**1. Introduction**

Reaction of a racemic acid or base with an optically active base or acid gives a pair of diastereomeric salts. Members of this pair exhibit different physicochemical properties (e.g., solubility, melting point, boiling point, adsorbtion, phase distribution) and can be separated owing to these differences. The most important method for the separation of enantiomers is the crystallization. This is the subject of this chapter.

Preparation of enantiopure (ee~100%) compounds is one of the most important aims both for industrial practice and research. Actually, the resolution of racemic compounds (1:1 mixture of molecules having mirror-imagine relationship) still remains the most common method for producing pure enantiomers on a large scale. In these cases the enantiomeric mixtures or a sort of their derivatives are separated directly. This separation is based on the fact that the enantiomeric ratio in the crystallized phase differs from the initial composition. In this way, obtaining pure enantiomers requires one or more recrystallizations. (Figure 1).

The results of these crystallizations (recrystallizations) of mixtures of chiral compounds differ from those observed at the achiral compounds. Expectedly, not only the stereoisomer in excess can be crystallized, because the mixture of enantiomers (with mirror image relationship) follows the regularities established from binary melting point phase diagrams, and ternary composition solubility diagrams, respectively, as a function of the starting enantiomer proportion. According to this fact, we talk about conglomerate behaviour when the enantiomeric excess is crystallized, and racemate behaviour when it remains in the mother liquor.1

At the same time, there are some enantiomeric mixtures having racemate properties (based on binary phase diagram) which show conglomerate behaviour during its purification by fractionated precipitation. Always the enantiomeric excess is crystallized independently from the starting isomeric composition. This is explained by the kinetic crystallization of the enantiomeric excess.2 Consequenlty, if the enantiomeric purity obtained after recrystallization or by other partial crystallization (as the result of splitting between the two phases) is

<sup>\*</sup> Corresponding Author

Separation of the Mixtures of Chiral Compounds by Crystallization 5

The above mentioned behaviour depends on the substituents of the base skeleton of the racemic compound. It means that different substituents can determine the change in behaviour. For example, the formyl -, acetyl - and propionyl-derivatives of phenyl alanine

NHCOCH3

racemate conglomerate kinetic conglomerate

At separations based on the distribution between solid and another (liquid or melt) phase formation of a crystalline material is needed. The chiral discriminating effect can be explained by the presence and reactions of homo- and heterochiral aggregates (the simplest members of them are the dimers), and by their different physical and chemical properties. Thus in the solution or in the melt of racemic mixtures of enantiomers (S and R) two homodimers (SS and RR) and one heterodimer (SR) should be present, while in a hypothetic enantiomeric mixture (S>R, ee = 50%) presence of two dimmers, namely SS and SR, is expected. Considering that homo- and heterodimers are in diastereoisomeric relation with

The behaviour of a mixture of chiral compounds, in which the resolving agent is a substituted derivative of one of the enantiomers (which are also present in the mixture in racemic form) is similar to the behaviour of the above mentioned enantiomeric mixtures. Under such conditions real diastereoisomeric pairs are formed containing an enantiomer

If the racemic compound (mixture of enantiomers in 1:1 ratio) is reacted with equimolar amount of a derivative of one of the enantiomers (e.g. R\*, having opposite chemical

S.R + R\*R\* SR\* + RR\*

ee0~ quasi 50% diastereomers

In these cases non-symmetric conglomerate or racemate biner phase diagrams are expected and "quasi-conglomerate" (*RR*\*) or "quasi-racemate" (*SR*\*) precipitate may be obtained. In the former case the enantiomeric purity of R or S in the crystalline diastereoisomeric salt (*RR*\* or *SS*\*) can be anything, but in the latter ("quasi-racemate") case an enantiomeric purity (ee) usually reflects the eutectic composition for the enantiomeric mixture of original

**FoPA AcPA PPA**

NHCOCH2CH3

COOH

COOH

(**FoPA**, **AcPA, PPA**, see below) show different behaviour.

each other, their solubility and reactivity are different.4

and the structurally similar resolving agent, respectively.

character) a quasi-enantiomeric mixture is formed.

racemic compound.

NHCHO

COOH

plotted against the initial enantiomeric composition, either racemate or conglomerate behaviour is expected, or a conglomerate like curve is obtained (hereinafter: kineticconglomerate) (Figure 2).3

Fig. 1. The essential processes of enantiomeric separation starting from the racemic compound

Fig. 2. The composition of enantiomeric mixtures obtained by crystallization (ee) in function of starting enantiomeric purity (ee0). a). conglomerate melting point diagram; b). racemate melting point diagram; The diagrams of expected results of c). conglomerate crystallization, d). racemate crystallization, e) kinetic-conglomerate like crystallization

plotted against the initial enantiomeric composition, either racemate or conglomerate behaviour is expected, or a conglomerate like curve is obtained (hereinafter: kinetic-

Fig. 1. The essential processes of enantiomeric separation starting from the racemic

Fig. 2. The composition of enantiomeric mixtures obtained by crystallization (ee) in function of starting enantiomeric purity (ee0). a). conglomerate melting point diagram; b). racemate melting point diagram; The diagrams of expected results of c). conglomerate crystallization,

d). racemate crystallization, e) kinetic-conglomerate like crystallization

**ee (%)**

0 10 20 30 40 50 60 70 80 90 100 **ee0 (%)**

e). kinetic conglomerate-like (under kinetic control)

II frakció

I frakció

conglomerate) (Figure 2).3

compound

The above mentioned behaviour depends on the substituents of the base skeleton of the racemic compound. It means that different substituents can determine the change in behaviour. For example, the formyl -, acetyl - and propionyl-derivatives of phenyl alanine (**FoPA**, **AcPA, PPA**, see below) show different behaviour.

At separations based on the distribution between solid and another (liquid or melt) phase formation of a crystalline material is needed. The chiral discriminating effect can be explained by the presence and reactions of homo- and heterochiral aggregates (the simplest members of them are the dimers), and by their different physical and chemical properties. Thus in the solution or in the melt of racemic mixtures of enantiomers (S and R) two homodimers (SS and RR) and one heterodimer (SR) should be present, while in a hypothetic enantiomeric mixture (S>R, ee = 50%) presence of two dimmers, namely SS and SR, is expected. Considering that homo- and heterodimers are in diastereoisomeric relation with each other, their solubility and reactivity are different.4

$$\begin{array}{c} \text{3S}, \text{3R} \xrightleftharpoons \text{S.S} + \text{R.R} + \text{S.R} \\\\ \text{3S}, \text{R} \xrightleftharpoons \text{S.S} + \text{S.R} \end{array}$$

The behaviour of a mixture of chiral compounds, in which the resolving agent is a substituted derivative of one of the enantiomers (which are also present in the mixture in racemic form) is similar to the behaviour of the above mentioned enantiomeric mixtures. Under such conditions real diastereoisomeric pairs are formed containing an enantiomer and the structurally similar resolving agent, respectively.

If the racemic compound (mixture of enantiomers in 1:1 ratio) is reacted with equimolar amount of a derivative of one of the enantiomers (e.g. R\*, having opposite chemical character) a quasi-enantiomeric mixture is formed.

$$\underbrace{\text{S.R.} + \text{R\*R\*}}\_{\mathbf{e}\mathbf{e}\_0 \sim \text{quasi 50\%}} \underbrace{\text{\bf S} \text{R\*} + \text{RR\*}}\_{\text{diastereomers}}$$

In these cases non-symmetric conglomerate or racemate biner phase diagrams are expected and "quasi-conglomerate" (*RR*\*) or "quasi-racemate" (*SR*\*) precipitate may be obtained. In the former case the enantiomeric purity of R or S in the crystalline diastereoisomeric salt (*RR*\* or *SS*\*) can be anything, but in the latter ("quasi-racemate") case an enantiomeric purity (ee) usually reflects the eutectic composition for the enantiomeric mixture of original racemic compound.

Separation of the Mixtures of Chiral Compounds by Crystallization 7

If the diastereoisomeric salt can not be separated by fractionated precipitation, it is feasible to get its crystalline solvate by fractionated precipitation from a solvate forming solution.12 When the solvent, unsuitable for separation of the diastereoisomers, contains structurally (partly) similar compound(s) to the solvate forming solution,13 the separation of enantiomers became feasiable by fractionated precipitation of the diastereoisomeric salt. It is particularly striking, when the wanted crystal composition is obtained by using a structurally similar (either with racemic compound or resolving agent) achiral

It is possible that the recrystallization from an adequate solvent does not give pure enantiomers, but a good enrichment can be often achieved by fractionated precipitation.15

The racemate and conglomerate like behaviour of enantiomers can also be observed both at the recrystallization and at the liberation of the enantiomers from their salts formed with

Based on own and other's experimental results some conclusions can be drawn according to

The regularities of crystallization of the systems containing at least two chiral compounds can not be described by linear correlations.17 At the same time, the behaviour of the enantiomeric mixtures of the racemic compound will be one of the determining factor of the

To characterize the obtained fractions not only their yield (Y), but the enantiomeric purity of the products (*ee*) is also relevant. Therefore it is advisable to use the parameter F characterizing the efficiency of the procedure (F=ee\*Y).18 This factor is actually the yield of enantiomeric excess separated. (Earlier this factor was marked with the letter S, but it could

Hereinafter, the possibilities of enantiomer and diastereoisomer separations based on

At first examples will be given for separation of mixtures, containing two or more chiral

Among the next examples we refer to the results derived from earlier considerations, too. We demonstrate that behaviour of these enantiomeric and diastereoisomeric mixtures raised from interactions between chiral compounds are not allways the expected ones. The shown examples relate mainly to calculable regularity, but often a minor modification in the molecular structure can induce significant change of results. For justification, the two essential perception of Pasteur19, are shown at first, then the consequences of the "slight changing" of the molecular structures will be presented in the light of our present

It was recognized by Pasteur, that the enantiomers of racemic tartaric acid can be separted by induced crystallization, if the supersaturated aqueous solution of its sodium-ammonium salt was seeded with the crystals of a pure enantiomer. In this case significant amount of the pure enantiomer could be find in the solid phase and a mixture of enantiomers remaind in the saturated solution in which the other enatiomer was in excess. That other enantiomer

compound.14

knowledge.

achiral compounds.16

the fractionated crystallization of chiral compounds.

behaviour of the systems containing chiral compounds.

crystallization are shown by known examples.

refer to the configuration even if it was marked by a different font.)

compounds in solventless conditions or using solvent, respectively.

The resolving agent has a decisive role at the separation of diastereoisomers. Previously, we referred to the fact that the resolving agent (having related structure with one of the enantiomers of the racemic compound) may form well-crystallizing diastereoisomer. But usually separations based on crystallization of diastereoisomers obtained from chiral reagents with significantly different structures are performed. One of these frequently used reagents is the dibenzoyltartaric acid (**DBTA**), which is suitable for the resolution of racemic bases. It was observed, that it has also an ability to form relatively stable molecular complexes with racemic alcohols, and its Ca and Mg salts form coordinative complexes both with alcohols and phospholenes. In these cases pure enantiomers can also be obtained by fractionated precipitation of the diastereoisomeric complexes.5,6

It is assumed based on the results of the resolutions (both via salt-formation, and complexformation) that the composition of the crystalline diastereoisomer is determined by the properties of the enantiomeric mixture of the racemic compound even if the resolving agent has not a similar structure to the racemic compound.

The enantiomeric mixture obtained by recrystallization (fractionated precipitation) and decomposition of diastereoisomers usually needs further purification to obtain the pure (single) enantiomer. The above mentioned behaviour of the stereoisomeric mixtures is expected at these enrichment processes, too.

However, during the purification of enantiomeric mixtures (having diastereoisomeric relationship and –behaviour of the homo- and heterochiral aggregates) both the kinetic and thermodynamic control can be observed, and certainly these phenomena can be observed at the (re)crystallization of diastereoisomers as well.7 At the same time in case of reciprocal resolution (one of the enantiomers of the original racemic compound is applied as resolving agent for resolution of the racemic mixture of the initial chiral agent) the former behaviour is expected inevitably (namely the previously experienced kinetic- or thermodynamic control can be observed).

So, the crystallization rules (based on expected chiral-chiral interaction) of enantiomeric mixtures can be applied even if two or more chiral compounds are present.

However, the mode of separation of the crystalline fraction is very important. For example, the separation of enantiomers can be effectuated even if a mixture from the melt of enantiomeric mixtures is crystallized. The crystalline material can be separated from the residue by filtration, distillation, sublimation or extraction.8

A similar separation can be achieved even if the amount of the resolving agent applied is less than an equivalent to the racemate. Then the enantiomeric mixture can be separated from the crystalline diastereisoomer by sublimation or distillation, in accordance with the above mentioned methods.

The dielectrical constant of the solvent (if solvent is used at the resolutions) changes the formation, composition and enantiomer recognition of the crystalls.9 The composition of crystalline diastereoisomers is also influenced by the pH of the reaction mixture.10

The purity (*de*) of the diastereoisomer can be improved using a mixture of structurally related resolving agents. It is often referred as "Dutch resolution" in the literature.11

The resolving agent has a decisive role at the separation of diastereoisomers. Previously, we referred to the fact that the resolving agent (having related structure with one of the enantiomers of the racemic compound) may form well-crystallizing diastereoisomer. But usually separations based on crystallization of diastereoisomers obtained from chiral reagents with significantly different structures are performed. One of these frequently used reagents is the dibenzoyltartaric acid (**DBTA**), which is suitable for the resolution of racemic bases. It was observed, that it has also an ability to form relatively stable molecular complexes with racemic alcohols, and its Ca and Mg salts form coordinative complexes both with alcohols and phospholenes. In these cases pure enantiomers can also be obtained by

It is assumed based on the results of the resolutions (both via salt-formation, and complexformation) that the composition of the crystalline diastereoisomer is determined by the properties of the enantiomeric mixture of the racemic compound even if the resolving agent

The enantiomeric mixture obtained by recrystallization (fractionated precipitation) and decomposition of diastereoisomers usually needs further purification to obtain the pure (single) enantiomer. The above mentioned behaviour of the stereoisomeric mixtures is

However, during the purification of enantiomeric mixtures (having diastereoisomeric relationship and –behaviour of the homo- and heterochiral aggregates) both the kinetic and thermodynamic control can be observed, and certainly these phenomena can be observed at the (re)crystallization of diastereoisomers as well.7 At the same time in case of reciprocal resolution (one of the enantiomers of the original racemic compound is applied as resolving agent for resolution of the racemic mixture of the initial chiral agent) the former behaviour is expected inevitably (namely the previously experienced kinetic- or thermodynamic control

So, the crystallization rules (based on expected chiral-chiral interaction) of enantiomeric

However, the mode of separation of the crystalline fraction is very important. For example, the separation of enantiomers can be effectuated even if a mixture from the melt of enantiomeric mixtures is crystallized. The crystalline material can be separated from the

A similar separation can be achieved even if the amount of the resolving agent applied is less than an equivalent to the racemate. Then the enantiomeric mixture can be separated from the crystalline diastereisoomer by sublimation or distillation, in accordance with the

The dielectrical constant of the solvent (if solvent is used at the resolutions) changes the formation, composition and enantiomer recognition of the crystalls.9 The composition of

The purity (*de*) of the diastereoisomer can be improved using a mixture of structurally

crystalline diastereoisomers is also influenced by the pH of the reaction mixture.10

related resolving agents. It is often referred as "Dutch resolution" in the literature.11

mixtures can be applied even if two or more chiral compounds are present.

residue by filtration, distillation, sublimation or extraction.8

fractionated precipitation of the diastereoisomeric complexes.5,6

has not a similar structure to the racemic compound.

expected at these enrichment processes, too.

can be observed).

above mentioned methods.

If the diastereoisomeric salt can not be separated by fractionated precipitation, it is feasible to get its crystalline solvate by fractionated precipitation from a solvate forming solution.12 When the solvent, unsuitable for separation of the diastereoisomers, contains structurally (partly) similar compound(s) to the solvate forming solution,13 the separation of enantiomers became feasiable by fractionated precipitation of the diastereoisomeric salt. It is particularly striking, when the wanted crystal composition is obtained by using a structurally similar (either with racemic compound or resolving agent) achiral compound.14

It is possible that the recrystallization from an adequate solvent does not give pure enantiomers, but a good enrichment can be often achieved by fractionated precipitation.15

The racemate and conglomerate like behaviour of enantiomers can also be observed both at the recrystallization and at the liberation of the enantiomers from their salts formed with achiral compounds.16

Based on own and other's experimental results some conclusions can be drawn according to the fractionated crystallization of chiral compounds.

The regularities of crystallization of the systems containing at least two chiral compounds can not be described by linear correlations.17 At the same time, the behaviour of the enantiomeric mixtures of the racemic compound will be one of the determining factor of the behaviour of the systems containing chiral compounds.

To characterize the obtained fractions not only their yield (Y), but the enantiomeric purity of the products (*ee*) is also relevant. Therefore it is advisable to use the parameter F characterizing the efficiency of the procedure (F=ee\*Y).18 This factor is actually the yield of enantiomeric excess separated. (Earlier this factor was marked with the letter S, but it could refer to the configuration even if it was marked by a different font.)

Hereinafter, the possibilities of enantiomer and diastereoisomer separations based on crystallization are shown by known examples.

At first examples will be given for separation of mixtures, containing two or more chiral compounds in solventless conditions or using solvent, respectively.

Among the next examples we refer to the results derived from earlier considerations, too. We demonstrate that behaviour of these enantiomeric and diastereoisomeric mixtures raised from interactions between chiral compounds are not allways the expected ones. The shown examples relate mainly to calculable regularity, but often a minor modification in the molecular structure can induce significant change of results. For justification, the two essential perception of Pasteur19, are shown at first, then the consequences of the "slight changing" of the molecular structures will be presented in the light of our present knowledge.

It was recognized by Pasteur, that the enantiomers of racemic tartaric acid can be separted by induced crystallization, if the supersaturated aqueous solution of its sodium-ammonium salt was seeded with the crystals of a pure enantiomer. In this case significant amount of the pure enantiomer could be find in the solid phase and a mixture of enantiomers remaind in the saturated solution in which the other enatiomer was in excess. That other enantiomer

Separation of the Mixtures of Chiral Compounds by Crystallization 9

enantiomeric excess (conglomerate type) or the racemic fraction (racemate type) crystallizes

In such cases the enantiomeric excess is crystallized with a higher purity than that of in the initial composition, in a certain range of temperature. For example, the common intermediate of the synthesis of several prostaglandines is a lactone (**PGL**). Its enantiomeric mixtures (ee0) can be enriched by crystallization (eesolid) from melt, while the racemic ratio

In racemate forming enantiomeric mixtures the enantiomeric excess with a higher enantiomeric purity than that the initial composition remains in the melt and the crystalline phase formed has a lower *ee.* For instance, at the crystallization of the enantiomeric mixture of *trans*-chrysanthemic acid (**CHRA**) from melt the liquid phase contains a higher purity

At the crystallization of melts of racemate forming enantiomeric mixtures the eutectic composition usually determinates the composition of the crystallized mixture and the oily residue. That eutectic composition can be known from the binary melting point phase diagram. When the initial isomeric composition (ee0) is higher than the eutectic composition, the pure optical isomer cam be crystallized. By way of illustration the eutectic composition (it is approximately at *ee* 40%) of flumequine intermediate (**FTHQ**) cannot be enriched, but by starting from a mixture of *ee*0 > 40%, significant enrichment can be achieved, especially

21.5 29.2 52.3 79.5

ee0 % eesolid % eeliquid %

69.2 72.5 76.9 93.0

15.5

42.6 83.3

ee0 % eesolid % eeliquid %

6.2 2.6 29.2 54.2

from the melt. Sometimes these phases may be separated by filtration.

(liquid residue, eeliquid) can be recovered for repeated resolution.20

crystallization from melt at 0-50C

crystallization from melt

at 0-10 0C

**2.1.1 Separation with filtration** 

**2.1.1.1 Conglomerates** 

O

(1*S*,5*R*>1*R*,5*S*)*-***PGL**

**2.1.1.2 Racemates** 

H3C

CH3

O

fraction than the *ee0* value of the initial mixture.21

because it has a "conglomerate like" behaviour.22

CH3 CH3

COOH

(1*R*>1*S*)**-CHRA**

could be crystallized in pure form from the suprasaturated solution of this latter enatiomeric mixture. This experiment demonstrated the fact, that the excess of an anantiomer can crystallize from an enantiomeric mixture of the above mentioned tartaric acid salt. According to our present knowledge, it means that the enantiomers of sodium-ammonium salt of tartaric acid form a conglomerate in their mixtures.

When the same experiment, namely crystallization of the non-racemic enantiomeric mixture of sodium-ammonium tartarate, was effectuated at a temperature above 27 °C, the racemic fraction (the racemate) crystallized, because the sodium-ammonium salts of racemic tartaric acid have a racemate like behaviour at around 30 °C. In this case the derivative of tartaric acid (the mixed salt) was suitable for fractioned enantiomeric separation, but only at a lower temperature than 27 °C (influence of temperature).

Pasteur also recognized, that more efficient separation of the enantiomers of racemic tartaric acid could be achieved by application of another chiral base (Quinotoxine (**Q**)) as resolving agent to the enantiomers of tartaric acid was obtained a better enantiomeric separation. In this case a diastereoisomeric salt ((*R,R*)-**TA.Q.6H2O**) crystallized while the better soluble diastereoisomeric salt((*S,S*)-**TA.Q**) remained in solution.

When cinkotoxine (a chiral base, similar to quinotoxine, without CH3O- substituent) was used, the other tartaric acid enantiomer ((*S,S*)-**TA**) crystallized in the diastereoisomeric salt.

It is supposed that the crystal solvate was a decisive role during crystallizationof the first salt or the lack of methoxy substitution (H-bridge acceptor) on common molecular configuration of the resolving agent changed its enantiomeric recognition ability in the second case. Keeping these experimental results in mind, the known methods of enantiomer separation *via* crystallization will be discussed in the next sections

#### **2. Crystallization without any solvent**

Both the enantiomeric mixtures and the mixtures of true diastereoisomeric pairs and free enantiomers can form crystalline and melt fractions, which are separable by an adequate method.

#### **2.1 The crystallization of the enantiomeric mixtures**

When the non-racemic mixture of enantiomers may be melted without decomposition, depending on whether the homochiral or the heterochiral associations are more stable, the enantiomeric excess (conglomerate type) or the racemic fraction (racemate type) crystallizes from the melt. Sometimes these phases may be separated by filtration.

#### **2.1.1 Separation with filtration**

#### **2.1.1.1 Conglomerates**

8 Advances in Crystallization Processes

could be crystallized in pure form from the suprasaturated solution of this latter enatiomeric mixture. This experiment demonstrated the fact, that the excess of an anantiomer can crystallize from an enantiomeric mixture of the above mentioned tartaric acid salt. According to our present knowledge, it means that the enantiomers of sodium-ammonium

When the same experiment, namely crystallization of the non-racemic enantiomeric mixture of sodium-ammonium tartarate, was effectuated at a temperature above 27 °C, the racemic fraction (the racemate) crystallized, because the sodium-ammonium salts of racemic tartaric acid have a racemate like behaviour at around 30 °C. In this case the derivative of tartaric acid (the mixed salt) was suitable for fractioned enantiomeric separation, but only at a lower

Pasteur also recognized, that more efficient separation of the enantiomers of racemic tartaric acid could be achieved by application of another chiral base (Quinotoxine (**Q**)) as resolving agent to the enantiomers of tartaric acid was obtained a better enantiomeric separation. In this case a diastereoisomeric salt ((*R,R*)-**TA.Q.6H2O**) crystallized while the better soluble

NH

+ 2 + (*S,S*)*-***TA. Q** water

OH

H

When cinkotoxine (a chiral base, similar to quinotoxine, without CH3O- substituent) was used, the other tartaric acid enantiomer ((*S,S*)-**TA**) crystallized in the diastereoisomeric salt. It is supposed that the crystal solvate was a decisive role during crystallizationof the first salt or the lack of methoxy substitution (H-bridge acceptor) on common molecular configuration of the resolving agent changed its enantiomeric recognition ability in the second case. Keeping these experimental results in mind, the known methods of enantiomer

Both the enantiomeric mixtures and the mixtures of true diastereoisomeric pairs and free enantiomers can form crystalline and melt fractions, which are separable by an adequate

When the non-racemic mixture of enantiomers may be melted without decomposition, depending on whether the homochiral or the heterochiral associations are more stable, the

N

O

**Q**

separation *via* crystallization will be discussed in the next sections

**2. Crystallization without any solvent** 

**2.1 The crystallization of the enantiomeric mixtures** 

(*R,R*)*-***TA**.

**Q. 6 H2O**

crystalls in solution

salt of tartaric acid form a conglomerate in their mixtures.

temperature than 27 °C (influence of temperature).

diastereoisomeric salt((*S,S*)-**TA.Q**) remained in solution.

CH3O

(*R,R*)-**TA**

HOOC OH

(*S,S*)-**TA**

method.

HO COOH

HO COOH

HOOC OH

In such cases the enantiomeric excess is crystallized with a higher purity than that of in the initial composition, in a certain range of temperature. For example, the common intermediate of the synthesis of several prostaglandines is a lactone (**PGL**). Its enantiomeric mixtures (ee0) can be enriched by crystallization (eesolid) from melt, while the racemic ratio (liquid residue, eeliquid) can be recovered for repeated resolution.20


#### **2.1.1.2 Racemates**

In racemate forming enantiomeric mixtures the enantiomeric excess with a higher enantiomeric purity than that the initial composition remains in the melt and the crystalline phase formed has a lower *ee.* For instance, at the crystallization of the enantiomeric mixture of *trans*-chrysanthemic acid (**CHRA**) from melt the liquid phase contains a higher purity fraction than the *ee0* value of the initial mixture.21


At the crystallization of melts of racemate forming enantiomeric mixtures the eutectic composition usually determinates the composition of the crystallized mixture and the oily residue. That eutectic composition can be known from the binary melting point phase diagram. When the initial isomeric composition (ee0) is higher than the eutectic composition, the pure optical isomer cam be crystallized. By way of illustration the eutectic composition (it is approximately at *ee* 40%) of flumequine intermediate (**FTHQ**) cannot be enriched, but by starting from a mixture of *ee*0 > 40%, significant enrichment can be achieved, especially because it has a "conglomerate like" behaviour.22

Separation of the Mixtures of Chiral Compounds by Crystallization 11

In this chapter we discuss on such separations in which the racemic compound is reacted with a resolving agent, so the mixture contains three chiral compounds: the two enantiomers and another chiral compound. At this time the more stable diastereoisomer crystallizes and it can be separated from the non racemic enantiomeric mixture by several

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 L-

menthol (L-**MEN**)), while the remained melt is enriched in the other enantiomer24

<sup>+</sup> 1. melt

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

PhOCO COOH

HOOC OCOPh

2.crystallization 3. filtration

If the racemic compound is reacted with half an equivalent amount of resolving agent, the enantiomeric mixture remained after crystallization can be separated by distillation. Such a method was accomplished at the resolution of *N*-methyl-phenylisopropylamine (**MA**) by (*R,R*)-dibenzoyl-tartaric acid ((*R,R*)-**DBTA**). In this case the (*S*)-**MA** was distilled off beside

> 3.distillation in vacuum

1. melt 2.crystallization (1*R*,2*S*,5*R*)-**MEN.**(*R*,*R*)-**DBTA**

crystallized diastereomer

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

distillated crystallized residuum (*S*)-**MA** + (*R*)-**MA.**(*R*,*R*)-**DBTA**

+

in melt

**2.2 Crystallization of diastereoisomers** 

**2.2.1 Separation by filtration** 

OH

OH

**2.2.2 Separation by distillation** 

of crystalline (*R*)-**MA.(***R,R***)-DBTA** salt. 25

+

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

PhOCO COOH

HOOC OCOPh

NHCH3

NHCH3

(*R*)-**MA**

(*S*)-**MA**

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

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

methods.

