Barbiturates, Methylated

The pseudo-barbiturate , 2-methyl-3-o-tolylquinazolin-4(3H)-one (methaqualone, Revonal 1017) has an even wider spectrum of activities than do the barbiturates proper it appears to be quite widely used as- a sedative, hypnotic, anticonvulsant, antispasmodic and local anaesthetic agent (63MI21301, b-75MI21301>. 

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). 

As expected, heterocyclic enols and potential enols (i.e, compounds existing mainly in the CH form) behave toward diazomethane similarly to the open chain and isocyclic enols, i.e. they form enol methyl ethers by reactions of the SnI type (cf. footnote 29). Examples of this behavior are barbituric acid, picrolonic acid, dchydroacetic acid (64), 3-methyl-l-phenylpyrazolin-5-one, 1-phenylpyrazoli-dine-3,5-dione, 1,2-diphenylpyrazolidine-3,5-dionc, 3-hydroxy-... 

In an interesting variation on this theme, the bis acid chloride of diethylmalonate (138) is condensed with the 0-methyl ether of urea to afford the imino ether of the barbituric acid (139). Heating this ether at 200°C results in 0 to N migration of the methyl group and formation of metharbital (140). ... 

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. 

The combined ether extracts were washed with 5% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and fractionally distilled in vacuo. The fraction boiling at about 145° to 150°C at the pressure of 0.5 mm of mercury, weighing 61 g and consisting of 1-methyl-5-allyl-5-(1-methyl-2-pentynyl) barbituric acid, was collected. The only distillate was substantially pure, and could be used as such In pharmaceutical preparation or a salt could be prepared therefrom according to the procedures disclosed hereinafter. On standing, the oil crystallized. The crystalline 1-methyl-5-allyl-5-( 1-methyl-2-pentynyl) barbituric acid melted at about 60° to 64°C after recrystallization from dilute ethanol. 

Preparation of Sodium 1-Methyl-5-Allyl-5-(1-Methyl-2-Pentynyl) Barbiturate A solution of 61 g of 1-methyl-5-allyl-5-(1-methyl-2-pentynyl) barbituric acid in 100 ml of ether was extracted with 465 ml of 2% aqueous sodium hydroxide solution. The aqueous extract was washed with successive 75 ml and 50 ml portions of ether. The pH of the aqueous solution was adjusted to 11.7, using 5% aqueous sodium hydroxide solution. 5 g of decolorizing carbon were added to the solution with stirring the mixture was permitted to stand for 20 minutes at room temperature, and the carbon was removed by filtration. A solution containing 4 g of sodium carbonate in 25 ml of water was added to the aqueous solution, and the mixture was filtered sterile through a porcelain filter candle of 02 porosity into sterile bottles. The aqueous solution was then dried from the frozen state, whereupon a sterile residue of sodium 1-methyl-5-allyl-5-(1-methyl-2-pentynyl) barbiturate, weighing about 62 g was obtained. 

Propyl-methyl-carbiny I barbituric acid Allyl bromide Sodium hydroxide... 

Propyl-methyl-carbinyl allyl barbituric acid (also called allyl 1-methyl-butyl barbituric acid) may be prepared as follows 1 mol of propyl-methyl-carbinyl barbituric acid is dissolved in a suitable vessel In a 10 to 35% aqueous solution of 1 mol of potassium hydroxide. To this are added somewhat in excess of 1 mol of allyl bromide, and alcohol equal to about 10% of the total volume of the solution. The vessel Is agitated for 50 to 75 hours. At the end of this time, the solution, which may still exhibit two layers, is concentrated to about one-half its volume to remove the excess allyl bromide and the alcohol. On cooling, an oily layer, which is propyl-methyl-carbinyl allyl barbituric acid, separates out as a sticky viscous mass. It is dried, washed with petroleum ether, and dissolved in the minimum amount of benzene. Any unreacted propyl-methyl-carbinyl barbituric acid, which does not dissolve, is filtered off. The addition of petroleum ether to the clear filtrate causes the propyl-methyl-carbinyl allyl barbituric acid to precipitate as an oily mass. 

One part by weight of propyl-methyl-carbinyl allyl barbituric acid is added to enough alcohol to facilitate handling, in this case conveniently about six times its weight. To this is added a solution of sodium hydroxide, preferably carbonate-free or substantially so, containing °%38 parts by weight of sodium hydroxide, which is the amount of sodium hydroxide necessary to combine in equal molecular proportions with the propyl-methyl-carbinyl allyl barbituric acid. This solution is filtered clear, and is then evaporated under vacuum until the sodium propyl-methyl-carbinyl allyl barbiturate (alternatively named sodium allyl 1-methyl-butyl barbiturate) separates out in solid form. The salt as thus obtained in solid form contains a varying amount of moisture. 

Sodium propyl-methyl-carbinyl allyl barbiturate is a white hygroscopic solid, readily soluble in water and alcohol, and insoluble In ether. 

Heating MethElute (Pierce 49300X) with drug-containing extracts from body fluids gives quantitative methylation of barbiturates, sedatives, and so on. Follow the procedure provided by Pierce Chemical Company using the MethElute reagent. 

Barbituric add 374 condenses at 125-145 °C with N,N-bis(trimethylsilyl)formamide 22 c in unspecified yield [137] to give 375, which is, however, also obtained, in quantitative yield, by heating free barbituric acid 374 in formamide for 1 h at 130°C [137a]. N-Ethylrhodanines 376 and 2-methyl-N-ethyl-benzothiazole tosylate 378 react with 22c to give the dimers 377 and 379 in 55 and 75% yields, respectively [137] (Scheme 4.51). 

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

Ethyl-5-phenyl-2,4,6(l//,3//,5//)-pyrimidinetrione synonym 5-ethyl-5-phenylbarbituric acid. 5-Ethyl-1-methyl-5-phenylbarbituric acid. 5-Ethyl-5-phenyldihydro-2-thioxo-4,6(lEf,5H)-pyrimidine-dione synonym 5-ethyl-5-phenyl-2-thiobarbituric acid. 5-Ethyl-5-hexyl-2-thiobarbituric acid. 5-Ethyl-5-isopentylbarbituric acid. 5-Ethyl-5-(l-methylbutyl)-2-thiobarbituric acid. 5-(l-Cyclo-hexen-l-yl)-l,5-dimethylbarbituric acid. 5-Ethyl-5-(l-methylbutyl)barbituric acid. 5-(l-Cyclohexen-l-yl)-5-ethylbarbituric acid. 

Methyl 2-benzoylamino-3-dimethylaminopropenoate reacts with barbituric acid or its 1,3-dimethyl derivative to give a pyranopyrimidine 118 (89JHC1273). 

The pharmacological activity of a series of 3,5,6-trialkyluracils was studied, considering them as analogues ofbarbitone, and it was found that they did possess sedative action. The 3,5-dibutyl-6-methyl derivative (XLVlll) was reported to be a comparatively potent sedative agent [372]. Partition coefficient and metabolic studies would be of interest in comparing such compounds with the barbiturates. 

---