Benzoylacrylic Acid

Submitted by Oliver Gruitmitt, E. 1. Becker, and C. Miesse. Checked by Arthur C. Cope and Claude F. Spencer. 

In a 1-1. three-necked round-bottomed flask fitted with a mercury-sealed stirrer and a reflux condenser are placed 34 g. (0.347 mole) of maleic anhydride (Note 1) and 175 g. (200 ml., 2.24 moles) of dry, thiophene-free benzene. Stirring is started, and, when the maleic anhydride has dissolved, 100 g. (0.75 mole) of anhydrous reagent grade aluminum chloride powder is added in 6-8 portions through the third neck of the flask at a rate so that the benzene refluxes moderately. The addition requires about 20 minutes. The mixture is then heated under reflux on a steam bath and stirred for 1 hour. The reaction flask is cooled thoroughly in an ice bath, a 250-ml. dropping funnel is attached to the third neck, and the mixture is hydrolyzed by adding 200 

The hydrolyzed mixture is transferred to a 1-1. Claisen flask, the transfer of material being completed by rinsing with about SO ml. of warm water. The flask is heated in a water bath at 50-60°, and the benzene and some water arc distilled at 20-30 

A good grade of commercial maleic anhydride was used, m.p. 52-54°. 

When /3-benzoylacrylic acid is heated with dilute hydrochloric acid, /3-bcnzoyllactic acid is formed, which makes the purification of the product very dillicult. Eor this reason the 

---

Enalapril Enalapril, (S)-l-[iV-[l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline (22.7.12), is synthesized by reacting the benzyl ester of L-alanyl-L-proline with the ethyl ester of 3-benzoylacrylic acid, which forms the product 22.7.11, the reduction of which with hydrogen using a Raney nickel catalyst removes the protective benzyl group, giving the desired enalapril (22.7.12) [24], Alternative methods of syntheses have also been proposed [25-29]. 

The bacteriostatic activity of a series of substituted trans-3-benzoylacrylic acids has been successfully correlated by Hansch linear free energy relations involving polar and partition substituent constants. The activity-lipophilicity relations for this series closely parallel those found previously for other antibacterial agents, with an ideal lipophilic character for gram-positive cells of 6.1 and, for linear dependence, a slope of 0.7. A polar reaction constant, p, of about —0.6 to —0.7 is given. A possible mode of action for these acids and their related substituted cis- and trans-3-benzoyl acrylic acids and esters is discussed as an enzyme-inhibitor interaction. 

In this study we report a Hansch analysis of the activity of a series of substituted trans-3-benzoylacrylic acids. The bacteriostatic and fungistatic activity of several series of substituted cis- and trans-3-benzoyl-acrylic acids and their methyl esters are given. The structure—activity relations observed are discussed. 

Table IV. Correlations of Bacteriostatic Activity of the Substituted trans-3-Benzoylacrylic Acids"...

Table V. Bacteriostatic and Fungistatic Activities for Substituted cis- and r Mw-3-Benzoylacrylic Acids and Their Methyl Esters...

The benzene solution of i3-benzoylacrylic acid is concentrated under reduced pressure to avoid overheating, and the crude product is separated from aqueous hydrochloric acid without long standing in order to minimize the possibility of forming /3-benzoyllactic acid (Note 2). 

Heating a mixture of 8-benzoylacrylic acid and excess sodium carbonate causes hydrolysis to acetophenone and other products, which decreases the yield and interferes with purification of the product. 

The evidence indicates that this is the trans form of /3-benzoylacrylic acid. > Inhalation of b-benzoylacrylic acid dust should be avoided because of its sternutatory action. 

Benzoylacrylic acid has been prepared by the condensation of acetophenone and chloral to l,l,l-trichloro-2-hydroxy-3-benz-oylpropane, followed by hydrolysis to the corresponding acid and dehydration by the action of iodine, potassium iodide, and sodium carbonate on 7-phenylisocrotonic acid by bromination of /3-benzoylpropionic acid and subsequent dehydrohalogena-tion 1 and by the action of phenylzinc chloride on maleic anhydride. The present method is based on the work of von Pech-mann and others. ... 

Pyrimidinylpyridazines were prepared either from 90 to give 91 (96RRC109) or when barbituric acid was reacted with a benzoylacrylic acid and the adducts were thereafter cyclized to 92 (94MI2). 

The adduct 2-(4,4-dimethyl-2,6-dioxocyclohexyl)-4-oxo-4-phenylbu-tanoic acid 261 was obtained from the reaction of dimedone and / -benzoylacrylic acid, which upon reaction with ammonium acetate in acetic acid led to the pyridine ring that accompanied by decarboxylation to give 262. When the reaction was done in the presence of methylamine, benzylamine, or p-toluidine, it gave quinolines 263 whose oxidation by chromic acid in pyridine gave 264 (01CHE1111) (Scheme 48). 

Michael condensation of 1 and frans-/)-benzoylacrylic acid afforded butanoic acid derivative 315 that can be cyclized, with ammonia in an autoclave at 150-160 °C, to give 7,7-dimethyl-4-phenyl-l,2,6,7,8,8a-hexahydro-pyrrolo[4,3,2-d,e]quinolin-2-one (316) (97JOU1048). The pyr-rolo[3,4-fr]quinoline 317 was reported as inhibitor of Aurora A Kinase (07EUP60) (Scheme 59). 

The synthesis of diclomezine starting from l-(3,5-dichloro-4-methylphenyl)-ethanone, according to the literature [56], is shown in Scheme 21.4. It starts with an aldol condensation of the acetophenone with glyoxylic acid, yielding the corresponding benzoylacrylic acid. Addition of sodium methanethiolate in water affords 4-(3,5-dichloro-4-methylphenyl)-2-methylsulfanyl-4-oxo-butyric acid. The latter can be cyclized with hydrazine hydrate in ethanol to afford 6-(3,5-dichloro-4-methylphenyl)-4-methylsulfanyl-4,5-dihydro-(2H)-pyridazin-3-one, which can be aromatized under acidic conditions by elimination of methyl mercaptan to generate diclomezine. 

---