**2.2.1 Separation by filtration**

10 Advances in Crystallization Processes

When a part of an enantiomeric mixture is transformed into a crystalline salt and the residue can be distilled, the solid phase may contain either the racemic composition or the excess of the enantiomer. In the former case the distilled fraction should be the enriched mixture relative to *ee*0, but the less pure mixture can be found in the distilled fraction when the *ee*0 > *ee*Eu. This is applied even if the salt of the enantiomeric excess proportion is the more stable, as well. An example for this phenomenon is the purification of the enantiomeric mixture of phenylethylamine (**PEA**). The mixture was treated with less than an equivalent amount of dicarboxylic acid (oxalic acid, succinic acid, fumaric acid or phthalic acid = **DCA**) (see Table 1, the molar ratio: **PEA**/**DCA**~ 3,3/1,25), and the excess of the amine was distilled. The **PEA**-**DCA** salt behaved as a racemate because eedeszt > ee0 In case of the salts of oxalic- and

at 0 - 100C

N

malonic acids this is changed above of eutectic composition.23

COOH COOH Oxalic acid

CH2COOH CH2COOH Succinic acid

Fumaric acid

Phthalic acid

COOH

COOH

COOH

Table 1. The enrichment of enantiomeric mixtures of (R>S) – **PEA** via partial salt formation

HOOC

CH3

**2.1.2 Partial crystallization, distillation** 

crystallization from melt

(*S*>*R*)-**FTHQ**

F

H

CH3

(R>S)-**PEA**

followed by distillation.

NH2

40 92

ee0% eesolid% eeliquid%

40 47

40 50

Salt forming acid *ee*0 (%) *ee*distillate (%) *eeresidue* (%)

12.5 26.6 7.8 25.0 44.6 18.5 50.0 63.6 45.5 75.0 65.7 78.1 87.5 71.5 92.8

12.5 51.2 0.0 25.0 63.1 12.3 50.0 62.7 45.8 75.0 57.4 82.9 87.5 49.9 100

12.5 41.8 2.7 25.0 68.5 10.5 50.0 95.4 34.9 75.0 96.3 67.9 87.5 97.6 84.1

12.5 42.5 2.5 25.0 84.2 5.3 50.0 94.6 35.1 75.0 94.4 68.5 87.5 95.0 85.0 In this case the resolving agent should be added to the racemic compound and the mixture should be warmed until it melted then is should be cooled while one of the diastereoisomers crystallizes from the melt. The crystalline material can be separated by filtration from the residue of the melt (as in case of enantiomeric mixtures). An example for this method is the resolution of racemic menthol (**MEN**) with O,O'-dibenzoyl-(*R,R*)-tartaric acid ((*R,R*)-**DBTA**). The crystalline molecular complex (diastereoisomer) contains the (1*R*,2*S*,5*R)*-menthol (the Lmenthol (L-**MEN**)), while the remained melt is enriched in the other enantiomer24

(1*S*,2*R*,5*S*)-**MEN**
