Aryl acetic Acid Derivatives

I he potent antiinflammatory action exerted by many aryl acetic acid derivatives has led to the continued exploration of this class. It is apparent from a consideration of the structures of compounds that have become prominent that considerable structural latitude is possible without loss of activity. 

The synthesis of fenclofenac ), a nonsteroidal antiin-Ilammatory agent (NSAI), starts with condensation of -chloro- 

A structure more distantly related to these is amfenac (10). Like most of the others, amfenac, frequently used after tooth extraction, is an antiinflammatory agent by virtue 

A closet member of this little group, revelation of whose i( al nature requires metabolic transformation of an acetylenic linkage to an acetic acid moiety, is fl uretofen (14). The .ynthesis begins by Friedel-Crafts acylation of 2-fluorobi-phenyl (11) with acetic acid to give ketone 1. Heating with 

Phenyl acetamides have a variety of pharmacological actions depending upon the nature of the amine-derived component. 

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Homocoupling of aryl acetic acid derivatives has been achieved by deprotonation and oxidation by I2 as outlined... 

For therapeutical purposes, a likewise frequently used group of drug compounds are the nonsteroidal anti-inflammatory drugs (NSAID). Among the best known representatives of the aryl acetic acid derivatives is diclofenac as well as ibuprofen, an aryl propionic acid derivative. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions these amphiphilic organic acids may form lyotropic mesophases with water even at room or body temperature, for example, diclofenac diethylamine... 

Aryl acetic acid derivatives are notable for their failure to... 

A sequence of bromination of a 3-indolyl acyl group followed by azide displacement and reduction, provides an effective route to 3-(a-aminoacyl)indoles <88JHC469>. Indoles react readily with oxalyl chloride at C-3 and the products have been used in combination with aryl acetic acid derivatives to generate indolyl-substituted maleic anhydrides and imides, as precursors for indolocarbazole antibiotics <90TL2353,93TL5623>. 

Suzuki T, Hamashima Y, Sodeoka M. Asymmetric fluorina-tion of a-aryl acetic acid derivatives with the catalytic system NiCl2-Binap/R3SiOTf/2,6-lutidine. Angew. Chem. Int. Ed. 2007 46 5435-5439. 

GooUen has also reported a palladium-catalyzed cross<oupling reaction between aryl boronic acids or esters and a-bromoacetic acid derivatives which allows the synthesis of various substituted aryl acetic acid derivatives in good to excellent yields under mild conditions [72]. Aryl boronic acids with a range of electron-withdrawing and -donating substituents are tolerated in this reaction (Scheme 3.50). 

Treatment of the < -arylhydrazono-3-thiazoline-2-acetic acid derivatives (141 R=H,Me,Et,6Bu,R1=H,Me,Ar=Ph,2,4,6-MegCgH2) with an alkali metal hydroxide (Lil/pyridine/DMF or lithiumpropane thiolate) effects rearrangement to the 2-aryl-6-thia-2,3,8-triazabicyclof3.2.1]-oct-3-en-4-carboxylates(142). An X-ray crystal structure showed the product (R=Me,R1=H,Ar=Ph) to exist as (142) in the solid. However, in solution an equilibrium between (142) and (143) occurs. Alkylation and acylation occur only through (143)1". A large number of mono-,di-,tri-,or tetraalkyl-A -thiazolines have been synthesised... 

Another basic difference between the two materials is that Oasis HLB is macroporous (80 A pores) while LiChrolut EN and Isolut ENV+ are basically nanoporous materials with the maximum pore size distribution located at 20—30 A. For this reason, the latter sorbents perform much better in extracting smaller molecules with molecular masses less than 500 Da, as is the case with the above halogenated acetic acid derivatives [326, 327] or aryl sulfonates [328]. On the contrary, macroporous Oasis HLB is the material of choice when larger analytes are the target of pre-concentration procedures, as was the case with tetracycline and macroHde antibiotics [321-324]. Another vivid example of this kind is pre-concentration of soy isoflavones [331], where Oasis HLB and macroporous Strata X display by far higher recovery values. On the other hand, the size exclusion effect can be exploited purposefully when only smaller molecules have to be retained with the elimination of the major sample matrix. The best example of this type of applications is the analysis of drugs and drug metaboHtes in whole blood or blood plasma [273-275]. Here the microporous hypercrosslinked polystyrene Purosep-270 is the best possible SPE material since it functions as an RAM. 

The various aryl and alkyl groups directly bound to the methylene reacting group exert a major influence on reactivity. Benzylaryl sulfones (entries 1-5) are efficiently monomethylated at 180 °C. AllQ laryl sulfones (entries 6-8) require a higher temperature (200-210 °C) for the reaction to be completed. This behaviour seems to be clearly related to the stabilization, by resonance with the adjacent Ar group, of arylsulfonyl carbanions, ArSOaCH Ar , formed during the reactions. In all likelihood, the methylation of sulfones 1-5 in Table II follows the mechanistic pattern reported for aryl- and aroxy-acetic acid derivatives. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

The majority of the semisynthetic cephalosporins are not effective when administered orally. The main exceptions are cephalexin and cephradine, and recently reported compounds such as cefaclor, cefadroxyl and cefatrizine. In view of the fact that oral activity is observed primarily in derivatives of a-amino aryl acetic acids, we designed our synthetic course on the basis of modification of the aryl part of a readily available a-amino acid, in such a way that initial functionalization of the aromatic ring would provide a "handle , which could in turn be easily converted into a variety of functional groups. The second in5)ortant criterion was the necessary optical activity of the amino acids. In order to avoid the resolution of each individual compound thus obtained, it was deemed important to start with an optically active amino acid whose modification would proceed without racemization. These two requirements were fulfilled upon chloromethylation of D-a-amino-4-hydroxyphenyl acetic acid 1. ... 

The formation of substituted isoquinolines was achieved by E. Awuah and A. Capretta. In the first step an amine reacted with an aryl acetic acid in POCI3 and toluene under microwave (MW) irradiation at 140°C for 30 min to afford 2-(3,4-dimethoxyphenyl)ethylamine (92). Subsequent oxidation of tetrahydroisoquinolines 92 with air using Pd/C in toluene led to the final products, acylisoquinoline derivatives 93 (Scheme 34) (10JOC5627). 

Protonation of the anion [SN2] by acetic acid in diethyl ether produces the thermally unstable sulfur diimide S(NH)2. Like all sulfur diimides, the parent compound S(NH)2 can exist as three isomers (Scheme 5.5). Ab initio molecular orbital calculations indicate that the (cis,cis) configuration is somewhat more stable than the (cis,trans) isomer, while the (trans,trans) isomer is expected to possess considerably higher energy. The alternative syn,anti or E,Z nomenclatures may also be used to describe these isomers. The structures of organic derivatives S(NR)2 (R = alkyl, aryl) are discussed in Section 10.4.2. 

It is by now apparent that the nature of the aryl group in the aryl acetic and aryl propionic acid antiinflammatory agents can be varied quite widely without loss of activity. The corresponding derivatives of homologous xanthones and thioxanthones thus both show activity as nonsteroid antiinflammatory agents. 

Alkyl and aryl thiohydrazide derivatives react with orthoesters and trihalomethyls to afford 1,3,4-thiadiazoles. The reactions proceed via a thiosemicarbazone intermediate which cyclizes to eliminate either alcohol or hydrogen chloride. Treatment of the iV-thiohydrazide pyrazole 143 with triethyl orthoformate in acetic acid at reflux gave the 5-acetamido-l,3,4-thiadiazol-2-ylpyrazole 144 (Equation 51), and in the absence of acetic acid the 5-amino-l,3,4-thiadiazol-2-ylpyrazole 145 in 76% yield <2000JCM544>. 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

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