Patent GB-1304202-A (GB)
IPC: C07D499/00
Filed: 1970-04-15
Abstract: 1304202 Esterified α-carboxy penicillins PFIZER Inc 15 April 1970 [11 Dec 1969] 18072/70 Headings C2A and C2C Penicillins having the general formula wherein M is hydrogen, Na, K or tri-(lower alkyl)amine; R 1  is thienyl, furyl, pyridyl, phenyl or substituted phenyl in which the substituent is lower alkyl, lower alkoxy, di-(lower alkyl)amino, chloro, bromo or trifluoromethyl; and R 2  is isopropylphenyl, a group of formula wherein X 1  is Cl, Br, F, lower alkyl or lower alkoxy; X 2  is lower alkyl or Cl; X 3  is hydrogen, methyl, phenyl, carboxyvinyl, carbo-(lower alkoxy)vinyl, carboxy-(lower alkyl) or carbo- (lower alkoxy)(lower alkyl); and X 4  is nitro, di- (lower alkyl )amino, or mono-substituted phenyl wherein, the substituent is phenyl, carboxyvinyl, carbo-(lower alkoxy)vinyl, carbo- (lower alkoxy)(lower alkyl) or carboxy-(lower alkyl); or R 2  is indanyl which may be substituted by methyl, chloro or bromo; or is tetrahydronaphthyl which may be substituted by methyl, chloro or bromo; or is 1-(lower alkoxy)-2,2,2- trichloroethyl, 1 - (lower alkoxy) - 2,2,2 - trifluoroethyl, [carbo-(lower alkoxy)] (lower alkoxy)methyl or [dicarbo-(lower alkoxy)] (lower alkoxy)-methyl; or R 2  is 3-[1-(R 5 -substituted)- piperidyl, -(CH 2 ) m -NR 5 R 6 , -CH 2 CH(CH 3 )- NR 5 R 6 , -CH(CH 3 )-CH 2 -NR 5 R 6  or -(lower alkylene)-Y 1  wherein m is 2 or 3; R 5  is H, lower alkyl or benzyl; R 6  is lower alkyl, lower alkanoyl, benzyl, phenyl or carbo-(lower alkoxy), with the proviso that when R S  is H, R 6  is lower alkanoyl or carbo-(lower alkoxy); and Y 1  is azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-(lower alkyl)- piperazino, pyrrolo, imidazolo, 2-imidazolino, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidino, 4-methylpiperidino or 2,6-dimethylpiperidino; or R 2  is a group of formula: wherein n is 3 or 4 and X 5  is H, CH 3 . Cl or Br; or is a group of formula: wherein X 6  is H or one or more of Cl, Br, F, NO 2 , lower alkoxy, lower alkyl or methylenedioxy; or is a group of formula: wherein X 7  is H, Cl, Br, NO 2 , lower alkoxy or lower alkyl ; and lower alkyl. lower alkoxy and lower alkanoyl groups each have 1-4 carbons and lower alkylene has 1-3 carbons, are prepared by acylating 6-aminopenicillanic acid or a sodium, potassium or tri-(lower alkyl)amine salt thereof, with an acylating agent of formula: wherein B is lithium, sodium or potassium and R 1  end R 2  have the aforesaid meaning, in a reaction-inert solvent at about 0‹ to 50‹ C. and a pH of about 5 to 8. The aforesaid penicillins are usually isolated as the N-ethylpiperidine salts which are then converted to salts wherein M is Na, K or tri-(lower alkyl)amine. o-Trifluoromethylphenylacetic acid is prepared by converting o-trifluoromethylbenzonitrile to trifluoromethylacetophenone by a Grignard reaction with methyl-magnesium iodide followed by hydrolysis, reacting the said acetophenone with sulphur and morpholine and treating the product with glacial acetic acid and HCl. Arylmalonic acids of general formula wherein R 1  is o-, m-, or p-methoxy- or o-, m- or p-trifluoromethyl-phenyl, o-isopropylphenyl, 3-furyl, 3- or 4-pyridyl, o-, m-, or p-dimethylamino phenyl, or o-butoxy- or o-diethylaminophenyl, are prepared by condensing diethyl carbonate with an appropriate ethyl aryl acetate in the presence of sodium ethylate and then hydrolysing the resulting ester. Arylchlorocarbonyl ketenes of general formula wherein R 1  is phenyl, o-, m- or p-chloro-, o-, m- or p-methoxy-, or o-, m- or p-trifluoromethylphenyl, o-, m- or p-tolyl, o-bromo-phenyl, o-, m- or p-dimethylamino-phenyl, o-butoxy- or odiethylaminophenyl, 2- or 3-thienyl, 2- or 3- furyl or 2-, 3- or 4-pyridyl, are prepared by reacting a corresponding arylmalonic acid with PCl 5 , PCl 3 , POCl 3  or SOCl 2 . The lithium and sodium salts of 2-phenyl-2-(5- indanyloxycarbonyl)acetic acid are prepared by treating a methylene chloride solution of the acid with a methanolic solution of lithium or sodium hydroxide. Amirioisopropcianls wherein the amino group is dimethylamino, diethylamino, di-n-propylamino, di - isopropylamino, di - n - butylamino, 1,4,5,6 - tetrahydropyrimidino, N - ethylpiperazino, piperidino, pyrrolidino, pyrrolo, morpholino, thiomorpholino, imidazolino or imidazolidino are prepared by condensing propylene oxide with the appropriate amine by reaction at elevated temperature in a sealed tube. Aminopropanols wherein the amino group is as listed for the aminoisopropanols are prepared by LiAlH 4  reduction of the ethyl ester of corresponding aminopropionic acid, the latter compounds being prepared by reacting the appropriate amine with ethyl α-bromopropionate. Pharmaceutical compositions having antibiotic activity against gram-positive and gramnegative bacteria comprise a penicillin as previously defined and a pharmaceutical carrier.