Dávid Kozma

CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation

INTRODUCTION BASIC CONCEPTS AND NOMENCLATURE OF STEREOCHEMISTRY Chirality, Enantiomers and Diastereomers Stereochemical Nomenclature Principles of Separation of Diastereomers and Enantiomers RESOLUTION BY FORMATION AND FRACTIONAL CRYSTALLISATION OF DIASTEREOMERIC SALTS The Concept of Resolvability Stoichiometry of Resolution Resolution with One Equivalent of Resolving Agent Resolution with Half Equivalent of Resolving Agent in Combination with an Achiral Additive Use of Half Molar Equivalent of Resolving Agent without an Achiral Additive Salt-Salt Resolution Resolution with the Enantiomer of the Resolving Agent Reciprocal Resolution Mutual Resolution Resolution with Difunctional Resolving Agents Resolution of Amphoteric Racemates Resolution by Salt Formation of Compounds Lacking Acidic or Basic Groups Asymmetric Transformations during Resolution by Salt Formation RESOLVING AGENTS Basic Resolving Agents Acidic Resolving Agents (Including Amino Acids) RESEARCH ON RESOLVING AGENTS Attempts to Devise A Generally Applicable Resolving Agent Correlation of the Efficiency of Resolution with the Structure of Racemate and Resolving Agent. Resolutions with a Derivative of the Racemate Resolutions with a Mixture of Structurally Similar Resolving Agents SELECTION OF THE RESOLVING AGENT SELECTION OF THE RESOLVING AGENT BY EXPERIMENTATION Selection of the Resolving Agent by Small-Scale Preliminary Preparative Experiments Selection of the Resolving Agent by Combined Application of Several Resolving Agents Selection of the Resolving Agent by Distillation Tests Selection of the Resolving Agent Based on the Principle of Maximum Similarity Selection of the Resolving Agent by Statistical Evaluation SELECTION OF A RESOLVING AGENT BASED ON THE DETERMINATION OF PHYSICO-CHEMICAL PARAMETERS Solubility Selection of a Resolving Agent Based on Melting Point Phase Diagrams of Diastereomeric Salt Pairs Calculation of Resolvability by DSC of a Mixture of Diastereomeric Salts Formed from the Racemate Determination of the Optical Rotation of Diastereomeric salts SELECTION OF THE RESOLVING AGENT BASED ON THEORETICAL CONSIDERATIONS RESOLUTION IN PRACTICE, SELECTION OF THE OPTIMAL PARAMETERS Reacting the Components Initiation of Crystallisation Role of Temperature in Resolution Further Purification of Diastereomeric Salts with the Aid of a Chiral Additive Recovery of the Components from the Diastereomeric Salts Upgrading of Optical Purity without a Chiral Additive (Enantiomeric Enrichment) ALTERNATIVE METHODS OF RESOLUTION BY DIASTEREOMERIC SALT FORMATION Classification of Alternative Resolution Processes by Type of Phase Transition Resolution by Distillation Resolution by Extraction Resolution by Supercritical Extraction Resolution by Sublimation Mechanical Separation of Diastereomeric Salt Mixtures DETAILED DESCRIPTIONS OF SELECTED RESOLUTIONS APPENDIX 1: Resolutions Ordered According to the Resolving Agent APPENDIX 2: Commercially Produced Resolving Agents and Optically Active Industrial Products which may be Eligible as Resolving Agents APPENDIX 3. Chiral Selective Chromatographic Analysis

Optical Resolution of Racemic Alcohols via Diastereoisomeric Supramolecular Compound Formation with O,O′-Dibenzoyl-(2R,3R)-tartaric Acid

Abstract O , O ′-Dibenzoyl-(2 R ,3 R )-tartaric acid (DBTA) forms a hydrogen bonded supramolecular compound with alcohols. The supramolecular compound formation is enantioselective for a large number of chiral alcohols, therefore DBTA can be used as resolving agent, also for compounds having no basic group. The condition of the complex formation is that the guest molecule should contain a proton donating group and a fitting aliphatic chain or cycloalkane ring.

Study of the diastereoisomers formed between (N-alkyl)-pipecolic acid-anilides and 2R,3R-tartaric acid or O,O′-dibenzoyl-2R,3R-tartaric acid. Do the tartaric acids form molecular-complexes, instead of salts during optical resolutions?

It was found that during the optical resolution of (N-alkyl)-pipecolic acid-anilides by 2R,3R- tartaric acid and O,O′-dibenzoyl-2R,3R-tartaric acid that the precipitated diastereoisomer was not the salt but a diastereoisomeric complex in 8 cases from 13. The results indicate that tartaric acids may be used as general resolving agents for optical resolution of racemates even having no basic group.

Predictions of which diastereoisomeric salt precipitates during an optical resolution via diastereoisomeric salt formation

Abstract The DSC data of sixteen conglomerate forming diastereoisomeric salt pairs were analysed. It was demonstrated that during optical resolution via fractional crystallization of diastereoisomeric salt pairs always that diastereoisomeric salt precipitates which has the higher melting point. When one of the salts is amorphous that remains in the mother liquor. If one of the diastereoisomeric salt crystallizes with solvate that will precipitate during optical resolutions.

Racemic compound formation–conglomerate formation. Part. 1. Structural and thermoanalytical study of hydrogen malonate, hydrogen phthalate and hydrogen succinate of α-phenylethylamine

The crystal structure of (R,S)-α-phenylethylammonium hydrogen phthalate (RACPHP)[P21/a; a= 8.503(3), b= 16.748(5), c= 10.544(3)A, β= 104.48(2)°; Z= 4; R= 0.058 based on 2412 observed reflections] and (R,S)-α-phenylethylammonium hydrogen malonate (RACPHM)[P; a= 8.768(1), b= 9.014(1), c= 7.485(1)A, α= 104.31(1), β= 96.95(1), γ= 91.68(1)°; Z= 2; R= 0.069 based on 2061 observed reflections] were determined and compared with each other and with the known crystal structure of the (R)-α-phenylethylammonium hydrogen succinate (KACBEV). The structural and thermoanalytical investigations of the salts proved that the hydrogen phthalate and hydrogen malonate anions form racemic compounds while the hydrogen succinate anion forms a conglomerate, the latter being the only one which could be resolved by preferential crystallization.The comparison of the structures revealed that the hydrogen bonding network of RACPHP [S(7)C22(9)R44(18)R88(30)C44(12)] and RACPHM [S(6)C22(8)R44(12)R44(16)] are very similar (represented by graph theory), while KACBEV [C11(7)C22(9)R33(8)R33(13)] is different. Intramolecular hydrogen bonds through acidic hydrogens are formed only between the carboxylic groups of the racemic compounds.

Enantiomeric enrichment by the use of density differences between racemic compounds and optically active enantiomers

Abstract A new method for enantiomeric enrichment has been elaborated. Enantiomeric mixtures in an inert solvent having a difference between the densities of the racemate and the optically pure enantiomer separate into upper and lower layers having different optical purity. A new method for enantiomeric enrichment has been elaborated. Enantiomeric mixtures in an inert solvent having a difference between the densities of the racemate and the optically pure enantiomer separate into upper and lower layers having different optical purity.

ISOMER AND ENANTIOMER SEPARATION OF 2- AND 4-ALKYL-CYCLOHEXANOLS BY STEREOSELECTIVE COMPLEX FORMATION WITH O,O′-DIBENZOYL- (2R,3R)-TARTARIC ACID

Stereoisomeric mixtures of 2- and 4-alkyl-cyclohexanols form complex with O,O′-dibenzoyl-(2R,3R)-tartaric acid. The diastereoisomer complex formation can be used for isomer and enatiomer separation as it is trans- and enantioselective in the case of 2-alkyl-cyclohexanols and trans-selective in the case of 4-alkyl-cyclohexanols.

Optical resolution of mandelic acid by cinchonine in different solvents

Abstract During optical resolution of racemic mandelic acid by cinchonine the S-mandelate as a hydrate, the R-mandelate or the R-mandelate with ethylacetate solvate precipitates depending on the solvent.

Investigation of the physicochemical basis of enantiomeric enrichment: The example of ?-phenylethylamine with achiral dicarboxylic acids

We investigated the enantiomeric enrichment of enantiomeric mixtures of alpha-phenylethylamine by achiral dicarboxylic acids. As achiral agents oxalic, malonic, fumaric, and phthalic acids were used. The results of the enantiomeric enrichment via partial salt formation followed by distillation were compared with enantiomer separation via crystallization of the neutral salt. Without the presence of a solid phase, enantiomeric separation is impossible. Our results show that the properties of the solid phase determine the separation. It is also confirmed by our observation that the eutectic points, which are observed on the 3-phase solubility diagrams of the solid neutral salts, can be found at the same initial enantiomeric composition as the point of intersection of distillate and residue of the distillation curves and the point of intersection of precipitated salt and mother liquor of the crystallization curves. Copyright 2000 Wiley-Liss, Inc.

Study of the Mechanism of Optical Resolutions Via Diastereoisomeric Salt Formation Part 4. The Role of the Crystallization Temperature in Optical Resolution of Pipecolic Acid Xylidides

Abstract The role of the crystallization temperature was investigated during the optical resolutions of some pipecolic acid xylides by 2R,3R-tartaric acid and O,O-dibenzoyl-2R,3R-tartaric acid. In 4 cases from 5 the temperature optimum of the crystallization was found between 45-50 °C, which is much higher than the usual crystallization temperature. A few trial resolutions may be enough to determine the temperature optimum of the crystallization graphically.