A-Phenylbutyric acid

It is of interest to note that by substituting alkyl bromides for cyciohexyl bromide the corresponding a-phenyl-a-alkyl-acetonitriles are obtained, which may be hydrolysed to the a-phenylaliphatic acids thus with ethyl iodide a-phenyl-lwt3Tonitrile is produced, hydrolysed by ethanoUo potassium hydroxide to a-phenylbutyric acid. 

IB.2 grams of a-phenylbutyric acid chloride are dissolved in 25 ml of toluene. To this solution, there is slowly added a solution of 16.1 grams of diethylaminoethoxyethanol in 25 ml of toluene, the reaction mixture thereby becoming hot. It is then heated for B hr under reflux. The reaction mixture, after cooling, is carefully poured onto 75 grams of ice and made alkaline with dilute ammonia. After thorough shaking of the solution, the toluene layer is removed and washed until neutral with water. The toluene solution is treated with carbon and dried over sodium sulfate. The toluene is distilled off from the filtered solution. 

The residue is a-phenylbutyric acid diethylaminoethoxyethyl ester. The basic ester is purified by distillation in a high vacuum. 10 grams of ester are added to a solution of 7 grams of citric acid in 30 ml of warm acetone. After standing for some time, the citrate of the ester crystallizes out. After suction filtration and washing with acetone the ester citrate is recrystallized from acetone. The melting point of the citrate is 75°C. 

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

It has been empirically established (Horeau, 1961) that an alcohol with three groups of varjdng size (S = small, M = medium, L = large) arranged as indicated in 6 leads to recovered a-phenylbutyric acid... 

It was found that the signs of rotation of the recovered a-phenylbutyric acid corresponded to the known absolute configurations of the deuteriated alcohols if and only if the size relationships CH3 > CD 3 and H>D were valid. In the case of (-t-)-(S)-2-propanol-l,l,l-d3 (4), the optical yield was between 0-4 and 0 5% (Horeau et al., 1965), corresponding to A AG value of about 23 cal mol at 25°C. For the primary alcohols, quite analogous results were obtained (Horeau and Nouaille, 1966). 

Recently, Juge and Kagan (68) reported that a more efficient kinetic resolution of racemic sulfoxides takes place in the Pummerer-type reaction with optically active a-phenylbutyric acid chloride 38 in the presence of N,A-dimethylaniline. In contrast to the asym-... 

Figure 17 shows the results of this experiment with a-phenylbutyric acid replacing alanine. In this reaction, the asymmetric transformation is first order. 

Figure 17. Asymmetric transformation using a-phenylbutyric acid...

Hydrolysis of amides may be carried out in acid or alkaline medium. For example, the former is used for a-phenylbutyric acid (90%) and the latter for 2- and 4-dibenzofurylacetic acids (87%). ° A mixture of hydrochloric and acetic acids is employed for insoluble amides. Amides obtained... 

This reaction furnishes the best method for the preparation of nineteen esters of y-diethylamino-a-phenylbutyric acid, ... 

Horeau deduced that an alcohol of the R-configuration shown (L= large M = medium S = small) should react with an excess of a-phenylbutyric acid to give an ester and that the excess acid should be optically active and of the (+)-S-configura-tion. An alcohol of the S-configuration would lead to recovery of the R-acid. 

Preparation. By refluxing a-phenylbutyric acid (suppliers Aldrich, Eastman) with acetic anhydride for 6 hrs. and removal of the solvent. 

Acid chlorides can be cyclized by PPE.12 In the example formulated the mixture of the acid chloride from 4.65 g. of a-phenylbutyric acid with 23 g. of freshly pre-... 

Long-range substituent effects of unknown mechanism influence the esterification of 5-en-3)3-ols by racemic a-phenylbutyric anhydride. Hydrolysis of the resulting esters gave a-phenylbutyric acid with modest optical activity, the sign depending upon the nature of C-17 substitution in the steroid employed. "... 

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]. 

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