was systematically evaluated with regards to resolving agent, solvent composition, resolving agent stoichiometry, and racemate concentration. An isothermal solubility phase diagram was obtained, and solid-state characterization was performed on the diastereomeric salts to understand their phase behaviors under the optimal resolution conditions. The highest resolution efficiency was achieved when the diastereom...

Factors determining the pattern of a hydrogen‐bonding network in the diastereomeric salts of 1‐arylethylamines with enantiopure P‐chiral acids

In order to clarify factor(s) determining the pattern of a hydrogen-bonding network in the diastereomeric salts of 1-arylethylamines (1) with enantiopure P-chiral acids, three kinds of enantiopure P-chiral alkylphenylphosphinothioic acids (3) were synthesized, and their chiral recognition abilities for racemic 1 were examined. The characteristics of the diastereomeric salt crystals of 1 with 3 were then studied on the basis of their X-ray crystallographic analyses. Statistical analysis on the molecular conformations observed in the diastereomeric salts with 3 as well as those with P-chiral O-alkyl arylphosphonothioic acids (2), which have a chemical structure similar to that of 3, and molecular orbital calculations for 2 and 3 in a gas phase revealed that the torsion angle between the aromatic plane and the P--O(alkoxy in 2) or P--C(alkyl in 3) plays an important role in determining the pattern of a hydrogen-bonding network in the diastereomeric salts, either a closed globular cluster or an infinite 2(1) column type. The calculations also indicated that there is a hydrogen-bonding-like interaction between the ammonium hydrogen atom of 1-arylethylammonium cations and the P--O(alkoxy) oxygen atom of phosphonothioate anions in the clusters.

Synthesis and resolution of new paramagnetic α-amino acids

New, paramagnetic unnatural α-amino acids were synthesized by the O'Donnell method. In the new amino acids nitroxide is condensed with thiophene, benzene, and tetrahydroisoquinoline ring, or linked through a methylene, benzyl or propargyl spacer. Some of the racemic paramagnetic α-amino acid esters described earlier or in this work were resolved by fractional crystallization of diastereomeric salts. Another approach for optically active paramagnetic amino acids is the modification of S-tyrosine derivatives with Pd-catalyzed cross-coupling reactions with paramagnetic acetylene and with a paramagnetic boronic acid.

An Alternative Approach to Achieve Enantiopure (3S)-4-Benzyl-3- (4-fluorophenyl)morpholin-2-one: A Key Intermediate of Aprepitant, an NK1 Receptor Antagonist

An efficient and alternative synthesis of enantiomerically pure (3S)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one (S)-(+)-2), a key intermediate in the synthesis aprepitant (1), is described. The key resolution of N-benzylglycinamide, (±)-9, is achieved via diastereomeric salt crystallization using (+)-di-p-toluoyltartaric acid (DPTTA) as the resolving agent to furnish (S)-(+)-9. Alkylation of (S)-(+)-9 with 2-bromoethanol followed by stereocontrolled cyclization of obtained (S)-(+)-10 afforded the desired enantiomer (S)-(+)-2 with good yields and enantiopurity (>98%). The reaction conditions were optimized to make the process robust in order to implement at the commercial scale.

Substrate Modification Approach to Achieve Efficient Resolution: Didesmethylcitalopram: A Key Intermediate for Escitalopram

Research work presented here describes an approach to achieve the enantiopure escitalopram (1) via didesmethyl escitalopram (4), which is easily resolvable compared to citalopram (1a) through diastereomeric salt crystallization. The resolved intermediate (didesmethylcitalopram) was subsequently used for the preparation of the desired drug. This simple modification of the substrate makes a remarkable difference in the chemical resolution process. The first resolution of didesmethylcitalopram (±)-4 to furnish (+)-4, a novel key intermediate to assemble escitalopram (1) was achieved via diastereomeric salt resolution using (−)-di-p-toluoyltartaric acid (DPTTA). The resolution conditions were optimized; a key feature of this process is the addition of specific quantity of water at a specific temperature to the reaction mixture.

Diastereomeric salt crystallization synthesis for chiral resolution of ibuprofen

AbstractConceptual design and experimental investigations are integrated for synthesizing diastereomeric salt crystallization processes for chiral resolution. An anti‐inflammatory drug ibuprofen and a common resolving agent N‐methyl‐D‐glucamine were chosen to illustrate this integrative approach. Bench data were generated in a systematic manner. Solvent screening was conducted first to identify the right solvent to precipitate the diastereomeric salts. Solid–liquid equilibrium data of the diastereomeric salt system were then measured. Seeding was used to facilitate the precipitation of the desired component. All of this information was used to generate flow sheet alternatives to recover the desired diastereomeric salts. © 2007 American Institute of Chemical Engineers AIChE J 2007

The role of CH/π interaction in the stabilization of less‐soluble diastereomeric salt crystals

Enantiopure 2-naphthylglycolic acid (NGA) and cis-1-aminobenz[f]indan-2-ol (ABI) were rationally designed as new resolving agents on the model of mandelic acid (MA) and cis-1-aminoindan-2-ol (AI), respectively. As expected, NGA and ABI showed superior chiral recognition ability to racemates, compared with MA and AI. In order to clarify any factors governing the chiral recognition abilities of NGA and ABI, the crystal structures of their less- and more-soluble diastereomeric salts were determined by X-ray crystallographic analyses and revealed that CH/pi interactions play an intrinsic role in chiral recognitions. A theoretical investigation was also performed with the periodic ab initio method by using the X-ray crystal structures of the less-soluble salt crystals with AI and ABI to find the unique properties of CH/pi interaction in the crystalline state, which largely contributed to the stabilization of the crystals.

A Facile Synthesis of Optically Active Four Stereoisomers of 1‐Aminobenz[f]indan‐2‐ol.

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A Facile Synthesis of Optically Active Four Stereoisomers of 1-Aminobenz[f]indan-2-ol

Optically active cisor trans-1-aminoindan-2-ol (1) has been utilized as chiral auxiliaries and ligands and as chiral resolving agent for racemic arylalkanoic acids. As an effort to improve the chiral recognition ability of optically active cisor trans-1, recently optically active cisand trans-1aminobenz[f]indan-2-ol (2) were prepared. By enlarging the phenylene group of cisor trans-1 to the naphthalene group of cisor trans-2, the chiral recognition ability was significantly improved because of the more effective CH/π interactions, which have been recognized to play a remarkable role in molecular arrangement in crystals, in the less soluble diastereomeric salt crystals.

Synthesis and chiral recognition ability of O-phenyl ethylphosphonothioic acid with a conformationally flexible phenoxy group for CH/π interaction

Enantiopure O-phenyl ethylphosphonothioic acid 1 was easily obtained by the enantioseparation of racemic 1, which was prepared from commercially available phosphorothioic trichloride in four steps. Enantiopure 1 was found to show an excellent chiral recognition ability for various 1-arylethylamine derivatives during the diastereomeric salt formation. In particular, enantiopure 1 was able to recognize the chirality of o- and m-substituted 1-arylethylamine derivatives, of which the chirality is generally difficult to establish by conventional resolving agents. X-ray crystallographic analyses of the less-soluble diastereomeric salts revealed that the conformation of the phenoxy group in enantiopure 1 could change in the diastereomeric salt crystals and that the excellent chiral recognition ability of enantiopure 1 resulted from the effective CH/π interaction of the phenoxy phenyl group.

Enantiopure O-Substituted Phenylphosphonothioic Acids: Chiral Recognition Ability during Salt Crystallization and Chiral Recognition Mechanism

[structure: see text] The chiral recognition ability of enantiopure O-methyl, O-ethyl, O-propyl, and O-phenyl phenylphosphonothioic acids (1a-d) for various kinds of racemic amines during salt crystallization and the chiral recognition mechanism were thoroughly investigated. The chiral recognition abilities of enantiopure 1a-d for a wide variety of racemic amines varied in a range of 6 to >99% enantiomeric selectivity. Deposited less-soluble diastereomeric salts were classified into two categories, prism- and needle-type crystals; the prism-type crystals were composed of a globular molecular cluster, while there existed a 2(1) column in the needle-type crystals. In contrast to a general observation of a similar 2(1) column in the less-soluble diastereomeric salt crystals of chiral primary amines with chiral carboxylic acids, the globular molecular cluster is a very unique hydrogen-bonding motif that has never been constructed in diastereomeric salt crystals. Excellent chiral recognition was always achieved when the less-soluble diastereomeric salts were prism-type crystals. Significant correlations were found between the degree of the chiral recognition with 1a-d, the crystal shape of the less-soluble diastereomeric salts, and the hydrogen-bonding motif (molecular cluster/2(1) column). The chiral recognition mechanisms via the molecular cluster and the 2(1) column formations are discussed in detail on the basis of X-ray crystallographic analyses.