**3.1.2.2 Racemates**

16 Advances in Crystallization Processes

In several cases the recrystalllization fails to result in enantiomeric enrichment. The solution for the purification of such enantiomeric mixtures may be the fractionated precipitation.32 In order to carry out such a purification step the enantiomeric mixture or its derivative (e.g. its salt formed with an achiral reagent) is dissolved in a solvent. Then a part of the dissolved material is liberated from its salt (or a salt is prepared from a part of it) with a reagent in a way that the liberated fraction (or salt) can precipitate from the solution, while the other proportion of the initial mixture remains in the solution. For example, the salts (e.g. watersoluble) of acids or bases are dissolved and a part of the free acid or base is precipitated by

Similar to the experiences shown at the recrystallization of enantiomeric mixtures, the conglomerate behaviour can also be observed at fractioned precipitation. An application of this method was effectuated at the resolution of racemic tisercine (**TIS**) with half an equivalent of (*R,R*)-tartaric acid. The (*S*)-**TIS** enantiomer, the active pharmaceutical ingredient. remained in the filtrate of the diastereoisomeric salt formation process. Consequently, it contaminated with its mirror imge isomer. The enantiomeric enrichment was accomplished by selective precipitation. The (*S*>*R*)-**TIS** mixture was dissolved in water as a hydrochloric acid salt, then less than an equivalent amount of potassium hydroxide was added to the solutionin order to liberate the excess of (*S*)-**TIS**. The pure (*S*)-**TIS** base precipitated from the solution and an almost racemic hydrochloride salt remained in the

aquaeous sol.

 non eq. KOH aqueous sol.

The conglomerate-like behaviour during the fractionated precipitation was observed in case of several chiral acids, too. A good example is the enantiomeric enrichment of *N*-acetylphenylalanine (**AcPA**). The pure (*R*)-**AcPA** isomer was obtained in two steps from its

recrystallization

water

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

**3.1.2.1 Conglomerates** 

solution..33

N

(*S*>*R*)-**TIS.**HCl

S

**3.1.2 Fractionated precipitation.** 

Cl N H2

CH3

addtion of less than equimolar achiral acid or base.

OCH3

CH3

N CH3

HCl

CH3

nonracemic enantiomeric mixtures.2

F

10.3 97.0

ee0% eesolid% eeliquid%

81.4 93.8

eesolid% eeliquid%

5 7

100 100

ee0%

25 67

42.1 95.7

> As it was already discussed in the above cases, enantiomeric enrichment of racemate forming enantiomeric mixtures result in an almost racemic crystalline phase when the starting enantiomer purity is smaller than the eutectic composition (*ee*0 < *ee*eu), but highly enriched mixture or the sole enantiomer can be crystallized when the initial composition is bigger than the eutectic one (*ee*0 > *ee*eu)

> This type of selective precipitation was applied in the cases of *N*-acyl-aminoacids when their recrystallization from water failed. However, additon of less then an equimolar amount of hydrochlororic acid to the solution of their sodium salt get good enrichment. It is therefore not surprising that considerable enrichment could be attained with a mixture of *ee*0 = 49.6 %, while two stage precipitation starting from an aqueous solution of **FoPA**.**Na** with *ee*0 = 73.4% (composition near the eutectic point), did not resulted in significant enrichment.11


The situation was almost the same at the separation of the enantiomeric mixtures of *N*acetyl-phenylglycine (**AcPG**) where *ee*eu could not be exceeded (*ee*eu ≈ 86 % in both cases, according to the binary phase diagrams).34

