Barbituric acid hydrolysis

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). 

Bromocresol green (3.8...5.4) aliphatic carboxylic acids[103,187 — 204] triiodobenzoic acid [205], derivatives of barbituric acid [206] amphetamine derivatives [207, 208] phenazones, morazone [209] alkaloids [91, 209] nephopam [210] phenyramidol metabolites [211] diethylalkylacetamide derivatives [212] zipeprol (Mirsol) [213] thalidomide and hydrolysis products [214] cyclohexylamine derivatives [215] herbicide residues [216]... 

It is, however, more likely that the discrepancies observed in the periodate oxidation of malonaldehyde concern mainly the hydroxylation step. In the mechanism proposed (5) for this reaction, it is the enol form of malonaldehyde which is hydroxylated. However, titrations of a solution of malonaldehyde, prepared by hydrolysis of an aqueous solution (33) of carefully distilled 1, 3, 3-tri-ethoxypropene (46, 47), both with strong base and with iodine, indicate that only about 80% of the enol form is present in the equilibrium solution. On the other hand, the thio-barbituric acid test (58, 59) gave consistently higher values for the malonaldehyde content of the solution. The fact that only about 80% of the enol form is present in the equilibrium solution is all the more important as it can be shown (56) by titration with strong base that the enolization is slow, and moreover does not seem to go to completion. 

The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. 

Six-membered ring heterocycles 708 are obtained in the reaction of carbodiimides with malonyl chloride. Hydrolysis of the dichlorodihydropyrimidine-diones affords barbituric acid derivatives. ... 

Stxlium salts of the barbiturates are readily prepared and are water soluble. Their aqueous. solutions generate an alkaline pH. A classic incompatibility is the addition of an agent with an acidic pH in solution, which rc.sults in formation and precipitation of the free water-insoluble disubsliluied barbituric acid. Sodium salts of barbiturates in aqueous solution decompose at varying rates by base-catalyzed hydrolysis, generating ring-opened sails of carboxylic acids. 

Kinetic studies showed that undissociated and monoanionic barbiturate acid hydrolyzed with different pseudo-first-order rates at constant pH 308,3i i,3i s.319-337 -pjje jQg pjj profiles for hydrolysis of barbiturates in neutral and alkaline media indicate that degradation takes place by hydroxide ion attack on the undissociated and monoanion species or by the kinetically equivalent attack of water on the mono- and dianion forms.319,326,329-331,338... 

Several authors pointed out that this relatively simple kinetic model is complicated by some reversible processes. Eriksson presented kinetic evidence for the reversible reaction between the undissociated form of barbiturates and its tetrahedral hydroxide ion complex.339-341 The existence of mono-, di-, and trianionic tetrahedral addition intermediates formed from the monoanionic form of barbituric acid in alkaline medium has been postulated by Khan and Khan.336 Garrett et al. demonstrated, a reversible reaction between the product of hydrolysis 120 and the parent barbiturate 119 in the case of barbital.329 This finding was confirmed342 and also demonstrated for other barbiturates.308,315,330 Reversible reactions have been shown to exist in the hydrolysis of tetrasubstituted barbiturates.314,343 Leslie reported a biexponential degradation rate of 1,3-dimethylphenobarbital in 0.02-0.32 M KOH, but at lower and higher OH- concentrations it approached first-order kinetics.315... 

For 1,3,5,5-tetrasubstituted barbiturates the 1-6 versus 1-2 or 3-4 ring opening depends on the nature of the substituents and on hydrolysis conditions.312,313,354 2-Thiobarbiturates are less stable than their 2-oxo analogs in an alkaline medium.304,329,355,356 The barbituric acid ring is quite stable in an acidic medium (undissociated molecule)4 and the only barbiturates whose ring opens under these conditions are 5-allyl-5-(2 -hydroxypropyl)barbituric acid (proxibarbal)357-359 and l-benzoyl-5-ethyl-5-phenylbarbituric acid (benzonal).353... 

During the photolysis of barbiturates with a-branched substituents at C-5, the ring-opening reaction is accompanied by dealkylation of these substituents.383-387 The elimination of the allyl group has also been observed in the case of photolysis of 5-allyl-5-(r-methylbutyl)barbituric acid.387 On the other hand, comparative studies on hydrolysis and photolysis of 5-allyl-5-(2 -hydroxypropyl)barbituric acid showed only an increase of the rate of hydrolysis by UV light with no differences in the isolated products.359,388... 

The Hammett-type correlation for the rate constants of 5-allyl-5-R-barbiturates has been reported by Carstensen et al. and suggested for use in stability predictions.569 Similar correlations were also found for the hydrolysis of 5-arylidenebarbituric acids.363,567 Linear free energy relationships have also been reported for dissociation constants,45,51 polarographic half-wave potentials,570 fluorescence70 and luminescence phenomena,71 and 13C-NMR chemical shifts129 for different classes of barbituric acid derivatives. Application of the dual substituent parameters method in LFER analysis of barbiturates, using Taft s polar and steric constants for various chemical and physicochemical properties, was also evaluated.571... 

Barton, H., Mokrosz, J., Bojarski, J., and Klimczak, M. (1980) Photochemical degradation of barbituric acid derivatives. I. Products of photolysis and hydrolysis of pentobarbital, Pharmazie, 35, 155-158. 

Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive. Barbituric acids such as barbital, phenobarbital, amobarbital, and metharbital undergo ring-opening hydrolysis, as shown in Scheme 15.80-81 Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation. The hydrolysis rates of these substances depend on the substituents Ri, R2, and R3. For some allylbarbituric acids, the effects of these substituents on hydrolysis rates can be explained in terms of Hammett s o value.82... 

The cyanopyridine cation is obtained by the addition of chlorocyane to pyridine. During its hydrolysis, the pyridine ring is opened, forming gluta-cone aldehyde 0CH-CH=CH-CH2-CH0. This reacts with barbituric acid to form a colour whose intensity is proportional to the hydrogen cyanide concentration [18]. 

Methylphenobarbital can also be prepared by the interaction of ethylphenyl malonie ester and dicyandiamide when it results into the formation of 5-ethyl-5-phenyl-3-cyano barbituric acid, which on methylation with dimethyl sulphate yields 5-ethyl-5-phenyl-3-cyano-1-methyl barbituric acid. This on acid hydrolysis converts the cyano moiety at position 3 into a free COOH group which on decarboxylation finally gives methylphenobarbital. 

Paluchowska M, Ekiert L, Jochym K and Bojarski J, Hydrolysis of barbituric acid derivatives. Part V. Hydrolysis of l-benzoyl-5-ett yl-5-phenylbarbituric add, Pol. f. Chem., (7-8-9), 799-807 (1983) CA 102,5311m, 1985. 

Siegmund Gabriel (Berlin ii November 1851-22 March 1924), professor in Berlin, synthesised isoquinoline, discovered a preparation of primary amines by the action of potassium phthalimide on halides and acid hydrolysis of the resulting ester of phthalylglycocoll, synthesised pyrrolidine from S-chlorobutylamine and piperidine from co-chloramylamine, pyrimidine from barbituric acid, and quinazoline. ... 

Another enzyme, barbiturase, which catalyzed the hydrolysis of barbituric acid to urea and malonic acid (Fig. 13), has been partially purified and freed of urease activity. The mechanism involved in this reaction has not yet been established. It seems most plausible that the initial cleavage would yield a half ureide of malonic acid, since it is not likely that a single enzyme could simultaneously cleave two linkages in the same molecule. So far there has been no evidence to support the formation of a half ureide of malonic acid. 

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