Hydrocinnamic 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 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 ... 

Hydrocinnamic acid may also be prepared by the reduction of cinnamic acid with sodium and alcohol or with sodium amalgam or with hydrogen in the presence of Adams platinum oxide catalyst (Section 111,150) ... 

Hydrocinnamic Acid.—The preparation illustrates the use of sodium amalgam as a reducing agent It should be noted that hydiocinnamic acid may be also obtained from m.donic ester by acting upon the sodium compound nith benzyl chloride, then hydrolysing and removing carbon dioxide,... 

Cognate preparations. 3-Phenylpropanoic acid (hydrocinnamic acid). Reflux a mixture of 53.5 g (0.4mol) of propiophenone (Expt 6.126), 20.5 g (0.64mol) of sulphur and 46 g (46 ml, 0.53 mol) of morpholine for 6 hours. Pour the reaction product into 400 ml of 10 per cent ethanolic sodium hydroxide solution and reflux for 7 hours. Distil off- the ethanol, dilute with water, acidify with hydrochloric acid (to Congo red paper) and extract three times with ether. Wash the ether extracts with water, dry, remove the ether and distil. Collect the hydrocinnamic acid at 125-129 °C/6mmHg it solidifies completely on cooling, m.p. 46-47 °C. The yield is 39 g (65%). 

Phenylethylamine has been made by a number of reactions, many of which are unsuitable for preparative purposes. Only the most important methods, from a preparative point of view, are given here. The present method is adapted from that of Adkins,1 which in turn was based upon those of Mignonac,2 von Braun and coworkers,3 and Mailhe.4 Benzyl cyanide has been converted to the amine by catalytic reduction with palladium on charcoal,5 with palladium on barium sulfate,6 and with Adams catalyst 7 by chemical reduction with sodium and alcohol,8 and with zinc dust and mineral acids.9 Hydrocinnamic acid has been converted to the azide and thence by the Curtius rearrangement to /3-phenyl-ethylamine 10 also the Hofmann degradation of hydrocinnamide has been used successfully.11 /3-Nitrostyrene,12 phenylthioaceta-mide,13 and the benzoyl derivative of mandelonitrile 14 all yield /3-phenylethylamine upon reduction. The amine has also been prepared by cleavage of N- (/3-phenylethyl) -phthalimide 15 with hydrazine by the Delepine synthesis from /3-phenylethyl iodide and hexamethylenetetramine 16 by the hydrolysis of the corre-... 

Benzylacetophenone has been prepared by the reduction of benzalacetophenone with zinc and acetic acid1 and catalytic-ally with palladium and hydrogen 2 by the reduction of 8-duplo-benzylidene acetophenone monosulfide 3 by the oxidation of the corresponding carbinol with chromic acid 4 by the hydrolysis of ethyl benzyl benzoylacetate 5 from acetophenone and benzyl chloride by the action of sodamide 6 and from benzoic and hydrocinnamic acids using as catalysts manganese oxide 7 and ferric oxide.8... 

Hydrocinnamic acid has been prepared by the reduction of cinnamic acid with sodium amalgam, (1) with hydriodic acid at 100°, (2) and with phosphorus and hydriodic acid (3) by the action of potassium... 

Norris, J.F. Cummings, E.O. Electrolytic Preparation ofp-Phenylene-diamine, Aminosalicylic Acid, Succinic Acid, and Hydrocinnamic Acid Industrial and Engineering Chemistry 1925 17 (3) 305-307... 

The large scale preparation of (S)-2 [(tert-butylsulfonyl)-methyl]hydrocinnamic acid [(S)-4], a chiral building block in the synthesis of the potential rennin inhibitor Remikiren (not in use since it failed in the clinical phase), was performed via Subtilisin Carlsberg-catalyzed racemic resolution of the ester roc-3. The substrate was emulsified at 39-43 °C in 29% concentration in aqueous buffer and the pH was controlled using a 2-4 M NaOH solution. Work-up proved to be the rate-limiting step, nevertheless, the desired product could be isolated in 41.6% yield on a 100 kg scale. The product was obtained with excellent chemical (>99.5%) and enantiomeric (>99%) purity (Scheme 4.8). 

B. Wirz, S. Doswald, E. Kupfer, W. Wostl, T. Weisbrod, H. Estermann, Protease-Catalyzed Preparation of (S)-2-[(tert-butylsulfonyl)-methyl]-hydrocinnamic Acid for Rennin Inhibitor RO0425892, in H.-U. Blaser, E. Schmidt (Eds.), Asymmetric Catalysis on Industrial Scale, Wiley-VCH, Weinheim, 2004, pp. 385-398. 

Protease-Catalyzed Preparation of (S)-2-[(tert-Butylsulfonyl)-methylj-hydrocinnamic Acid for Renin Inhibitor RO0425892... 

For the preparation of 3-phenylpropionic acid (hydrocinnamic acid), as described by Henle,26 cinnamic acid (15 g) is dissolved in 5% sodium hydroxide solution (75 ml) with warming, the solution is cooled, and freshly prepared 2.5 % sodium amalgam is added slowly... 

In all of the syntheses discussed, alkoxy derivatives of a-aminoaceto-phenone or of /3-phenethylamine were employed to supply the main structural outline of the isoquinoline system. Some of these amines are hard to obtain, especially if the resistant aromatic methoxyl groups are replaced by more sensitive substituents which may serve in the preparation of partly demethylated derivatives of papaverine or laudanosine. A significant innovation (60) which avoids the preparation of such unstable amines is the degradation of j3-phenylpropionic acid azides (hydrocinnamic acid azides) to the corresponding isocyanates, which add to the required phenylacetic acids probably with the intermediate formation of four-membered cyclic hemiacetals. The latter are transformed to A-carboxylic acids, which lose carbon dioxide and yield amides needed in the isoquinoline syntheses. In practice, the azide is heated with the phenylacetic acid in benzene solution for several hours, and the amide is isolated from the reaction mixture without difficulty. 

This reaction was first reported by Drechsel in 1888 and then by Borsche in 1904. It is the reaction involving the cyclization of arylhydrazones of cyclohexanone to tetrahy-drocarbazoles and the subsequent oxidation of tetrahydrocarbazoles into carbazoles. In this reaction, cyclohexanone phenylhydrazone is converted into tetrahydrocarbazole when heated with dilute sulfuric acid, a process that is completely analogous to the Fischer Indole Synthesis. However, Borsche was the first to realize the full scope of this reaction, and had prepared many substituted tetrahydrocarbazoles. Other acids can also be used in this reaction—for example, acetic acid has been found to give cleaner products. Different oxidants have been applied for converting the tetrahydrocarbazoles into carbazoles, such as lead oxide, mercury acetate, palladium chloride, and chloranil. However, only chlo-ranil was found to be a good reagent in this reaction. In addition, a mixture of cinnamic acid and palladium black is another excellent reagent for the preparation of carbazoles, in which cinnamic acid was reduced to hydrocinnamic acid. 

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