A fast, new method to enhance the enantiomeric purity of non-racemic mixtures: self-disproportionation of enantiomers in the gas antisolvent fractionation of chlorine-substituted mandelic acid derivatives

Abstract

Gas antisolvent precipitation is a particle formation technique, when typically pressurized carbon dioxide is added to an organic solution resulting in immediate and high oversaturation and precipitation of fine particles. Provided that a reasonable share of the originally dissolved material remains dissolved in the carbon dioxideorganic mixed solvent, these components can be extracted during the washing phase. Then the method is called gas antisolvent fractionation (GASF). GASF has been applied for the first time for enantiomeric enrichment of non-racemic mixtures, demonstrated on the example of chlorinated mandelic acid derivatives. Due to self-disproportionation of enantiomers, the precipitated solid and the extracted fractions have different enantiomeric excesses if GASF is done on a non-racemic mixture. However, there is a limit in the enantiomeric excess (ee) that can be achieved correlating strongly with the atmospheric melting eutectic behavior of the compounds. Thus, if initial enantiomeric mixtures have a higher than eutectic ee, a >99% ee can be reached in the crystalline product. The strong correlation between the high-pressure experiments and the atmospheric melting eutectic behavior suggests that despite the very large oversaturation during the antisolvent precipitation, the composition of the products (i.e. the crystalline and the extracted phases) is thermodynamically determined. Technological advantages such as short operational time, or the possibility of controlling the crystal morphology suggest that the development of an efficient technique of enantiomeric purification is possible based on gas antisolvent fractionation.

The self-disproportionation of enantiomers (SDE): a menace or an opportunity?

“…But despite the long history of crystallization, even now new crystallization methodologies are being developed to effect the SDE. For example, it has recently been reported 73 that gas antisolvent fractionation (GASF) using carbon dioxide caused SDE via precipitation of ortho , meta , and para -substituted chlorinated mandelic acid scalemates from acetonitrile solution. The behavior in terms of enantiopurification was very similar to the recrystallization of racemic compounds under thermodynamic control.…”

The self‐disproportionation of enantiomers (SDE): The effect of scaling down, potential problems versus prospective applications, possible new occurrences, and unrealized opportunities?

“…This has overtones obviously for such applications as supercritical fluid chromatography (SFC) and supercritical fluid extraction (SFE) — processes though for which the SDE has yet to be observed — which utilize CO 2 or other highly esoteric solvent systems. An example of such an application along these lines is the observed SDE in the gas antisolvent fractionation of chlorine‐substituted mandelic acid derivatives .…”

Model Building on Selectivity of Gas Antisolvent Fractionation Method Using the Solubility Parameter

“…While for typical GAS applications the goal is to completely precipitate the solute in a desired size, crystallization habit and morphology, gas antisolvent fractionation (GASF) is a combination of the precipitation and an extraction step [5,6]. The GASF technique can be efficiently used in diastereomeric salt based optical resolutions [7][8][9][10][11] and purification of scalemic mixtures as well [7,12,13]. However, the efficiency of GASF is influenced by various operational parameters.…”