Enantioseparation - Diastereomeric Salt Formation

The first chemical enantioseparation has been also performed by Pasteur in 1853 [10]. Thereafter, the enantioseparation by the diastereomeric salt formation is most frequently applied to the separation of various racemates in laboratorial and industrial scales. 

Amine (R-) Yield (%) Enantiomeric excess(%) Resolution efficiency 

Yield is based on a half amount of the racemate. Enantiomeric excess is ofthe recovered amine. Resolution efficiency = yield x e.e. 

On the other hand, in the cases with low resolution efficiencies, both diastereo- 

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In the case of the salt of a racemic acid and a racemic amine, six crystal modifications are possible (Table 5.7), while there are three crystal modifications for the salt of a racemic acid or amine with an enantiopure amine or acid (Table 5.8). If the successful enantioseparation of an amine with an enantiopure acid by diastereomeric salt formation is assumed, the diastereomers in Table 5.8 should obviously be more stable than the double salt and pseudo-diastereomer. Then, the diastereomers in Table 5.7 should be more stable than the other crystal modifications. On the other hand, this assumption leads to the conclusion that the solubilities of the diastereomers in Table 5.8 are largely different from each other. This... 

Process Research on the Enantioseparation of Racemates by Diastereomeric Salt Formation 1143... 

These results strongly suggest that the probabihty of formation of a conglomerate, which can be enantioseparated by the preferential crystallization, is considerably high for the combinations of racemic acids and racemic amines when the enantiopure component is an efficient resolving agent for its counterpart in the diastereomeric salt formation. 

Duloxetine (LY-248686), (S)-(-i-)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propyl-amine, is expected to be not only a new potent antidepressant but also a NE (norepinephrine) reuptake inhibitor, a 5-HT (serotonin) reuptake inhibitor, and a new treatment drug for stress urinary incontinence [18]. In order to produce an enantiopure key intermediate for the synthesis of the (S)-amine, the Eli Lilly group proposed various strategies [19]. As a result, they selected the enantioseparation of racemic 3-(dimethylamino)-l-(2-thienyl)propan-l-ol with (S)-mandelic acid by diastereomeric salt formation as the most economic and suitable process for industrial-scale production with efficient supporting techniques such as the racemization of the antipode and recycling the recovered materials [20]. However, in the process of demethylation for the preparation of (S)-Duloxetine from (S)-3-(di-methylamino)-l-(2-fhienyl)propan-l-ol, there are some critical problems, such as low yield and considerable decomposition to give impurities. Thus, a direct synthesis of (S)-Duloxetine starting from (S)-3-(methylamino)-l-(2-thienyl)propan-l-ol is expected to be a new route for the production of (S)-Duloxetine. 

Table 5.14 Enantioseparation of drugs and their intermediate by diastereomeric salt formation.

The important advantage of a direct crystallization is that a chiral compound does not necessarily possess functional groups which are required for diastereomeric salt formation. The disadvantages include its limited applicability because less than 10% of all crystalline race-mates occur as a conglomerates, poor predictability and very sensitive dependence from the experimental conditions. Thus, as mentioned by some authors, even Louis Pasteur would not have succeeded with his very first enantioseparation had he performed the experiment with the mixed cesium-rubidium salt of tartaric acid at temperatures higher than 27 °C [4]. 

The diastereomeric crystallization relies on a different solubility of diastereomeric salts. The first enantioseparation based on a diastereomeric salt formation was performed by Pasteur in 1853 [2,10]. In this example, racemic tartaric acid was resolved as diastereomeric salts with (-t-)-cinchotoxine or (+)-quinotoxine. Diastereomeric complexes may also be of charge-transfer or inclusion type. 

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