Patent GB-1243207-A (GB)
Title: Acylpenicillins and process for their preparation
IPC: C07C59/84
Filed: 1968-07-08
Abstract: 1,243,207. Penicillins. PFIZER Inc. 8 July, 1968 [5 Jan., 1968], No. 32571/68. Heading C2A. The invention relates to penicillins of general Formula IIIa . . wherein R 1  is thienyl, furyl, pyridyl, phenyl or substituted phenyl wherein the substituent is C1-C4 alkyl, chloro, bromo, C1-C4 alkoxy, di- (C1-C4) alkylamino or trifluoromethyl; X<SP>1</SP> is -OR 2  or -SR, wherein R 2  is isopropylphenyl (wherein X 1  is Cl, Br, F, C1-C4 alkyl or C1-C4 alkoxy; X 2  is C1-C4 alkyl or Cl ; X 3  is H or CH 3 ; and X 4  is N0 2  or di(C1-C4 alkyl)amino); furyl, quinolyl, methyl substituted quinolyl, phenazinyl, 9,10 - anthraquinonyl, phenanthrenequinonyl, anthracenyl, phenanthryl, 1,3 -  benzodioxolyl, 2 - (2 - methyl - 4 - pyronyl), 3 - (4 - pyronyl) or N - methyl - pyridyl (wherein Z<SP>1</SP> is C1-C3 alkylene and is-(CH2) 3 - and-(CH 2 ) 4 - or CH 3 , Cl- or Br-substituted derivatives thereof); benzyl substituted by Cl, Br, F, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, carbo(Cl-C4 alkoxy), N0 2  and di (C1-C4) alkylamino) with the proviso that R 1  cannot be thienyl or furyl; phthalimidomethyl, benzohydryl, trityl, cholesteryl, alkenyl having up to 8 carbon atoms, alkynyl having up to 8 carbon atoms, cycloalkyl, C1-C4 alkyl substituted cycloalkyl having 3-7 carbon atoms in the cycloalkyl moiety, bicyclo [4.4.0] decyl, thujyl, fenchyl, isofenchyl, 7-adamantanyl, (2- pyrrolidino) methyl, (4-imidazolyl) methyl, 1- indanylmethyl, 2 - indanylmethyl, [2,2 - di- (C1-C4 alkyl) - 1,3 - dioxolon - 4 - yl] methyl, furylmethyl, pyridylmethyl, ac indanyl or CH3, Cl or Br substituted derivatives, ac tetrahydronaphthyl and CH 3 , Cl or Br substituted derivatives; 1 - (C1-C4) alkoxy - 2,2,2 - trichloroethyl, 1 - (C1-C4) alkoxy - 2,2,2 - trifluoroethyl, [carbo (C1-C4) alkoxy] - C1-C4 alkoxymethyl, [di-carbo-C1-C4 alkoxyl C1- C4 alkoxymethyl; or -(C1-C3 alkylene)-Y 1  (wherein-NK 5 R 6  is - NH(C1-C4 alkanoyl),  or -N-(C1-C4 alkyl) anilino) and Y 1  is azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-(C1-C4 alkyl) piperazino, pyrrolo, imidazolo 2-imidazolino, 2,5-dimethylpyrrolidino, 1,4,5,6-terra. hydropyrimidino, 4 - methylpiperidino or 2,6- dimethylpiperidino; and R 7  is H, phenyl, mono-, di-or tri-substituted phenyl, the substituents being Cl, Br, F, C1-C4 alkyl, C1-C4 alkoxy or CF 3 , with the proviso that only one of the positions ortho to the thio group of the phenyl moiety may be substituted; and the pharmaceutically acceptable salts thereof. The penicillins are prepared by reacting 6-aminopenicillanic acid or a salt thereof with an arylcarboxy- or arylcarbothiolic ketone ester of formula wherein R 1  and X<SP>1</SP> have the above meanings. The ketene esters are prepared according to Specification 1,243,209. The free acid form is obtained from the ester forms by hydrolysis with acid, treatment with an esterase such as liver homogenate or catalytic hydrogenation (when R 2  is benzyl or substituted benzyl), or hydrolysis with aqueous sodium or potassium bicarbonate. Salts are formed with sodium, potassium, calcium, magnesium, ammonium and amines e.g. procaine and N-ethyl piperidine.  Pharmaceutical compositions for oral or parenteral use comprise a penicillin according to Formula IIIa and a carrier e.g. tablet, capsule, elixir, aqueous or oily suspension.