Drugs optically pure

The thalidomide tragedy, described in chapter 7, started to focus the pharmaceutical industry on synthesis of single enantiomers rather than racemic mixtures. Even if there are no antagonistic or undesirable side effects from the other enantiomer, a racemic mixture may waste 50 percent of the mass of a drug. Optically pure compounds such as vitamin B]2, morphine, and L-dopa are available naturally. In some cases (e.g., vitamin B12), the natural source is really the only practical source. For simpler compounds like L-dopa, chemical synthesis is very practical but resolution of enantiomers may double the production cost. 

Optically active drugs now occupy centre stage status and some agrochemicals like (S)-metolachlor, have also been introduced as optically pure isomers, so that the ballast of the unwanted isomer is avoided. Asymmetric synthesis is a topic of great interest in current research, and there is a steady flow of articles, reviews and books on almost every aspect of this subject. Table 4.8 lists examples of industrially important asymmetric synthesis. 

L-699,392, Merck s drug for the treatment of chronic asthma, is an example of asymmetric amplification on an industrial scale (see Figure 13.19). The ketone reduction can be carried out stoichiometrically with a borane-(-)-a-pinene reagent. The terpene natural products are often mixtures of isomers and enantiomers. A reagent prepared from 98% optically pure (-)-a-pinene gives a product e.e. of 97%, but a reagent prepared from less expensive 70% optically pure (-)-a-pinene yields a product e.e. of 95%, which can be pushed to >99.5% by using an excess [30]. 

Before an asymmetric synthesis appeared of levofloxacin (1, (—)-ofloxacin), (—)- ofloxacin was isolated via optical, enzymatic, and crystallization resolution of the racemic ofloxacin (17) Drugs Future, 1992 Hayakawa et al., 1986, 1991). For instance, tricyclic core 52 was converted to ( + )-3,5-dinitrobenzoyl derivative 54 in 75% yield (Scheme 4.5). The enantiomers were then separated via high-performance liquid chromatography (HPLC) with a SUMIPAX OA-4200 column to deliver optically pure benzoyl esters 55a and 55b (Drugs Future, 1992 Hayakawa et al., 1986, 1991). 

In 1982, the percentage of optically pure chiral drugs was around 12% (Scheme 1). By 1987 it had already been increased to 26% 2c, with a likely projection of 80% by the end of the century 2d. 

Even if both enantiomers have similar biological effects, optically pure samples must be available for pharmacological tests. In conclusion, the problem of EPC synthesis should no longer be neglected and will be of ever increasing importance in the development of new drugs and pesticides. 

In the area of rheumatology, the importance of using optically pure drugs is well illustrated by penicillamine o-penicillamine has been used for many years in treatment of Wilson s disease and cystinuria and is now widely used in rheumatoid arthritis. It is well established now that this drug, which is chiral, should only be given in the pure d (or S) form, because the toxicity of the l (or R), or the dl (RS) racemic forms, is much greater. This fact was found by trial and error, with some earlier patients on DL-penicillamine experiencing severe adverse side reactions such as optic neuritis. Now only the pure d form is available for prescription (see also 62.2.3.4).61... 

This drug has had a disastrous medical history due to its teratogenicity, however, its recently found efficacy toward so-called incurable diseases, such as leprosy, AIDS, and various cancers, has revived researchers interest, in particular for the production of optically pure isomers. From this point of view, this article may be attractive to medicinal and pharmaceutical chemists, and also heterocyclic and synthetic chemists. 

Racemic l-azido-3-aryloxy-2-propanols 35 was resolved by the lipase-catalyzed kinetic resolution using different acyl donors to access to the enantiomers in optically pure form.66 The reduction of the azide group can afford the l-amino-3-aryloxy-2-propanols, which is present in numerous biologically active compounds such as [3-adrenolytic drugs (/ -blockers) used in the treatment of angina pectoris, hypertension and other cardiac diseases. 

Arylpropionic acids are important class of non-steroidal anti-inflammatory drugs (NSAID). Their pharmacological activity is mainly in one of both enantiomers. Thus, efforts had been made to access to the enantiomerically pure substance. The kinetic resolution of racemic 2-(2-fluoro-4-biphenyl) propanoic acid 56 and 2(4-isobutylphenyl) propanoic acid 59 (Ibuprofen) was performed via enzymatic esterification and transesterification using an alcohol and vinyl acetate, respectively in a membrane reactor. The unreacted acid is obtained in highly enantiomerically enriched form. A consecutive approach consisting of the enzymatic hydrolysis of the resulted esters is needed to achieve the alcohol in optically pure form.77... 

The use of membrane bioreactors in the pharmaceutical field has been documented for the production of amino acids, antibiotics, anti-inflammatories, anticancer drugs, vitamins, and optically pure enantiomers [10, 29-31]. 

The majority of the new drugs approved and the most often prescribed drugs in the United States have at least one asymmetric center [169]. Approximately half of these chiral drugs are of a racemic composition. Many of the optically pure drug substances are of natural origin, while the majority of the synthetically derived products are in racemic form [172]. Enantiomers can differ in their pharmacological activity or one may be inactive or... 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug (NS AID) in an optically pure form. The original manufacturing process (Scheme 6.1) before product launch started from P-naphthol (1), which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give... 

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... 

Hydroformylation of styrene and its analogues has attracted particular attention, since this provides a general method for the preparations of optically pure arylpropionic acids. Apart from Naproxen , the drug ibuprofen is another ar-ylpropionic acid-based nonsteroidal anti-inflammatory agent. As shown by 9.9, ibuprofen may in principle be synthesized by enantioselective hydroformylation reactions followed by oxidation of the aldehydic functionality. 

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