GB1350238A - Cephalosporin derivatives - Google Patents

Abstract

1350238 Cephalosporins R & L MOLECULAR RESEARCH Ltd 19 April 1971 [13 March 1970 19 June 1970(2) 19 Aug 1970 (3)] 24062/71 Headings C2A and C2C Novel cephalosporins having the Formula I wherein A is acetoxy or pyridinium and M is hydrogen, a non-toxic cation, or anionic charge when A is pyridinium, and non-toxic acidaddition salts thereof, are prepared by acylating a corresponding 7-aminocephalosporanic acid with an acid of Formula II wherein the amino group has a conventional protective group, or with an N-acylating derivative thereof, in an inert organic solvent at - 20‹ C. to + 70‹ C. and subsequently removing the amino protective group, and if desired when A is acetoxy, converting the acetoxy group to a pyridinium group by a conventional method. Such conversion may be effected by reacting the 3-acetoxymethyl compound with pyridine in aqueous medium or by reacting the said compound with thiopicolinic acid and reacting the product of formula with a mercuric perchlorate-pyridine complex which probably has the formula (p-Aminomethylphenylthio) acetic acid is prepared by the following procedure: ethylphenylthioacetate, paraformaldehyde, anhydrous ZnCl 2 and chloroform are saturated with dry HCl and the chloromethylation product is hydrolysed with water to give ethyl (p-chloromethylphenylthio) acetate. This ester is hydrolysed with acetic acid/HCl to (p-chloromethylphenylthio) acetic acid which is reacted with concentrated ammonium hydroxide to give the title acid. An alternative procedure consists of reacting (phenylthio) acetic acid with N-methylolohloroacetamide in the presence of C.H 2 SO 4 , treating the resulting N-methylolchloroacetamidophenyl compound with c. HCl to hydrolyse the amide linkage and give the hydrochloride salt of the (aminomethylphenylthio) acetic acid which is brought to pH5 to give (p-aminomethylphenylthio) acetic acid. The amino group of the aforesaid acid is protected with either a p-nitrocarbobenzoxy group using p-nitrobenzylchloroformate, or a p-tertbutoxycarbonyl group using tert.-butoxycarbonyl azide. (o-Aminomethylphenylthio) acetic acid is prepared by reducing thiosalicylic acid with LiAlH 4 to the corresponding alcohol, o-mercaptobenzyl alcohol, converting the latter to methyl (o-hydroxymethylphenylthio) acetate by reaction with methyl chloroacetate in methanolic sodium methoxide, reacting the hydroxy compound with SOCl 2 to give methyl (o-chloromethylphenylthio) acetate which is hydrolysed to (o-chloromethylphenylthio) acetic acid with acetic acid/ HCl, followed by treatment with NH 4 OH to give the desired o-aminomethyl compound. The amino group of this compound is protected as described above for the p-aminomethyl analogue. (m-Aminomethylphenylthio) acetic acid is prepared via a corresponding series of reactions and intermediates starting from m-mercaptobenzoic acid. The amino group is subsequently protected as a m-tert.-butoxycarbonylamino group, by reaction with the above-mentioned azide. The inventive cephalosporins (I) and their non-toxic salts may be formed into antibacterially active pharmaceutical compositions together with a pharmaceutical carrier or diluent.