Resolution methodology

Dynamic kinetic resolution is a technique that combines a racemization with a simultaneous resolution to overcome the inherent 50 % yield limit of kinetic resolution allowing a theoretical 100 % yield. Recently, a novel chemoenzymatic system has been developed for the dynamic kinetic resolution of 6,7-dimethoxy-l-methyl-1,2,3,4-tetrahydroisoquino-hne, building on kinetic resolution methodology developed by Breen. The corresponding (/f)-carbamate was isolated in high yield and enantiomeric excess (Figure 4.2). 

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

Disubstituted (cyclobutadiene)Fe(CO)3 complexes in which the two substiments are different may exist as enantiomers. Racemic cyclobutadiene carboxylic acids or cyclobutadiene amine complexes of this type have been separated by classical resolution methodology ". These optically active (cyclobutadiene)l e(CO)3 complexes are stable with respect to racemization at 120 °C for 24 h. This stability contrasts with acyclic... 

Optimization of this synthetic route to LY414197 positioned it as a reasonable candidate as a production process, provided a scalable resolution methodology is developed. Much effort was thus expended in hnding an acceptable resolution process of the TH(3C. 

An obvious disadvantage of achieving high resolution methodology through efficiency lies in the fact that chromatographic resolution is only... 

ESR imaging in solid phase down to submicron resolution methodology and applications. Blank, A., Suhovoy, E., Halevy, R., Shtirberg, L., and Harneit, W. (2009) Phys. Chem. Chem. Phys., 11 (31), 6689. 

All packing materials produced at PSS are tested for all relevant properties. This includes physical tests (e.g., pressure stability, temperature stability, permeability, particle size distribution, porosity) as well as chromatographic tests using packed columns (plate count, resolution, peak symmetry, calibration curves). PSS uses inverse SEC methodology (26,27) to determine chromatographic-active sorbent properties such as surface area, pore volume, average pore size, and pore size distribution. Table 9.10 shows details on inverse SEC tests on PSS SDV sorbent as an example. Pig. 9.10 shows the dependence... 

R. R. Ernst (Eidgenbssische Technische Hochschule, Zurich) contributions to the development of the methodology of high resolution nmr spectroscopy. 

The strategy described here explains the different possibilities of enzymatic ammonolysis and aminolysis reaction for resolution of esters or preparation of enantiomerically pure amides, which are important synthons in organic chemistry. This methodology has been also applied for the synthesis of pyrrolidinol derivatives that can be prepared via enzymatic ammonolysis of a polyfunctional ester, such as ethyl ( )-4-chloro-3-hydroxybutanoate [30]. In addition, it is possible in the resolution of chiral axe instead of a stereogenic carbon atom. An interesting enzymatic aminolysis of this class of reaction has been recently reported by Aoyagi et al. [31[. The side chain of binaphthyl moiety plays an important role in the enantiodis-crimination of the process (Scheme 7.14). 

In recent years, a great variety of primary chiral amines have been obtained in enantiomerically pure form through this methodology. A representative example is the KR of some 2-phenylcycloalkanamines that has been performed by means of aminolysis reactions catalyzed by lipases (Scheme 7.17) [34]. Kazlauskas rule has been followed in all cases. The size of the cycle and the stereochemistry of the chiral centers of the amines had a strong influence on both the enantiomeric ratio and the reaction rate of these aminolysis processes. CALB showed excellent enantioselec-tivities toward frans-2-phenylcyclohexanamine in a variety of reaction conditions ( >150), but the reaction was markedly slower and occurred with very poor enantioselectivity with the cis-isomer, whereas Candida antarctica lipase A (GALA) was the best catalyst for the acylation of cis-2-phenylcyclohexanamine ( = 34) and frans-2-phenylcyclopropanamine ( =7). Resolution of both cis- and frans-2-phenyl-cyclopentanamine was efficiently catalyzed by CALB obtaining all stereoisomers with high enantiomeric excess. 

This methodology avoids the inherent 50% yield limit of KR and the difficult separations often encountered in the resolution of racemates. The potential of enzymes, especially lipases, to catalyze the aminolysis and ammonolysis of prochiral... 

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