Resolution salt formation

Racemic mixtures of sulfoxides have often been separated completely or partially into the enantiomers. Various resolution techniques have been used, but the most important method has been via diastereomeric salt formation. Recently, resolution via complex formation between sulfoxides and homochiral compounds has been demonstrated and will likely prove of increasing importance as a method of separating enantiomers. Preparative liquid chromatography on chiral columns may also prove increasingly important it already is very useful on an analytical scale for the determination of enantiomeric purity. 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

Optica] resolution of these and related carboxylic acids were achieved using salt formation with alkaloids (strychnine, brucine, cinchonidine) 33,39,44 or with optically active amines [1-phenyl- or l-( 3-naphthyl)ethylamine]4o,44). The following rotations [a]D have been reported [8]paracyclophanecarboxylic acid (13) +18° (chloroform)441 [10]homologue (14) +80° (chloroform)39 and +67° (chloroform)40 its methyl-derivative (75) —28° (methanol)44 . Dioxa[10]paracyclophanecarboxylic acid (16) + 104° (ethanol)36 and bromo-dioxa[12]paracyclophanecarboxylic acid (79) —37° (acetone)33). 

This was first experimentally verified for the [2.2]metacyclophane-4-carboxylic acid (55) which had to be prepared by an elaborate 7-step synthesis 771 in order to avoid an electrophilic substitution which might have led to a transanular ring closure (as had been observed in so many cases of [2.2]metacyclophanes)12). The resolution of 55 was accomplished via salt formation with (-t-)-l-phenylethylamine and gave the levorotatory acid ([a]D —9° in CHC13) which then was transformed into several optically active derivatives. The enantiomeric purity of 55 (and therefore of all compounds correlated with it) was confirmed by nmr spectroscopy of the diastereo-meric esters with (—)-l-phenylethanol77) as well as by HPLC of its diasteromeric naphthylamides 55). 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

Acs, M., Fogassy, E., Kassai, Cs., Kozma, D., and Nogradi, M. CRC Handbook of Optical Resolutions via Diastereoisomeric Salt Formation, Ed. Kozma, D., CRC Press, Boca Raton, 2002. 

Fogassy, E., Acs, M., Faigl, F., Simon, K., Rohonczy, J., and Ecsery, Z. Pseudosymmetry and chiral discrimination in optical resolution via diastereoisomeric salt formation. The crystal structures of (R)- and (5)-N-methylamphetamine bitartarates, J. Chem. Soc. Perkin Trans 2. 1986, 1881-1885 Acta Cryst. S. 1985, 40A C81. 

Kozma, D., and Fogassy, E. Solvent-free optical resolution of N-methylamphetamine by distillation after partial diastereoisomeric salt formation, Chirality, 2001,13, 428-430. 

New Industrial-scale Resolution by Diastereomeric Salt Formation Utilizing Molecular Recognition Mechanism... 

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. 

PROSPECT OF INDUSTRIAL RESOLUTION BY DIASTEREOMERIC SALT FORMATION... 

Kozma, D. Ed., (2002) CRC handbook of Optical Resolution via Diastereomeric salt Formation, CRC Press, Boca Raton Florida. 

Sakai, K., Saigo, K., Murakami, H., Nohira, H. (1993) Relation between molecular structure and resolvability on optical resolution via diastereomeric salt formation, Symposium on Chiral Compounds (Tokyo), Oct 22. 

Sakai, K., Sakurai, R., Yuzawa, A. and Hirayama, N. (2003) Practical continuous resolution of a-amino-E-caprolactam by diastereomeric salt formation using a single resolving agent with a solvent switch method, Tetrahedron Asymmetry 14, 3713-3718. 

Another classic resolution process developed by Ethyl Corp. for (S)-ibuprofen production uses (S)-(-)-a-methylbenzylamine (MAB) as the chiral base for diastereomeric salt formation 49 The difference in solubility between (S)- and (ft)-ibuprofen MAB salts is so substantial that only half an equivalent of MAB is used for each mole of racemic ibuprofen, and no seeding is needed. The process can also be performed in a wide range of solvents, and the unwanted (ft)-ibuprofen can be recycled conveniently by heating the mother liquor in sodium hydroxide or hydrochloric acid. Other designer amines have been developed for resolution of ibuprofen with good stereoselectivities,50 but these chiral amines were prepared specifically for ibuprofen resolution and are thus unlikely to be economical for industrial production. 

CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation, Kozma, D., Ed., CRC Press Boca Raton, 2002. 

In this chapter some of the recent developments in crystallization-induced resolution are presented. After an introduction to the state-of-the-art of resolution by diastereoisomeric salt formation and some recent developments in identifying new resolving agents, the new and coming generation of automated screening and speed in development will be discussed. 

The typical technologies used for the preparation of amines have also been used for the synthesis of optically pure (R)- or (S)-l-aminoindane. For example, resolution approaches include the diastereoisomeric salt formation of racemic A-bcnzyl- l -aminoindane with (,S )-mandclic acid41 or (R,R) tartaric acid,42 which resulted in, after hydrogenation, (R)-l-aminoindane with >99% ee. Also, resolutions that use enzymatic acylation concepts have been described.43 44 The maximum theoretic yield of 50% is a clear limitation of these methods. Asymmetric synthetic approaches to chiral 1-aminoindanes have been described, including enantioselective hydrosilylation of l-indanoxime45 46 and hydroboration of indene 47 However, ee values were low to moderate. 

The possibility of separating dilevalol from labetalol was considered as an option at the commencement of the dilevalol project. However, it quickly became clear, from work carried out in both Research and Development, that this approach might not be a viable option. Although the racemic pairs (RR + SS and RS + SR) were separable by crystallization, and although the optical resolution of the RR and SS enantiomers could be achieved through salt formation with a chiral acid, the direct yield of dilevalol was less than 20%. Nevertheless, it was recognized that if the recovery and recycling of the waste streams from the physical and optical resolutions could be carried out efficiently, considerable economies would be obtained (Scheme 1). 

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