Resolution process research

Instrumentation for experimental observation and measurement is paramount in microstmcture-related research. One reason that surfaces, interfaces, and more complicated microstructures are a frontier of chemical engineering and processing research is that modem science has recently spawned a number of microstractural probes of unprecedented resolution and utility. For the first time, we have the proper tools to attack the molecular and chemical basis of microstructures. 

May O., Verseck, S., Bommarius, A. and Drauz, K. (2002) Development of dynamic kinetic resolution processes for biocatalytic production of natural and nonnatural L-amino acids. Organic Process Research Development, 6 (4), 452-457. 

Upon the resolution process development, finding the optimum resolving agent is the first concern for the chemist. Although various attempts have been made by numerous researchers, a useful concrete theory to find a satisfactory resolving agent has not yet been proposed. 

Resolutions of racemic mixtures are by far the most frequent applications of biocatalysts in the pharmaceutical industry. Repic et al., of the process research and development group at Novartis, recently published work to develop a method for the resolution of racemic (3-amino acid esters, an important class of intermediates for the preparation of peptidomimetics [21]. The Novartis group used Chiro-CLEC -EC [22] in 2% aqueous toluene to selectively acylate several different 3-amino esters (Fig. 4). The authors were able to isolate the desired (S) isomer of the amino esters in >95% ee in a simple one-step reaction and described it as a method which could be amenable for large-scale preparation. 

For assaying the enantiomeric purity of dilevalol in the DBTA salt, the Schering Research Analytical Department worked out an efficient glc procedure, utilizing methylboronic acid. Although the method did not separate RR and SS enantiomers or RS and SR enantiomers, it served to quickly indicate the efficiency of the resolution process since no racemization of the R-amine moiety was ever found. A typical glc trace was as follows ... 

Sales of single enantiomer drugs exceeded 159 billion in 2002. Some of these come from biological sources, but the majority are synthetic. For this reason, the development of synthetic methods that produce only a single enantiomer of chiral compounds is a very active research area in both academic and pharmaceutical research labs. Chiral or asymmetric syntheses, which produce only the desired enantiomer, are much preferred over resolution processes, in which at least half of the initial compound is discarded. 

SCHEME 10.5 Resolution of racemic UK-350,926 with brucine hydrate. S. Challenger/Organic Process Research and Development/ACS/2005. 

However, this facile epimerization phenomenon was viewed as an opportunity, rather than a liability, to dramatically refine the oxazinone route. Within our process research group, it is commonplace to consider a crystallization-driven racemization resolution protocol whenever an epimerizable stereocenter exists in a molecule. Such an approach towards diastereomerically pure substrates simply relies on differences in the solubility of the diastereomeric products and on the ability of the undefined stereocenter to epimerize under the conditions used in the crystallization. In fact, these processes can effectively rival catalytic asymmetric synthesis and the literature is replete with recent examples of resolution/racemization approaches to chiral molecules. ... 

Goswami A, Howell JM, Hua EY, et al. Chemical and enzymatic resolution of (R,S)-N-(tert-butoxycarbonyl)-3-hydroxymethylpiperidine. Organic Process Research and Development 5 4), 415, 2001. 

Micro-PIXE offers a powerful nondestructive analytical method of micrometer-scale lateral resolution for research in art and archeology. Among other fields of application studies in corrosion processes, searching for characteristic features of painting and fabrication techniques, identification of art objects through trace element qualifications, and testing of restoration methods can be mentioned here. 

The recycling of the undesired enantiomer from the enzymatic resolution is of crucial importance particularly on an industrial scale [107]. The classical chemical method consists of the thermal racemization of an amino acid ester at about 150-170°C. Milder conditions can be employed for the racemization of the corresponding amides via intermediate formation of Schiff bases with aromatic aldehydes such as benzaldehyde or salicylaldehyde (Scheme 2.14). More recently, intense research has been devoted to the use of isomerase enzymes (such as amino acid racemases [108]) aiming at the development of dynamic resolution processes. 

Damon, D. B., Dugger, R. W., Magnus-Aryitey, G., Ruggeri, R. B., Wester, R. T., Tu, M., Abramov, Y. (2006). Synthesis of the CETP inhibitor torcetrapib the resolution route and origin of stereoselectivity in the imininm ion cychzation. Organic Process Research and Development, 10, 464-471. 

Temporal and Spatial Resolution. Once the issue of nomenclature is resolved, the team must select a baseline temporal and spatial resolution. Scientists studying plate deformations and the behavior of internal earth processes use time scales of millions and billions of years. Scientists studying the dynamics at the surface of the earth are concerned with solar driven processes and use time scales ranging from days to centuries. These researchers may assume that internal earth processes are static for purposes of their studies. If the temporal baseline selected is days, then those researchers interested in phenomena that require years or centuries will withdraw from the team. 

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