Phenylacetic acid, derivative

The phenylacetic acid derivative 469 is produced by the carbonylation of the aromatic aldehyde 468 having electron-donating groups[jl26]. The reaction proceeds at 110 C under 50-100 atm of CO with the catalytic system Pd-Ph3P-HCl. The reaction is explained by the successive dicarbonylation of the benzylic chlorides 470 and 471 formed in situ by the addition of HCl to aldehyde to form the malonate 472, followed by decarboxylation. As supporting evidence, mandelic acid is converted into phenylacetic acid under the same reaction conditions[327]. 

A highly-substituted phenylacetic acid derivative shows activity as a shortacting narcotic and as an injectable general anesthetic. This agent, propanidid (90), is obtained by alkylation of... 

The Hammett equation is the best-known and most widely studied of the various linear free energy relations for correlating reaction rate and equilibrium constant data. It was first proposed to correlate the rate constants and equilibrium constants for the side chain reactions of para and meta substituted benzene derivatives. Hammett (37-39) noted that for a large number of reactions of these compounds plots of log k (or log K) for one reaction versus log k (or log K) for a second reaction of the corresponding member of a series of such derivatives was reasonably linear. Figure 7.5 is a plot of this type involving the ionization constants for phenylacetic acid derivatives and for benzoic acid derivatives. The point labeled p-Cl has for its ordinate log Ka for p-chlorophenylacetic acid and for its abscissa log Ka for p-chloroben-zoic acid. The points approximate a straight line, which can be expressed as... 

Replacement of the p-aminoacyl moiety with an a-aminoacid derivative such as isoleucyl or cyclohexylglycyl led to a 2- to 4-fold decrease in potency. This was the first indication that SAR between this series and the a-amino acid series was distinct. Early on it was discovered that the "right hand side" amide could be replaced with an ester or acid moiety. This result led to a more systematic exploration of acid substitutions. Ortho-, meta- and para-substituted phenylacetic acid derivatives were prepared, and the latter analog (11, Figure 5) proved to be the first submicromolar inhibitor prepared in this series (IC50 = 510 nM). Grati-fyingly, 11 was devoid of thrombin inhibitory activity [31]. 

Toniolo reported the carbonylation of aromatic aldehydes containing electron-donating substituents with a Pd/PPh3 catalyst system in the presence of HC1 to give phenylacetic acid derivatives [64]. No activity was observed in the absence of PPI13 or HC1, and high yields could be achieved with alkanols as solvent (e.g., EtOH). It is believed that the mechanism involves HC1 addition to the aldehyde, with the resultant chlorohydrin being subject to oxidative addition to Pd, CO insertion, and alcoholysis. Upon Cl -o- OR substitution with the formed mandelic acid derivative, a second carbonylation takes place,... 

Benzyl halides are easily carbonylated to phenylacetic acid derivatives which are valuable intermediates for Pharmaceuticals, cosmetics and fragrances [2,3], Several papers report the aqueous/organic biphasic realization of this reaction [1,19-22] (Scheme 5.3). The main characteristics of these processes are summarized in Table 5.1. 

Diclofenac is a phenylacetic acid derivative, non-steroidal anti-inflammatory drug. It is available as the potassium and sodium salts. Potassium salts are slightly more soluble than the sodium salts. Diclofenac can be used in breastfeeding mothers since the amount that passes through breast milk is too small to be harmful to the baby. However, diclofenac is contraindicated in pregnancy, especially during the last trimester. 

Diclofenac Voltaren) is a phenylacetic acid derivative that is a potent inhibitor of COX and that has analgesic, antiinflammatory, and antipyretic effects. Its use is accompanied by side effects similar to those of other NSAIDs. Indications for the drug include rheumatoid arthritis, osteoarthritis, and ophthalmic inflammation (use of an ophthalmic preparation). 

Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor. Pharmacokinetic and dosage characteristics are set forth in Table 36-1. 

Most possibilities and most examples in the syntheses of 1,4-dihydro-3(2//)-isoquinolinone (2) and its derivatives involve the cyclization of the corresponding arylacetic acid derivatives. The opportunity arises from the lactam structure of compound 2. With suitable reagents, different o-aminomethyl-, o-hydroxymethyl-, or o-chloromethyl-phenylacetic acid derivatives (25LA225 66JPR12 69CJC864 84JHC297) and o-hydroxymethyl phenylacetonitriles (85S114) can be cyclized. 

Diclofenac is a phenylacetic acid derivative used mainly as sodium salt for the treatment of various pain and inflammation. Intramuscular injection occasionally causes tissue damage at the injection site. Suppositories may cause local irritation transient burning and stinging are reported when used for the eye and large doses can cause aplastic anemia.14... 

Crystalline dimers of type (27) have been synthesized under thermal conditions for the first time from phenylacetic acid derivatives (25) (79CB1650). The structure of (27 R = Me) was established by X-ray analysis (78TL671). The dimer (27 R = Me) is stable in solution, whereas the analogous alkylthio-substituted dimers are in a temperature and solvent dependent equilibrium with the monomeric 1,3-dithiolone (26). The monomers (26), generated from the dimers (27), display the same propensity towards [3 + 2] cycloaddition as do the mesoionic dithiolones which are generated in situ from the precursors (25). A photochemical dimerization of (9) has also been described (80CL717) (see Section 4.32.3.1.8(iii)). 

Scheme 8.5 Metabolism of metoprolol, 28, is thought to involve "...rapid cleavage of the methoxyethyl chain at the methoxy group to afford a 2-phenylethanol derivative" [92] which is subsequently oxidized to the corresponding phenylacetic acid derivative, 28a [97]. Another metabolite is produced by oxidation of the...

Ketorolac tromethamine is contraindicated in patients while wearing soft contact lenses. Caution should be used with patients who have previously exhibited sensitivity to acetylsalicylic acid,phenylacetic acid derivatives, and other NSAIDs because a potential exists for cross-sensitivity. 

Difenpiramide, a phenylacetic acid derivative, is less efficacious but has fewer adverse effects than indometacin or phenylbutazone. The most frequent reactions are in the gastrointestinal tract and skin (1). However, gastrointestinal tolerance is, as one would expect, better (2). 

From a commercial point of view, organic halides are in principle a less attractive feedstock for the synthesis of alkanoic or benzoic acid derivatives compared with alkenes or toluenes, which can lead to the corresponding acids via hydroformyla-tion and oxidation, hydrocarboxylation, or direct air oxidation, respectively. Thus, apart from methanol, an economically viable carbonylation of C-X compounds is restricted to the synthesis of higher-value fine chemicals in cases where alternative starting materials are not easily accessible, e. g., phenylacetic acid derivatives (cf. Section 2.1.2.1). 

Phenylacetic acid derivatives and related agents were introduced fairly recently. Those used therapeutically include diclofenac, ketorolac and tolmetin. They are reasonably well tolerated in use against skeletal muscle and joint pain. Diclofenac is sometimes used (by injection) for preoperative medication. Also, it is available in a preparation combined with a prostaglandin in an attempt to counteract its ulcerogenic effects (see ANTIULCEROGENIC AGENTS). 

Phenylacetic acid derivatives.3 The reagent undergoes Knoevenagel-type condensation with benzaldehyde (Triton B) to give l-methylsulfinyI-I-methylthio-2-phenyl-ethylene (2). When (2) is treated with hydrochloric acid in ethanol at room temperature ethyl phenylacetate (3) is obtained in 78% yield. 

Monoacetals of quinones are accessible by T1(N02)3 oxidation of hy-droqulnone monomethyl ethers. The unprotected carbonyl group can be condensed with anions to afford products which give substituted phenylacetic acid derivatives on aromatization. 

Tolmetin sodium is a NSAID, which decreases inflammation, pain, and fever, probably through inhibition of cyclooxygenase activity and prostaglandin synthesis. It is indicated in the treatment of chronic and acute rheumatoid arthritis and osteoarthritis and juvenile rheumatoid arthritis. Tolmetin and ketoroiac are structurally related heteroaryl acetic acid derivatives with different pharmacological features. Diclofenac is a phenylacetic acid derivative that was developed specifically as an antiinflammatory agent. 

Oxidations. Photochemical degradation of a-hydroxy acids and phenylacetic acid derivatives (oxidative decarboxylation) takes place in the presence of a mesoporous silica. 

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