Micronization processes involving supercritical carbon dioxide are rapid methods to produce fine particles. They also might offer the possibility of using less organic solvent than conventional crystallization methods leading to an environmentally friendlier processing. The separation capabilities of such processes are now demonstrated on the diastereomeric resolution of mandelic acid using (R)-1-phenylethanamine as a resolving agent, utilizing the batch type gas antisolvent fractionation as the separation method. A detailed study was conducted on the effects of the operational parameters pressure (12-20 MPa), temperature (35-55 °C) and co-solvent concentration (33-99 mg/ml). At 12 MPa, 35 °C and 99 mg/ml methanol concentration, a selectivity of 0.52 and a diastereomeric excess of 62% was reached. The same operational parameters were applied during the investigation of the recrystallization-based further purification of the diastereomeric salts, applying the resolving agent in molar equivalent quantity to a non-racemic mixture of mandelic acid. It has been found that the more stable (R)-1-phenylethylammonium-(R)-mandelate salt can be purified to de>98% through four additional recrystallization steps following the initial, half-molar equivalent resolution step.
A novel, green possibility of the further purification of the diastereomeric salt of 4-chloromandelic acid and 1-phenylethane-1-amine was developed. Gas antisolvent method using supercritical carbon dioxide was applied for the first time to precipitate the diastereomeric salts with increased purity followed by the supercritical fluid extraction of the dissolved diastereomers. The RR-salt can be purified to >99%, while fractionation-based purification of the SR-salt is limited to ~80%. The limiting initial diastereomeric excess correlates strongly with the atmospheric melting eutectic composition of the same salts, which suggests that despite the fast precipitation, the diastereomeric excess of the solid product is not kinetically determined. The efficiency of the diastereomeric enrichment is in the same range as that of the atmospheric reference experiments; however, technological advantages provided by the antisolvent precipitation method such as fast processing and dry product obtained suggest that this novel procedure is a promising alternative to the atmospheric methods.
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 number of crystal structures of diastereomeric salt pairs and especially of double salts is limited in the literature. This work exceptionally presents the structures of two constitutional isomer double...
Optical resolution
by diastereomeric salt formation based on gas
antisolvent fractionation is influenced by the chemical equilibrium
of the salt formation, the solubility, and the extraction of the compounds.
Selectivity, also known as resolution efficiency, is highly solvent-dependent
and is also affected by process parameters both in atmospheric and
supercritical processes. For the first time in the literature, a mathematical
model that employs all three Hansen parameters and operating parameters
is constructed to describe the selectivity of a gas antisolvent fractionation
process. The satisfying goodness of fit of the models suggests that
the outcome of the three subprocesses in the gas antisolvent fractionation
process (i.e., salt formation reaction, precipitation, and extraction)
can be described in a single model. A new formula for pressure and
temperature correction of the hydrogen-bonding component of the Hansen
parameter for non-ambient conditions for liquid methanol, ethanol,
and n-propanol is also suggested in this paper.
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