Patent GB-1348421-A (GB)
Title: Alpha-sulpho- and alpha-sulphoalkylacylpenicillins
IPC: C07D499/62
Filed: 1971-04-19
Abstract: 1348421 α-Sulphopenicillins PFIZER Inc 19 April 1971 [8 Sept 1970] 20429/71 Headings C2A and C2C [Also in Division C3] The invention comprises α-sulpho and α- sulphoalkylacylpenicillins of general Formula I and pharmaceutically acceptable cationic salts thereof, in which R 1  is phenyl or phenyl substituted by alkyl, alkoxy, chloro, bromo, dialkylamino or trifluoromethyl, R 2  is hydrogen or R 1  and R 2  together with the carbon atom to which they are attached represent cyclobutyl; R 3  is hydrogen, or acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy, benzoyloxy or benzoyloxy substituted by chloro, bromo, fluoro, alkyl, alkoxy or trifluoromethyl and n is 0 or an integer from 1 to 8. A process for the preparation of the above compounds comprises reacting 6-aminopenicillanic acid or an amine salt, mono- or disilyl ester or ester derivative thereof wherein the ester moiety is -OR 3 , with the appropriate reactant selected from a compound of the Formula III where X is OH, Cl, Br, and a compound of the Formula IV -OR<SP>11</SP> or -N 3  and R<SP>1</SP> is the remainder of an anhydride group, R<SP>11</SP> is the remainder of an ester group and M is hydrogen or an alkali metal or amine cation. If required, a penicillin of the above formula in which R 3  is hydrogen is converted to a compound where R 3  is acyloxyalkyl by reacting an alkali metal or t-alkylamine salt of such a compound with an acyloxyalkyl halide of formula R 3 -halide and, if desired, forming pharmaceutically acceptable salts thereof. Pharmaceutical preparations having antibiotic properties may be prepared from the above penicillins, possibly together with other antibiotics and also pharmaceutically acceptable excipients. The anhydride of α-sulphophenylacetic acid with ethyl carbonate is prepared by reacting α- sulphophenylacetic acid with ethyl carbonate in the presence of triethylamine The triethylamine salt of α-phenyl-#-sulphopropionic acid chloride is prepared by treating α-phenyl-#-sulphopropionic acid with triethylamine followed by thionyl chloride. 2-Phenyl-6-sulpho-n-caproic acid is prepared by reacting diethyl phenylmalonate with tetramethylene bromide to give diethyl 4-bromobutylphenyl-malonate, hydrolysing this to give 2- phenyl-6-bromo-n-caproic acid and reacting this with sodium sulphite. 4-Trifluoromethylphenylacetic acid is prepared by reacting 4-trifluorobenzoyl chloride with an ethereal solution of diazomethane, reacting the resulting diazo ketone with concentrated ammonium hydroxide and silver nitrate solution and hydrolysing the resulting amide. 1-Carboxy-1-bromomethylcyclobutane is prepared by reacting 1-carboxy-1-carboxymethylcyclobutane with methanol to give 1-carbomethoxy - 1 - carbomethoxymethylcyclobutane, partially hydrolysing this to give 1-carbomethoxy-1- carboxymethylcyclobutane and treating this first with silver nitrate and then with bromine to give the desired compound. Other 1-carboxy- 1-(bromoalkyl)cyclobutanes can be similarly prepared. 1 - Carboxy - 1 - (2 - carboxyethyl)cyclobutane is prepared by reacting 1-carboxymethoxy-1- bromomethylcyclobutane to give diethyl-(1- carbomethoxy - 1 - cyclobutylmethyl)malonate and hydrolysing this with aqueous KOH. Other 1- carboxy-1-(carboxyalkyl)cyclobutanes can be similarly prepared. 1 - Carboxy - 1 - sulphomethylcyclobutane is prepared by reacting the tosylate of 1-hydroxymethyl-1-carbethoxycyclobutane with ammonium sulphite and hydrolysing the resulting ammonium salt, or by reacting 1-carboxy-1- bromomethylcyclobutane with sodium sulphite.