Patent GB-604563-A (GB)
Title: Improvements in and relating to the purification of penicillin salts
IPC: C07D499/00
Filed: 1945-11-27
Abstract: Salts of penicillin of a high degree of purity are prepared by dissolving a crude metallic (preferably sodium or calcium) salt of penicillin (preferably of not less than 20 per cent purity) in water (preferably in such quantity as to give a concentration of about 1 per cent w/v.), acidifying (preferably to about pH 2.5) with a strong acid, and combining the liberated penicillin acid with one or more tertiary organic bases selected from N-alkylated piperidines, with or without one or more methyl groups as substituents on the carbon atoms of the ring, or N-alkylated pyrrolidines, with or without one or more methyl or ethyl groups (or both) as substituents on the carbon atoms of the ring, the total number of exocyclic carbon atoms in either case not exceeding 5.  Preferably, the free penicillin is extracted, before combination with the base, into a suitable solvent (i.e. one into which penicillin can be extracted readily from acidified aqueous solution and which is relatively inert to penicillin, and in which the tertiary base salts of penicillin are relatively insoluble), preferably so as to give a concentration of penicillin therein of 0.25-5 per cent w/v, and advantageously after adding to the aqueous solution a highly soluble neutral inorganic salt commonly used for salting out purposes, and there is added to the extract a suitable secondary solvent (capable of retaining the tertiary base salts of the impurities in solution).  As an alternative or in addition to adding the secondary solvent, the precipitate subsequently produced by the addition of at least (and usually considerably more than) one molar equivalent of the tertiary base or bases is washed with (or crystallized from) the secondary solvent or a mixture thereof with the first solvent, and may, if desired, be further purified by recrystallization from an organic solvent or mixture of solvents.  To obtain a metal salt of penicillin of a similar high degree of purity, an aqueous solution of the tertiary base salt is treated with a mineral acid, the liberated penicillin is extracted into an organic solvent, and there is added to the extract an aqueous solution or suspension of a metallic hydroxide.  In examples: (1) crude penicillin sodium or calcium salt is dissolved in ice-cold water with the addition of sodium chloride followed by ether and then by dilute phosphoric acid, the ether layer is separated the residue extracted with more ether, the combined ethered extracts filtered at -80 DEG C. and shaken with charcoal which is separated by filtration and eluted with ether, then acetone is added to the eluate, followed by a solution of N-ethyl-piperidine in ether, the precipitated salt is filtered off, washed with acetone, dried, and recrystallized if desired by dissolving in warm methylene chloride, adding acetone and then slowly adding carbon tetrachloride; the product may be converted into the pure sodium salt by dissolving it in ice-cold water, shaking with chloroform while adding dilute phosphoric acid, again extracting the aqueous layer with chloroform, neutralizing the combined extracts with aqueous sodium hydroxide, freeze-drying and crystallizing from acetone; (2) the ethereal solution obtained as in (1) is treated with N-n-propylpiperidine, either with the preliminary addition of acetone or with recrystallization of the precipitated salt therefrom; (3) crude penicillin calcium salt is treated as in (1) but using methyl isobutyl ketone instead of ether; (4) crude penicillin calcium salt is treated as in (1) but using methyl ethyl ketone as the secondary solvent and N-ethylhexahydro-a -picoline as the base; (5) the N-ethylpiperidine in (1) is replaced by N-ethylpyrrolidine.  Amyl acetate is additionally specified as a suitable first solvent, and sodium nitrate, sodium sulphate, ammonium sulphate, magnesium sulphate and potassium chloride as salting out agents.