Preparation of Barbituric Acid

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... 

This reaction is often used to prepare urea derivatives, an important example being the preparation of barbituric acid ... 

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

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

The discovery of the sedative/hynoptic activity of derivatives of barbituric acid has led to very extensive dissections of that molecule. One outcome of this work is the realization that acylurea and acylamide derivatives often exhibit CNS depressant activity. A fair number of such molecules have been prepared that contain a succinimide or glutarimide pharmacophore. For example, Michael addition of cyanide to the stereochemically xmdefined cinnamate... 

The preparation of barbiturates illustrates many of the synthetic methods covered in this chapter. The preparation employs the reaction of urea (C0(NH2)2) with malonic ester to form barbituric acid. The general reaction is presented in Figure 15-30. The stable pyrimidine and other resonance forms help drive the reaction. By alternating the substituent at carbon number five (C5), various pharmacologically active substances can be formed. Barbital, a sedative, and phenobarbital, a sleeping aid, are shown in Figure 15-31. 

Nitrobarbituric acid has been prepared by oxidation of vio-luric acid,1 and by treatment of barbituric acid with fuming nitric acid.2... 

The submitters report that a single attempt to use the aqueous-alcoholic solution of barbituric acid obtained in Org. Syn. 18, 8, before recrystallization of the product gave an excellent yield of an apparently isomeric product unsuited for the preparation of alloxan. 

For the preparation of derivatives on a micro scale (at the microgram and picogram levels) reaction with methyl iodide was recommended [510] 100—200 /il of an acetone solution of barbituric acids was mixed with a 3- to 1000-fold molar excess of methyl iodide and refluxed with 3—5 mg of potassium carbonate. After about 30 min, 0.2 /A of the supernatant was injected directly into a column with 3% of OV-225, with temperature programming at 8°C/min from 100 to 240°C. The advantage of the method is that no toxic and hazardous chemicals are used. The method was further modified for the micro-determination of barbiturates in blood [511]. Only 20-25 /d of blood were necessary for the determination, and with the use of a detector sensitive to nitrogen down to 1 ng of barbiturate could be determined in this sample. The derivatization reaction was performed in a micro-refluxer (see Fig. 2.6). 

The chemistry of barbituric acid and its derivatives has been studied for over 100 years if we consider 1864, the year the parent compound of this class was prepared by von Baeyer,1 as its starting point. In 1903 the therapeutic... 

Prepared by Adolf Von Baeyer (1835-1917) as early as 1864, barbituric acid was not used before 1903, at that time Emil Fischer (1852-1919) had already prepared the first derivative of barbituric acid, one of which, diethylmalonylurea, would be marketed under the trade... 

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