Patent GB-1309375-A (GB)
Title: Phosphono substituted acylpenicillins
IPC: C07D499/44
Filed: 1971-04-19
Abstract: 1309375 Phosphono-substituted acyl penicillins; phosphonic acid derivatives PFIZER Inc 19 April 1971 [4 Nov 1970] 25317/71 Headings C2A C2C and C2P  The invention comprises phosphono-substituted acyl penicillins of general Formula I and pharmaceutically acceptable cationic salts thereof wherein R 1  is hydrogen, C 1 -C 6  alkyl, phenyl or phenyl substituted by Cl, Br, F, C 1 -C 6  alkyl, C 1 -C 6  alkoxy or trifluoromethyl; R 2  is hydrogen or R 1  and R 2  together with the carbon to which they are attached are alicyclic groups having 3 to 7 carbon atoms; R 3  is hydrogen or acyloxy alkyl, wherein the acyloxy group is alkanoyloxy, benzoyloxy, or benzoyloxy substituted by Cl, Br, F, alkyl, alkoxy or trifluoromethyl; each of R 4  and R 5  is hydrogen, alkyl, alkyl substituted by alkoxy or fluoro, phenyl or phenyl substituted by Cl, Br, F, alkyl, alkoxy or trifluoromethyl; and n is zero or an integer from 1 to 8. Such compounds may be prepared from 6-aminopenicillanic acid by any of several known methods for acylating primary amines. For example, they may be prepared by acylating 6-aminopenicillanic acid in a reaction-inert solvent with a derivative of the carboxy group of the desired phosphonoalkanoic acid or phospho-cycloalkanoic carboxylic acid reactant,  e.g. the acid chloride, bromide or anhydride, particularly the mixed anhydride with other carboxylic acids such as ethoxy or isobutoxy carbonic acid at pH values between about 6 and about 9 and at temperatures from about 0 to about 50 C. The reaction medium may be an unstable emulsion of water and a waterimmiscible organic solvent over a pH range of about 2-4 and a temperature range of about 0-50 C., or it may be an aqueous medium such as water/acetone or water in the pH range from about 6 to 9 and temperature range about 0 to 50 C. Alternatively, 6-aminopenicillanic acid may be reacted with the appropriate acid reactant in presence of a condensing agent, e.g. a carbodiimide such as 1,3-dicyclohexylcarbodiimide or an alkoxyacetylene such as ethoxyacetylene. Further, the appropriate acid azide or an active ester or thio ester of the carboxy group of the acid reactant with a phenol or thiophenol can be used as acylating agent. Still further, the 6-aminopenicillanic acid may first be converted to a mono- or di-silyl derivative by reaction with a trialkylsylyl halide or a trialkylsilylamine which is then acylated with an appropriate organic acid acylating agent (carboxylic acid, acid anhydride or acid halide) and hydrolysed to remove the protecting group. The phosphonoalkanoic acid or phosphonocycloalkanoic carboxylic acid reactant, when R 4  and/or R 5  is hydrogen, may be used as the free acid or alkali metal or amine salt of the phosphonic acid derivative depending upon the pH of the reaction mixture. In non-aqueous solvents, the initial acylation temperature may be as low as - 40 C., being increased up to approximately 50 C. if necessary. The compounds of Formula I may be admixed with suitable pharmaceutical carriers to form pharmaceutical compositions for oral or parenteral administration. The mixed anhydride of α-phosphonophenylacetic acid with ethyl carbonate is prepared by reacting α-phosphonophenylacetic acid in cooled acetone solution with ethyl chloroformate in presence of triethylamine. α-Phosphonophenylacetyl chloride is obtained by the action of thionyl chloride on α-phosphonophenylacetic acid. The same reaction, carried out at - 20 C. in the presence of triethylamine gives α-triethyl ammoniumphosphonylphenylacetyl chloride. # - Phosphono - (triethylammonium) - propionyl chloride is produced by the action of thionyl chloride on a mixture of #-phosphonopropionic acid and triethylamine.  The triethylammonium salt of 1-phosphono-1- chlorocarbonylcyclohexane is prepared by reacting thionyl chloride with a cooled methylene chloride solution of 1-phosphono-1-carboxycyclohexane in the presence of triethylamine. 2 - Phenyl - 6 - (0,0 - diethylphosphono) - ncaproic acid is obtained by reacting sodium with diethyl phosphite in hexane and then adding 6- bromo-2-phenyl-n-caproic acid sodium salt dropwise. 6 - Bromo - 2 - phenyl - n - caproic 'acid is produced by adding diethyl phenylmalonate and pentamethylene bromide to a solution of sodium in ethanol to give diethyl 6-bromohexylphenylmalonate and refluxing the latter with aqueous hydrobromic acid until CO 2  is no longer evolved. 1 - Carboxy - 1 - (2 - bromoethyl) - cyclobutane is prepared by (a) refluxing 1-carboxy-1-carboxy methylcyclobutane with methanol and sulphuric acid to give the diester 1-carbomethoxy - 1 - carbomethoxy - methylcyclobutane, (b) hydrolysing the latter to the monoester 1 - carbomethoxy - 1 - carboxymethylcyclobutane, (c) reacting the silver salt of the latter with bromine to give 1-carbomethoxy-1- bromomethylcyclobutane, (d) using this product to alkylate diethyl malonate and thereby obtain diethyl (1 - carbomethoxycyclobutylmethyl) malonate, (e) hydrolysing this to 1- carboxy - 1 - carboxy - ethylcyclobutane and then (f) converting this by the method of steps (a) to (c) to 1-carboxy-1-(2-bromoethyl)cyclobutane.