Synthesis of Pharmaceutical Compounds

Welton, Chem. Rev., 1999, 2071-2083 J. Holbrey and K.R. Seddon, Clean Prod. 

1391-1398 R Wasserscheid and W. Keim, Angew. Chem. Int. Ed. English, 2002,3773-37S4. 

---

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

The reduction of ketones by borane catalyzed by chiral oxazaborolidines such as (136), derived from the enantiomeric amino alcohols, has been applied to the synthesis of several drug candidates (127). This system is known as the CBS (Corey, Bakshi, Shibata) reduction (153), and Corey himself has applied it to the synthesis of pharmaceutical compounds (154). A further example is provided by the synthesis of MK-499 (137), a... 

Ionic liquids have been extensively used in the synthesis of pharmaceutical compounds. A representative example is the synthesis of pravadpline. The method consists the alkylation of 2-methylindole with l-(N-morpholino)-2-chloroethane in [bmin] [PFJ to give 95% yield of the corresponding N-alkyl derivative. Subsequent Friedel Craft reaction with p-methoxybenzoyl chloride in chloroaluminium (III) ionic liquid gives pravadoline (Scheme 12). 

Montiel V, Saez A, Exposito E, Garcia-Garcia V, Aldaz A (2010) Use of MEA technology in the synthesis of pharmaceutical compounds the electrosynthesis of IV-acetyl-L-cysteine. Electrochem Commun 12 118-121... 

The use of MOFs for HPLC separation of products and intermediates in the pharmaceutical industries has received little if any attention, despite the potential advantages of MOFs in adsorption and separation. Cen-trone et alP reported the separation of four small intermediates and byproducts on MOFs columns. Two closely related amines can be well-separated on MOFs columns using methanol as the mobile phase, but not with Cl8 columns using an optimized mobile phase. The separation of these intermediates on ZIF-8 is the result of the interactions between the thermodynamic driving force for analytes adsorption within the framework pores and the kinetics of analytes diffusion into the ZIF-8 pores, whereas the separation on MIL-lOO(Fe) is achieved via the specific interactions between the analytes and Fe sites. This work points to the prospects for using MOF materials for the continuous separation and synthesis of pharmaceutical compounds. 

R.L. Hanson, Preparation of chiral amino acid intermediates for synthesis of pharmaceutical compounds using amino acid dehydrogenases. Asymmetric Synthesis and Application of ( Amino Acids, Chapter 19, pp. 306-321 ACS Symposium Series, vol. 1009. 

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). 

It is often important to control the CSD of pharmaceutical compounds, eg, in the synthesis of human insulin, which is made by recombinant DNA techniques (1). The most favored size distribution is one that is monodisperse, ie, all crystals are of the same size, so that the rate at which the crystals dissolve and are taken up by the body is known and reproducible. Such uniformity can be achieved by screening or otherwise separating the desired size from a broader distribution or by devising a crystallization process that will produce insulin in the desired form. The latter of these options is preferable, and considerable effort has been expended in that regard. 

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. 

As already mentioned, the most important industrial application of homogeneous hydrogenation catalysts is for the enantioselective synthesis of chiral compounds. Today, not only pharmaceuticals and vitamins [3], agrochemicals [4], flavors and fragrances [5] but also functional materials [6, 7] are increasingly produced as enantiomerically pure compounds. The reason for this development is the often superior performance of the pure enantiomers and/or that regulations demand the evaluation of both enantiomers of a biologically active compound before its approval. This trend has made the economical enantioselective synthesis of chiral performance chemicals a very important topic. 

Designed synthesis of organic compounds whether in the pharmaceutical, macromolecular, biological or pure chemical field is an art as well as a science. Of all branches of chemistry, synthesis is today the most vibrant with new techniques and methodologies and is most rapidly developing. The techniques used a decade ago have become outmoded today. 

The asymmetric reduction of prochiral ketones to their corresponding enantiomerically enriched alcohols is one of the most important molecular transformations in synthetic chemistry (20,21). The products are versatile intermediates for the synthesis of pharmaceuticals, biologically active compounds and fine chemicals (22,23). The racemic reversible reduction of carbonyls to carbinols with superstoichiometric amounts of aluminium alkoxides in alcohols was independently discovered by Meerwein, Ponndorf and Verley (MPV) in 1925 (21—26). Only in the early 1990s, first successful versions of catalytic... 

Aryl-acetic or -propionic acids as well as benzylketones are versatile intermediates for the synthesis of pharmaceuticals, agrochemicals, or fragrances. Many methods have already been explored, notably using electrochemistry and transition metal compounds. 

The nitration of aromatic hydrocarbons is one of the most widely studied and well-documented reactions in organic chemistry. Aromatic nitro compounds are of huge industrial importance in the synthesis of pharmaceutical drugs, agrochemicals, polymers, solvents and perfumes, and for the synthesis of other industrially important chemicals containing amine and isocyanate functionality. However, early research into aromatic nitration was fuelled exclusively by their use as explosives and intermediates in the synthesis of dyestuffs. The former is the subject of this chapter. 

Asymmetric allylic C-H activation of cydohexadiene systems has been used for the asymmetric synthesis of several compounds of pharmaceutical relevance. The key step in the asymmetric syntheses of the monoamine reuptake inhibitor (-i-)-indatrahne 185 was the C-H insertion reaction of the aryldiazoacetate 183 with 1,4-cyclohexadiene (Scheme 14.24). The product 184, obtained in 83% yield with 93% enantiomeric excess, is readily converted to (-i-)-indatraline using standard synthetic procedures [132]. 

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]. 

The use of this kind of lyases has been exploited in organic synthesis by several groups using (R)-and (S)-oxynitrilases for the synthesis of a great variety of organic compounds. A representative example of the utility of this reaction in the synthesis of pharmaceuticals is the preparation of adrenergic bronchodilators [51]. Scheme 10.22 shows a chemoenzymatic route to (R)-terbutaline. 

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... 

Over the past ten years, ILs have moved out of the realm of academic study and are being used in a diverse range of industrial processes [44]. It is true to say that the apphcation of ILs in the synthesis of pharmaceuticals and fine chemicals has been hampered by much green wash and focus on single-issue sustainability claims such as that ILs are better than all other solvents because they have essentially no vapor pressure and are not classified as volatile organic compounds (VOCs). Other factors hmiting take-up have been the lack of ecotoxicity and life... 

Only a little research on the separation and synthesis of chiral compounds has been published so far. Because enzymes have extremely high selectivity, and owing to the great importance of enantioselective synthesis or enantiomeric resolution in the pharmaceutical industry, the most intense research in this area can be expected, along with minimizing the use of substances and maximizing their effect. 

---