Patent GB-1382596-A (GB)
Title: Penicillin and cephalosporin compounds
IPC: C07D501/20
Filed: 1971-06-15
Abstract: 1382596 Penicillins and cephalosporins KONINKLIJKE NEDERLANDSCHE GISTEN SPIRITUSFABRIEK NV 15 June 1972 [15 June 1971] 28075/71 Headings C2C and C2P Penicillins and cephalosporins having the general Formulae (VII) and )VIII) and alkali metal, alkaline earth metal and amine salts, esters and imides thereof, wherein Q represents a penicillanic or cephalosporanic acid group of Formula (IX) or (X) in which Y is a hydrogen atom or a C 1-4  alkanoyloxy group; R 4  is a hydrogen atom, an optionally substituted C 1-4  alkyl or phenyl group, a C 1-4  alkoxy group, a benzyl group which may be substituted on the ring, an optionally substituted C 5-8  cycloalkyl group, a carboxy group or an esterified carboxy group; and R 5  is a phenyl group optionally substituted by one or more C 1-4  alkyl, C 1-4  alkoxy, di-(C 1-4  alkyl)- amino and nitro groups and halogen atoms or is a tertiary C 1-4  alkyl group or an adamantyl group, are prepared by reacting a compound of Formula (XI) or (XII) (wherein Y is as defined above; U is a hydroxy group, an imido group or a group -OF in which E is a radical easily replaceable by hydrogen to give a hydroxy group; and R 4 <SP>1</SP> has the same meaning as R 4  above except that any group reactive with a nitrile oxide is suitably protected) with a nitrile oxide of Formula (XIII): R 5 -C#N#O in an organic solvent medium, and if necessary subsequently removing any protecting group on the group R 4 <SP>1</SP> and/or U in the product, and if desired converting the penicillanic or cephalosporanic acid product into a salt or ester. Substituents present on the optionally substituted alkyl, phenyl, benzyl and cycloalkyl groups may be hydroxy, alkoxy, carboxy, esterified carboxy, halogen and dialkylamino. Instead of the nitrile oxide reactant there may be used a hydroxamoyl halide of Formula (XIV) (wherein Hal means halogen and R 5  is as defined above) in the presence of a tertiary amine. The compounds (XI) and (XII) above are novel. They are prepared by reacting a 6-isocyanatopenicillanic acid or 7-isocyanatocephalosporanic acid suitably protected at the carboxyl group, with an organometallic alkynyl compound of formula: R 4 <SP>11</SP>-C#C-X wherein R 4 <SP>11</SP> has the meaning of R 4  above except that any hydroxyl or carboxy group is protected, and X is Me<SP>I</SP> or Me<SP>II</SP>-hal, Me being a metal of valence 1 or 2 and hal being halogen; and subsequently treating the resulting organo-metallic compound to remove the atom Me<SP>I</SP> or the group Me<SP>II</SP>-hal. The compounds (VIII) and some of the compounds (VII) above are also novel. Of the compounds (VII), those wherein R 4  is C 1-4  alkyl, phenyl, benzyl or cycloalkyl and is substituted by one or more alkoxy, carboxy, esterified carboxy or di-(C 1-4  alkyl)amino, or R 4  is carboxy or esterified carboxy, and the compound 6 - [3 - (2,4,6 - trimethylphenyl) - 5 - methylisoxazol-4-yl-carbonamido] penicillanic acid and its salts, esters and imides, are specified as being novel. The compounds (VII) and (VIII) have antibacterial properties and in admixture with a pharmaceutical carrier may be used to provide pharmaceutical compositions. A complex salt of 1 mol 6-[3-(2,6-dichlorophenyl) - 5 - hydroxymethyl - isoxazole - 4 - ylcarbonamido] penicillanic acid and 1 mol hexamethylphosphontriamide, which is a compound of Formula (VII) above, is prepared by carrying out the preparative reaction of 6-[(3-hydroxypropyn - 1 - yl) - carbonamido] penicillanic acid with 2,6-dichlorobenzonitrile oxide in a mixture of ethyl acetate and hexamethylphosphontriamide.