Sales, enantiomers

Resolution of a racemic mixture is still a valuable method involving fractional crystallization [113], chiral stationary phase column chromatography [114] and kinetic resolutions. Katsuki and co-workers demonstrated the kinetic resolution of racemic allenes by way of enantiomer-differentiating catalytic oxidation (Scheme 4.73) [115]. Treatment of racemic allenes 283 with 1 equiv. of PhIO and 2 mol% of a chiral (sale-n)manganese(III) complex 284 in the presence of 4-phenylpyridine N-oxide resulted... 

Ephedrine has not been extensively studied in humans despite its long history of use. Its ability to activate 3 receptors probably accounted for its earlier use in asthma. Because it gains access to the central nervous system, it is a mild stimulant. Ingestion of ephedrine alkaloids contained in ma huang has raised important safety concerns. Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. However, the use of pseudoephedrine as a precursor in the illicit manufacture of methamphetamine has led to restrictions on its sale. 

TABLE 2 Sales (U.S., Millions) of Enantiomeric Intermediates and Single Enantiomer Drugs... 

The importance of this mode of separation lies in the shear scale of the market for optically pure molecules. The sales of single enantiomer chiral drugs is currently U 180 billion per annum and —65% of active pharmaceutical ingredients (APIs) currently in development have at least one chiral centre. Apart... 

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. 

Herbicides. Herbicides are used in great quantities globally, accounting for over 15 billion in sales in 2001. A number of herbicides are produced as racemates and, as is the case for many pharmaceuticals, one enantiomer is often more potent than the other. Examples include Frontier, produced by BASF and Metolochlor, a Syngenta product. The active enantiomer, (S)-metolachlor, was introduced in 1999. BASF introduced Outlook , the S-enantiomer of Frontier, in 2001. 

The hydrolysis of racemic 3-acetoxyacid esters by Candida utilis was carried out in micro-sale and the configuration of the obtained 3-hydroxycompounds was determined by capillary GC investigation of R-(+)-MTPA derivatives. As shown in Figure 4, the stereochemical course of the hydrolysis also depends on the chain length of the acids, and the presence of several yeast hydrolases leading to opposite enantiomers of 3-hydroxyacid esters seems probable. 

In the mid-1980s researchers in the pharmaceutical industry demonstrated that single enantiomers of pharmaceutical compounds often functioned better as therapeutic agents than racemic mixtures. There are many examples for which one particular chiral form (enantiomer) of a compound demonstrated therapeutic efficacy, while the other chiral form was ineffective or produced deleterious effects. (For example, dextro-methorpan is commonly used as a cough suppressant, while its enantiomer, levomethorphan, is a powerful narcotic.) By 2002 annual sales of the top 10 singleenantiomer drugs totaled 34.2 billion. ... 

The demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals from prochiral precursors has advanced the field of catalytic asymmetric hydrogenation.1 In 2002 worldwide sales of single enantiomer pharmaceutical products approached 160 billion.2... 

Chiral drugs represent a significant part of the global pharmaceutical market. Of the top 100 drugs world-wide, 50 are marketed as pure enantiomers. Their sales were to the value of 42.8 billion in 1997, or 51% of the total of 85.2 billion for these top 100 [9]. 

Zoxamide consists of two enantiomers however, its biological activity is due almost entirely to the S-enantiomer [23]. Although more active than the racemic mixture, manufacture and sale of the purified S-enantiomer was not economically attractive. Consequently, the commercial product is currently sold as the racemic mixture. 

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