Process for preparing 3-alkoxymethylcephalosporins

A process for preparing a 3-alkoxymethyl-3-cephem-4-carboxylic acid represented by the formula (II) or its derivative at the carboxyl group, or a pharmaceutically acceptable salt of said carboxylic acid or said derivative ##STR6## wherein R.sub.1 represents an amino group, R.sub.2 represents a hydrogen atom or a lower alkoxy group and R.sub.3 represents a lower alkyl group unsubstituted or substituted with a halogen atom, an aryl group, an alkoxy group, an alkylthio group, a nitro group, a cyano group, an alkylamino group, a dialkylamino group, an acylamino group and an acyl group, said derivative at the carboxyl group being selected from the group consisting of esters, amides and condensation products with N-hydroxysuccinimide, N-hydroxyphthalimide, dimethylhydroxylamine, diethylhydroxylamine, 1-hydroxypiperidine and an oxime, and protecting group-protected derivatives thereof, the process comprising the steps of:

• reacting a cephalosporanic acid represented by the formula (I) or its derivative at the carboxyl group, or a pharmaceutically acceptable salt of said cephalosporanic acid or said derivative ##STR7## wherein R.sub.1 and R.sub.2 have the same meanings as defined above, and X represents an acetoxy group, said derivative at the carboxyl group being selected from the group consisting of esters, amides and condensation products with N-hydroxysuccinimide, N-hydroxyphthalimide, dimethylhydroxylamine, diethylhydroxylamine, 1-hydroxypiperidine and an oxime, and protecting group-protected derivatives thereof,
• with an alcohol represented by the formula (III):
• R.sub.3 --OH (III)
• wherein R.sub.3 has the same meaning as defined above,
• in the presence of at least one first member selected from the group consisting of halides of antimony, tin, iron, zinc and bismuth and complexes of said halides with dimethyl ether, diethyl ether, dibutyl ether, methyl acetate ethyl acetate, acetic acid and phenol
• in combination with at least one second member selected from the group consisting of boron trifluoride and complexes of boron trifluoride with dialkyl ethers, amines, fatty acids, phenols, and alcohols represented by the formula R.sub.4 --OH wherein R.sub.4 represents a lower alkyl group.

The process for preparing a 3-alkoxymethyl-3-cephem-4-carboxylic acid represented by the formula (II) or its derivative at the carboxyl group, or a pharmaceutically acceptable salt of said carboxylic acid or said derivative ##STR8## wherein R.sub.1 represents an amino group, R.sub.2 represents a hydrogen atom or a lower alkoxy group and R.sub.3 represents a lower alkyl group unsubstituted or substituted with a halogen atom, an aryl group, an alkoxy group, an alkylthio group, a nitro group, a cyano group, an alkylamino group, a dialkylamino group, an acylamino group or an acyl group,

• said derivative at the carboxyl group being selected from the group consisting of esters, amides and condensation products with N-hydroxysuccinimide, N-hydroxyphthalimide, dimethylhydroxylamine, diethylhydroxylamine, 1-hydroxypiperidine and an oxime, and protecting group-protected derivatives thereof, the process comprising:
• reacting a cephalosporanic acid represented by the formula (I) or its derivative at the carboxyl group, or a pharmaceutically acceptable salt of said cephalosporanic acid or said derivative ##STR9## wherein R.sub.1 and R.sub.2 have the same meanings as defined above, an X represents an acetoxy group, said derivative at the carboxyl group being selected from the group consisting of esters, amides and condensation products with N-hydroxysuccinimide, N-hydroxyphthalimide, dimethylhydroxylamine, diethylhydroxylamine, 1-hydroxypiperidine and an oxime, and protecting groupprotected derivatives thereof,
• with an alcohol represented by the formula (III):
• R.sub.3 --OH (III)
• wherein R.sub.3 has the same meaning as defined above, in the presence of at least two first members selected from the group consisting of halides of antimony, tin, iron, zinc and bismuth and complexes of said halides with dimethyl ether, diethyl ether, dibutyl ether, methyl acetate ethyl acetate, acetic acid and phenol.