**4. Conclusions**

32 Advances in Crystallization Processes

enantiomeric excess (conglomerate like behaviour), namely its faster crystallization

In general, at the fractionated precipitation if is expected a conglomerate like behaviour on base of binary phase diagram of diasteroemeric mixture, the filtration is efffectuated when the quantity of crystalline precipitate is constant. However if the difference between the crystállization rate of diastereomers is not large enough, can be occured that both diastereomers are crystallized in near similar quantity. In this case we cold not talk about enantiomeric enrichment. If instead of quick filtration is given time for stabilition of thermodynamic equilibrium, in turn is obtain a separation with good result. This can be demonstrate via resolution of tamsulosin intermediate (**TAI**) using as resolving agent **DBTA**  in the mixture of water and ethanol, when at the end of crystallization was not carried out enantiomweric enrichment, but if the crystalline mixture was allowe to stand for 2 days, was

*(R*)**-TAI.**(*R,R*)**-DBTA**

*(R*)**-TAI.**(*R,R*)**-DBTA** crystalline

5 min.

2 hours

48 hours

Similar phenomenon was also observed at the resolution of racemic oxirane derivatives,

Accordingly to the previously examples would appear to be advantageous that the time of crystallization to be more longer but if one of the diastereomers crystallizes quickly and the

Thus in the resolution of the intermediate of flumequine (**FTHQ)** in ethyl acetate with diparatoluyl-tartaric acid (*R,R*)-**DPTTA,** after a crystallizing of 5 minutes the (*R*)-**FTHQ**.(*R,R*)- **DPTTA** salt predominates, but on standing 3 weeks its antipode (*S*)-**FTHQ**.(*R,R*)-**DPTTA**

> 1.solvent 2.crystallization

crystalline mixture

+

*(S*)**-TAI.**(*R,R*)**-DBTA**

*(R*)**-FTHQ.**(*R,R*)**-DBTA** crystalline

crystalline

3 weeks *(S*)**-FTHQ.**(*R,R*)**-DBTA**

determines the separation (kinetic conglomerate).

reached a very high enantiomeric excess.60

CH3

CH3

containing two terciary aminogroups.61 **3.2.5.2 Kinetic controlled crystallization** 

will be in excess in the crystals.48

CH3

CH3 (*R,R*)-**DPTTA**

MeC6H5OCO COOH

+

(*R*)-**FTHQ** N H

(*S*)-**FTHQ**

N H

F

F

+

(*R,R*)-**DBTA**

other is wrong solvable, then neverthless its opposite is also favourable.

HOOC OCOC6H5Me

PhOCO COOH

HOOC OCOPh

CH3O NHCH2Ph

CH3O NHCH2Ph

(*R*)-**TAI**

(*S*)-**TAI**

H2NO2S

H2NO2S

**3.2.5.1 Thermodinamic control** 

The behaviour of the enantiomeric mixtures can be interpretated by formation of their homo- and heterochiaral aggregates having diastereomeric property. Due to spontaneous formation of these aggregates the non-racemic mixtures of enantiomers can be enriched by processes required some selective crystallization. The running of biner meltingpoint/composition phase diagrams (conglomerate or racemate), and the kinetic controlled crystallizations (kinetic conglomerates), respectively, determine the fact, that the crystalline phase contains the enantiomer or the racemic proportion. These regularities are also reflected by the running of curves where the enantiomeric purity of the product obtained (ee) during the selective crystallizations and precipitations were plotted against the initial composition (ee0).

At the separation of racemic compounds using another chiral material (namely resolution) the behaviour of enantiomeric mixture forming the racemate determines the efficiency of

Separation of the Mixtures of Chiral Compounds by Crystallization 35

[1] a) Eliel, E. L.; Wilen, S. H.,: *Stereochemistry of Organic Compounds* Eds.; Wiley New York,

[2] Bereczki, L.; Pálovics, E.; Bombicz, P.; Pokol, G.; Fogassy, E.; Marthi, K.:.*Tetrahedron:* 

[3] Faigl, F., Fogassy, E.; Nógrádi, M.; Pálovics, E.; Schindler, J.; *Tetrahedron: Asymm.,* 2008, *4*,

[5] Novák, T; Schindler, J; Ujj, V; Czugler, M; Fogassy, E; Keglevich, Gy: *Tetrahedron:* 

[6] Ujj V; Schindler J; Novák T; Czugler M; Fogassy E; Keglevich Gy: *Tetrahedron: Asymm.* 

1994 b).Roozeboom, H. W. B.: *Z. Physik. Chem*. 1899, *28*, 494.

[4] Scheldon, R. A. *Chirotechnology*, Marcel Dekker Inc. N.Y 1993

**DCA** dicarboxylic acid

**FoPA** formyl-phenylalanine

**IC** Iodo-cyclohexanol

**DMAD** dimethlyamino-1,3-propanediol **DPTTA** di-para-toluoyl-tartaric acid

**MA** methyl-phenylizopropylamine

**MePA** phenylalanine methyl ester **MePG** phenylglycine methyl ester

**PEGA** phenyl-ethyl-glutaric acid

**DIL** diltiazem

**EPh** ephedrine

**FTHQ** flumequine **IBU** Ibuprofen

**MEN** menthol

**PA** phenylalanine **PEA** Phenylethylamine

**PG** phenylglycine **PGA** phenylglycine amide **PGL** Prostaglandine **PHO** phospholene oxides **POAA** phenooxy-acetic acid **PPA** propionyl-phenylalanine **PPEA** phthaloyl-phenylethylamine **PPG** propionyl-phenylglycine

**Q** Quinotoxine **TA** Tartaric acid **TAD** Taddol.

**TIS** Tisercine **TOF** Tofizopam

*Asym.* 2007, *18*, 260

*Asymmy*. 2006, 2599.

2008, 1973-1977

**7. References** 

519

**TAI** tamsulosin intermediate

**TPA** tosylphenylalanine

resolution. If the racemic compound and resolving agent have similar molecule structure, the diastereomers form quasi-racemate, and quasi-conglomerate respectively.

If the structures of racemic compound and resolving agent are not considered structurally related compounds, at separation of the diasteremers also exist the complementarity between compounds form the diastereomer, which is in advanced insured in case of structurally similar compounds. In all probability the results of separation of diastereomers are also determined by the behaviour of enantiomeric mixtures of racemic compound and resolving agent.

The probability of this statement is underlined near the experimental data, the fact that the conditions, separation methods, typical behaviours observed at the separation of diastereomers based on the fractionated crystallization were similar to the experienced one at the separation of mixtures containing only enantiomers.

The rulings of chiral-chiral recognitions are valid even if the aim is to isolate by crystallization a chiral compound, having a higher purity than the initial one (*ee*>*ee*0), from a mixture containing more than two chiral component.
