Barbituric

In a 2-1. round-bottomed flask fitted with a reflux condenser protected by a calcium chloride tube 11.5 g. (0.5 gram atom) of finely cut sodium is dissolved in 250 cc. of absolute alcohol. To this solution is added 80 g. (0.50 mole) of ethyl malonate followed by 30 g. (0.50 mole) of dry urea dissolved in 250 cc. of hot (70°) absolute alcohol. After being well shaken the mixture is refluxed for seven hours on an oil bath heated to 1 io°. A white solid separates rapidly. After the reaction is completed, 500 cc. of hot (50°) water is added and then enough hydrochloric acid (sp. gr. 1.18) to make the solution acidic (about 45 cc.). The resulting dear solution is filtered and cooled in an ice bath overnight. The white product is collected on a Buchner funnel, washed with 50 cc. of cold water, and then dried in an oven at 105-1 io° for three to four hours. The yield of barbituric acid is 46-50 g. (72-78 per cent of the theoretical amount). 

Barbituric acid has been prepared by the action of phosphorus oxychloride on malonic add and urea,1 by treating an acetic add solution of urea and malonic acid with acetic anhy- 

In a i-l. three-necked flask fitted with a stirrer, a thermometer, and an ice-cooled spiral condenser (Org. Syn. Coll. Vol. i, 515) is placed a solution of 98 g. (0.80 mole) of ethyl chloroacetate in 200 cc. of absolute alcohol. The solution is cooled to o° by stirring in a salt-ice bath, and, after the stirrer is stopped, 74 cc. (49 g., 0.83 mole) of trimethylamine, measured after precooling to —5°, is added all at once. The exothermic reaction is controlled sufficiently by cooling so that the temperature of the mixture rises to 6o° in the course of about one hour (Note 1). When there is no longer any heat effect, the mixture is allowed to stand at room temperature for twenty hours (without replenishment of the condenser ice). 

Without external cooling the temperature rises to about 75° and it is difficult to avoid some loss of amine. 

The product supplied by Fraenkel and Landau, Germany, is satisfactory. 

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C. Has hypnotic properties similar to barbitone but its action is less prolonged. For manufacture, see barbiturates. 

White crystals, m.p. 191°C. A barbituric acid derivative. The sodium salt is administered orally as a sedative. 

CaH,3N02. White flaky or crystalline powder, m.p. 126-128°C. Used in (he treatment of barbiturate poisoning, by intravenous injection. 

It is the parent substance of a group of compounds which includes cytosine, thymine and uracil, which are constituents of nucleic acids and barbituric acid and its derivatives, which are important medicinally. 

Barbituric acid and 2-thiobarbituric acid are readily prepared by the condensation of diethylmalonate with urea and thiourea respectively, in the presence of sodium ethoxide. The use of substituted derivatives of urea and thiourea and of diethyl malonate will clearly lead to a wide range of barbituric and thiobarbituric acids having substituents in the i, 3, or 5 positions. 

Uramll (aminobarbituric acid) (III) may be prepared by the oxidation of barbituric acid (I) to nitrobarbiturlc acid (II), followed by reduction of the latter ... 

Ethyl malonate condenses with urea in the presence of sodium ethoxide to yield barbituric acid (malonylurea) ... 

Supplement 1936 3458-3793 Picrolonic acid, 51. Hydantoin, 242. Uracil, 312. Indigo, 416. Barbituric j acid, 467. Alloxan, 500. ... 

Urea derivadves are of general interest in medicinal chemistry. They may be obtained cither from urea itself (barbiturates, sec p. 306) or from amines and isocyanates. The latter are usually prepared from amines and phosgene under evolution of hydrogen chloride. Alkyl isocyanates are highly reactive in nucleophilic addidon reactions. Even amides, e.g. sulfonamides, are nucleophilic enough to produce urea derivatives. 

The nucleophilicity of the nitrogen atom survives in many different functional groups, although its basicity may be lost. Reactions of non-basic, but nucleophilic urea nitrogens provide, for example, an easy entry to sleeping-pills (barbiturates) as well as to stimulants (caffeine). The nitrogen atoms of imidazoles and indole anions are also nucleophilic and the NH protons can be easily substituted. 

Barbituric acid was first pre pared in 1864 by Adolf von Baeyer (page 112) A histori cal account of his work and the later development of barbiturates as sedative-hypnotics appeared in the October 1951 issue of the Journal of Chemical Education (pp 524-526)... 

Diethyl malonate has uses other than m the synthesis of carboxylic acids One particu larly valuable application lies m the preparation of barbituric acid by nucleophilic acyl substitution with urea... 

Barbituric acid is the parent of a group of compounds known as barbiturates The bar biturates are classified as sedative-hypnotic agents meaning that they decrease the responsiveness of the central nervous system and promote sleep Thousands of deriva lives of the parent ring system of barbituric acid have been tested for sedative-hypnotic activity the most useful are the 5 5 disubstituted derivatives... 

These compounds are prepared m a manner analogous to that of barbituric acid itself Diethyl malonate is alkylated twice then treated with urea... 

Barbituric acids as their name implies are weakly acidic and are converted to then-sodium salts (sodium barbiturates) m aqueous sodium hydroxide Sometimes the drug is dispensed m its neutral form sometimes the sodium salt is used The salt is designated by appending the word sodium to the name of the barbituric acid—pentobarbital sodium for example... 

The various barbiturates differ m the time required for the onset of sleep and m the duration of their effects All the barbiturates must be used only m strict accordance with instructions to avoid potentially lethal overdoses Drug dependence m some mdi viduals IS also a problem... 

Section 21 8 Alkylation of diethyl malonate followed by reaction with urea gives derivatives of barbituric acid called barbiturates, which are useful sleep promoting drugs... 

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