IE33334L - Penicillin salts - Google Patents

Abstract

1,261,648. Crystalline alkali metal salts of α- carboxybenzyl-penicillin; penicillins and phenyl malonic acid derivatives. PFIZER Inc. 10 April, 1969 [17 Oct., 1968; 4 March, 1969], No. 18574/69. Headings C2A and C2C. Crystalline alkali metal salts of α-carboxybenzyl-penicillin are prepared by admixing a solution of α-carboxybenzylpenicillin (in a solvent selected from ethyl acetate, n-butanol, methylethyl ketone or methyl isobutylketone; the solution containing from 3 to 20% by weight of water) with an alkali metal compound selected from (a) an alkali metal salt of an organic acid selected from 2-ethyl hexanoic, caproic, oleic, ascorbic, glycolic, propionic, acetic, succinic, cinnamic, caprylic and nitric acids; (b) an alkali metal hydroxide; and (c) an alkali metal methoxide, wherein the alkali metal is sodium or potassium, and the product is isolated. The mono- or di-alkali metal salt may be prepared by employing a molar ratio of about 1 : 1 or at least 2 : 1 respectively of an alkali metal salt of group (a) to α-carboxybenzylpenicillin. The alkali metal salt of 2-ethyl hexanoic acid may be used in a solvent selected from acetone, ethyl acetate, n-butanol and isopropanol. A crystalline alkali metal salt of α-carboxy-benzylpenicillin may be prepared by (a) adjusting the pH of an aqueous alkaline solution of α-carboxybenzylpenicillin to 2 to 3À5; (b) extracting the acid solution thus produced with a waterimmiscible organic solvent selected from ethylacetate, n-butanol, methylethyl ketone and methyl isobutyl ketone; (c) back-extracting the water-immiscible organic solvent extract with water at pH 6À5 to 8À0; (d) adjusting the pH of the aqueous extract thus produced to a value of from 2 to 3À5; (e) extracting the aqueous acid solution thus produced with a water-immiscible organic solvent selected from n-butanol and methyl isobutyl ketone; (f) drying the water-immiscible organic solvent extract to a water content of from 3 to 20% by weight; (g) admixing the dried extract with an alkali metal 2-ethyl hexanoate; and (h) separating the crystalline alkali metal salt. α-Carboxybenzylpenicillin phenyl ester is prepared by reacting 6-aminopenicillanic acid with phenylmalonyl chloride monophenyl ester; and its N-ethyl piperidine salt is prepared by reaction with N-ethyl piperidine. Phenylmalonic acid monophenyl ester is prepared by reacting phenylmalonic acid with phosphorous oxychloride and phenol. Phenylmalonyl chloride monophenyl ester is prepared by reacting phenylmalonic acid monophenyl ester with thionyl chloride. [GB1261648A]