CORE - European Training Network on Continuous Resolution and Deracemization of Chiral Compounds by Crystallization

A cocrystal screening of the chiral drug “proxyphylline” (PXL) and achiral coformers was performed using dry or solvent as-sisted grinding and evaporation methods, yielding 10 different original solid forms with a 1:1 stoichiometry. Among them three anhydrous cocrystals and a monohydrated conglomerate forming system have been identified with salicylic acid (SA). The crystal structures of the monohydrate and one of the race-mic anhydrous forms were determined by X-ray single crystal experiments. The dehydration mechanism of the hydrate has been investigated by thermal analysis, X-Ray powder diffrac-tion, and water sorption-desorption cycles. The importance of water molecule in the crystal structure and the concomitant loss of both water and SA (cocrystal former) during the dehy-dration suggest a destructive mechanism.

The monohydrated co‐crystal composed of the chiral active pharmaceutical ingredient proxyphyline, of salicylic acid and of water, was successfully resolved by preferential crystallization (PC) from a water/ethanol mixture. To the best of our knowledge, this is the first report of PC applied to such system and the results highlight unusually high enantiomeric excess values attainable in the mother liquor. Our robust and reproducible results underline the potential of PC to resolve co‐crystal systems.

We have established that ethylammonium chlocyphos also belongs to a family of conglomerate-forming systems composed of chlocyphos and alkyl-amine. The pure enantiomer and racemic mixture exhibit very close X-ray powder diffraction patterns but with some peak shifts. This led to consider that ethylammonium chlocyphos could crystallize as a conglomerate but with partial solid solutions close to the pure enantiomer. The crystal structures of the pure (S)- and (R)-ethylammonium chlocyphos have been solved using single crystal data. The temperature-composition binary phase diagram between the two enantiomers of ethylammonium chlocyphos system has been investigated to determine the limit of the solid solutions. This was confirmed by a Tammann plot related to the eutectic invariant characterizing the melting of the conglomerate. The limit of the composition range of the partial solid solutions was confirmed by X-ray powder diffraction measurements on different enantiomeric compositions.

The picture displays a population of racemic conglomerate crystals of a BINOL derivative undergoing deracemization through Viedma ripening, leading to the formation of enantiopure crystals. The combined use of UV light and an organic base is an essential prerequisite to allow the compound to continuously racemize in solution via an ESPT (excited state proton transfer) mechanism. This research represents the first successful Viedma ripening deracemization of a chiral compound with the use of a cheap and green source, such as UV light, as a racemization tool. More information can be found in the Full Paper by S. B. Tsogoeva, E. Vlieg et al. (DOI: 10.1002/chem.201904382).

Viedma ripening is a deracemization process that has been used to deracemize a range of chiral molecules. The method has two major requirements: the compound needs to crystallize as a conglomerate and it needs to be racemizable under the crystallization conditions. While conglomerate formation can be induced in different ways, the number of racemization methods is still rather limited. In order to extend the scope of Viedma ripening, in the present research we applied UV light‐induced racemization in a Viedma ripening process, and report the successful deracemization of a BINOL derivative crystallizing as a conglomerate. Irradiation by UV light activates the target compound in combination with an organic base, required to promote the excited‐state proton transfer ( ESPT ), leading thereafter to racemization . This offers a new tool towards the development of Viedma ripening processes, by using a cheap and “green” catalytic source like UV light to racemize suitable chiral compounds.

Invited for the cover of this issue is the group of Gérard Coquerel at Université de Rouen Normandie. The image depicts pyramid‐like tetrahedron of the quaternary phase diagram showing where symmetry breaking can take place. Read the full text of the article at 10.1002/chem.201903338. “In our daily life, map apps are essential for many people to access their destinations. Phase diagrams play a similar role to map apps in the crystallization.” Read more about the story behind the cover in the Cover Profile and about the research itself on page ▪ ▪ ff. (DOI: 10.1002/chem.201903338).

In this work, we demonstrate a semi-batch solid-state deracemization process for N-(2-chlorobenzylidene)-phenylglycine amide (NCPA), a complex chiral polymorphic system that involves three types of crystalline racemates (racemic compound and conglomerate forms I and II). In this process, gradually fed metastable racemic compound crystals are converted in situ to crystals of the preferred (seeded) enantiomer under grinding conditions through a series of solvent-mediated transformations in a racemizing solution. The phase diagram for this system shows that while conglomerate form II is stable at the conditions examined (acetonitrile at 21°C), form I crystals of a single enantiomer (used as seeds) are unstable at (nearly) racemic compositions and convert to the racemic compound upon addition of the racemization catalyst. Thus, care needs to be exercised in order to fully convert form I to form II before addition of the racemization catalyst in order to prevent the undesired crystallization of the racemic compound. This can be achieved by adding a small amount of water, which is found to enhance the nucleation and growth kinetics of the most stable conglomerate form II, eventually leading to complete deracemization. Importantly, we show that this special deracemization process can be easily monitored online by Raman spectroscopy, which gives access to the evolution of the solid phase composition. For the studied system, this information can in turn be used to directly estimate the solid-phase enantiomeric excess online throughout the process, as long as conglomerate crystals of the counter enantiomer do not form.

Phase diagrams play a critical role for tuning crystallization. This study explains the basics of phase diagrams starting from the ternary system to a quaternary system with and without fast racemization in the liquid phase. Experimentally, an atropisomeric naphthamide derivative in MeOH/H2O serves as an example. Deracemization is ensured by a second‐order asymmetric transformation up to 97% ee. Readers are encouraged to look at the animation (in the Supporting Information) detailing the construction of the degenerated quaternary system in a step‐by‐step manner. More information can be found in the Full Paper by G. Coquerel et al. (DOI: 10.1002/chem.201903338).

The present study aimed at screening conglomerate derivatives of racemic chlocyphos (4-(2-chlorophenyl)-5, 5-dimethyl-2-hydroxy-1, 3, 2-dioxaphosphorinane 2-oxide) and to perform enantiomeric separation by preferential crystallization. A list of more than twenty chlocyphos salt derivatives were characterized by various techniques (SHG, DSC and X-ray powder diffraction). A family of salts formed with various alkyl amines crystallize as conglomerates is evidenced. The first attempts to resolve these conglomerates by preferential crystallization at small scale were successful. The mitigated performances of these entrainments are discussed.

We report herein, a productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative. New racemic compounds of an atropisomeric naphthamide derivative were discovered, and a quarternay phase diagram was constructed which indicated that four solids were stable in a methanol/H2O solution. Based on the heterogeneous equilibria study showing the stable domain of the conglomerate, a second‐order asymmetric transformation was achieved up to 97% ee. Further, the methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any typical limitations of deracemization, but application is still limited to conglomerate forming systems. We anticipate that this demonstration will serve as a fundamental model for the design of sophisticated chiral separation processes.

Herein, we report the chiral symmetry breaking of 2-methoxy-1-naphthamide atropisomers through temperature cycling with-out the use of any racemization reagent. The racemization rate (k1) controls the deracemization process when the cooling of the slurry is slow enough to keep the system close to equilibri-um. The productivity appears proportional to the racemization rate (k1) multiplied by the solubility.

Stable NH-form of the threonine-based Schiff base 4, (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(((E)-(2-hydroxynaphthalen-1-yl)methylene)amino)butanamide, was synthesized and characterized in the crystalline state by means of IR spectroscopy and X-ray crystallographic analysis. This is the first X-ray determination of an amino acid-based Schiff base that was locked in the NH-form. Comparison of the characteristic bond lengths based on the X-ray structure of 4 with previously reported NH-forms of other Schiff bases revealed that the structure of 4 was a hybrid of two canonical structures, namely, zwitterion and quinoid, contributing to the resonance. It was also found that 4 exist in the OH-form in solution and its phenolic proton is well-constrained via intramolecular hydrogen bonding with the imine functionality.

Temperature-cycle-induced deracemization (TCID) has been widely studied in the field of chiral separation, ranging from fundamental research to applications. In this study, the second-order asymmetric transformation (SOAT) of 2-methoxy-1-naphthamide in an azeotropic mixture of ethyl acetate and cyclohexane is compared with TCID, in terms of process productivity. The results indicate that the volumetric productivity using SOAT was over 100-times higher than that using TCID, such that a scale-up by a factor of 10 was easily implemented.

The chiral symmetry breaking and deracemization of sodium chlorate was investigated when varying the agitation speed and cooling rate in cooling crystallization. At a low agitation speed, almost zero crystal enantiomeric excess occurred at the induction period. When increasing the agitation speed, the crystal enantiomeric excess at the induction period (called the ‘initial CEE’) increased due to the promotion of chiral symmetry breaking. The chiral symmetry breaking at the induction period (called the ‘initial chiral symmetry breaking’) also varied with the cooling rate. At a low cooling rate of 0.0738oC/min, the initial CEE reached up to about 90% and was rapidly reduced when increasing the cooling rate. The experiments also showed enhanced deracemization of the chiral crystals when increasing the initial CEE. Thus, complete deracemization was achieved when the initial CEE was over 60%. The influence of the agitation speed and cooling rate on the initial CEE originated from secondary nucleation depending on the supersaturation at the induction period (called the ‘induction supersaturation’). Using a nucleation rate equation, the initial CEE was found to correlate well with the induction supersaturation. Also, varying the final setting temperature and agitator confirmed that secondary nucleation was significantly involved in the chiral symmetry breaking at the induction period.