**2.2.2 Separation by distillation**

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

Separation of the Mixtures of Chiral Compounds by Crystallization 13

1.sublimate

We think that this method for separation of the crystalline diastereoisomeric salt and the enantiomeric mixture can also be placed to the methods where the crystallization is accomplished without a solvent, and based on the instantiated examples we can declare that both the diastereoisomeric salt and molecular complexes may be separated by supercritical

When the racemic acid or base is treated with less than an equivalent amount of chiral compound (resolving agent) one can obtain a good enantiomer separation if crystallization occures in the mixture. For example, at the resolution of racemic ibuprofen (**IBU**) with (*R*)- **PEA,** the free enantiomer (*S*)-**IBU** can be separated from the salt ((*R*)-**IBU.**(*R*)-**PEA)** by

The pure enantiomers of racemic 1,2-cyclohexane-diol (**CHD**) could be obtained with the same method using (*R,R*)-Tartaric acid (**TA**) as resolving agent. In this case the (*S,S*)-**CHD**  isomer could be extracted and the crystalline molecular complex of (*R,R*)-**CHD** and (*R,R*)-

time

T2>T1

staying (1*S*, 2*S*)-**IC.**(*R,R*)-**DBTA** <sup>+</sup> (1*R* 2*R*)-**IC.**(*R,R*)-**DBTA**

(1*R* 2*R*)-**IC** + (1*S*, 2*S*)-**IC.**(*R,R*)-**DBTA**

2.sublimate

crystalline diastereomeric mixture

vacuum-sublimation

(1*S*, 2*S*)-**IC** + (*R,R*)-**DBTA**

(*S*)-**IBU** <sup>+</sup> (*R*)-**IBU.**(*R*)-**PEA** 1.crystallization 2.supercritical CO2 extract crystalline residuum

vacuum-sublimation 1. crystalline residuum

T1

2.residuum

I

+

2

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

**2.2.4 Separation by a supercritical fluid (carbon dioxide)** 

extraction with a supercritical fluid, most often with carbon dioxide28

(*R*)-**PEA**

PhOCO COOH

HOOC OCOPh

I

OH

OH

carbon dioxide.

COOH

(*S*)-**IBU** <sup>+</sup> NH2

COOH

(*R*)-**IBU**

**TA** remained in the solid phase**.**29

(1*S*, 2*S*)-**IC**

(1*R* 2*R*)-**IC**

When the racemic phenylisopropylamine (**A**) is resolved with (*S*)-*N*-phthaloylphenylethylamine (**PPEA**) according to the abover mentioned method, further separation can be accomplished starting from the residue of the first distillation. When the temperature is increased, the residual crystalline diastereoisomeric salt decomposes and the liberated enantiomer ((*R*)-**A**), constituting the diastereoisomeris salt) can also be distilled off while the resolving agent is transformed into a phthalimide derivative.26

The situation is essentially the same when the racemic **A** is resolved by (*R,R*)-TADDOL (**TAD**). The first crystalline residuum is the molecular complex of (*R*)-**A**.(*R,R*)-**TAD**. At higher temperature this complex is decomposed and the regenerated **TAD** remais in the flask as the final residuum. 28

#### **2.2.3 Separation by sublimation**

Sublimation method for indirect separation of enantiomers is very similar, in principle to the above mentioned distillation-based procedure. In the next example the diastereoisomeric molecular complexes could be separated using the significant difference between their thermal stability.

The solid phase reaction between the racemic compound (*transz*-2-iodo-cyclohexanol = **IC**)) and the resolving agent ((*R,R*)-**DBTA)** occurs during a long-term staying.27 Then the enantiomers could be separated from the mixture by two sublimation steps.

When the racemic phenylisopropylamine (**A**) is resolved with (*S*)-*N*-phthaloylphenylethylamine (**PPEA**) according to the abover mentioned method, further separation can be accomplished starting from the residue of the first distillation. When the temperature is increased, the residual crystalline diastereoisomeric salt decomposes and the liberated enantiomer ((*R*)-**A**), constituting the diastereoisomeris salt) can also be distilled off while the

> (*S*)-**A** 1.distillated

(*R*)-**A** 2.distillated

+

T1

2.residuum

The situation is essentially the same when the racemic **A** is resolved by (*R,R*)-TADDOL (**TAD**). The first crystalline residuum is the molecular complex of (*R*)-**A**.(*R,R*)-**TAD**. At higher temperature this complex is decomposed and the regenerated **TAD** remais in the

Sublimation method for indirect separation of enantiomers is very similar, in principle to the above mentioned distillation-based procedure. In the next example the diastereoisomeric molecular complexes could be separated using the significant difference between their

The solid phase reaction between the racemic compound (*transz*-2-iodo-cyclohexanol = **IC**)) and the resolving agent ((*R,R*)-**DBTA)** occurs during a long-term staying.27 Then the

enantiomers could be separated from the mixture by two sublimation steps.

N O O

+ (*R*)-**A.**(*S*)-**PPEA** 1. crystalline residuum

T2>T1 vacuum

resolving agent is transformed into a phthalimide derivative.26

(*S*)-**PPEA**

NHCO COOH

<sup>+</sup> vacuum

NH2

flask as the final residuum. 28

thermal stability.

**2.2.3 Separation by sublimation** 

NH2

(*R*)-**A**

(*S*)-**A**

#### **2.2.4 Separation by a supercritical fluid (carbon dioxide)**

We think that this method for separation of the crystalline diastereoisomeric salt and the enantiomeric mixture can also be placed to the methods where the crystallization is accomplished without a solvent, and based on the instantiated examples we can declare that both the diastereoisomeric salt and molecular complexes may be separated by supercritical carbon dioxide.

When the racemic acid or base is treated with less than an equivalent amount of chiral compound (resolving agent) one can obtain a good enantiomer separation if crystallization occures in the mixture. For example, at the resolution of racemic ibuprofen (**IBU**) with (*R*)- **PEA,** the free enantiomer (*S*)-**IBU** can be separated from the salt ((*R*)-**IBU.**(*R*)-**PEA)** by extraction with a supercritical fluid, most often with carbon dioxide28

The pure enantiomers of racemic 1,2-cyclohexane-diol (**CHD**) could be obtained with the same method using (*R,R*)-Tartaric acid (**TA**) as resolving agent. In this case the (*S,S*)-**CHD**  isomer could be extracted and the crystalline molecular complex of (*R,R*)-**CHD** and (*R,R*)- **TA** remained in the solid phase**.**29

Separation of the Mixtures of Chiral Compounds by Crystallization 15

At the recrystallization of racemate forming (the most common) enantiomeric mixtures the enriched enantiomeric mixture usually can be recovered from the mother liquor after filtration of the crystalline fraction having near to racemic composition. However, the composition of the crystalline material can be changed when the initial enantiomeric purity is higher then the eutectic composition. A certain example is the recrystallisation of the enantiomeric mixtures of tofizopam (**TOF**) from ethyl acetate. Almost racemic composition crystallized from small or medium pure enantiomeric mixtures. However the sole enantiomer crystallized from the solution when the initial composition was higher than the

The above example demonstrates that one can prepare the enantiomerically pure product from almost any samples having medium *ee0,* with two recrystallizations if the enantiomeric mixture recovered from the filtrate of the frst crystallization is applied as starting material of the second recrystallization. This technique was adapted at the purification of the

ee0 % eesolid % eeliquid %

66 100 0

ee0% eesolid% eeliquid%

recrystallization ethyl acetate

N

**3.1.1.2 Racemates** 

O (CH2)2N(CH3)2.HCl

(*S,S* > *R,R*)-**DIL .** HCl

eutectic one (ee0>85%).31

CH3O

CH3O

(*S*>*R*)-**TOF**

CH3O

H2C

N N

CH3

OCH3

recrystallization ethyl acetate

hydrochloride salt of a flumequine intermediate (**FTHQ.HCl**), too.23

CH3

OAc

OCH3

S
