Phenylsuccinic acid

Ethyl 0-phenyl-p-cyanopropionate. In a 5-1. round-bottomed three-necked flask suspended in an oil bath and fitted with a mechanical stirrer, a reflux condenser, and a 250-ml. dropping funnel is placed a solution of 200 g. (0.806 mole) of diethyl ben-zalmalonate 1 in 2 1. of absolute ethanol. The stirrer is started, and a solution of 56 g. (0.87 mole) of potassium cyanide in 100 ml. of water is added rapidly from the separatory funnel a small amount of the potassium cyanide precipitates. The temperature of the oil bath is raised to 70° and maintained at 65-75° for 18 hours. 

The mixture is cooled to 15°, and the precipitated potassium bicarbonate is collected on a Buchner funnel. The solid (weight 70-72 g.) is washed on the funnel with 100 ml. of 95% ethanol. The combined filtrate and wash liquor is transferred to a 5-1. round-bottomed flask and made slightly acid (Caution Note 1) with dilute hydrochloric acid (about 15-20 ml. of the 10% acid is required). The solution is then concentrated under reduced pressure to a semi-solid residue (Note 1). The cooled residue is shaken with a mixture of 300 ml. of water and 500 ml. of ether. The material dissolves completely the water layer is separated and washed with 200 ml. of ether. The ether solutions are combined, dried over 20 g. of calcium chloride, filtered into a 2-1. round-bottomed flask equipped with a glass joint, and concentrated by distillation (heating on a steam bath). The crude ethyl /3-phenyl-/3-cyanopropionate remains as a clear red oil weighing 130-140 g. It is sufficiently pure for use in the next step (Note 2). 

Phenylsuccinic acid. To the crude ester obtained above is added 500 ml. of concentrated hydrochloric acid (sp. gr. 1.19). The flask is fitted to a condenser (Note 3), and the mixture is heated under reflux for 18 hours (Note 4). At the end of this time only a small amount of red oil remains (Note 5). The mixture is cooled, and the nearly solid cake which forms is broken up and collected on a glass filter cloth (Note 5). The crude tan-colored phenylsuccinic acid is washed with 300 ml. of cold water and 

Since hydrogen cyanide may be liberated during the acidification and the subsequent concentration, both operations should be carried out in a well-ventilated hood. 

The pure ester can be obtained by distillation under reduced pressure (b.p. 161-164°/8 mm.). 

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Pyridyl)-3-p-bromophenyl-N,N-dlmethylpropylamlne (racemic) d-Phenylsuccinic acid Potassium carbonate Maleic acid... 

The following is taken from U.S. Patent 3,061,517. Sixteen grams of racemic 3-(2-pYridyl)-3-p-bromophenyl-N,N,-dimethylpropylamine and 9,7 grams of d-phenylsuccinic acid are dissolved in 150 ml of absolute alcohol and kept at room temperature until crystallization is effected. The crystals are filtered, washed with absolute ethyl alcohol, and recrystallized from the same solvent using 5 ml thereof per gram of solid. Three subsequent crystallizations from 80% alcohol give d-3-(2-pYridYl)-3-p-bromophenYl-N,N-dimethylpropYlamine-d-phenylsuccinate MP 152°-154°C 91 (concentration, 1% in dimethylformamide). 

Twenty grams of d-phenylsuccinic acid and 28 grams of 3-(2-pyridyl)-3-p-chlorophenyl-N,N-dimethylpropylamine are dissolved in 400 ml of absolute ethyl alcohol and allowed to stand at room temperature until crystallization is effected. The crystals are filtered, washed with absolute ethyl alcohol and recrystallized from 300 ml of this solvent in the same manner. The crystals are recrystallized twice from 80% ethyl alcohol using 3.5 ml per gram of compound in the manner described above and pure d-3-(2-pyridyl)-3-p-chlorophenyl-N,N-dimethylpropylamine-d-phenylsuccinate is obtained, melting point 145°-147°C. 

C. Hydrolysis of Ethyl a, fi-Dicyano- -phenyl Propionate — The product thus obtained is hydrolyzed by boiling under a reflux condenser for four hours with 80 cc. of concentrated hydrochloric acid (sp. gr. 1.19). The substance goes into solution and this clear solution, on cooling, deposits phenylsuccinic acid in small crystals which are nearly colorless. These are filtered off, washed with cold water and dried. The yield of product melting at 164-166° is 17.6-18.4 g. (91-95 per cent of the theoretical amount based on the weight of ester used) (Notes 1 and 2). 

The phenylsuccinic acid, if slightly off color, may be recrystallized easily from a hot water solution by rapid cooling. Five grams is dissolved in 400 cc. of hot water and then 60 cc. more of hot water is added. This solution is filtered and cooled in ice water with stirring until crystals separate. After standing the crystals are filtered off. The yield is 4.5 g. (90 per cent) of product melting at 167°. 

Phenylsuccinic acid has been prepared by the action of potassium cyanide and alcohol upon a-chlorostyrene 1 by the reaction... 

Phensuximide Phensuximide, l-methyl-3-phenylpyrrolidine-2,5-dione (9.3.5) is synthesized by the reaction of phenylsuccinic acid or its anhydride with methylamine [10,11]. 

Dexchlorpheniramine Dexchlorpheniramine, d(+)-3-(p-chlorophenyl)-3-(2-pyridyl) propyldimethylamine, is synthesized by separating the racemate obtained from the synthesis of chlorpheniramine (16.1.12) using o-phenylsuccinic acid [22-24]. 

Phenylacetylene, 72 /ra X-TPHENYL-l,3-BUTAniENE, 75 a-PHENYL-a-CARBETHOXYGLUTARO-NITRILE, 80, 82 0-Phenylenediamine, 56, 86 a-Phenylglutaric acid, 82 a-PHENYLGLUTARIC ANHYDRIDE, 81 Phenylhydrazine, 90 Phenylmagnesium bromide, 97 Phenylsuccinic acid, 83 Phenylsuccinic anhydride, 85 Phosphoric acid, ortho-, 33, 34 Phosphoric anhydride, 33 Phosphorus oxychloride, Tl Phosphorus pentoxide, 22, 46 Potassium, 19, 20 directions for safe handling of, 20 Potassium lerl.-butoxide, solution of, 19... 

The preparative methods for phenylsuccinic acid have been listed in an earlier volume. The procedure given above is more economical of time and materials than that previously published. Applications of the present method, due originally to Bredt and Kallcn, have been published in more recent literature. - ... 

This conclusion is wholly proved by the ozonization (36) of polymers of alkyl sorbates and of alkyl styryl-acrylates obtained by anionic mechanism, which yielded optically active methylsuccinic, and respectively phenylsuccinic acid. 

A two step process involving an intermediate radical or carbonium ion has been suggested as mechanism because of the fact that both meso- and d,7-2,3 -di-phenylsuccinic acid yield 35-40% trans-stilbene 314 A cationic intermediate however seems improbable for the bisdecarboxylations of aliphatic bicyclic carboxylic acids (Eq. (139-144) ), since no products with reananged carbon skeleton, as expected from carbonium ions, have been isolated. 

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