Diethyl malonate barbiturates from

Beryllium, calcium, boron, and aluminum act in a similar manner. Malonic acid is made from monochloroacetic acid by reaction with potassium cyanide followed by hydrolysis. The acid and the intermediate cyanoacetic acid are used for the synthesis of polymethine dyes, synthetic caffeine, and for the manufacture of diethyl malonate, which is used in the synthesis of barbiturates. Most metals dissolve in aqueous potassium cyanide solutions in the presence of oxygen to form complex cyanides (see Coordination compounds). 

Another Methodfor 5 5-Diethyl Barbituric Acid. (This is a scaled down version.) 16 g of clean sodium is dissolved in 300 g of absolute ethanol. To this cooled solution is added 20 g of dry urea and 50 g of diethyl malonic ester (diethyl diethyl malonate). The mixture is heated in an autoclave (pressure cooker, very strong) for 4 to 5 hours at 100-110°. After removing from the autoclave, the mixture is cooled. Upon cooling, the sodium salt of diethyl barbituric acid separates, is filtered off, dissolved in water, and the free acid precipitated by the addition of hydrochloric acid. The acid is filtered and recrystallized from water, using decolorizing carbon, if necessary. Yield Depends on your ability to exclude H2O from the beginning of reaction. 

Barbituric acid, usually represented as the trione (1014 R1 = R2 = H), was first made about 1864 and it has no hypnotic properties. It may be made conveniently from diethyl malonate and urea in ethanolic sodium ethoxide <43OSC(2)60) and it does have a variety of biological properties without much practical use (71MI21301). The origin of the name is lost, although there are several plausible explanations associated with St. Barbara s feast day, a favourite Miinchen Kellnerin rejoicing in that given name, and even the Latin barba which is a beard or the business end of a key. 

Most barbiturates are made from diethyl malonate. The methylene protons between the two carbonyl groups are acidic and will give a highly stabilized enolate anion. 

Heterocycles. Base-catalyzed condensation of urea with diethyl oxalate gives parabanic acid (Murray ) condensation with diethyl malonate gives barbituric acid (Dickey and Gray ). The first procedure uses a solution prepared from sodium... 

Problem 16.51 Barbiturates are sedative-hypnotic varieties of 5,5-dialkyl substituted barbituric acids. Write the reaction for the formation of Veronal (5,5-diethylbarbituric acid) from the condensation of urea with diethyl-malonic ester. [See Problem 17.11(a)]. 

Diesters are malonates. Barbiturates are often made from substituted malonates by this route. Thus the reaction between diethyl fluoromalonate and (V-methylurea gave 5-fluoro-l-methyl-2,4,6(l//,3//,5//)-pyrimidinetrione (569) <84CL1573>. 

Dieckmann cyclization of, 835 Diethyl malonate acidity of, 842 barbiturates from, 845-846 enolate... 

Diesters also react smoothly with the urea derivatives, which undergo displacement of the alkoxy groups to create amide bonds. Barbituric acid can be made this way by reaction of diethyl malonate (9.122, R=R =H) with urea (Scheme 9.64). An important family of pharmaceutical agents results from the use of substituted malonic esters. Thus, with a phenyl and an ethyl substituent the important hypnotic agent, phenobarbital (9.123) is produced. Veronal, which is another important hypnotic, is prepared from diethyl-substituted malonates. 

The synthesis of barbituric acid can be best accomplished from diethyl malonate and urea, with an alkaline catalyst, such as sodium ethoxide in ethanol [113]. Barbituric acid-2- C has been prepared from urea- C and diethyl malonate [114]. The 4- C and 5- C compounds have been obtained by the pyrolysis of diethyl oxalacetate-3- C, which produced an equimolar mixture of 4- and 5- C barbituric acid after a rather lengthy procedure [115]. 

Barbiturates are prepared by treating a derivative of diethyl malonate with urea in the presence of sodium ethoxide as a catalyst. Following is an equation for the preparation of barbital, a long-duration hypnotic and sedative, from diethyl diethylmalonate and urea. 

Aprobarbital, a barbiturate once used in treating insomnia, is synthesized in three steps from diethyl malonate. Show how you wouid synthesize the necessary dialkylated intermediate, and then propose a mechanism for the reaction of that intermediate with urea to give aprobarbitai. 

Further labeled pyrimidines such as [2- C]barbituric acid (22, R, R = H) and its derivatives such as [2- C]barbital (22 R R = Et), and [2- C]pentobarbital (22 R = Et, R = 1-methylbutyl) are readily available from cyclocondensation of [ CJurea and the respective diethyl malonates in the presence of sodium ethoxide or butoxide. For phenobarbital (R = Et, R = Phe), decarboxylation of the malonate component was observed as a main side reaction, so that the respective malonyl dichloride had to be employed in order to achieve satisfactory yields. Analogous syntheses using unlabeled urea and labeled malonate derivatives are described in Chapter 6, Section 6.5. 

Many derivatives of barbituric acid with certain substituents at C-5, which are made by using C-substituted malonates, are very useful as hypnotics. The most famous is phenobarbital (4.24), whieh has been used clinically for many years. This compound can be made from diethyl ethylphenylmalonate (Scheme 4.23). 

Epilepsy is a disease that is characterized by recurring convulsive seizures. Phenobarbital, 58, possess specific usefulness in epilepsy. In general, barbituric acid derivatives are synthesized from phenylethyl-malonic diethyl ester [8]. 

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