Application in the Synthesis of Pharmaceuticals

The regiospecific ring opening of these epoxides is achieved with the appropriate amine to give advanced intermediates possessing the right configuration at the carbinol stereocenter. Sipsy has demonstrated the industrial feasibility of this approach and produced hundreds of kilos of related molecules. 

Along the same lines, several groups of chemists at Merck successfully produced substantial quantities of various important pharmaceutical intermediates used in the preparation of drugs under development. Among these are MK-0417 (7), a soluble carbonic anhydrase inhibitor used to treat glaucoma [27a]. the LTD4 antagonist L-699392 (8) [27b], and the antiarrhythmic MK-499 (9) [27c.d]. 

In the synthesis of another carbonic anhydrase inhibitor, we have successfully performed the following reduction with a very high enantioseleetivity. 

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. Because 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. 

I would like to thank everyone at Callery and Sipsy. and especially Dr. J. M. Barendt, Dr. J.-C. Caille, Dr. B. Laboue. and S. Frein for their contribution to the development of CBS technolog.  

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The condensation between an aldehyde, an amine and an active methylene compound, named after Carl Mannich, was first published in 1912 [4]. The products of the reaction, a-amino ketones or Mannich bases are important compounds with numerous applications in the synthesis of pharmaceuticals and of natural products [7]. 

Halogenothiophenes are finding increasing application in the synthesis of pharmaceuticals and plant protection reagents, but efforts to devise methods that specifically introduce a halogen to an a- or a j3-position have not always been completely successful. 

M. Beller, andK. Kumar, Hydroformylation Applications in the Synthesis of Pharmaceuticals and Fine Chemicals, in Transition Metals for Organic Synthesis, Second Ed. (Eds. M. Beller and C. Bolm, Wiley-VCH, Weinheim, 2004, Vol. 1, Chap. 2.1). 

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) drums weighing about 80 kg. Acetamide appears to have a wide spectrum of applications. It suppresses acid buildup in printing inks, lacquers, explosives, and perfumes. It is a mild moisturizer and is used as a softener for leather, textiles, paper, and certain plastics. It finds some applications in the synthesis of pharmaceuticals, pesticides, and antioxidants for plastics. 

Trifluoromethylated heteroarenes are widely applicable in the synthesis of pharmaceuticals. Using 10 mol% palladinm acetate as catalyst, TMSCF3 as trifluoro-methylating reagent, bidentate nitrogen-containing ligand L, and PhI(OAc)2 as oxidant, Liu and coworkers developed a novel palladium catalyzed oxidative trifluoromethylation of indoles at room temperatnre (Scheme 9.20). This reaction likely involves a palladium (II/IV) mechanism for the formation of the sp C—CF3 bond. 

The synthesis of 7-hydroxy-4-methylcoumarin (hymecromone) 17 from the reaction of resorcinol with EAA, in acid media and in solvent-free conditions was reported by V. Calvino-Casilda et al. The mechanism involves three steps, hydroxyalkylation, transesterification, and dehydration.The corresponding hymecromone, finds applications in the synthesis of pharmaceuticals and insecticides as a starting material (Scheme 10) (10MI279). 

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. 

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]. 

Sulfuryl chloride (also known as chlorosulfuric acid and thionyl chloride), SO2CI2, is used in a variety of applications, including the synthesis of pharmaceuticals, rubber-based plastics, dyestuff, and rayon. At a certain temperature, the rate of decomposition of sulfuryl chloride was studied. 

Alcohol dehydrogenases from I. kefir and L. brevis are enzymes with similar properties. Because of their wide substrate spectra and their high activities toward many carbonyl compounds their application potential is very broad. For example, they can be used in the synthesis of pharmaceuticals and natural products. Because LK-ADH has more advantageous properties than LB-ADH, such as an easier purification procedure and a higher expression rate in pET systems, we decided... 

While a number of supercritical fluids (SC) are known and have been studied as reaction media, probably only SC-CO2 and water are of practical use in the synthesis of pharmaceutical intermediates. The application of SC-CO2 as a greener eluent for chromatography has been discussed in Chapter 12. This medium is also used as an extraction solvent and in API isolation, although its use at any scale... 

The basic research in the future should be oriented towards novel materials for use in carbon dioxide as a solvent. These materials may have important applications in the synthesis of polymers, pharmaceuticals and other commodity chemicals, in the formation of thin films and foams, in coatings and extracts, and in the manufacture of microelectronic circuits. The full deployment of these applications would result in significant reductions in both volatile emissions and aqueous- and organic liquid wastes in manufacturing operations. 

Because of their suitable skeletal structure trans-CHD are applicable in the synthesis of compound classes of chemical, biological, and pharmaceutical interest. Regio- and stereoselective epoxidation of either one or two double bonds of 2, for example, opens up an approach to a group of naturally occurring cyclohexane epoxides which have attracted considerable attention because of their unusual structures, biogenesis, and biological activity [15]. 

Over the past 25 years, biomimetic model systems have been extensively studied and a wide variety of interesting oxidation processes such as the epoxidation of olefins, the hydroxylation of aromatics and alkanes, the oxidation of alcohols to ketones, etc., have been accomplished some of these are also known in enantioselective versions with spectacular ee s. The vast majority of these transformations were obtained using monooxygen donors such as those mentioned above as primary oxidants. The complexity of the catalysts and the practical impossibility to use dioxygen as the terminal oxidant have so far prevented the use of such systems for large industrial applications, but some small applications in the synthesis of chiral intermediates for pharmaceuticals and agrochemicals, are finding their way to market. 

Monocyclic aziridines and 2//-azirines have found broad application in the synthesis of complex natural products. The facility with which these small ring nitrogen-containing compounds can be converted to important pharmaceutical products under mild conditions with wide functional group compatibility makes these molecules quite useful for heterocyclic chemistry. 

Examples of Established Applications of Biocatalysts in the Synthesis of Pharmaceuticals 97... 

Enantiomerically enriched hetero Diels-Alder cycloadducts have found applications in the synthesis of other pharmaceutical intermediates such as compactin and mevinolin [4, 5]. The strategy described in this work should be applicable to these and similar compounds. 

PTC finds its widest applications in the synthesis of intermediates in the fine chemicals(agro-chemicals, pharmaceutical, dyes, paper, and so on) industries (Lindbloom and Blander, 1980 Reuben and Sjoberg, 1981 Freedman, 1986 Starks, 1990 Sharma, 1997). We summarize some typical representative industrially important reactions in Table 5. It should be noted that it is not our intention to review the hundreds of articles that report the use of PTC in industrially important reactions, and these are only illustrative examples. 

Thiophene is utilized in Organic Chemistry as an intermediate in the synthesis of pharmaceuticals and of phytoproducts. Moreover since the 80 s, the polymerization of thiophene has been extensively studied, polythiophene being a conductor polymer with potential application in Electrochemistry. 

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