Pharmaceuticals, chiral, synthesis

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

Application of Whole-Cell Biotransformation Process in the Synthesis of Chiral Pharmaceutical Intermediates... 

Patel, R.N. (2007) Biocatalysis for synthesis for chiral pharmaceutical intermediates, in Biocatalysis in the Pharmaceutical and Biotechnology Industries (ed. R.N. Patel), CRC Press, Boca Raton, FL, pp. 103-158. 

Chiral active pharmaceutical ingredients, 18 725-726. See also Enantio- entries Chiral additives, 6 75—79 Chiral alcohols, synthesis of, 13 667-668 P-Chiral alcohols, synthesis of, 13 669 Chiral alkanes, synthesis of, 13 668-669 Chiral alkenes, synthesis of, 13 668—669 Chiral alkoxides, 26 929 Chiral alkynes, synthesis of, 13 668-669 Chiral ammonium ions, enantiomer recognition properties for, 16 790 Chiral ansa-metallocenes, 16 90 Chiral auxiliaries, in oxazolidinone formation, 17 738—739... 

Optically active EP is an important C3 chiral building block for the synthesis of chiral pharmaceuticals such as j9-adrenergic blockers [11 -13], vitamins [14,15], pheromones [16], natural products [17], and new materials such as ferro-electric crystals [18]. Racemic EP can be made via 2,3-DCP and l,3-dichloro-2-pro-panol (1,3-DCP) synthesized from propylene by organic synthesis [19] however, a practical production method for optically active EP has not yet been established. Racemic 2,3-DCP, which is easily synthesized by the chemical... 

Enantiomeric purity - [ENZYLffiS IN ORGANIC SYNTHESIS] (Vol 9) -determination of, for chiral pharmaceuticals [PHARMACEUTICALS, CHIRAL] (Vol 18)... 

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

Several important examples of metabolic engineering, ranging from applications in basic chemicals, such as the manufacture of propanediol from glucose, to the synthesis of chiral pharmaceutical intermediates, such as (2i )-indanediol, a building block of the HIV protease inhibitor Crixivan (Indinavir , Merck see Chapter 13, Section 13.3.3.30.), are presented in Chapter 20. 

Despite the revolutionary advances achieved in the field of catalytic asymmetric synthesis, resolution methods both chemical and enzymatic are still probably the most used methods for preparation of optically pure organic compounds. This is especially true on large scale for the production of industrial fine chemicals. A very large number of chiral pharmaceuticals and pharmaceutical intermediates are manufactured by the process involving resolution. The reason behind the continued dominance of resolution in industrial production of optically pure fine chemicals is perhaps the reliability and scalability of these processes. 

The asymmetric reduction of ketones by borane catalyzed by oxazaborolidines has been widely studied since the beginning of the 1980s. Despite the use of borane complexes, which are hazardous chemicals, this reaction is an excellent tool to introduce the chirality in a synthesis and has demonstrated its usefulness in industrial preparation of chiral pharmaceutical intermediates. As a result of its performance, versatility, predictability, and scale up features, this method is particularly suitable for the rapid preparation of quantities of complex chiral molecules for clinical trials. 

A transaminase patented by Celgene Corporation (Warren, NJ), called an co-aminotransferase [(co-AT)E.C. 2.6.1.18] does not require an a-amino acid as amino donor instead it requires a primary amine and hence has the ability to produce chiral amines.125 126 A similar co-AT from Vibrio fluvialis has been described for the production of chiral amines along with chiral alcohols when coupled with AdH or chiral amino acids when coupled with an a-amino acid aminotransferase.127130 Another co-AT, ornithine (lysine) aminotransferase (E.C. 2.6.1.68), has been described for the preparation of a chiral pharmaceutical intermediate used in the synthesis of Omapatrilat, a vasopep-tidase inhibitor developed by Bristol-Myers Squibb, as well as the UAA A1 -piperidinc-6-carboxylic acid.131-132... 

Patel, R. N. 2004. Biocatalytic synthesis of chiral pharmaceutical intermediates. Food Technol. Biotechnol., 42(A), 305-325. 

The demand for enantiomerically pure compounds in fine chemical synthesis is growing rapidly. An obvious reason for this development is that the opposite hand of a chiral pharmaceutical or chemical with a desired biological activity has at best no activity, or worse, causes side effects. 

Another major trend in performance chemicals is towards the development of products - pharmaceuticals, pesticides and food additives, etc. - that are more targeted in their action with less undesirable side-effects. This is also an issue which is addressed by green chemistry. In the case of chiral molecules that exhibit biological activity the desired effect almost always resides in only one of the enantiomers. The other enantiomer constitutes isomeric ballast that does not contribute to the desired activity and may even exhibit undesirable side-effects. Consequently, in the last two decades there has been a marked trend towards the marketing of chiral pharmaceuticals and pesticides as enantiomeri-cally pure compounds. This generated a demand for economical methods for the synthesis of pure enantiomers [127]. 

Another example of how catalysis plays a key role in enabling our lives is in the synthesis of pharmaceuticals. Knowles s development, at Monsanto in the early 1970s, of the enantioselective hydrogenation of the enamide precursor to L-DOPA (used to treat Parkinson s disease), using a Rh-chiral phosphine catalyst (Section 3.5), led to a share in the Nobel prize. His colaureates, Noyori and Sharpless, have done much to inspire new methods in chiral synthesis based on metal catalysis. Indeed, the dramatic rise in the demand for chiral pharmaceutical products also fuelled an intense interest in alternative methodologies, which led to a new one-pot, enzymatic route to L-DOPA, using a tyrosine phenol lyase, that has been commercialized by Ajinomoto. 

The third major source of chiral pharmaceuticals involves synthesis using naturally occurring chiral molecules as starting materials (5,17). Those compounds most generally used are carbohydrates, amiiu) acids, terpenes, and smaller, microbiologically derived compounds such as lactic acid or tartaric add. In addition, the synthetic chemist now has in his or her repertoire a variety of rather standard building blocks derived by manipulation of the natural substances a list of such compounds has been compiled (5). 

The preparation of a chiral pharmaceutical in enantiomerically homogeneous form is dearly a viable proposition. The tools—resolution, asymmetric synthesis, and the chiral carbon pool—are available. As exemplified by the prostaglandins, the manner in which these tools are used is limited only by the imagination and inventiveness of the chemist. 

Maturation of the petro-chemical industry, environmental pressures for "clean chemistry" and the explosive development of biotechnology have increased interest in the application of enzymatic processes to organic synthesis. Enzymatic processes play an increasing role in the generation of chiral pharmaceutical intermediates, water-soluble materials and biopolymers. One problem in the development of enzymatic reactions for organic synthesis is the prediction of the stereochemistry of reaction. Reliable models for prediction of stereochemistry are needed to broaden the application of enzymes to organic synthesis. 

Selected prochiral and meso-substrates have been used with various esterases and lipases (Figure 2) and illustrate the wide variety of substrates that can be used with these enzymes. A complete listing of these types of substrates can be found in other sources [12,105,107,120,121]. It should be noted that the use of organic solvent can have a profound effect as to what product isomer is formed [127]. The use of porcine pancreatic lipase (PPL) to carry out an asymmetric hydrolysis of a meso-diacetate for the production of an intermediate in pheromone synthesis was recently reported [128]. Two specific examples are discussed here that used this approach directed at key chiral pharmaceutical intermediates. 

The earliest example of the industrial application of a biotransformation for the synthesis of chiral pharmaceuticals was the production of (I )-phenylacetylcarbi-nol ((K)-PAC) by fermenting bakers yeast. This transformation is still in use to obtain this compound as a chiral intermediate for the synthesis of (-)-ephedrine (Scheme 4.1) [14]. 

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