Process for the preparation of cephalosporin intermediate and its use for the manufacture of cephalosporin compounds

A process for the preparation of cephalosporin antibiotic of formula (II)

• 12
• wherein R1 represents CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C3)alkyl;
• R2 represents H, CH3, CH2OCH3, CH2OCOCH3, CH═CH2,
• 13
• R3 is carboxylate ion or COORd, where Rd represents hydrogen, esters which form a prodrug or a counter ion which forms a salt, by the condensation of an acid of formula (I) thus produced with 7-amino cephem derivative of formula (V) according to any of the preceding claims, said process comprising:
• (i) activating 4-halogeno-2-substitutedimino-3-oxo-butyric acid of formula (I)
• 14
• wherein R1 represents CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C3)alkyl, X represents halogen such as chlorine or bromine, using conventional activation agents at a temperature in the range of −50° C. to 10° C. to produce a compound formula (IV)
• 15
• wherein X and R1 are as defined earlier and X′ represents halogen such as chlorine or bromine or other activating groups selected from
• 16
• where Alk group represents (C1-C4)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl,
• (ii) condensing the activated compound of formula (IV) with 7-amino cephem derivative of formula (V)
• 17
• wherein R4 is hydrogen or trimethylsilyl, R2 and R3 are as defined above, in the presence of a solvent at a temperature in the range of −50° C. to 10° C. to produce a compound of formula (VI)
• 18
• where all symbols are as defined above,
• (iii) cyclising the compound of formula (VI) with thiourea in the presence of water miscible solvents at room temperature to produce cephalosporin compounds of formula (II) where all symbols are as defined earlier, and
• (iv) optionally converting the compound of formula (II) to its pharmaceutically acceptable salts.

A novel intermediate of formula (IV)

• 19
• wherein X represents halogen such as chlorine or bromine, R1 represents CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl and X′ represents chlorine, bromine or an activating group selected from
• 20
• where Alk group represents (C1-C4)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl.