GB1377817A - Penicillins and cephalosporins - Google Patents

Abstract

1377817 Penicillins and cephalosporins BEECHAM GROUP Ltd 23 June 1972 [9 June 1971] 29431/72 Divided out of 1364672 Heading C2C Novel compounds of Formula I wherein X and Y are the same or different and each represents oxygen or sulphur; Z represents a straight or branched, saturated or unsaturated, divalent hydrocarbon radical having from 1 to 7 carbon atoms, in which any two adjacent carbon atoms are joined in a carbocyclic ring system which may carry one or more substituents; R represents hydrogen, or an alkyl, alkenyl, alkynyl, aryl or aralkyl group, or a functional substituent; A represents a group of Formula II or III wherein B represents hydrogen, an acetoxy group and R<SP>1</SP> is an organic acylamino group, a group of Formula IV or a group of Formula V wherein R<SP>2</SP> and R<SP>3</SP> each represent a C 1-7 alkyl group, or R<SP>2</SP> and R<SP>3</SP> taken together with the nitrogen atom to which they are attached form a monocyclic ring provided that when A is of Formula II, R<SP>1</SP> is not D( - )-α-aminophenylacetamido when R is H, X and Y are both oxygen and Z is a 1,2-phenylene group and pharmaceutically acceptable acid addition salts of those compounds of Formula I containing a basic nitrogen atom, may be prepared by (1) reacting a compound of Formula IX or a reactive esterifying derivative thereof, in which A is as above defined, with a compound of Formula X or a reactive esterifying derivative thereof, in which X, Y, Z and R are as above defined or (2) by reacting a compound of Formula XIII or a silyl derivative thereof with a reactive N- acylating derivative of a compound of formula R<SP>1</SP>aOH wherein R<SP>1</SP>a is an organic acyl group which may carry a protected amino group, removing the silyl group, if present, by hydrolysis or alcoholysis, and, if a protected amino group is present, optionally converting it to a free amino group under acid or neutral conditions. The esters of Formula XIII are stated to be novel and may be prepared by reacting 6- aminopenicillanic acid, 7-amino cephalosporanic or 7-aminodesacetoxy-cephalosporanic acid or N-protected derivatives thereof with the appropriate 3-bromolactone and thereafter removing the protecting group, if present. 5,6 - Dimethoxyphthalide, 6 - methoxyphthalide and 4,5,6-trimethoxyphthalide are prepared by reacting the appropriate benzoic acid with formaldehyde in the presence of hydrochloric acid and the corresponding 3-bromophthalides are prepared by reaction with N-bromosuccinimide and α-azo-isobutyronitrile. 6-Chlorophthalide is prepared by reacting sulphuryl chloride with phthalide in a melt of aluminium chloride and sodium formate and 3-bromo-6- chloro-phthalide is prepared by reacting 6- chlorophthalide with N-bromosuccinimide and azobisbutyronitrile. 6 - Bromo - phthalide is prepared by reacting bromine with phthalide in a melt of aluminium chloride and urea and 3,6- dibromophthalide is prepared by reacting 6- bromophthalide with N-bromosuccinimide and azobisbutyronitrile. 6-Nitrophthalide is prepared by a known method and 2-hydroxymethyl-5- nitro-N,N-dimethylbenzamide is prepared by reacting 6-nitrophthalide with dimethylamine, while 2-carboxy-4-nitrobenzaldehyde is prepared by reacting 2-hydroxymethyl-5-nitro-N,N-dimethylbenzamide with glacial acetic acid and chromium trioxide. Peri-naphthaldehydic acid is prepared by the action of potassium hydroxide solution on acenaphthenequinone and perinaphthalide is prepared by the action of formalin and potassium hydroxide on peri-naphthaldehydic acid and 3-bromo-peri-naphthalide is prepared by reacting peri-naphthalide with N- bromo-succinimide and azoisobutyronitrile. 2- Thiophthalide is prepared by converting ocyanobenzylbromide to o-cyanobenzylthiocyanate which is converted to o-cyanobenzylmercaptan (using concentrated sulphuric acid) which in turn is converted to the desired product by the action of boiling water. 3-Bromo-2-thiophthalide is prepared by the reaction of 2-thiophthalide with N-bromosuccinimide and azoisobutyronitrile. o-Acetylphenylacetic acid is prepared by a dichromate oxidation of 3-methyl indene prepared by dehydrating the carbinol with acid formed from the Grignard reaction of 1-indanone with methyl magnesium iodide. Chlorodimethylformiminium chloride is prepared by the reaction of oxalyl chloride with dimethylformamide. Pharmaceutical compositions having antibacterial activity preferably for oral administration comprise the compounds of Formula I and a pharmaceutically acceptable carrier.