Synthesis of pharmaceuticals

Microbial Oxidations with P450s for Synthesis of Pharmaceuticals 

Pimaricin is an important antifungal agent used in human therapy for the treatment of fungal keratitis as well as in the food industry to prevent mold contamination. The enzymes and the gene cluster responsible for their production by Streptomyces natahnsis was identified recently. The cluster contains a P450 that is responsible for ring decoration [99]. 

Biosynthesis of the sesquiterpene antibiotic albaflavenone in Streptomyces codicolor A3(2) was studied in detail. The mechanism and stereochemistry of the enzymatic formation of epi-isozizaene by multistep cyclization of famesyl diphosphate was investigated [101] and a P450 (CYP170A1) was identified to carry out two sequential allylic oxidations to convert epi-isozizaene to an epimeric mixture of albaflavenols and thence to albaflavenone [102], 

Another example is P450eryF (CYP107A1) from Saccharopdyspora erythraea, which catalyzes a hydroxylation step leading to the functional molecule in the biosynthesis of the macrolide antibiotic erythromycin [110]. The crystal structures of OxyB and OxyC [111, 112] as well as that of P450eryp [113] have been published. 

Nonrecombinant wild-type strains are often used as biocatalysts for the production of pharmaceutically relevant metabolites, as in many of the examples described above. The application of wild-type strains, however, has some drawbacks. These include product degradation, by-product formation, and catabolite repression [75]. Further, there is little or no possibility of engineering the biocatalyst itself. The application of recombinant engineered strains, combined with bioprocess and 

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A -dialkylchloroalkylamines, R2N(CH2)nCI. Formed by treating the alkanolamine with thionyl chloride. Of importance in the synthesis of pharmaceuticals, particularly tranquillizers, e.g. amidons. 

Amino-5-bromoselenazole has been used as an intermediate in the synthesis of pharmaceutical compounds (42). 

Heico Chemicals is the only producer of acetamide in the United States. Small amounts are imported from Europe and Asia. It is shipped in 32-L (35-gal) dmms weighing about 80 kg. Acetamide appears to have a wide spectmm of appHcations. It suppresses acid buildup in printing inks, lacquers, explosives, and perfumes. It is a mild moisturi2er and is used as a softener for leather, textiles, paper, and certain plastics. It finds some appHcations in the synthesis of pharmaceuticals, pesticides, and antioxidants for plastics. 

Uses. The principal uses of NaBH are ia synthesis of pharmaceuticals (qv) and fine organic chemicals removal of trace impurities from bulk organic chemicals wood-pulp bleaching, clay leaching, and vat-dye reductions and removal and recovery of trace metals from plant effluents. 

Ketene trimer can be recovered from the tarry residue of diketene distillation and converted into valuable building blocks like 1,3-cyclobutanedione and squaric acid [2892-51-5] (140,141), an important intermediate in the synthesis of pharmaceuticals and squaryHum dyes used in photostatic reproduction (142,143). 

Another large-volume use for organ olithium compounds is in the synthesis of pharmaceutical and agricultural chemicals, eg, antibiotics (qv), antihistamines, antidepressants, anticoagulants, vasodilators, tranquiU2ers, analgesics, fungicides, and pesticides (116—119). 

The synthetic process proceeding under physiological conditions can be imitated in vitro with the object of establishing the validity of biogenetic hypotheses (293) as well as finding new potential routes for the synthesis of pharmaceuticals (294). 

The main use of acrolein is to produce acrylic acid and its esters. Acrolein is also an intermediate in the synthesis of pharmaceuticals and herhicides. It may also he used to produce glycerol hy reaction with isopropanol (discussed later in this chapter). 2-Hexanedial, which could he a precursor for adipic acid and hexamethylene-diamine, may he prepared from acrolein Tail to tail dimenization of acrolein using ruthenium catalyst produces trans-2-hexanedial. The trimer, trans-6-hydroxy-5-formyl-2,7-octadienal is coproduced. Acrolein, may also he a precursor for 1,3-propanediol. Hydrolysis of acrolein produces 3-hydroxypropionalde-hyde which could he hydrogenated to 1,3-propanediol. ... 

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

King AO, Yasuda N (2004) Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals. 6 205-246 King NP, see Nicolaou KC, He Y (1998) 1 73-104... 

Quinuclidinol 1619-34-7 Hypotensive agent Probably used in synthesis of pharmaceuticals BZ 2.65... 

Chiral Synthesis of Pharmaceutical Intermediates Using Oxynitrilases... 

Enantiometrically pure alcohols are important and valuable intermediates in the synthesis of pharmaceuticals and other fine chemicals. A variety of synthetic methods have been developed to obtain optically pure alcohols. Among these methods, a straightforward approach is the reduction of prochiral ketones to chiral alcohols. In this context, varieties of chiral metal complexes have been developed as catalysts in asymmetric ketone reductions [ 1-3]. However, in many cases, difficulties remain in the process operation, and in obtaining sufficient enantiomeric purity and productivity [2,3]. In addition, residual metal in the products originating from the metal catalyst presents another challenge because of the ever more stringent regulatory restrictions on the level of metals allowed in pharmaceutical products [4]. An alternative to the chemical asymmetric reduction processes is biocatalytic transformation, which offers... 

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

The usefulness of the carbonyl reductase from Candida magnoliae as an enzyme catalyst in the synthesis of chiral alcohol intermediates has been demonstrated by carrying out the reduction of several ketones on a preparative scale [56]. The isolated yields and enantiomeric excess of the product alcohols are summarized in Table 7.1, from which it can be seen that these chiral alcohols were obtained in essentially optically pure forms in excellent yields. These chiral alcohols are important intermediates in the synthesis of pharmaceuticals and agrichemicals. For example, optically active 2-hydroxy-3-methylbutyrate is an important chiral synthon... 

Zaks, A. and Dodds, D.R. (1997) Application of biocatalysis and biotransformations to the synthesis of pharmaceuticals. Drug Discovery Today, 2, 513-531. 

Panke, S. and Wubbolts, M. (2005) Advances in biocatalytic synthesis of pharmaceutical intermediates. Current Opinion in Chemical Biology, 9 (2), 188-194. 

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