Patent GB-905778-A (GB)
Title: Improvements in or relating to penicillins
Inventor: DOYLE FRANK PETER
IPC: C07D499/74
Filed: 1960-03-31
Abstract: Relates to penicillins of the general formula:  <FORM:0905778/IV (b)/1> and non-toxic salts thereof, where Z is the residue of a substituted or unsubstituted heterocyclic ring system and R1 and R2 are the same of different and are each an alkyl, aryl, acyl, aralkyl, cycloalkyl, heterocyclic, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkylthio group which may be substituted or a halogen atom, or R1 or R2 may form part of a further substituted or unsubstituted cyclic system fused to the ring containing Z.  The Specification contains many examples of penicillins of the above formula of which the following are typical:- 5 - methyl - 3 - phenyl-4-isoxayolyl, 3-methyl-5-phenyl-4-isoxayolyl, 3 - p-chlorophenyl-5-methyl-4-isoxayolyl, 2:4-dichloro-6-methyl-3-pyridyl, 3-ethoxy-2-methyl-4-quinolyl, and 3:7-dimethoxy-4-coumarinyl penicillins.  The penicillins may be prepared by reacting 6-amino-penicillanic acid or a liqour containing it with an acid chloride, bromide, anhydride or mixed anhydride derived from a carboxylic acid of the general formula <FORM:0905778/IV (b)/2> where Z, R1 and R2 are as above. 2,4,5-Triphenyl-3-furoyl chloride is prepared by warming the corresponding acid with thionyl chloride and a trace of pyridine. 2,4-Dimethoxyquinoline-3-carboxylic acid is prepared by the action of methanolic sodium methoxide on ethyl 2,4-dichloroquinoline-3-carboxylate, followed by saponification. 5-Benzyl-3-methylisoxazole-4-carboxylic acid is obtained by reacting ethyl a -(phenylacetyl) acetoacetate and hydroxylamine hydrochloride in aqueous ethanol followed by hydrolysis of the ester product. Reaction of the acid with thionyl chloride gives 5-benzyl-3-methylisoxazole-4-carbonyl chloride. 5-(2-furyl)-3-methylisoxazole - 4 - carboxylic acid is prepared by reacting ethyl a -(2-furoyl)-acetoacetate and hydroxylamine hydrochloride in aqueous ethanol, followed by hydrolysis of the ester product.  3 - Methyl - 5 - (31,51-dimethyl-41-isoxazolyl) -isoxazole-4-carboxylic acid is prepared by reacting ethyl a -3,5 - dimethylisoxazole-4-carbonyl)-acetoacetate and hydroxylamine hydrochloride in aqueous ethanol, followed by hydrolysis of the ester product.  3 - Methyl-5-(2-thienyl),isoxazole-4-carboxylic acid is prepared by hydrolysis of the ester product of the reaction between ethyl a -(2-thenoyl) - acetoacetate and hydroxylamine hydrochloride in aqueous alcohol.  3 - p-chlorophenyl-5-methylisoxazole-4-carboxylic acid is prepared by hydrolysis of the ester product of the reaction between p-chlorobenzo-hydroxamic chloride and ethyl acetoacetate in methanolic sodium methoxide.  4,5-Dimethyl-2-phenyl-3-furoic acid is obtained by condensing acetoin with ethyl benzoylacetate in the presence of anhydrous zinc chloride, followed by saponification of the resulting ester.  2,4 - Dimethoxy-6-methylpyridine-3-carboxylic acid is prepared by reacting 2,4-dichloro-3-ethoxycarbonyl-6-methylpyridine with sodium methoxide followed by hydrolysis.  2 - Diethylamine - 4,6-dimethylpyrimidine-5-carboxylic acid is obtained by treating 5-bromo-4,6-dimethyl-2-hydroxypyrimidine, first with phosphorus oxychloride to give 5-bromo-4,6-dimethyl-2-chloropyrimidine, then with diethylamine to give 5-bromo-2-diethylamino-4,6-dimethylpyrimidine which on treatment with butyl lithium followed by CO2 gives the desired pyrimidine acid. 4,6-Dimethyl-2-methoxypyrimidine-5-carboxylic acid is obtained from 5-bromo-4,6-dimethyl-2-methoxypyrimidine by reaction with butyl lithium followed by carbonation with carbon dioxide, the starting material having been obtained by the reaction of 5-bromo-2-chloro-4,6-dimethylpyrimidine with sodium methoxide. 4,6-Dimethoxypyrimidine-5-carboxylic acid is obtained from 5-bromo-4,6-dimethoxypyrimidine by reaction with butyl lithium followed by carbonation, the starting material having been prepared by the reaction of 5-bromo-4,6-dichloropyrimidine with sodium methoxide.  5 - Bromo-4-chloro-6-methoxyprimidine is prepared by reacting 5-bromo-4,6-dichloropyrimidine with one mole of sodium methoxide, and converted to 4-chloro-6-methoxypyrimidine-5-carboxylic acid by reaction with butyl lithium followed by carbonation. 2-Ethylbenzofuran-3-carbonyl chloride is obtained by reacting oxalyl chloride and 2-ethylbenzofuran in carbon disulphide in the presence of aluminium chloride.  2,4-dichloroquinoline-3-carbonyl chloride is prepared by refluxing 2,4-dihydroxquinoline-3-carboxylic acid in phosphorus oxychloride.  2-Ethyl-3-methoxyquinoline-4-carboxylic acid is obtained from 2-ethyl-3-hydroxy-quinoline-4-carboxylic acid by treatment with diazomethane in ether, followed by saponification. The Specification refers also to the acid chlorides of the above carboxylic acids (other than the penicillins) and to 3-methyl-5-methyl-mercaptoisoxazole-4-carbonyl chloride, 2-carbethoxy-3,5-dimethyl-pyrrole-4-carbonyl chloride, 1,3,5-triphenylpyrazole-4-carbonyl chloride, 3,7-dimethoxycoumarin-4-carbonyl chloride, acridine-9-carbonyl chloride and 1,2-dimethylindole-3-carbonyl chloride.  The penicillins and non-toxic salts thereof may be used pharmaceutically in admixture with suitable carriers, and are suitable for oral administration. Specification 876,662 also is referred to.