Combining Diastereomeric Resolution and Viedma Ripening by Using a Racemic Resolving Agent

Abstract

In spite of the many resolution techniques available to separate enantiomers, diastereomeric resolution still remains the most widely used technique in industry. However, drawbacks of this technique are the limited yield of the desired enantiomer and the expensive enantiopure resolving agent that is required. We show here for the first time that a combination of diastereomeric resolution with Viedma ripening using a racemic resolving agent can also provide a single stereoisomer when using an excess of the racemic resolving agent, without the need for the resolving agent to racemize. The requirements of this process are, like for an enantiomeric system, that the compound crystallizes as a racemic conglomerate and that at least one chiral center in the target molecule is racemizable. In addition, owing to the presence of the racemization reaction, substantial improvement in the yield can be obtained. We here demonstrate this approach using a metastable conglomerate salt of rac-2-phenylglycinamide with rac-N-acetyl tryptophan.

Influence of Ostwald’s Rule of Stages in the Deracemization of a Compound Using a Racemic Resolving Agent

“…The evolution of enantiopurity of PGA and NAT species in the solid phase for the simultaneous deracemization of rac -salt (containing rac -PGA and rac -NAT) via Viedma ripening was investigated by HPLC following the method used previously 23 with details described in Supporting Information . The result is shown in Figure 2 .…”

“…All chemicals were used as received. The salt preparation was implemented following the procedure reported in the literature 23 with quantitative yield. The formation of the racemic conglomerate salt was further confirmed by the agreement of the experimental powder X-ray diffraction (PXRD) pattern and the simulated pattern from the reported structure (CCDC 2093020) (see Figure S1 , Supporting Information).…”

“… 8 , 12 , 13 , 15 , 17 − 21 The application of deracemization has recently been extended to compounds that contain more than one chiral center; however, the number of studies is still limited. 22 , 23 …”

“…In our previous work, 23 we have demonstrated a chiral purification approach for a racemic compound via salt formation with a racemic resolving agent. A successful example was shown using a racemic conglomerate salt of rac -2-phenylglycinamide (PGA) and rac - N -acetyl tryptophan (NAT).…”

Attrition‐Enhanced Asymmetric Transformation of Axially Chiral Nicotinamides by Dynamic Chiral Salt Formation

“…Many successful examples have been reported for the deracemization of racemic conglomerates, [15] which is also considered to be effective for de-epimerization from diastereomeric mixtures. [16] In this paper, we examined the effect of attrition-enhanced asymmetric transformation on the chiral L-DBTA salts of racemic nicotinamides to provide highly pure axially chiral nicotinamides.…”