Phenylacetic acid, preparation

The ketones are readily prepared, for example, acetophenone from benzene, acetyl chloride (or acetic anhydride) and aluminium chloride by the Friedel and Crafts reaction ethyl benzyl ketones by passing a mixture of phenylacetic acid and propionic acid over thoria at 450° and n-propyl- p-phenylethylketone by circulating a mixture of hydrocinnamic acid and n-butyric acid over thoria (for further details, see under Aromatic Ketones, Sections IV,136, IV,137 and IV,141). 

The preparation of a-phenylclnnamlc acid from benzaldehyde, phenylacetic acid, acetic anhydride and triethylamine is described. Presumably equilibria are set up between phenylacetic acid and acetic anhydride to form phenylacetic anhydride, a mixed anhydride or both ... 

The dibenzyl ketone has a very high b.p. (ca. 200°/21 mm.) and this remains in the flask when the unsymmetrical ketone has been removed by distillation. The dialkyl ketone has a comparatively low b.p. and is therefore easily removed by fractionation under normal pressure acetone is most simply separated by washing with water. In this way methyl benzyl ketone (R = CHj), ethyl benzyl ketone (R = CHgCH,) and n-propyl benzyl ketone (R = CHjCHjCH,) are prepared. By using hydrocinnamic acid in place of phenylacetic acid ... 

This product is sufficiently pure for the preparation of phenylacetic acid and its ethyl ester, but it contains some benzyl tso-cyanide and usually develops an appreciable colour on standing. The following procedure removes the iso-cyanide and gives a stable water-white compound. Shake the once-distilled benzyl cyanide vigorously for 5 minutes with an equal volume of warm (60°) 60 per cent, sulphuric acid (prepared by adding 55 ml. of concentrated sulphuric acid to 100 ml. of water). Separate the benzyl cyanide, wash it with an equal volume of sa+urated sodium bicarbonate solution and then with an equal volume of half-saturated sodium chloride solution- Dry with anhydrous magnesium sulphate and distil under reduced pressure. The loss in washing is very small (compare n-Butyl Cyanide, Section 111,113, in which concentrated hydrochloric acid is employed). 

Diphenylbutadiene has been obtained from phenylacetic acid and cinnamaldehyde with lead oxide, by the dehydrogenation of l,4-diphenyl-2-butene with butyllithium, and by the coupling reaction of benzenediazonium chloride and cinnamyl-ideneacetic acid." The present method gives better yields than those previously reported, is adaptable to the preparation of a variety of substituted bistyryls, and is relatively easy to carry out. 

This procedure is an adaption of one described by Hauser and Chambers. Previous preparations include the benzylation of diethyl phenylmalonate followed by hydrolysis, the benzylation of phenylacetonitrile followed by hydrolysis, the benzylation of phenylacetic acid through the Ivanov reagent, and the reduction of oi-phenylcinnamic acid using sodium amalgam. ... 

Preparation of 3 5-diiodo-4-(4 -hydroxyphenoxy)phenylacetic acid (diac) A solution of ethyl 3 5-diiodo-4-(4 -methoxyphenoxy)phenyl acetate (9.5 g) in acetic acid (60 ml) was heated under reflux with hydriodic acid (SG 1.7, 50 ml) and red phosphorus (0.5 g) for 1 hour. The hot solution was filtered and the filtrate concentrated at 50°C and 15 mm of mercury to above 20 ml. The residue was treated with water (70 ml) containing a little sodium thiosulfate to decolorize the product. The solid was collected by filtration and purified by the method of Harington and Pitt-Rivers [Biochem. J. (1952), Vol. 50, page 438]. Yield 8,36 g (95%). After crystallization from 70% (v/v) acetic acid it melted at 219°C. 

Inclusion of basic nitrogen in the p-position is also compatible with antiinflammatory activity in this series. Nitration of phenylacetic acid (27) affords 28. Methyl iodide alkylation of the enolate prepared from 28 using two equivalents of sodium hydride gives 29. This appears to involve an Ivanov intermediate (28a). Catalytic reduction of the... 

The (S)-MTPACI is prepared by Mosher s method5 from (R)-a-methoxy-a-(trifluoromethyl)phenylacetic acid purchased from Aldrich Chemical Company, Inc. 

The hydrochloride of 3-amino-4-hydrazinopyridine 65 was prepared by reaction of the 4-chloro-3-nitropyridine derivative with ethoxycarbonyl-hydrazine in phenol to give the hydrochloride of ethyl 3-(3-nitro-4-pyridyl)carbazate 64 (R2 = OEt), which on successive heating in concentrated hydrochloric acid and hydrogenation over Pd/C gave 65. Its reaction with phenylacetic acid or with phenoxyacetic acid gave the hydrochloride... 

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]. 

The benzyl cyanide, prepared according to the procedure as outlined, is collected over a 50 range. It varies in appearance from a colorless to a straw-colored liquid and often develops appreciable color upon standing. For a product of special purity, it should be redistilled under diminished pressure and collected over a 1-20 range. For most purposes, such as the preparation of phenylacetic acid or ester, the fraction boiling i35-i40°/38 mm. is perfectly satisfactory. 

Ethyl phenylacetate may be prepared by the treatment of benzyl cyanide with alcohol and hydrochloric acid gas.1 It is much more convenient in the laboratory, however, to use sulfuric acid in place of hydrochloric acid in fact, the yields obtained are better than those recorded in the literature. This ester may also be made by the esterification of phenylacetic acid with hydrochloric acid and alcohol 2 or with alcohol and sulfuric acid 3 the following less important methods of preparation may be mentioned the action of benzyl magnesium chloride upon ethyl chlorocarbonate,4 and the action of copper on a mixture of bromobenzene and ethyl chloroacetate at 1800.5... 

For the preparation of small quantities of phenylacetic acid, it is convenient to use the modified method given in the Notes. 

The standard directions for the preparation of phenylacetic acid specify that the benzyl cyanide is to be treated with dilute sulfuric acid prepared by adding three volumes of sulfuric acid to two volumes of water. There action, however, goes so vigorously that it is always necessary to have a trap for collecting the benzyl cyanide which is blown out of the apparatus. The use of the more dilute acid, as described in the above directions, is more satisfactory. 

The standard method of preparation of phenylacetic acid is by the hydrolysis of benzyl cyanide with either alkali1 or acid.2 The acid hydrolysis runs by far the more smoothly and so was the only one studied. There are numerous other ways in which phenylacetic acid has been formed, but none of them is of practical importance for its preparation. These methods include the following the action of water on phenyl ketene 3 the... 

In a 5-I. round-bottom flask, fitted with a mechanical stirrer and reflux condenser, are mixed 1150 cc. of water, 840 cc. of commercial sulfuric acid and 700 g. of benzyl cyanide (preparation III, p. 9). The mixture is heated under a reflux condenser and stirred for three hours, cooled slightly and then poured into 2 1. of cold water. The mixture should be stirred so that a solid cake is not formed the phenylacetic acid is then filtered off. This crude material should be melted under water and washed by decantation several times with hot water. These washings, on cooling, deposit a small amount of phenylacetic acid which is filtered off and added to the main portion of material. The last of the hot water is poured off from the material while it is still molten and it is then transferred to a 2-1. Claisen distilling flask and distilled in vacuo. A small amount of water comes over first and is rejected about 20 cc., containing an appreciable amount of benzyl cyanide, then distils. This fraction is used in the next run. The distillate boiling i76-i89°/5o mm. is collected separately and solidifies on standing. It is practically pure phenylacetic acid, m. p. 76-76.5° it amounts to 630 g. (77.5 per cent of the theoretical amount). As the fraction which is returned to the second run of material contains a considerable portion of phenylacetic acid, the yield actually amounts to at least 80 per cent. 

FIGURE 3. The NMR spectra of the two racemic diastereomers of lV-(4-methyl-2-pentyl)-a-methoxy-a-trifluoromethylphenylacetamide prepared from racemic a-methoxy-a-(trifluoromethyl)phenylacetic acid [MTPA, ( )-83] and racemic 4-methyl-2-pentylamine [( )-84] (A) 60-MHz proton spectrum in chloroform-4 with tetramethylsilane (TMS) as the internal standard (B) 94.1-MHz fluorine-19 spectrum in chloroform-4 with trifluoroacetic acid as the internal standard. Reprinted with permission from Reference 76. Copyright (1969) American Chemical Society... 

Carbonvlation of Benzyl Halides. Several organometallic reactions involving anionic species in an aqueous-organic two-phase reaction system have been effectively promoted by phase transfer catalysts(34). These include reactions of cobalt and iron complexes. A favorite model reaction is the carbonylation of benzyl halides using the cobalt tetracarbonyl anion catalyst. Numerous examples have appeared in the literature(35) on the preparation of phenylacetic acid using aqueous sodium hydroxide as the base and trialkylammonium salts (Equation 1). These reactions occur at low pressures of carbon monoxide and mild reaction temperatures. Early work on the carbonylation of alkyl halides required the use of sodium amalgam to generate the cobalt tetracarbonyl anion from the cobalt dimer(36). 

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). 

Fused 2-substituted thiazoles are most conveniently synthesized by condensing an a-haloketone with a thiono-amide. Thiazolo[5,4- ]indoles 118 were prepared via the Gunch reaction using bromindoxyl 117 and primary thionoamides of phenylacetic acid, phenylpropionic acid, and cyanoacetic acid affording the products as either... 

The literature on the preparation of phenylacetic acid is reviewed in an earlier volume of this series.3... 

C15H14O2, Mr 226.27, is prepared by esterification of p-cresol with phenylacetic acid. It forms crystals (mp 75—76 °C) with a narcissus odor and a honey note. It is used in blossom compositions with a slight animal note. 

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