Crystallization diastereomeric salt formation

Sulfoxides were first prepared in optically active form in 1926 by the classical technique of diastereomeric salt formation followed by separation of the diastereomers by recrystallization16 17. Sulfoxides 1 and 2 were treated with d-camphorsulfonic acid and brucine, respectively, to form the diastereomeric salts. These salts were separated by crystallization after which the sulfoxides were regenerated from the diastereomers by treatment with acid or base, as appropriate. Since then numerous sulfoxides, especially those bearing carboxyl groups, have been resolved using this general technique. 

Success or failure in resolution by the diastereomeric salt formation method is not determined only by the molecular structures of compounds used and physical properties of the salt crystals but also by the resolution environment such as solvent. Therefore, the proposed working hypothesis may not always be effective in all combinations of the resolution system. However, this idea will be helpful in minimizing tedious trial error experimental efforts in the laboratory. 

H. Hiramatsu, K. Okamura, 1. Tsujioka, S.-l. Yamada, R. Yoshioka, Crystal structure-solubility relationships in optical resolution by diastereomeric salt formation of DL-phenylglycine with (lS)-(+)-camphor-10-sulfonic acid, J. Chem. Soc. Perkin Trans. 2 (2000) 2121-2128. 

Leusen et al. studied the crystal packing of ephedrine with several phosphoric acid stereoisomers to verify whether a relationship between enthalpy of formation and separation of enantiomers via diastereomeric salt formation exists.They considered four different force fields and determined that the CHARMM program, as implemented in QUANTA, was the best for their application. Their decision was based mainly on the knowledge that non-bonded cutoff distances are larger in CHARMM. A larger cutoff distance is necessary to account for the interaction between different hydrophobic layers in the crystal (interlayer distances of 14—16 A). These authors were unable to quantitatively determine the validity of their hypothesis, although qualitative explanations were derived for their observations. 

The Bridge Between Preferential Crystallization and Diastereomeric Salt Formation 1141... 

In the case of the salt of a racemic acid and a racemic amine, six crystal modifications are possible (Table 5.7), while there are three crystal modifications for the salt of a racemic acid or amine with an enantiopure amine or acid (Table 5.8). If the successful enantioseparation of an amine with an enantiopure acid by diastereomeric salt formation is assumed, the diastereomers in Table 5.8 should obviously be more stable than the double salt and pseudo-diastereomer. Then, the diastereomers in Table 5.7 should be more stable than the other crystal modifications. On the other hand, this assumption leads to the conclusion that the solubilities of the diastereomers in Table 5.8 are largely different from each other. This... 

These results strongly suggest that the probabihty of formation of a conglomerate, which can be enantioseparated by the preferential crystallization, is considerably high for the combinations of racemic acids and racemic amines when the enantiopure component is an efficient resolving agent for its counterpart in the diastereomeric salt formation. 

The important advantage of a direct crystallization is that a chiral compound does not necessarily possess functional groups which are required for diastereomeric salt formation. The disadvantages include its limited applicability because less than 10% of all crystalline race-mates occur as a conglomerates, poor predictability and very sensitive dependence from the experimental conditions. Thus, as mentioned by some authors, even Louis Pasteur would not have succeeded with his very first enantioseparation had he performed the experiment with the mixed cesium-rubidium salt of tartaric acid at temperatures higher than 27 °C [4]. 

The diastereomeric crystallization relies on a different solubility of diastereomeric salts. The first enantioseparation based on a diastereomeric salt formation was performed by Pasteur in 1853 [2,10]. In this example, racemic tartaric acid was resolved as diastereomeric salts with (-t-)-cinchotoxine or (+)-quinotoxine. Diastereomeric complexes may also be of charge-transfer or inclusion type. 

If the decision is made to use a resolution rather than a synthetic route, the question then arises of whether this should be a classical crystallization, a kinetic resolution, or a chromatographic separation. If the compound either contains ionic groups (and a suitable reagent for diastereomeric salt formation is inexpensive and available) or even better, if it crystallizes as a conglomerate, then crystallization may seem the most suitable technique. 

The authors developed a scalable route for the synthesis of the intermediate core 45 in 12 steps and 0.4% yield and successfully implemented at a pilot plant scale. In this multistep synthesis, racemic hydantoin 43 was obtained after crystallization in 4 1 mixture of diastereomers. Separation of enantiomers by diastereomeric salt formation with (/ )-2-phenylglycerol and further crystallization followed by salt break gave single isomer (-)-44, with the targeted l-glutamic acid configuration. 

Probably the most popular and the most preferred method for the resolution of organic acids or bases is a chiral resolution via diastereomeric salt formation. Ionic salts are easily formed and easily crystallized, and after the separation process, an enantiomerically pure separated compound may be easily isolated, and the resolving agent can be recovered and reused (Figure 1.37). Resolution via diastereomeric salt formation involves the acid-base reaction of a racemate with an enantiomerically pure resolving agent. The resulting two diastereomers have different physical properties e.g., the difference in solubility is used to separate them by crystallization. 

Among aU the possible areas discussed previously, the focus of this chapter will be on the two mainstream crystallization processes chiral separation through diastereomeric salts formation and chiral purification by crystallization. To complete the topic, chiral resolution by preference crystallization will also be reviewed and recent development in this area will be highlighted. 

Another interesting example of combining diastereomeric salt formation and racemization was reported by Bhattacharya." In this work, selective crystallization of ibuprofen/lysinate from 1 mol of (/ ,5)-(racemic) ibuprofen and <0.5 mol of (5)-lysine in aqueous ethanol affords either (S)-(- -)-ibuprofen/(5)-lysinate or (/ )-ibuprofen/(5)-lysinate (in preponderance) depending on the crystallization conditions. Then, the unwanted enantiomeric ibuprofen could be recovered from the mother liquor and racemized by a simple, relatively waste-free thermal process. The combination of the thermal racemization process and the selective crystallization technology provides an efficient and environmentally friendly means to prepare (S)-(- -)-ibuprofen lysinate in an overall essentially quantitative yield (Figure 56.8). 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

A second method requires the formation of diastereomeric salts or covalent derivatives, which are in a mobile equilibrium in solution ( First-Order Asymmetric Transformation"). Again, one of the diastereomers crystallizes ( Second-Order Asymmetric Transformation ). 

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