Patent GB-614581-A (GB)
Title: Improvements in or relating to the preparation of penicillin salts of alkali and alkaline earth metals
IPC: C07D499/16
Filed: 1946-07-15
Abstract: Penicillin salts of alkali and alkaline-earth metals (the latter including magnesium) are manufactured by reacting penicillin dissolved in a substantially anhydrous organic solvent (e.g. an ester, ketone, halogenated hydrocarbon, ether, cyclic ether, alcohol, ether alcohol, nitrile, hydrocarbon or keto-ester) with an alkali or alkaline-earth metal organic compound of one of the following kinds: salts of organic carboxylic acids, alcoholates, phenolates or especially derivatives of organic compounds containing at least one activated hydrogen atom attached to a carbon atom (such as compounds having a malonic ester, b -keto-ester, 1 : 3-cyano-carbalkoxy, 1 : 3-cyano-carbonyl or 1 : 3-dicarbonyl structure), which compound is preferably employed in stoichiometric amount and may be added in the dry form or in solution or suspension in an anhydrous organic solvent.  The resulting penicillin salt may be insoluble in the reaction medium, in which event it is separated by filtration, or it may be soluble, in which case it may be precipitated by the addition of a second solvent in which it has a low solubility or may be recovered by concentrating or drying the solution.  When necessary, the initial solution of penicillin in an organic solvent is submitted to a drying treatment, e.g. by the use of a drying agent such as anhydrous sodium sulphate or by removal of water by azeotropic distillation or by freezing.  If sterile penicillin salts are required, the process is carried out under aseptic conditions and with sterile reactants.  The following specific materials are mentioned as suitable, with examples of the use of a number of them: organic solvents for penicillin: ethyl, butyl, isopropyl, amyl and benzyl acetate, ethyl butyrate, benzoate and furoate, diethyl malonate, acetone, cyclohexanone, cyclopentanone, ethyl- and isobutylmethyl ketone, diethyl ketone, acetophenone, chloroform, carbon tetrachloride, ethylene dichloride, chlorobenzene, ethyl bromide, diethyl, dibutyl and di-isopropyl ether, dioxane, tetrahydrofurane, isopropyl, amyl, butyl and tetrahydrofurfuryl alcohol, cyclohexanol, cyclopentanol, acetonitrile, benzonitrile, propionitrile, benzene, toluene, xylene, cyclohexane, ethyl and butyl acetoacetate, 2-carbethoxycyclohexanone-1,2-carbethoxycyclopentanone-1 and levulinic acid methyl and ethyl esters; metal organic compounds: calcium oleate and barium linoleate (e.g. in ether), sodium butoxide (e.g. in butyl alcohol or cyclohexanol), sodium isopropoxide (e.g. in isopropyl alcohol or butyl acetate), potassium isopropoxide (e.g. in isopropyl alcohol), sodium and potassium benzyloxides, the corresponding cyclohexanol derivatives, sodium phenolate (e.g. in butyl acetate or acetone), sodium guaiacolate, sodium b -naphthoxide, potassium phenolate (e.g. in butyl alcohol), alkali and alkaline-earth metal compounds of salicylic acid esters, calcium diethyl malonate (e.g. in diethyl malonate, butyl or amyl acetate, methyl-isopropyl ketone or cyclohexanol), sodium diethyl malonate (e.g. dry or in diethyl malonate, butyl or isopropyl acetate, methyl - isopropyl ketone or cyclohexanol), potassium diethyl malonate (e.g. in diethyl malonate or amyl acetate), magnesium diethyl malonate (e.g. in diethyl malonate, butyl acetate, methyl-isopropyl ketone, cyclohexanol or toluene), lithium diethyl malonate (e.g. in butyl acetate), sodium and calcium ethyl acetoacetate (e.g. in ethyl acetoacetate, butyl acetate, chloroform, ether or benzene), strontium and lithium ethyl acetoacetate (e.g. in ethyl p  acetoacetate), sodium acetylacetone (e.g. in acetylacetone, butyl acetate or chloroform), calcium acetylacetone (e.g. in amyl acetate), sodium and potassium 2 - carbethoxycyclo - hexanone-1 (e.g. in butyl acetate), potassium 2-carbethoxycyclopentanone-1 (e.g. in methylisobutyl ketone) and alkali and alkaline-earth metal compounds of malonic acid dimethyl ester or dibutyl or higher esters, of esters of mono-substituted (e.g. methyl or ethyl) malonic acids, of esters of a - and g -methyl-and a  : g -dimethylacetoacetic acids, of esters of cyanoacetic, a -cyanopropionic and cyanosuccinic acids, and of 2 - cyanocyclohexanone - 1,2 - cyanocyclopentanone - 1, a  - cyanoacetophenone, a  - cyano - acetone, cyclohexane - 1 : 3 - dione, a - and g -methyl - acetylacetone and benzoylacetone. Reference is also made to the preparation of barium salts of penicillin.