Barbituric acid and barbiturates

The terms barbituric acid and barbiturates are used interchangeably for a general description of derivatives of 1, while the subclasses and individual compounds are named according to the mode of substitution, e.g., 5,5-dialkylbarbituric acids (2) or 5-ethyl-l-methyl-5-phenylbarbituric acid (3). 

Barbituric acid and barbiturates can be synthesised by reacting a malonate with a urea, " or a bis primary amide of a snbstitnted malonic acid with diethyl carbonate. ... 

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. 

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... 

Reaction of chloroacetic acid with cyanide ion yields cyanoacetic acid [372-09-8] C2H2NO2, (8) which is used in the formation of coumarin, malonic acid and esters, and barbiturates. Reaction of chloroacetic acid with hydroxide results in the formation of glycoUc acid [79-14-1]. 

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). 

Alloxan forms an oxime (1007) which is the same compound, violuric acid, as that formed by nitrosation of barbituric acid likewise, a hydrazone and semicarbazone. Reduction of alloxan gives first alloxantin, usually formulated as (1008), and then dialuric acid (1004 R = OH) the steps are reversible on oxidation. Vigorous oxidation with nitric acid and alkaline hydrolysis both give imidazole derivatives (parabanic acid and alloxanic acid, respectively) and thence aliphatic products. Alloxan and o-phenylenediamine give the benzopteridine, alloxazine (1009) (61MI21300). 

The rather low values for the methylene groups of barbituric acid and its 2-thio derivative indicated a particularly easy adduct formation (84) which proceeds in water in excellent yield. 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

Preparation of 1-Methyl-5-Allyl-5-( 1-Methyl-2-Pentynyl) Barbituric Acid A solution of 23.8 g of sodium in 360 ml of absolute alcohol was prepared and thereto were added 38.3 g of methyl urea and 96.8 g of diethyl allyl (1-methyl-2-pentynyl) malonate. The mixture was refluxed for about 20 hours, cooled, and the ethanol was removed by distillation in vacuo. The residue was dissolved in about 300 ml of water and the aqueous solution was washed with ether, and the washings were discarded. The aqueous solution was then acidified with acetic acid, and extracted with three 150 ml of portions of ether. 

Parts of diallyl-barbituric acid are added to a precooled mixture of 1 5.5 parts of concentrated sulfuric acid and 0.5 part of water while stirring intensively, the mixture being cooled so that its temperature does not exceed 25°C. The honey-colored viscous solution Is stirred vigorously and all at once into 45 parts of water, whereupon the mixture warms up to 35°C to 40°C and, after several seconds, solidifies into a thick pulp, which Is then heated as quickly as possible to 95°C, at which temperature a clear solution Is formed. This is cooled slowly until the 5-allyl-5-((3-hydroxypropyl)-barbituric acid begins to form coarse-grained crystals, after which the mass is cooled rapidly to 20°C. 

The ureides hydantoin, parabanic acid, alloxan, barbituric acid, and 4-methyluracil show resonance energies of between 2.3 v.e. and 3.1... 

Charney et al. (2001), Harvey (1985), Matthew (1971), and Wesson and Smith (1977) have discussed the pharmacology of barbiturates. Barbiturates are derived from barbituric acid, which is the product of the fusion of malonic acid and urea. Barbituric acid lacks CNS activity. The two main classes of barbiturates are the highly lipid-soluble thiobarbiturates, in which sulfur replaces oxygen at the second carbon atom of the barbituric acid ring, and the less soluble oxybarbiturates, with oxygen at the second carbon atom (Table 3-3). Highly lipid-soluble barbiturates have a more rapid onset, a short duration of action, and greater potency than those with lower lipid solubility. 

Allopurinol, barbiturates, carbamazepine, cephalosporins, cyclophosphamide, ethambutol, fluconazole, ibuprofen, lamotrigine, macrolides, nitrofurantoin, penicillins, phenytoin, propranolol, quinolones, sulfonamide antimicrobials, sulindac, tetracyclines, thiazides, valproic acid, and vancomycin... 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

Cyanide content was controlled using argentometer and spectrophotometer with barbituric acid and pyridine by means of optimized method [6],... 

A reaction known as diazo group transfer produces diazo barbituric acid from barbituric acid and p-toluene sulfonyl azide. Additional barbituric acid affords azo barbituric acid [7]. Subsequent complexation with a nickel (II) salt yields a greenish yellow pigment. 

In another process [20] phthalonitrile, dissolved in an alcohol is reacted with a base and, without isolating, condensed with barbituric acid in a mixture of formic acid and water. 

Food (soybean and soybean products) Sample mixed with water, lead nitrate, tartaric acid, and anti-forming agent acidification and distillation treatment of distillate with pyridine-barbituric acid Spectrophotometry (total cyanide) No data 32-80 Honig et al. 1983... 

A collaborative study conducted by Britton et al. (1984) to determine the most reliable method among the three most commonly used methods (two colorimetric methods and the specific ion electrode method) showed that both pyridine-barbituric acid and pyridine-pyrazolone have similar statistical accuracy. The pyridine-barbituric acid method was preferred by Britton et al. (1984) over the pyridine-pyrazolone method for its convenience (quicker analysis time) rather than the statistical accuracy of data. The electrode method had higher data variability. 

Several new thenal and thenylbarbituric acids were synthesized in the authors laboratory. The 5-ethyl-5-(2-thenyJ)barbituric acid and the thioanalog (5-ethyl-5-(2-thenyl)-2-thiobarbituric) acid showed some activity as hypnotics. However, hyperexcitability and convulsions accompanied the hypnotic effect (62). 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

Water-based green protocol under conventional heating was used in another publication [112] to carry out three-component treatment between 3-substimted 5-aminopyrazoles, barbituric acids, and several isatines. The reaction gave up required spiroheterocycles 77 in excellent yields and purity (Scheme 33). 

The detailed study of the MCRs involving barbituric acids and 5-aminopyrazoles was published by Muravyova et al. [58]. The article describes the development of chemoselective cyclocondensations with help of microwave and ultrasonic irradiation. It was established that the temperature was the main factor in controlling the direction of the MCRs studied. 

S2S. Street, H. V., Gas-liquid chromatography of submicrogram amounts of drugs. IV. Identification of barbiturates, hydantoins, amides, imides, carbamates, phenylbutazone, carboxylic acids and hydrazine derivatives by direct derivative fonnation within the gas chromatograph. J. Chromaiogr. 41, 358-366 (1969). 

Barbiturates are derivatives of barbituric acid and are synthesized by condensation of malonic acid derivatives with urea derivatives. 

Under analogous conditions, the 3-cyanomethylene-2-indolones 213 react with barbituric acid and its derivatives 191 with the formation of spiro-annulated pyranopyrimidines 223 (88JIC202, 90H(31)31)... 

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