Chiral enantiopure drugs

It was apparent that the FDA recognized the ability of the pharmaceutical industry to develop chiral assays. With the advent of chiral stationary phases (CSPs) in the early 1980s [8, 9], the tools required to resolve enantiomers were entrenched, thus enabling the researcher the ability to quantify, characterize, and identify stereoisomers. Given these tools, the researcher can assess the pharmacology or toxicology and pharmacokinetic properties of enantiopure drugs for potential interconversion, absorption, distribution, and excretion of the individual enantiomers. 

In November 1997, the Department of Health and Human Services along with the International Conference on Harmonisation (ICH) released a draft guidance for the selection of test procedures, which included chiral drugs. For the development of an enantiopure drug substance, acceptable criteria shall include, if possible, an enan-tioselective assay. This assay should be part of the specification for the identification of an enantiopure drug substance and related enantioenriched impurities [16]. 

These policy decisions by the FDA were the driving force for chiral switches and the commercial development of chromatographic processes such as simulated moving bed (SMB) technology. Due to technological advances such as SMB and the commercial availability of CSPs in bulk quantities for process-scale purification of enantiopure drugs, the production of many single enantiomers now exists on a commercial scale. 

The evolution of FDA policies continues to be a significant driving force on the global pharmaceutical market. Several pharmaceutical firms have made new discoveries while evaluating enantiopure drugs originally discovered and marketed as race-mates by others. These pharmaceutical firms have merged, or other companies have appropriated portfolios of patents based on chiral switches. Thus, the FDA contin-... 

Preparative chromatography has been used for chiral separations for years, but examples of multi-kg separations (and hence larger ones) were rare until recently. The development of SMB techniques (both hardware and simulation software) has made major breakthroughs in this field. The ability of SMB as a development tool has allowed the pharmaceutical manufacturer to obtain kilo grams quantities of enantiopure drug substances as well benefit from the economics of large-scale production. 

Senanayake, C. H., Jacobsen, E. N. Chiral (Salen)Mn(III) Complexes in Asymmetric Epoxidations Practical Synthesis of Ci s - Am i n o i n d ano 1 and Its Application to Enantiopure Drug Synthesis, Process Chemistry in the Pharmaceutical Industry, Gadamasetti, K. G. Marcel Dekker New York, 1999, Chapter 18, 327. 

Efficiency in the synthesis of prostanoids has been an important aspect of organic chemistry for over two decades. Because the prostaglandins are chiral, synthesis of enantiopure drugs is highly desirable for clinical applications. The following examples of prostaglandin synthesis are taken from the work of Corey, much of which is summarized in Chapter 11 of his recent book [239]. The hydroxy acid shown in Scheme 6.52a has been used as a key intermediate in a number of... 

Chiral stationary phases (CSP) for preparative use have been developed tremendously over the past decade. After the introduction of the first commercially available phases in the early 1980s the reproducible synthesis of those phases in large quantities has improved significantly, so that today several multiton productions of enantiopure drugs are operated applying chiral chromatography. CSPs most often used in preparative chromatography are listed in Table 3.11. 

Several examples of drugs and drug candidates bearing a chiral enantiopure sulfoxide moiety are described, together with an example where the chiral sulfoxide is created via symmetric sulfoxidation, and it is exploited to drive a subsequent hydrogenation reaction in a stereoselective way on a C=C double bond directly connected to the sulfoxide. 

Harada N. Powerful chiral molecular tools for preparation of enantiopure alcohols and simultaneous determination of their absolute configurations by X-ray crystallography and/or H NMR anisotropy methods. In Francotte E, Lindner W, editors. Chirality in drug research. Weinheim Wiley-VCH 2006. p 283-321. 

A second example is the reciprocal DR of (R,S)-alaninol. Both (R)- and (,S )-alaninol are interesting chiral intermediates used in recent drug developments28 but are difficult to obtain by classical resolution.29 Alaninol is also one of the few examples that resisted the standard DR procedure. However, resolution of (f ,. S )-alaninol could be achieved with mandelic acid in isopro-panol/water (19 1) in the presence of enantiopure 2-amino-1-butanol.30 Whereas the latter amine... 

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