Patent GB-365135-A (GB)
Title: Improvements in and relating to the production of soluble salts of certain barbituric acids
Filed: 1930-08-16
Abstract: 5 : 5-Disubstituted barbituric acids, in which one substituent is a saturated secondary-aliphatic or cycloaliphatic radicle containing 4-7 carbon atoms and the other substituent is an ethyl or allyl group, are converted into their salts with an alkali metal, an alkaline-earth metal, ammonia or an organic base, by treating the acid dissolved in a solvent with the hydroxide or ethylate of the inorganic base or with ammonia or the organic base and evaporating to obtain the salt in solid form.  In the case of alkali metal salts, the solvent is water or water containing a small proportion of alcohol, whereas in the other cases water or an organic solvent such as alcohol may be employed.  The products possess enhanced therapeutic properties.  The salt components mentioned are sodium, potassium, lithium, ammonium, calcium, magnesium, mono- and di-methylamine and mono- and di-ethylamine. Examples are given of the preparation of ammonium sec-hexylethylbarbiturate and of the monomethylamine salt of cyclopentylethylbarbituric acid.  The salts of sec-butylethylbarbituric acid, sec-butylallylbarbituric acid and propylmethylcarbinyl-ethyl-barbituric acid are also referred to. Some of the acids which may be employed are not known and may be prepared either by interaction of the corresponding di-substituted malonic ester with urea, or by first forming the mono-substituted barbituric acid from the corresponding malonic ester and urea and then treating it with an alkyl bromide in the presence of alkali. The preparation of cyclopentylethylbarbituric acid, diethylcarbinyl-ethyl-barbituric acid, n-butylmethylcarbinyl-ethyl-barbituric acid and di-n-propylcarbinyl ethyl-barbituric acid is described by the first method, and of propylmethylcarbinyl-allyl-barbituric acid, diethylcarbinyl-allyl-barbituric acid and cyclopentylallylbarbituric acid by the second method.  The mono-substituted acids used in the second method are prepared by interaction of the corresponding mono-substituted malonic ester with urea, and examples are given of the preparation of propylmethylcarbinylbarbituric acid, diethylcarbinylbarbituric acid, and cyclopentylbarbituric acid. Specifications 122,778, [Class 2 (iii), Dyes &c.], and 364,041 are referred to.  The Specification as open to inspection under Sect. 91 (3) (a) describes also the preparation of alkali metal salts of the above-specified 5 : 5-disubstituted barbituric acids using solvents other than water or water containing a small proportion of alcohol, and includes examples of the production of the sodium salts of propylmethylcarbinyl-ethyl-barbituric acid and sec-butylallylbarbituric acid in alcoholic or substantially alcoholic solution.  This subject-matter does not appear in the Specification as accepted.  Malonic esters.--The di-substituted malonic esters used above are obtained by treating sodium ethyl-malonic ester with an aliphatic bromide.  The preparation is described of propylmethylcarbinyl-ethyl-malonic ester using 2-bromopentane, of diethylcarbinyl-ethyl-malonic ester using 3-bromopentane, of cyclopentylethylmalonic ester using cyclopentyl bromide, of n-butylmethylcarbinyl-ethyl-malonic ester using 2-bromohexane, and of di-n-propylcarbinyl-ethyl-malonic ester using 4-bromoheptane. The mono-substituted malonic esters are similarly prepared from sodium, malonic ester and an aliphatic bromide.  The preparation by this method of propylmethylcarbinyl-malonic ester using 2-bromopentane, of diethylcarbinyl-malonic ester using 3-bromopentane, and of cyclopentyl-malonic ester using cyclopentyl bromide, is described. Aliphatic bromides.--2-Bromopentane, 3-bromopentane, cyclopentyl bromide, 2-bromohexane and 4-bromoheptane are prepared by refluxing propylmethylcarbinol, diethylcarbinol, cyclopentanol, n-butylmethylcarbinol and di-n-propylcarbinol respectively with hydrobromic acid.  Reference has been directed by the Comptroller to Specifications 202,660, 244,122, and 271,837, [all in Class 2 (iii), Dyes &c.].