Crystallizationinduced Asymmetric Transformations

The 50% yield limit of a resolution can be exceeded if the diastereoisomers can be equilibrated in the solu tion (i.e. dD ^ ID) at a rate faster than the crystallization of the least soluble one. Such a phenomenon was first reported by Leuchs in 1913; he isolated in 94% yield a single diastereoisomeric salt after reaction of an easily racemizable racemic acid with brucine. In addition to the requirement that the diastereoisomers must epimerize easily, processes of this type can only be successful if the dias-tereoisomer system belongs to the eutectic type. In Figure 5, the starting material has composition O (overall concentration C0). In the liquid phase, the composition of the diastereoisomer mixture in chemical equilibrium is indicated by L, which in the case shown is slightly shifted towards the n species. The final equilibrium state is featured by N, representing the overall composition of the system at the end of the process. System N consists of pure solid p in equilibrium with liquid L. The yield in diastereoisomer p is proportional to LN/Lp, and can be derived from C0 and the composition of the liquid in equilibrium (Ceq):

Accordingly, yields approaching 100% can only be obtained in poor solvents, in which Ceq is very small. Typically, Ceq = 2 g% and C0 = 20 g% would give a Y of nearly 92%. In contrast to the case of a classical resolution, the yield does not depend directly on the location of the eutectic. However, it is the distance between the eutectic E and the equilibrium solution L which provides the driving force for the process, and this is why, again, a eutectic close to the edges of the phase diagram is preferable.

There are many examples of such processes in industry. They can be performed on diastereo-isomeric salts (e.g. phenylglycine camphorsulfonate) as well as on covalent diastereoisomers (e.g. in the Roussel-Uclaf synthesis of the insecticide deltameth-rin).

Figure 5 Crystallization-induced asymmetric transformation of diastereoisomers. In the solubility isotherm shown, L represents the composition of the liquid in which the two diastereoisomers are in chemical equilibrium (here with a slight excess of n). This liquid is itself in physical equilibrium with the solid, consisting of pure p. After completion of the chemical and physical equilibrations, the starting system Owill be converted into the final system N, consisting of solid pin equilibrium with liquid L.

Figure 5 Crystallization-induced asymmetric transformation of diastereoisomers. In the solubility isotherm shown, L represents the composition of the liquid in which the two diastereoisomers are in chemical equilibrium (here with a slight excess of n). This liquid is itself in physical equilibrium with the solid, consisting of pure p. After completion of the chemical and physical equilibrations, the starting system Owill be converted into the final system N, consisting of solid pin equilibrium with liquid L.

Crystallization-induced asymmetric transformations of enantiomers forming conglomerates can also be carried out by combining entrainment techniques with simultaneous racemization of the substrate in the solution. Although a number of examples have been described, and a number of patents have been filed, only a few processes of this type have reached commercial application.

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