IE36448B1 - New cephalosporin esters salts thereof and methods for their preparation - Google Patents

Abstract

1335317 Cephalosporin esters LOVENS KEMISKE FABRIK PRODUKTIONSAKTIESELSKAB 23 May 1972 [23 June 1971] 29449/71 Headings C2A and C2C The invention relates to novel cephalosporin esters having the general Formula (I) and salts thereof, wherein the asterisk indicates that the carbon atom can be asymmetric, n is an integer from 0 to 5 ; R 1 is a radical corresponding to the equivalent radical of a known semisynthetic cephalosporin ; R 2 is a hydrogen atom, an optionally substituted alkyl radical or an optionally substituted phenyl radical; R 3 , R 4 and R 5 each represents H or C 1 -C 6 alkyl; or R 2 and R 5 together with the intermediate carbon atom can form a 5-, 6- or 7-membered carbocyclic ring and either R 3 , R 4 and the intermediate nitrogen atom or R 4 , R 5 and the intermediate carbon and nitrogen atoms form a heterocyclic ring system: and R 6 is H, alkoxy, alkylthio, aryloxy, arylthio, acyloxy, acylthio, azido, pyridyl or 2-(1,3,4- thiadiazolyl)-thio. The cephalosporin esters (I) are produced by a procedure comprising: (1) reacting a cephalosporin salt of Formula II in which R 1 and R 6 are as defined above and X is a cation (e.g. Na<SP>+</SP>, K<SP>+</SP>, ammonium or trialkylammonium) with a compound of Formula III wherein Hal is a halogen atom (Cl or Br), Z is an amino group, a substituted or protected amino group or a group (e.g. azido, nitro or halogen) which is directly convertible to an amino group, by hydrogenation, hydrolysis or amination, and R 2 , R 5 and n are as previously defined; to give a mixture of #<SP>2</SP> and #<SP>3</SP> isomers of Formulae (IVa) and (IVb) (2) oxidizing these mixed isomers with a per-acid (e.g. peracetic acid or m-chloroperbenzoic acid) to the corresponding #<SP>2</SP>- and #<SP>3</SP>-cephem sulphoxides and treating the mixed sulphoxide isomers with a hydroxylic solvent (e.g. methanol) to convert the #<SP>2</SP> compound to the #<SP>3</SP> compound, thus yielding a pure #<SP>3</SP>-cephem sulphoxide of general Formula VII (these compounds, wherein R 1 , R 2 , R 5 and R 6 are as defined previously and Z is an unsubstituted, substituted or protected amino group, an azido group, a nitro group or a halogen atom, being novel and forming an aspect of the invention); (3) reducing the compound VII (e.g. with sodium dithionite in the presence of acetyl chloride) to give a compound (IVa) as set forth above, which is identical with the desired compound (I) when Z is amino or substituted amino; and (4) when Z is protected amino, or the aforesaid group which is directly convertible to an amino group, converting the compound IVa to a compound (I) by hydrolysis, hydrogenation or amination. In an alternative procedure the compound VII is prepared by either (a) reacting a cephalosporin sulphoxide salt of Formula VIII wherein R 1 , R 6 and X are as previously defined, with a compound (III) hereinbefore; or (b) reacting a chloromethyl ester of a cephalosporin sulphoxide, of Formula (IX) wherein R 1 and R 6 are as before, with an acid of Formula (V) in which R 2 , R 5 , Z and n are as defined above. The cephalosporin sulphoxide chloromethyl esters (IX) are said to be novel. They may be prepared by either reacting a cephalosporin salt (II) with chloroiodomethane or chlorobromomethane to give a mixture of #<SP>2</SP> and #<SP>3</SP> isomeric cephalosporin chloromethyl esters, which mixture is converted to the pure #<SP>3</SP> cephem sulphoxide ester (IX) by the oxidation/hydroxylic solvent treatment described above in step (2); or else by reacting the cephalosporin sulphoxide salt (VIII) above with chloroiodomethane or chlorobromomethane. N-tert. Butoxycarbonyl-L-valine chloromethyl ester is produced by esterifying the protected amino-acid with chloroiodomethane. Chloromethyl α-azido-α-methylpropionate is prepared by correspondingly esterifying α-azido-α- methylpropionic acid sodium salt. D,L-α-azido-iso valeric acid is resolved into the L-( - )- and D-( + )-isomers by fractional crystallization of the L-ephedrine salt. The isomeric ephedrine salts are converted to the corresponding free acids by treatment with HCl, and the acids are then used to prepare the sodium salts. The L-( - )- and D-( + )-isomers (as the Na salts) are reacted with chloroiodomethane to give chloromethyl L-α-azido-isovalerate (containing 25% methylene di-L-α-azido-isovalerate), and chloromethyl D-α-azido-isovalerate. Pharmaceutical compositions having broad spectrum antibacterial activity comprise a cephalosporin ester of Formula I as defined above or a salt thereof, together with a pharmaceutical carrier or diluent. The compositions are preferably in forms suitable for oral administration. [GB1335317A]