Effect of ultrasound-assisted crystallization in the diastereomeric salt resolution of tetramisole enantiomers in ternary system with O,O′-dibenzoyl-(2R,3R)-tartaric acid

Abstract

The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166°C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150°C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.

Enantiomeric separation of racemic amlodipine by sequential fractional crystallization through formation of diastereomeric salt solvates and co‐crystals of solvate‐like compounds with specific structure — A tandem resolution

“…In overall, the thermal (DSC, TG/DTA‐EGA‐MS and TG‐EGA‐FTIR), analytical (FTIR) and structural (XRD, indexing) comparisons 55–57 indicate, in overall, that the key‐intermediate crystalline diastereomeric salts—as solvates and co‐crystals—inherit a kind of structural similarity from their related additives—solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively 58…”

Strategies for chiral separation: from racemate to enantiomer

“…Hence, it will be a trendsetting topic to explore the mechanism of enantiospecific cocrystal formation using crystal structures and DFT calculations including the binding energy, crystal packing mode, and solvation free energy. 233 Besides, coupling crystallization with ultrasound waves or magnetic fields may also raise unexpected discoveries in conglomerate preparation, 89,158 enantioselectivity enhancing 216 and process development. 190…”

“…Hence, it will be a trendsetting topic to explore the mechanism of enan-tiospecic cocrystal formation using crystal structures and DFT calculations including the binding energy, crystal packing mode, and solvation free energy. 233 Besides, coupling crystallization with ultrasound waves or magnetic elds may also raise unexpected discoveries in conglomerate preparation, 89,158 enantioselectivity enhancing 216 and process development. 190 Meanwhile, the successful deracemization of complex racemates besides Cons through crystallization-based methods can also be attributed to the coupling strategy, as exemplied by chemical derivatization-VR-PC, 262 chemical derivatization-TCID-PC, 91 CBR-CIDT process with liquid-phase coupling, 239 TCID-PC process with suspension exchange 86 and reverse PC-VR-TCID.…”

“…Products with 70% ee could be harvested in DCM/H 2 O using a 4.3 W intensity within 15 min. 216 Similarly, Ge et al successfully enantio-separated ( R , S )-bupivacaine via an ultrasonic-assisted CCR process by adopting 12,4-dinitrodehydroabietic acid (12,14-dinitroDHAA) as the resolving agent. 217 After utilizing a Box–Behnken design with response surface methodology, the optimal conditions were obtained to prepare the ( S )-enantiomer with 69.8% ee and 87.5% yield.…”

Structural, analytical and DSC references to resolution of 2-methoxy-2-phenylacetic acid with chiral 1-cyclohexylethylamines through gas-antisolvent precipitation

“…The solid-liquid melting phase diagram for mixtures of (S)--MPAA and (R)--MPAA was formerly investigated by Raznikiewicz [34], where this binary system resembled also a type of melting phase diagram including a racemic compound, which showed higher melting point than the enantiomers (ibid). Beyond the results on various binary subsystems, the calculated eutectic parameters for ternary eutectic subsystems, according to the Schröder-van Laar equation [35][36][37] are also calculated and reported in Table 5. A schematic diagram of overall phase relation of the three-component ((S)--MPAA, (R)--MPAA, and (R)-1-CHEA) system, that allows the required resolution, is exhibited in Fig.…”