GB1377642A — Penicillanic and cephalosporanic acid derivatives

USPTO Abstract

1377642 Penicillins and cephalosporins KONINKLIJKE NEDERLANDSCHE GISTEN SPIRITUSFABRIEK NV 13 Jan 1972 [14 Jan 1971] 1960/71 Heading C2C [Also in Division C3] Novel penicillanic and cephalosporanic acid derivatives having the general Formulµ (I) and (II) and alkali metal, alkaline earth metal and amine salts thereof, wherein R is hydrogen, -OH or C 1 to C 4 alkanoyloxy, or the group -OH 2 R and -COOH in Formula II are linked to form a lactone group; R 1 and R 2 are the same or different and each is hydrogen, C 1 to C 4 alkyl, C 1 to C 4 alkoxy, C 5 to C 8 cycloalkyl, phenyl, phenoxy, chlorine or fluorine, or R 1 and R 2 together with the attached carbon atoms form a phenyl group or cycloalkylene group having at least one double bond, these groups optionally being substituted; R 3 is hydrogen, C 1 to C 4 alkyl, vinyl, allyl, C 5 to C 8 cycloalkyl, phenyl (C 1 to C 4 ) alkyl, or phenyl optionally substituted by one or more of C 1 to C 4 alkyl or alkoxy or chlorine; R 4 and R 5 are the same or different and each is hydrogen or C 1 to C 4 alkyl, or R 4 and R 5 together represent a keto oxygen; and n is zero or 1; are prepared by reacting an organo-metallic heterocyclic compound of Formula III wherein R 1 to R 5 are as before and X is a lithium atom or a magnesium chloride (-MgCl) or magnesium bromide (-MgBr) group, with an ester of 6-isocyanatopenicillanic acid or an ester or lactone of 7-isocyanatocephalosporanic acid, said acids having the Formulµ IV respectively, wherein R<SP>1</SP> is hydrogen, C 1-4 alkanoyloxy or a protected hydroxy group; and hydrolysing the resulting product to remove the metal atom and the esterifying group (and the hydroxy-protecting group if present). The organo-metallic compound (III) is prepared by reacting a compound of Formula III in which X is hydrogen with either (i) nbutyllithium, ethylmagnesium bromide or isopropylmagnesium chloride in an aprotic polar solvent (e.g. tetrahydrofuran) at - 40‹ to - 80‹ C.; or (ii) a complex of n-butyllithium and an N,N,N<SP>1</SP>,N<SP>1</SP>-tetrasubstituted alkylenediamine in a non-polar solvent (e.g. toluene). Pharmaceutical compositions having broad spectrum anti-bacterial activity comprise a penicillanic or cephalosporanic acid derivative of Formula I or II or an appropriate salt thereof, together with a pharmaceutically acceptable carrier.