Viedma ripening is ad eracemizationp rocess that has been used to deracemize ar ange of chiral molecules. The method hast wo major requirements:t he compound needs to crystallize as ac onglomerate and it needs to be racemizable under the crystallization conditions. Although conglomerate formation can be induced in different ways, the number of racemization methods is still ratherl imited. To extend the scope of Viedma ripening, in the present research we applied UV-light-induced racemization in a Viedmar ipening process, and report the successful deracemizationo faB INOL derivative crystallizing as ac onglomerate. Irradiation by UV light activatest he target compound in combination with an organic base, required to promote the excited-state proton transfer (ESPT), leadingt hereaftert o racemization. This offers an ew tool towards the development of Viedma ripening processes, by using ac heap and "green"c atalytic source like UV light to racemize suitable chiral compounds.

Temperature cycling, alongside Viedma ripening, has been established as a reliable method for deracemizing racemic mixtures of chiral compounds that crystallize as a conglomerate. Here we report that the speed of temperature cycling can be increased by using chiral additives. We also demonstrate that the chirality of the additive determines the final enantiomeric state of the solid phase. Viedma ripening experiments using equivalent conditions, with and without chiral additives, are always found to be slower.

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.

In this work, we demonstrate a semibatch solid-state deracemization process for N-(2-chlorobenzylidene)­henylglycine 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 under 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.

While much data are available for the Viedma ripening and temperature cycling deracemization processes, not much is known about the advantages (or disadvantages) of a combination of the two. We here try to elucidate what happens when Viedma ripening is used in combination with temperature cycling by comparing not only the deracemization times but also the change in the sizes of the crystals. We found that, in the case of NMPA ( rac -(2-methylbenzylidene)-phenylglycine amide) as a model compound, combined experiments significantly increase the deracemization time. By tuning the process parameters, it is possible to approach experimental conditions where both Viedma ripening and temperature cycling control the deracemization. Under those conditions, however, the deracemization time is not significantly improved. Following our results, it seems unlikely that a combination of Viedma ripening and temperature cycling would shorten the deracemization time. Nevertheless, these experiments might provide clues for unraveling the mechanism of temperature cycling.