Resolution diastereomeric

S.-W. Wong, C. Georgakis, G.D. Botsaris, K. Saranteas and R. Bakale, Online estimation and monitoring of diastereomeric resolution using FBRM, ATR-FTIR, and Raman spectroscopy, Ind. Eng. Chem. Res., 47, 5576-5584 (2008). 

The practical difficulty with carrying out a crystalhzation DTR process is the need to operate under conditions that allow selective crystalhzation of the least soluble diastereomer while permitting the racemization to take place. Amine racemization catalysts, such as SCRAM , Shvo, Pd/C, and Adam s, are more active at higher temperatures, which runs counter to the conditions required for crystaUization. A solution to this problem is to separate the diastereomeric resolution and racemization steps but couple them with a flow engineering design. In this way each reaction can be operated under optimal conditions for example, temperature, concentration and solvent, via an intermediary solvent exchange unit Since the racemization catalyst itself may affect the crystalhzation (or indeed the crystalhzation may affect the catalyst), it is preferred to keep them separate. This can be achieved by having the catalyst or product either permanently or temporarily in a different phase by immobilization, extraction, precipitation, distil-... 

There is no doubt that catalytic asymmetric synthesis has a significant advantage over the traditional diastereomeric resolution technology. However, it is important to note that for the asymmetric hydrogenation technology to be commercially useful, a low-cost route to the precursor olefins is just as crucial. The electrocarboxylation of methyl aryl ketone and the dehydration of the substituted lactic acids in Figures 5 and 6 are highly efficient. Excellent yields of the desired products can be achieved in each reaction. These processes are currently under active development. However, since the subjects of electrochemistry and catalytic dehydration are beyond the scope of this article, these reactions will be published later in a separate paper. 

II. Molecular Design of Novel Nonnatural Resolving Agents in Diastereomeric Resolution... 

Systematic Study on the Diastereomeric Resolution by Mandelic Acid... 

Although the basic principle and procedure of diastereomeric resolution are not difficult to understand, the chiral discrimination mechanism involved in the selective crystallization of one diastereomer from the mixture is very complicated. The chiral discrimination mechanism for diastereomeric resolution changes in accord with the resolving system, since not only the properties of diastereomeric crystals but also the conditions for crystallization strongly influence the chiral discrimination mechanism. In particular, the polymorphism of crystal, the severe solvent effect on solubility, and the kinetic factor for crystal growth are still not perfectly understood regarding this chiral discrimination phenomenon. The study is therefore limited in its investigation of the chiral discrimination mechanism for the diastereomeric resolution, as the mechanism involves both the crystal and solution properties of diastereomers.7... 

For convenience, a phase diagram of a pair of diastereomeric crystals is ordinarily studied in detail, and the mechanism of the diastereomeric resolution is interpreted in terms of the thermodynamic and physical properties of the bulk of the diastereomeric crystals.4,7-10 Such studies reveal the importance for diastereomeric resolution of the type of mixture of diastereomers in a target system. There are three types of diastereomer mixtures an eutectic mixture, a 1 1 addition compound, and a solid solution. To achieve successful resolution, it is essential that the mixture of the diastereomeric crystals of a target racemate with a resolving agent be an eutectic mixture. The classic studies are thoroughly reviewed by Collet and co-workers.4,12... 

II. MOLECULAR DESIGN OF NOVEL NONNATURAL RESOLVING AGENTS IN DIASTEREOMERIC RESOLUTION... 

More than one hundred crystal structures of the diastereomeric salts of 6 with chiral carboxylic acids are listed in the CSD. About 20% of them are related to the results of the studies on the diastereomeric resolution. The chemical structures of the acidic parts in these salts and the corresponding CSD reference codes are shown in Figure 4.37.115-125... 

As described in this chapter, it is useful to study the crystal structures of diastereomeric salt crystals, which precipitate upon resolution, for understanding the chiral discrimination mechanism of the diastereomeric resolution in a molecular level. The authors studies on the crystal structures described... 

The dynamic crystallization-induced diastereomeric resolution was further investigated in order to develop practical approaches to obtain one diastereomer by exploiting more diversity of the diastereomeric nitroaldol adducts in the dynamic system [77]. A larger and more diverse dynamic nitroaldol system (CDS-5C) was generated by equimolar amounts of nine different benzaldehydes, nitroethane 38, and triethylamine was used as catalyst as shown in Scheme 15. A total of 36 nitroaldol diastereomers were formed under thermodynamic control in chloroform-d, and the reaction was followed by H-NMR spectroscopy. 

Note should also be made that in some cases recrystallization reduces the enantiomeric excess, which can lead to crystallization of the racemate (94). In these cases the mother liquors contain moderately to highly enriched material. It is therefore important to plan the strategy at which point the enantiomer is recrystallized to optical purity. This may be from an enzymic resolution, or in the event that an asymmetric synthesis has failed, to deliver enantiopure product. As discussed in Section 3, the liquors from the diastereomeric resolution with DTTA of 88%de can be cleaved to the free base, and crystallization of the hydrochloride salt gives >98% ee. This is because of the fact that methylphenidate hydrochloride has a eutectic point of 30% ee. Davieset al. (95) and Winkler et al. (96) have prepared single enantiomer methylphenidate (29), Their approaches use an enantioselective synthesis the enantiomeric excesses are 86% and 69%, respectively, thus requiring recrystallization... 

In the synthesis of 173, the relative stereochemistry is set in the addition of a 4-(l-metallo-ethyl)-5-fluoropyrimidine derivative to l-(2,4-difluorophenyl)-2-(17/-l,2,4-triazol-l-yl)-l-ethanone 174 (Scheme 12.27). The diastereocontrol of this can be controlled by pyrimidine substitution pattern and reaction conditions of the metalation step. Good diastereoselectivity (12 1) is obtained using an zinc derivative of 175. After removal of the chlorine from the pyrimidine ring, of the desired stereoisomer of 173 is isolated via a diastereomeric resolution using salt (l/ )-10-camphorsulfonic acid (10-CSA). Synthetic routes to the pyrimidine partner have also been evaluated. Shown in Scheme 12.28, the initial six-step route from 5-fluorouracil 177 can be replaced by a four-step process, involving fluorination of methyl 3-oxopentanoate and cyclization with formami-dine acetate. ... 

Kinbara, K. Oishi. K. Harada. Y. Saigo. K. Effect of a substituent on an aromatic group in diastereomeric resolution. Tetrahedron 2000. 56, 6651-6655. 

Myriad applications for OSN exist in the pharmaceutical industry [135]. Specific applications include isolation and concentration of pharmaceutical intermediates and products [141], solvent exchange during pharmaceutical synthesis [142], diastereomeric resolution of chiral bases [143], and membrane based solvent back extraction [144]. 

F.C. Ferreira, H. Macedo, U. Cocchini, and A. G. Livingston, Development of a Liquid-Phase Process for Recycling Resolving Agents within Diastereomeric Resolutions, Org. Process Res. Dev., 10 (2006) 784-793. 

T Maoka, T Komori, T Matsuno. Direct diastereomeric resolution of carotenoids. J Chromatogr 318 122-124, 1985. 

Probably one of the empirical criteria for the selection of a suitable resolving agent, and therefore, for an efficient diastereomeric resolution could be that the molecular length of resolving agent in some cases has to be similar or a bit longer than that of a racemate, which has to be resolved. 

Diastereomeric Resolution Perceived Through Phase Diagrams... 

Marchand P, Lefebvre LC, Quemiard F, Cardinael P, Perez G, Counioux J-J, Coquerel G. Diastereomeric resolution rationalized by phase diagrams under the actual conditions of the experimental process. Tetrahedron Asymm. 2004 15 2455-2465. 

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