Separation of cephalosporin isomers

Abstract

Process of depleting 7-amino-3-[(E)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid in Z/E mixtures of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid a) by subjecting an amine salt of a Z/E mixture of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid to crystallization and converting this amine salt into 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, or b) by subjecting the Z/E mixture to chromatography.

1 . Process of depleting 7-amino-3-[(E)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid in Z/E mixtures of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid of formula  
                   a) by subjecting an amine salt of a Z/E mixture of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid to crystallization and converting this amine salt into 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, or    b) subjecting the Z/E mixture to chromatography.    
     
     
         2 . The process according to    claim 1     a ) in a process for the depletion or separation respectively of the E-isomer in Z/E mixtures of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid by 
 α) reacting the Z/E mixture of formula I according to    claim 1    with an amine of formula    NR 1 R 2 R 3      wherein R 1 , R 2  and R 3  are the same or different and independently of one another denote hydrogen, (C 1-8 )alkyl, unsubstituted or substituted benzyl or (C 4-8 )cycloalkyl, or R 1  and R 2  together with the nitrogen atom signify a 5- or 6-membered heterocycle, which may contain one or two further hetero atoms, and R 3  is as defined above, to form a compound of formula  
                 
   wherein R 1 , R 2  and R 3  are as defined above in a solvent or solvent mixture, in which the Z- and E-isomers of the compound of formula II are soluble to different degrees, or    β) a compound of formula II is dissolved or suspended in a solvent or solvent mixture and the solubility product of the isomers of formula II is adjusted,    and after isolating the Z-isomer of formula II or the compound of formula II with a low content of E-isomer, this compound is converted with the assistance of an acid into the compound of formula  
                 
   or into the compound of formula I with a low content of E-isomer.    
     
     
         3 . The process according to    claim 1     b ) in a process for the depletion or separation respectively of the E-isomer in Z/E mixtures of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid by means of adsorption chromatography, characterized in that an aqueous solution of the compound of formula I as an ammonium salt or as the salt of an inorganic acid is chromatographed with water or a solvent/water mixture over an adsorber resin or activated carbon, whereby the undesired E-isomer exhibits considerably different retention times when compared with the Z-isomer.  
     
     
         4 . An amine salt of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid.  
     
     
         5 . An amine salt according to    claim 4    of formula  
                 
 
       wherein R 1 , R 2  and R 3  are the same or different and independently of one another denote hydrogen, (C 1-8 )alkyl, unsubstituted or substituted benzyl or (C 4-8 )cycloalkyl, or R 1  and R 2  together with the nitrogen atom signify a 5- or 6-membered heterocycle, which may contain one or two further hetero atoms, and R 3  is as defined above.  
     
     
         6 . An amine salt according to anyone of claims  4  or  5 , wherein the hydrogen atoms at the C═C bond of the vinyl group have the cis configuration.  
     
     
         7 . An amine salt according to    claim 6    which is 
 7-amino- 3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid dicyclohexylammonium salt or  
 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid (2,4,4-trimethylpentyl-2)ammonium salt or  
 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid tert. -butylammonium salt.  
 
     
     
         8 . 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid and mixtures of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid and 7-amino-3-[(E)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid containing 15% and less of the E-isomer.  
     
     
         9 . Use of an amine salt of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid in the production of cephalosporins.  
     
     
         10 . Use of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid or of mixtures of 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid and 7-amino-3-[(E)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid containing 15% or less of the E-isomer in the production of cephalosporins.