Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates

A process for preparation of compound of formula (I) comprising reacting 4-halo-2-oxyimino-3-oxobutyric acid of formula (IV1),

• wherein
• X is chlorine or bromine;
• R is hydrogen, C1-4 alkyl group, an easily removable hydroxyl protective group, —CH2COOR5, or —C(CH3)2COOR5
• wherein R5 is hydrogen or an easily hydrolysable ester group.
• with N,N-dimethylformiminium chloride chlorosulphate of formula (VII)
• in an organic solvent at a temperature ranging from −30° C. to −15° C.

A process for preparation of a cephalosporin compound of formula (II),

• wherein
• R is hydrogen, C1-4 alkyl group, an easily removable hydroxyl protective group, —CH2COOR5, or —C(CH3)2COOR5
• wherein R5 is hydrogen or an easily hydrolysable ester group.
• R1 is hydrogen or —OCH3;
• R2 is hydrogen;
• R3 is hydrogen, a negative charge or together with the COO− group to which R3 is attached is an ester, or an alkali or alkaline earth metal,
• R4 is hydrogen or is a substituent useful in cephalosporin chemistry;
• comprising reaction of compound of formula (I)
• wherein X is chlorine or bromine;
• R is hydrogen, C1-4 alkyl group, an easily removable hydroxyl protective group, —CH2COOR5, or —C(CH3)2COOR5, wherein R5 is hydrogen or an easily hydrolysable ester group
• with 7-amino cephalosporanic acid of formula (V),
• wherein R1 is hydrogen or —OCH3;
• R2 is hydrogen;
• R3 is hydrogen, a negative charge or together with the COO− group to which R3 is attached is an ester, or an alkali or alkaline earth metal, or is a silyl group;
• R4 is hydrogen or is a substituent useful in cephalosporin chemistry;
• R6 is hydrogen or a silyl group with the proviso that, when R3 is hydrogen R6 is also hydrogen;
• when R3 is a silyl group R6 is also a silyl group;
• and when R3 is an ester, or an alkali or alkaline earth metal R6 is hydrogen
• to give 7-[(4-halo-2-oxyimino-3-oxobutyramido-3-substituted-3-cephem-4-carboxylic acid of formula (VIII),
• wherein X, R, R1, R2 and R4 have the same meanings as defined hereinearlier, and R3 is hydrogen, a negative charge or together with the COO− group to which R3 is attached is an ester, or an alkali or alkaline earth metal.
• followed by cyclisation of compound (VIII) with thiourea to give compound of formula (II),
• wherein R and R5 are as defined above;
• R1 is hydrogen or —OCH3;
• R2 is hydrogen;
• R3 is hydrogen, a negative charge or together with the COO− group to which R3 is attached is an ester or an alkali or alkaline earth metal;
• R4 is hydrogen or is a substituent useful in cephalosporin chemistry.