Synthesis of Enantiomerically Pure Drugs

Chiral separation of drng molecules and of their precursors, in the case of synthesis of enantiomerically pure drugs, is one of the important application areas of HPLC in pharmaceutical analysis. Besides HPLC, capillary electrophoresis (CE) is another technique of choice for chiral separations. Chapter 18 provides an overview of the different modes (e.g., direct and indirect ones) of obtaining a chiral separation in HPLC and CE. The direct approaches, i.e., those where the compound of interest is not derivatized prior to separation, are discussed in more detail since they are cnrrently the most frequently used techniques. These approaches require the use of the so-called chiral selectors to enable enantioselective recognition and enantiomeric separation. Many different molecnles have been nsed as chiral selectors, both in HPLC and CE. They can be classified into three different groups, based on their... 

Growing awareness of the relevance of drug stereochemistry has not only greatly stimulated the development of methods for asymmetric synthesis of enantiomerically pure drugs as well as the preparative separation of racemic pharmaceuticals, but also initiated the development of methods for precise and sensitive determination of enantiomeric proportions. On the other hand, access to pure stereoisomers has enabled scientists to study physiological activity and stereoselective metabolism of enantiomerically pure drugs. 

Examples of Stereoselective Synthesis of Enantiomerically Pure Drugs... 

The possibility of using a non-covalently bound chiral modifier to direct the steric course of a reaction represents a very appealing method for the stereoselective synthesis of enantiomerically pure drugs. The preparation of the single stereocenter-containing L-738,372 and L-743,726 illustrate this approach (Fig. 16) [57]. 

In addition, various formyl derivatives 243 have been reduced to afford (S)-244 [305] in 70-83% yield and e.e. values ranging from 46% to 91%. Aryl-substituted derivatives 245 were reduced to the corresponding alcohols 246 that served as valuable intermediates for the synthesis of enantiomerically pure drugs [358,359]. 

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