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, a hydroxyl protective group selected from trialkyl silyl ethers;
• trialkyl aryl silyl ethers;
• trialkyl stannyl ethers;
• trityl;
• tetrahydropyranyl;
• alkyl or aryl sulphonates selected from tosyl, mesyl, and besyl;
• boron or aluminum containig two alkyl groups;
• unsubstituted benzyl;
• or —CH2COOR5, or —C(CH3)2COOR5;
• wherein R5 is hydrogen;
• or a hydrolysable ester group selected from lower alkyl esters;
• alkanoyloxy alkyl esters selected from acetoxy methyl, pivaloxy methyl, 1-acetoxy ethyl, and 1-pivaloxyethyl;
• lower alkoxycarbonyloxyalkyl esters;
• alkoxymethyl esters;
• lower alkyl amino methyl;
• benzyl ester;
• and cyanomethyl ester
• 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, a hydroxyl protective group selected from trialkyl silyl ethers;
• trialkyl aryl silyl ethers;
• trialkyl stannyl ethers;
• trityl;
• tetrahydropyranyl;
• alkyl or aryl sulphonates selected from tosyl, mesyl, and besyl;
• boron or aluminum containing two alkyl groups;
• unsubstituted benzyl;
• or
• —CH2COOR5, or —C(CH3)2COOR5;
• wherein R5 is hydrogen;
• or a hydrolysable ester group selected from lower alkyl esters;
• alkanoyloxy alkyl esters selected from acetoxy methyl, pivaloxy methyl, 1-acetoxy ethyl, and 1-pivaloxyethyl;
• lower alkoxycarbonyloxyalkyl esters;
• alkoxymethyl esters;
• lower alkyl amino methyl;
• benzyl ester;
• and cyanomethyl ester,
• R1 is hydrogen or OCH3;
• R2 is hydrogen;
• R3 is hydrogen, a negative charge or ester selected from the group of lower alkyl esters;
• alkanoyloxy alkyl esters selected from acetoxy methyl, pivaloxymethyl, 1-acetoxyethyl, and 1-pivaloxyetyl ester;
• lower alkoxy carbonyloxyalkyl esters selected from methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxy-ethyl ester;
• alkoxy methyl esters;
• lower alkyl aminomethyl esters;
• acetamidomethyl ester;
• benzyl ester;
• and cyanomethyl ester,
• R4 is hydrogen or is a substituent selected from unsubstituted and substituted alkyl;
• and unsubstituted and substituted alkenyl;
• wherein substituted alkyl andlpr alkenvi beinzsubstituted by alkoxy, heterocyclicthio, heterocycyliccarbonylthio, alkylcarbonyloxy or heterocyclyl,
• comprising reaction of compound of formula (I)
• wherein X is chlorine or bromine;
• R and R5 are selected from corresponding groups listed for those of formula (II) above
• with 7-amino cephalosporanic acid of formula (V),
• wherein R1 and R2 are selected from corresponding groups listed for those of formula (II) above;
• R3 is selected from a group listed for R3 of formula (II) above or a trialkyl silyl group;
• R4 is selected from a group listed for R4 of formula (II) above;
• R6 is hydrogen or a trialkyl sily group with the proviso that, when R3 is hydrogen, R6 is also hydrogen;
• when R3 is a trialkyl silyl group, R6 is also a trialkyl silyl group;
• and when R3 is an ester, 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, R3 and R4 are corresponding groups listed for those of formula (I) or (II) above
• followed by cyclisation of compound (VIII) with thiourea.