Phenylacetic acids, substituted, preparation

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. 

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]. 

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... 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

The above method has been used in the preparation of other ring-substituted diphenylacetoacetonitriles. The method is equally successful when applied to the condensation of phenyl-acetonitrile with the ethyl ester of a 4-substituted phenylacetic acid. The table summarizes the results reported by the submitters. 

The allyl group in the allylphenols can be oxidized, after protecting the hydroxyl group, to yield substituted phenylacetaldehydes 78 - 76 76 and phenylacetic acids. Thus, homogentisic acid LXIII is prepared readily by ozonizing the dibenzoate of allylhydroqumone LXIV, which is obtained by rearrangement of the allyl ether of hydroquinone mono-... 

Oxidative degradation of substituted pyruvic acids is accomplished by treating an aqueous solution of the sodium salt with 30% hydrogen peroxide (Superoxol) at 0-15°. Good descriptions have been published for the preparations of o-hydroxyphenylacetic acid (34%), 3,4-dim.ethoxy-phenylacetic acid (60%), m-chlorophenylacetic acid (57%), and o-nitro-phenylacetic acid. ... 

For the preparation of long chain alkanes from fatty acids it is useful to extract the electrolyte contin-ously with a high-boiling nonpolar solvent, e.g. 2-methylheptane. Cyclopropanecarboxylic acids in some cases have been dimerized, e.g. or (15) in other cases the radical is further oxidized to a carbocation which then undergoes ring opening and solvoiysis to allylic compounds. Specifically substituted 1,2-diphenyiethanes have been prepared from phenylacetic acids (Table 2, entries 22 and 23). A variety of 2,3-disubstituted succinic acids and their derivatives have become accessible from malonic... 

Pecherer and co-workers have prepared a number of benzazocinones by heating the substituted 3-phenylpropionie acids 110240 or the substituted phenylacetic acid 111.241 Huisgen and co-workers242 have published a... 

Organo-tin and -silicon steroids have been prepared from 3a- and 3)S-halocho-lest-anes and 5-enes, and a number of steroidal esters of p-[AfAT-bis(2-chloro-ethyl)amino]phenylacetic acid and sulphides derived from p-bis(2-chloroethyl)-amino-thiophenol and ethylenimine derivatives of steroids have been prepared. The substituted phenylacetates showed good inhibition of certain tumours. ... 

Phenylacetic acid yields derivatives which contain substituents in either the side-chain or the nucleus. The methods by which the two classes of derivatives may be prepared are applications of the principles which have been discussed. The reactions by which the two chlorine substitution-products are formed are examples —... 

Penicillium chrysogenum on complex solid media, with the result that they were mixtures differing from one another in the identity of the side-chain moiety. When a sufficient supply of phenylacetic acid is present in liquid media, this is preferentially incorporated into the molecule to produce mainly benzylpenicillin (penicillin G in the old nomenclature). Use of phenoxyacetic acid instead leads to phenoxymethyl penicillin (penicillin V). More than two dozen different penicillins have been made in this way, but these two are the only ones that remain in clinical use. The bicyclic penicillin nucleus itself is prepared biosynthetically via a complex process from an acylated cysteinyl valyl peptide. The complete exclusion of side chain precursor acids from the medium produces the fundamental penicillin nucleus, 6-APA, but in poor yield. By itself, 6-APA has only very weak antibiotic activity, but when substituted on its primary amino group with a suitable... 

Synthesis of repaglinide involves condensation of an appropriately substituted and chi-rally pure benzylamine derivative with an appropriately substituted phenylacetic acid derivative (7) followed by saponification. The reported process for the key intermediate (7) described a five-step process with an overall yield of about 30% of theory (Scheme 23.4) We undertook development of an alternative synthetic strategy to prepare 7 and developed an efficient and commercially feasible synthesis starting from 2-hydroxy-4-methylbenzoic acid (9) in two steps. Thus, 9 was first alkylated with ethyl bromide in a polar aprotic solvent and in the presence of an inorganic base to afford ethyl 2-ethoxy-4-methylbenzoate... 

The first six-membered iodine(III) heterocycle, the cyclic tautomer of 2-iodosylphenylacetic acid, 221, was reported in 1963 by Leffler and coauthors [342]. This compound was synthesized by chlorination of 2-iodophenylacetic acid (220) followed by hydrolysis of the initially formed, unstable 2-(dichloroiodo)phenylacetic acid (Scheme 2.67). Compound 221 is stable at room temperature but decomposes in solution at 80-100 °C the proposed cyclic structure 221 is in agreement with its relatively low acidity (pXa = 7.45) [342]. 8-Iodosyl-l-naphthoic acid (222) was prepared by the peracetic oxidation of 8-iodo-1-naphthoic acid [343]. Anions of 2-iodosylphenylacetic acid (221) [328] and 222 [343] have a moderate reactivity in the cleavage of phosphate esters in aqueous micellar solution. The chiral, enantiomerically pure substituted 2-iodosylphenylacetic acid derivatives 223 and 224 were synthesized from the corresponding aryl iodides by oxidation with dimethyldioxirane [344]. 

Aldol-type condensation of an aromatic aldehyde with activated methylarene or phenylacetic acid is a useful reaction for preparing stilbene derivatives. Starting from para-substituted toluenes or para-substituted aromatic aldehydes, one can obtain 4,4 -disubstituted stilbenes. This reaction is relatively simple but has low yield. As an example, condensation of 2,4-dinitrotoluene and 4-nitrophenylacetic acid with aromatic aldehyde was studied [26]. The reaction involves carbanion addition to the carbonyl group. The carbanion is formed by the extraction of proton from the active methylene group of 2,4-dinitrotoluene by the base (usually, piperidine). The carbanion then adds to carbon atoms of the carbonyl group of the aldehyde. The reaction will therefore be facilitated by the ease of both the formation of the... 

A one-pot two-step synthesis of hydroxystilbenes with trans selectivity was developed through a modified Perkin reaction between benzaldehydes and phenylacetic acids bearing 4- or 2-hydroxy substitution at the aromatic ring [67]. The reaction was performed under mild conditions in the presence of piperidine-methylimidazole and polyethylene glycol under microwave irradiation. As a result, 71% yield of ( )-4-chloro-4 -hydroxy-3 -methoxystilbene from 4-hydroxy-3-methoxybenzaldehyde and 4-chlorophenylacetic acid was obtained. A microwave-induced one-pot process for the preparation of arylethenes has been patented [118]. For the preparation of a series of arylethenes (I R -R = H, OH, OMe, AcO, halo, NO2 R, R, R = OH, AcO R= H, substituted aryl), reaction of 2- or 4-hydroxy substituted cinnamic adds or derivatives in the presence of a base, under reflux or microwave irradiation, has been used. For example, a mixture of a-phenyl-4-hydroxy-3-methoxycinnamic acid, NaHC03, methylimidazole, and polyethylene glycol was microwaved at 200 W and 180 °C for 10 min to give 96% 4-hydroxy-3-methoxystilbene. 

A number cf -substituted phenylacetic and 2-phenylbutyric aqids have been prepared and tested by Canonica et al. [216]. The substituted phenylacetic acids were found to be devoid of hypocholesterolemic activity. In the a-phenylbutyric acid series the am-substituted hydroxyl and amino derivatives showed a decreased activity, while the am-substituted methyl, methoxy and chloro derivatives led to an increase of activity over the parent compound XLVIII. The aminoethanol salt of 2-phenylbut5nic acid caused a significant reduction in plasma cholesterol levels in patients. In subjects with normal plasma cholesterol concentration the drug was reported to be without effect [217, 218]. Cholesterol-lowering and antineuralgic properties have been claimed for the anihde LXIX of 2-phenylbut5nric acid [219]. 

A -Aiyloxindoles 192, which are intermediates for the preparation of pharmacologically active 2-(iV-arylamino)-phenylacetic acids 193 were obtained by the Smiles rearrangement of substituted iV-chloroacetyl-diarylamines 191. The rearrangement of 2-chloro-6-fluoro- and 2,6-difluoro-phenoxy- derivatives proceeded affording the expected product along with a major side reaction, which has been minimized by utilization of proper choice of reaction conditions. 

Cobaltcarbonyls are used for the carbonylation of benzyl halides or aromatic halides [74-76]. For example, as shown in eq. (17.31), benzylcarboxylic acid is prepared by the reaction of benzyl halide with carbon monoxide. The reaction mechanism is thought to be as follows at first the halogen atom of the halide is substituted by a cobalt atom and the Co-C bond formed is inserted into by a carbonyl. The phenylacetic acid is industrially produced by using this cobalt catalyst [77]. On aromatic halides, not only monocarbonylation but also double carbonylation is liable to proceed [74,75]. 

In the reaction of benzoic acid with a large excess of chlorosulfonic acid, the dichloride 273 may be an intermediate. 3-Chlorosulfonylbenzoyl chloride 273 was easily prepared by treatment of 3-chlorosulfonylbenzoic acid 271 widi thionyl chloride and was shown to reform the 3-sulfonyl chloride 271 by reaction with either water or chlorosulfonic acid (Scheme 6). Stewart" successMly reacted cinnamic, salicylic and phenylacetic acid with excess chlorosulfonic acid to obtain the corresponding sulfonyl chlorides. Several ortAo-substituted benzoic acids (274 X = Me, OMe, qjj 110,268-271 q 26 gj.267 treated with excess... 

A review of the literature of this reaction to 1941 has been made. The condensation is most valuable for the preparation of substituted cinnamic acids, particularly those containing halo, methyl, and nitro groups. Furfural has been condensed in good yields with acetic anhydride, butyric anhydride, and sodium phenylacetate in the... 

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