**5. Presence, role, and effect on the diastereomer separation of achiral additive**

#### **5.1. Achiral additive structurally related to the racemic compound**

After the resolution of *N*-acetyl phenylalanine (*N*-acetyl-**Phe**) with 1.0 equivalent (*R*)- 1-phenylethylamine ((*R*)-**PhEA**), (*S*)-*N*-acetyl phenylalanine of 5% enantiomer purity could be separated from the diastereomeric salt. However, when equivalent amount of the structurally related phenoxy acetic acid (**PhOAA**) was given to the racemic *N*-acetylphenylalanine and this mixture was resolved with 2 equivalents of (*R*)-1-phenylethylamine, (*S*)-*N*-acetyl-phenylalanine of 88% enantiomeric excess was enriched in the diastereomeric salt (**Scheme 23**) [79].

**Scheme 23.** Resolution of *N*-acetyl-phenylalanine in the presence of phenoxy acetic acid.

#### **5.2. Achiral additive structurally related to the resolving agent**

With the application of achiral additives, which are structurally related to the resolving agent, the efficiency of the enantiomer separations was significantly improved.

By changing the half of the phenylglycine methyl ester (**PhG-Me**) enantiomer resolving agent to the structurally related benzylamine (**BA**) in course of the resolution of *N*-acetyl phenylglycine (*N*-Ac**-PhG**), the enantiomer purity of the diastereomer salt of *N*-Ac-**PhG** increased by 54%, compared to the results of the 1 equivalent **PhG-Me** resolving agent (**Scheme 24**). Also in the case of 1-phenyl-ethyl amine (**PhEA**) resolving agent, by exchanging the half of **PhEA** to benzylamine, both the enantiomer purity and the efficiency of resolution values increased [79].

proven to be present in the solid phase; therefore the process of the crystallization was investigated by polarization microscopy. According to the results, the nucleation of the diastereomer salt of (*S*)- **PhEA**∙(*R*)-**PhEA-GA** starts on the surface of the initially appearing needle-like urea crystals [81].

extraction.

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**Scheme 25.** Effect of benzylamine on the resolution of racemic ibuprofen by scCO<sup>2</sup>

**Scheme 26.** Resolution of racemic 1-phenylethylamine in the presence of urea and its derivatives.

**Scheme 27.** Resolution of mandelic acid with the application of amphoteric achiral additives.

The resolution of racemic ibuprofen (IBU) with (*R*)-1-phenylethylamine ((*R*)-PhEA) and benzylamine (BA) as structurally related achiral additive was investigated. The unreacted enantiomer mixture of IBU was removed by scCO<sup>2</sup> extraction from the received diastereomeric salt. The addition of the achiral benzylamine resulted in higher efficiency of resolution (FSCS) values compared to the experiments without additive (**Scheme 25**) [80].

#### **5.3. Additive of similar structure to the polar part of the resolving agent**

Racemic 1-phenylethylamine (**PhEA**) was resolved with *N*-glutaryl-1-phenylethylamine (**PhEA-GA**) applying urea and its derivatives and thiourea additives of neutral character, which show structural similarity with a part of the resolving agent. Although the enantiomer purity of the **PhEA** received from the diastereomeric salt decreased (from *ee*: 62% to *ee*: 51–54%), the increased yields led to higher efficiency of resolution values (from F: 0.36 to F: 0.37–0.49) in all cases (**Scheme 26**). The urea was

**Scheme 24.** Resolution of N-acetyl-phenylglycine with 1-phenylethylamine and with benzylamine as achiral additive.

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**Scheme 25.** Effect of benzylamine on the resolution of racemic ibuprofen by scCO<sup>2</sup> extraction.

**5.2. Achiral additive structurally related to the resolving agent**

112 Laboratory Unit Operations and Experimental Methods in Chemical Engineering

**Scheme 23.** Resolution of *N*-acetyl-phenylalanine in the presence of phenoxy acetic acid.

tiomer mixture of IBU was removed by scCO<sup>2</sup>

the efficiency of the enantiomer separations was significantly improved.

values compared to the experiments without additive (**Scheme 25**) [80].

**5.3. Additive of similar structure to the polar part of the resolving agent**

With the application of achiral additives, which are structurally related to the resolving agent,

By changing the half of the phenylglycine methyl ester (**PhG-Me**) enantiomer resolving agent to the structurally related benzylamine (**BA**) in course of the resolution of *N*-acetyl phenylglycine (*N*-Ac**-PhG**), the enantiomer purity of the diastereomer salt of *N*-Ac-**PhG** increased by 54%, compared to the results of the 1 equivalent **PhG-Me** resolving agent (**Scheme 24**). Also in the case of 1-phenyl-ethyl amine (**PhEA**) resolving agent, by exchanging the half of **PhEA** to benzylamine, both the enantiomer purity and the efficiency of resolution values increased [79]. The resolution of racemic ibuprofen (IBU) with (*R*)-1-phenylethylamine ((*R*)-PhEA) and benzylamine (BA) as structurally related achiral additive was investigated. The unreacted enan-

salt. The addition of the achiral benzylamine resulted in higher efficiency of resolution (FSCS)

Racemic 1-phenylethylamine (**PhEA**) was resolved with *N*-glutaryl-1-phenylethylamine (**PhEA-GA**) applying urea and its derivatives and thiourea additives of neutral character, which show structural similarity with a part of the resolving agent. Although the enantiomer purity of the **PhEA** received from the diastereomeric salt decreased (from *ee*: 62% to *ee*: 51–54%), the increased yields led to higher efficiency of resolution values (from F: 0.36 to F: 0.37–0.49) in all cases (**Scheme 26**). The urea was

**Scheme 24.** Resolution of N-acetyl-phenylglycine with 1-phenylethylamine and with benzylamine as achiral additive.

extraction from the received diastereomeric

proven to be present in the solid phase; therefore the process of the crystallization was investigated by polarization microscopy. According to the results, the nucleation of the diastereomer salt of (*S*)- **PhEA**∙(*R*)-**PhEA-GA** starts on the surface of the initially appearing needle-like urea crystals [81].

**Scheme 26.** Resolution of racemic 1-phenylethylamine in the presence of urea and its derivatives.

**Scheme 27.** Resolution of mandelic acid with the application of amphoteric achiral additives.

#### **5.4. Application of achiral additives structurally related to amino acids [19]**

The resolution of racemic mandelic acid (**MA**) was carried out with mixtures of amphoteric resolving agents and structurally similar achiral compounds in 1:1 ratio, namely with the mixtures of (*S*)-**Phe** and **Gly**, (*S,S*)-**AP** and β-**Ala**, and (*S*)-**PG** and **GABA**, respectively (**Scheme 27**).

The results were compared to experiments carried out with the application of solely halfequivalent resolving agent. In the case of (*S*)-**Phe**, the addition of achiral glycine resulted in Δ*ee* = 15%, in the case of aspartame ((*S,S*)-**AP**), the achiral β-Ala led to Δ*ee* = 38%; while the combination of (*S*)-pregabalin ((*S*)-**PG**) and *γ*-aminobutyric acid (**GABA**) led to an increase of Δ*ee* = 9% in enantiomeric purity.

(**Scheme 29I**) [84]. From the mixture of N,N-dimethylformamide and cosolvents, the DMF sol-

**Scheme 30.** Resolution of amlodipine with (*S,S*)-tartaric acid in the presence of urea.

With the addition of urea, which has similar structure to the different solvates, to the resolving agent (*S,S*)-tartaric acid, from the mixture of 2-propanol and water enantiopure *S*-amlodipine can be received with good yield (**Scheme 30**) [86]. The reason of the selection of urea as additive is not explained by the inventors, but the structural similarity is easily recognizable, thus this patent can be considered as the first published form of the application of achiral additive

One of the possibilities for the separation of mixtures of chiral compounds (enantiomers, diastereomers) is their nonlinear distribution between two phases. The phase-distribution depends on the starting mixture, which follows well the curves of the binary and ternary phase diagrams. The equilibrium processes between the supramolecular associates, formed from the chiral molecules, as well as the solubility equilibriums and the catalytic interactions of the formed crystals lead to the phase distribution of the mixtures. Most probably the helical structure of the associates, resulting in another mirror-image relation, determines their phase-distribution. In the case of enantiomeric mixtures, the macroscopic manifestation of the helical associates is the formation of crystals of helical structure, related to the configuration of the enantiomer in excess. The phase-distribution is determined by the eutectic composition of one of the present chiral molecules through the effects of the solvent and the time-dependence of the phase equilibriums. The equilibriums can be affected by the partial replacement of the chiral compounds

It has a more beneficial effect, if the molecules composing the diastereomer have different size

The authors thank the financial support of the Hungarian OTKA Foundation (K 124180 for

∙(R,R)-**TA** crystallized, with high enantiomeric purity (**Scheme 29II**) [85].

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vate of ((S)-**AML**)

**7. Conclusion**

and bond lengths.

E. Fogassy).

**Acknowledgements**

2

having similar structure as the solvate.

by structurally related chiral or achiral molecules.
