Drugs enantiomerically pure

The preparation of enantiomerically pure drugs is one factor that makes enantioselective synthesis and the resolution of racemic drugs (separation into pure enantiomers) active areas of research today. 

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... 

An advanced type of column selectivity is chiral discrimination. Since enantiomers have identical physical properties they are not separable on conventional GC columns. However, if chiral analytes are allowed to interact with a chiral environment they will form transitory diastereomeric complexes which result in their being retained by the column to a different extent. As increasing numbers of enantiomerically pure drugs are synthesised in order to reduce side-effects, this type of separation will become increasingly important. 

Figure 25-8 Baseline separation of enantiomers of the drug Ritalin by HPLC with a chiral stationary phase. One enantiomer is pharmacologically active for treating attention deficit disorder and narcolepsy. The other enantiomer has little activity but could contribute to undesired side effects. Pharmaceutical companies are moving toward providing enantiomerically pure drugs, which could be safer than mixtures of optical isomers. [From R. Bakhtiar, L Ramos, and F. L. S. Tse, "Quantification of Methylphenidate in Plasma Using Chiral Uquid-Chromatography/Tandem Mass Spectrometry Application to Taxicokinetic Studies," Anal. Chim. Acta 2002, 469.261.]...

Enantiomerically Pure Drugs or Advanced Pharmaceutical Intermediates (APIs)... 

Cheminor Drugs (part of Dr. Reddy s Group, Mumbai, India) have developed a process based on a chiral synthesis to (S)-ibuprofen. (S)-Ibuprofen is 160 times more active than the (R) form, so with an enantiomerically pure drug the dosage could be cut in half. As the human body has been reported to racemize (R)-ibuprofen partially into the (S) form and as (R)-ibuprofen is not harmful, nearly all the ibuprofen taken becomes active. The process discovered by Cheminor is therefore unlikely to have commercial significance. 

A special case of host-guest inclusion is the resolution of a racemic mixture of chiral guests. This has important implications for the pharmaceutical industry, where the production of enantiomerically pure drugs has recently become increasingly important. A common method of chiral resolution is via the formation and separation of diastereomers. For example, a racemic acid AH may be treated with a chiral base B [21] ... 

Chiral alcohols are useful starting materials for the synthesis of various biologically active compounds. The need for enantiomerically pure drugs and agrochemicals has increased in recent years [13]. Derivatives of enantiopure 1-phenylethanol are important chiral building blocks, which can be used as synthetic intermediates for the production of pharmaceuticals, fine-chemicals agrochemicals, and natural products. In particular (R)-1-phenylethanol is in widespread use as an ophthalmic preservative, an inhibitor of cholesterol intestinal adsorption, a solvatochromic dye, a fragrance, and so on. 

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. 

A major hurdle on the road to enantiomerically pure drugs is the development of efficient methods of asymmetric synthesis. In many cases, small chiral compounds of synthetic or natural origin are used as starting... 

The production of enantiomerically pure drugs by resolution and biocatalyzed processes are the topic of other chapters of this book. 

Examples of Stereoselective Synthesis of Enantiomerically Pure Drugs... 

The different stereoselective routes explored toward the synthesis of the tricyclic p-lactam sanfetrinem cilexetil (GV 118819) [45] perfectly illustrate advantages and drawbacks of the approach to enantiomerically pure drugs based on the use of commercially available chiral non-racemic substrates. 

This topically active carbonic anhydrase inhibitor is a powerful controller of the elevated intraocular pressure associated with glaucoma, and has been prepared by Merck in > 32% yield in a multistep synthesis starting from (R)-3-hydroxybutyrate [49]. Although the key ketone reduction step has been recently improved by researchers at Zeneca by replacing a chemical process with a biological one [50], the Merck synthesis well illustrates the potentialities of the approach to enantiomerically pure drugs based on the use of chiral non-racemic substrates. 

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