Derivatives—Building Blocks for Pharmaceuticals

Phenol and cresol derivatives, particularly p-cresol derivatives, have provided important building blocks for the pharmaceutical industry. There are a number of pharmaceutical compounds derived from p-cresol derivatives dilitiazem hydrochloride, the largest one. Trimethoprim, Nadifloxacin, and sulmetozin are other prominent examples. 

Para-anisic aldehyde and p-anisic alcohol are two important p-cresol derivatives which have provided critical feedstocks for some of the important bulk drugs. Trimethoprim made from 3,4,5-trimethoxybenzaldehyde is another example. p-Cresol has already replaced gallic acid as the preferred starting material for 3,4,5-trimethoxy benzaldehyde. As more R D work is undertaken, there will no doubt emerge more finished pharmaceutical items not only from p-cresol but also from o-cresol and m-cresol. Growth of meZo-cresol has indeed been remarkable after the process was commercialized for 

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The Suzuki reaction of arylboronic acid derivatives with aryl halides is one of the most powerful methods for construction of an unsymmetrically substituted biaryl derivative [11, 23, 85]. Due to the importance of substituted biaryls as building blocks for pharmaceuticals, there is currently a great deal of interest in the coupling of economically attractive aryl halides with arylboronic acids [86-98]. 

Carbamic acid esters (methanes) and their derivatives are important precursors to agrochemicals (herbicides, fungicides, and pesticides) as well as to pharmaceuticals. Also, they can be transformed to isocyanates, which are major building blocks for polyurethanes, widely used in construction, transportation, and several other fields. Presently, the main technical process for the manufacture of isocyanates is phosgena-tion of the corresponding amines. Since the global consumption of polyurethane raw... 

As indicated in the preceding sections, amides and their derivatives are important versatile building blocks for the (agro)chemical and pharmaceutical industry. Owing to the selectivity of amidases (both regio- and enantioselectivity) and the fact that... 

Substituted nicotinic acid derivatives, such as 6-hydroxy nicotinic acid are important building blocks for the synthesis of pesticides and pharmaceuticals, acting as specific inhibitors of NAD/NADP-dependent enzymes. In a process developed by Lonza (Switzerland), 6-hydroxy nicotinic acid is produced by whole-cell microbial hydroxylation of nicotinic acid with Achromobacter xylosoxidans (yield > 100 g 1 ) (Fig. 16). A similar process for the production of 6-hydroxypicolinic acid (98 g l-1) and derivatives from picolinic acid (derivatives), based on Alcaligenes faecalis, has also been established [174,175]. 

Today, acetone and butanol are used as solvents and chemical building blocks for a diverse range of applications from paints, adhesives, and inks to food ingredients, cosmetic and personal care applications, to pharmaceuticals, plastics, and polymers. According to ICIS market data, the annual global markets for butanol is 3.4 million tonnes (worth over 5 billion) and for acetone it is 6 million tonnes (worth 6 billion). Today, the solvent markets are supplied petroleum-derived acetone and butanol. There is increasing demand for renewable chemicals derived from sustainable feedstocks as replacements for chemicals derived from oil. At present, renewable chemicals comprise about 10% of the chemical market and this is forecast to grow at 18% per year to 98.5 billion by 2020 [176]. 

For pharmaceutical purposes 2000-3000 tonnes of amino acids are required annually worldwide. More than half of this amount ends up in infusion solutions for artificial nutrition. Many amino acid derivatives are pharmacologically important acetylcysteine is mucolytic, (L)-DOPA an active agent to combat Parkinson s disease, and Oxitriptan ((S)-5-hydroxytryptophan) is an antidepressant. Specifically substituted, (D)-configured, a- and /3-amino acids find widespread application as building blocks for drug synthesis. 

Isosorbide derivates are of considerable importance for the replacement of fossil resource-based products. Applications include building blocks for new polymers and functional materials, new organic solvents, for medical and pharmaceutical applications, as weU as fuels (36). The derivatization of isosorbide is somewhat problematic because of the different configurations of the 2- and 5-positions and thus of the different reactivity of the hydroxyl groups. 

Pyrazole-3(5)-carboxylic acid esters derivatives are also another important motif of considerable pharmacological relevance and also represent useful synthetic building blocks in both organic and medicinal chemistry. The approach most often used to prepare these involves [3 + 2] cycloadditions between hydrazines and 1,3-diketoesters. In general, Claisen condensation of the enolate of a ketone 21 with diethyl oxalate is the method most commonly employed in the preparation of the 1,3-diketoesters, 22. These, in turn, constitute important building blocks for most of the pyrazole-3(5)-carboxylic acid derivatives 23 reported in the literature, some of which have been found to display important pharmaceutical activities. ... 

The double dehydration of sorbitol yields D-isosorbide (l,4 3,6-dianhydrohexitol), a white, biodegradable, nontoxic solid. It is used in medicine to treat glaucoma. Other medications are derived from isosorbide, including isosorbide dinitrate and isosorbide mononitrate used to treat angina pectoris. The high thermal stability makes isosorbide interesting as a monomeric building block for thermoplastic polymers such as polyester and polycarbonates. The electrophilic alkylation of isosorbide with dimethyl sulfate yields dimethyl isosorbide, a colorless liquid which is used as a plasticizer for vinyl polymers and as a solvent in pharmaceutical and cosmetic preparations. 

The enantioselective synthesis of optically active butanedioic acid derivatives is of interest as they are important intermediates of pharmaceuticals [67] and building blocks for rennin inhibitors [68]. These products are formed by the bis-alkoxycarbo-nylation of alkenes (Scheme 3.5), a reaction that was first reported by Heck in the early 1970s [42]. However, the first asymmetric version of this reaction was described more than 20 years later [69]. 

Besides these vast pharmaceutical applications, they are also of use as building blocks for the synthesis of organic semiconductors, dyes, rigid subunits of macrocyclic receptors, and chemically controllable switches [9-12], The prominent place of benzimidazoles in organocatalysis and materials chemistry is due to two reasons stemming from their molecular architecture (1) the imidazole is a precursor to N-heterocyclic carbenes (NHCs) and (2) the benzene ring provides a convenient moeity to which additional functionality may be easily added to modify the spatial and electronic characteristics of a benzimidazole derivative. 

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