**6. Effect of solvate forming solvents and molecules having similar structure on the results of diastereomer separation**

In the case of resolution of amlodipine with (*S,S*)-tartaric acid ((*S,S*)-**TA**) from dimethyl-sulfoxide solvent, the dimethyl-sulfoxide solvate of (*S*)-amlodipine-hemi-(*S,S*)-tartrate salt crystallizes with high purity (**Scheme 28I**) [82]. The diastereomer salt enriched in (*S*)-amlodipine precipitates also from *N*,*N*-dimethylacetamide (**DMA**) solvent (**Scheme 28II**) [83] from 2-butanone solvent, the diastereomer salt of (S)-amlodipine crystallized applying (R,R)-tartaric acid as resolving agent

**Scheme 29.** Resolution of amlodipine with (*R,R*)-tartaric acid.

Separation of Chiral Compounds: Enantiomeric and Diastereomeric Mixtures http://dx.doi.org/10.5772/intechopen.76478 115

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

(**Scheme 29I**) [84]. From the mixture of N,N-dimethylformamide and cosolvents, the DMF solvate of ((S)-**AML**) 2 ∙(R,R)-**TA** crystallized, with high enantiomeric purity (**Scheme 29II**) [85].

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 having similar structure as the solvate.

### **7. Conclusion**

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

114 Laboratory Unit Operations and Experimental Methods in Chemical Engineering

**6. Effect of solvate forming solvents and molecules having similar** 

In the case of resolution of amlodipine with (*S,S*)-tartaric acid ((*S,S*)-**TA**) from dimethyl-sulfoxide solvent, the dimethyl-sulfoxide solvate of (*S*)-amlodipine-hemi-(*S,S*)-tartrate salt crystallizes with high purity (**Scheme 28I**) [82]. The diastereomer salt enriched in (*S*)-amlodipine precipitates also from *N*,*N*-dimethylacetamide (**DMA**) solvent (**Scheme 28II**) [83] from 2-butanone solvent, the diastereomer salt of (S)-amlodipine crystallized applying (R,R)-tartaric acid as resolving agent

**structure on the results of diastereomer separation**

**Scheme 28.** Resolutions of amlodipine with (*S,S*)-tartaric acid.

**Scheme 29.** Resolution of amlodipine with (*R,R*)-tartaric acid.

Δ*ee* = 9% in enantiomeric purity.

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

> 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 by structurally related chiral or achiral molecules.

> It has a more beneficial effect, if the molecules composing the diastereomer have different size and bond lengths.

## **Acknowledgements**

The authors thank the financial support of the Hungarian OTKA Foundation (K 124180 for E. Fogassy).
