Enantiomers crystallization-based separation

Because the physical properties of enantiomers are identical, they seldom can be separated by simple physical methods, such as fractional crystallization or distillation. It is only under the influence of another chiral substance that enantiomers behave differently, and almost all methods of resolution of enantiomers are based upon this fact. We include here a discussion of the primary methods of resolution. 

An interesting synthesis of a 17-phosphasteroid system is based on the Diels-Alder reaction of the optically active benzyl phenyl Pw7.i-(2-methoxycarbonylethenyl)phosphine oxide (30) which adds to 1-vinylnaphthalene (31) regioselectively, albeit with low diastereoselectivity 70% d.r. [(17 .2/J)/(1S,2,S)] 65 35). The major 32 and the minor 33 adduct are separated by fractional crystallization and separately converted into the 17-phosphasteroid system 34 and its enantiomer 35, respectively12. 

The second important observation on stereoisomer separation also involved ammonium sodium tartrate. Thirty-four years after Pasteur s observation, Jungfleisch (1882) observed that carefully introducing crystals of the individual isomers into different areas of a supersaturated solution of ammonium sodium tartrate resulted in the growth of isomerically pure crystals. These two observations form the basis for most industrial scale crystallizations for the purification of enantiomers or diastereoi-somers. However, it is more common for a solute to crystallize with the thermodynamically stable crystal form being a compound of the two isomers. This is typically denoted as a racemic compound. Secor (1963) made the first systematic review of optical isomer separation by crystallization, based upon phase behavior. Collet, Brienne, and Jacques (1980) applied systematic thermodynamics to the phase behavior, and developed straightforward methods for correlating the solubilities of isomers. 

One striking example mentioned in this final chapter requires us to bend the term racemate, to include very near racemates that contain a very small enantiomeric excess. Enrichment of such samples by direct crystallization-based methods would typically only be attempted by committed optimists. In such a situation, we could synthesize more of the excess enantiomer preferentially if we had an appropriately asymmetric autocatalytic reaction - our initial excess enantiomer could replicate at the expense of the other. Preparatively, this is the effective separation of the enantiomers we used at the outset. Such a system has its physical realization in the Soai autocatalysis in which a very small enantiomeric excess of a pyrimidyl alcohol is amplified over several cycles to give an almost enantiopure sample of the alcohol (Scheme 1.10) [19]. 

Hereinafter, the possibilities of enantiomer and diastereoisomer separations based on crystallization are shown by known examples. 

On the left are the enantiomers of 1-phenylethylamine. When a racemic mixture of these enantiomers is treated with (5)-malic acid, a proton transfer reaction produces diastereomeric salts. Diastereomers have different physical properties and can therefore be separated by conventional means (such as crystallization). Once separated, the diastereomeric salts can then be converted back into the original enantiomers by treatment with a base. Thus (5)-malic acid is said to be a resolving agent in that it makes it possible to resolve the enantiomers of 1 -phenylethylamine. 

The overall process, illustrated in Scheme 10.4, intercepts the racemate (2) by crystallization from heptane. After separation of the enantiomers using the MCC process, the radafaxine free base is converted to the desired salt directly on treatment with anhydrous HCl. Any mixed fractions from the MCC separation are combined with the epimerized R,R)-enantiomer and fresh racemate for processing, hence generating further radafaxine free base for conversion to the hydrochloride salt. These results were subsequently confirmed in a Proof of Concept study performed on the medium- to large-scale in-house MCC equipment prior to scale-up. 

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