Patent GB-1208014-A (GB)
Title: Cephalosporins
Inventor: LONG ALAN GIBSON
IPC: A61K31/545
Filed: 1967-03-23
Abstract: 1,208,014. Cephalosporins. GLAXO LABORATORIES Ltd. 12 March, 1968 [23 March, 1967], No. 13867/67. Headings C2A and C2C. [Also in Division A5] The invention comprises 7 - arylglyoxamido cephalosporanic acids of Formula I wherein Ar is an aromatic group (including a heterocyclic aromatic group e.g. pyridyl or thienyl) having an atomic weight of at least 78; a salt thereof and an α - carbonyl derivative thereof e.g. oxime, methoxime, hydrazone, semicarbazone, thiosemicarbazone and isonicotinoylhydrazone. Ar may be the group where R is NH 2 , substituted NH 2 , halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxycarbonyl, NO 2  or CN, n is 1 to 4, the groups R when n is greater than 1 being the same or different. Ar may be 1 - naphthyl or 2 - phenanthryl. Typical compounds are 7 - (p - dimethylaminophenylglyoxamido) cephalosporanic acid and 7 - (p - chlorophenylglyoxamido) cephalosporanic acid. The compounds are produced by acylating 7 - amino cephalosporanic acid with an aromatic glyoxylic acid Ar.CO.CO.COOH wherein Ar has the above meaning, or a reactive derivative thereof e.g. acid halide, reactive azide, anhydride or mixed acid anhydride with e.g. butyric, valeric, isovaleric, trifluoroacetic or pivalic acids. Salts are formed with the alkali and alkaline earth metals, organic bases e.g. procaine, acids (where Ar contains a basic group) and resins e.g. a polystyrene resin containing amino, quarternary amino or sulphonic acid groups or a resin containing carboxyl groups e.g. a polyacrylic acid resin. 5 - chloro - 2 - methoxy - 4 - methylphenylglyoxylic acid is prepared by reacting 2 - chloro - 5 - methoxy toluene with ethyl oxalyl chloride in the presence of aluminium chloride, followed by treatment with hydrochloric acid and hydrolysis with NaOH to remove the ester group. m - iodophenylglyoxylic acid is prepared by nitrating acetophenone to produce m - nitroacetophenone, subjecting m - nitroacetophenone to reduction, diazotization and treatment with potassium iodide to give m - iodoacetophenone, and treating m - iodoacetophenone with KMnO 4  and KOH, followed by acidification with hydrochloric acid. 4 - chloro - 3 - nitrophenyl glyoxylic acid is produced by reacting 4 - chloro - 3 - nitrobenzaldehyde with sodium metabisulphite and sodium cyanide to give 4 - chloro - 3 - nitromandelic acid, esterifying the 4 - chloro - 3 - nitromandelic acid with CH 3 OH and H 2 SO 4  and treating the resultant methyl ester with lead tetra acetate and then with NaOH followed by acidification. o - Bromophenylglyoxylic acid is produced by the diazotization of isatin and the addition of the resultant diazonium salt to a boiling mixture of CuSO 4 , copper, NaBr, H 2 SO 4  and water. p - Formamidophenylglyoxylic acid is prepared by reducing p - nitrophenylglyoxylic acid with ferrous sulphate in aqueous NH 4 OH to give p aminophenylglyoxylic acid, which is then treated with dry formic acid and acetic anhydride. α - methoximinophenylacetyl chloride is prepared by reacting phenylglyoxylic acid with methoxyammonium chloride previously treated with potassium acetate in methanol to form α - methoximinophenylacetic acid which is then treated with thionyl chloride. The cephalosporins are active antibiotics which may be administered orally (see Division A5). Specification 1,104,937 is referred to.