Process for the purification of a 3-cephem-4-carboxylic acid derivative

A process for the production of a pharmaceutically effective cephalosporin comprising the steps of

• i) preparing a (Z)-isomer enriched 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid in free acid or salt form by depleting 7-amino-3{(E)-1-propen-1-yl}-3-cephem4-carboxylic acid in a mixture of 7-amino-3-{(Z)-1-propen-1-yl}-3-cephem4-carboxylic acid and 7-amino-3-{(E)-1-propen-1-yl}-3-cephem-4-carboxylic acid by reacting a mixture of the (Z)- and (E)-isomers of the compound of formula
• with hydrochloric acid, a lithium, sodium or potassium base, ammonia, or an amine of formula IV to form a salt of formula I
• wherein R1, R2 and R3 are independently hydrogen, (C1-8)alkyl, benzyl, (C4-8)cycloalkyl;
• or
• R1 with R2 and the nitrogen atom together form a 5 or 6-membered heterocycle which may contain one or two additional heteroatoms and R3 is as defined above, wherein one of R1,
• R2 and R3 is other than hydrogen;
• in a solvent or solvent mixture in which the Z- and E-isomers of said salt of formula I have different solubilities and where the E isomer is better soluble than the Z isomer and if desired, isolating a (Z)- isomer enriched 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid in free acid or salt form obtained by recovering said salt of (Z)- isomer enriched 7-amino-3-(1-propen-1-yl)-3-cephem4-carboxylic acid after precipitation and where required, converting the enriched (Z)-isomer of the salt of formula I into the free acid of formula I;
• and
• ii) further acylating said (Z)-isomer enriched 7-amino-3-(1-propen-1-yl)-3-cephem4-carboxylic acid in free acid or salt form at the amine group in position 7 to obtain a pharmaceutically active cephalosporin antibiotic.

A process for the production of cefprozil of the formula

• comprising the steps of
• i) reacting a mixture of (Z)- and (E)-isomers of the compound of formula
• with hydrochloric acid, a lithium, sodium or potassium base, ammonia, or an amine of formula IV to form a salt of formula I
• wherein R1, R2 and R3 are independently hydrogen, (C1-8)alkyl, benzyl, (C4-8)cycloalkyl;
• or R1 with R2 and the nitrogen atom together is a 5- or 6-membered heterocycle which may contain one or two additional heteroatoms and R3 is as defined above, wherein one of R1, R2, and R3 is other than hydrogen;
• in a solvent or solvent mixture in which the Z- and E-isomers of said salt of formula I have different solubilities and where the E isomer is better soluble than the Z isomer and if desired, isolating a (Z)-isomer enriched 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid in free acid or salt form obtained by recovering said salt of (Z)-isomer enriched 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid after precipitation and where required, converting the enriched (Z)-isomer of the salt of formula I into the free acid of formula I ;
• and
• ii) further acylating said Z-isomer enriched 7-amino-3-(1-propen-1-yl)-3-cephem-4-carboxylic acid in free acid or salt form at the amine group in position 7 to obtain cefprozil in free form, in the form of a solvate, such as a hydrate or a hemihydrate, or in the form of a salt.