Process for the preparation of cefixime via alkyl-or aryl-sulfonates

A process for the preparation of Cefixime (I)

• comprising the following steps:
• a) reacting a 7-amino-3-vinyl-3-cephem-4-carboxylic acid derivative of formula (II)
• wherein
• R1 is hydrogen or a trimethylsilyl group;
• R2 is hydrogen or a trimethylsilyl, tert-butyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, benzhydryl or bis(p-methoxyphenyl)methyl group;
• with a 2-(aminothiazol-4-yl)-2-(carboxymethoxyimino) acetic acid derivative of formula (III)
• wherein
• R3 is hydrogen, a trityl, tert-butoxycarbonyl or p-methoxybenzyloxycarbonyl group;
• R4 is tert-butyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, benzhydryl, bis(p-methoxyphenyl)methyl or trityl group;
• Z is a carboxy-activating group selected from:
• —Cl, —S-mercaptobenzothiazolyl, —O—P+(Ph)3Cl, —O—P(S)(OEt)2, —O—P(O)(OEt)2, —O—SO2Me, —O—SO2Ph, —O—SO2-pTol, —O—COtBu, —O—C(O)OEt, —O-benzotriazol-1-yl, —S-(2-methyl-thiadiazol-5-yl), —O—CH═N+(CH3)2Cl− or-benzotriazol-1-yl-3-oxide,
• to give a 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivative of formula (IV)
• wherein R2, R3 and R4 have the meanings defined above,
• b) directly reacting a 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivative of formula (IV), from step a), with RSO3H alkyl- or aryl- sulfonic acids to give crystalline salts (IA)
• wherein
• n is an integer ranging from 0 to 3,
• R is a C1-C6 straight or branched chain;
• or a benzene or naphthalene ring optionally substituted with one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, carboxy, nitro, sulfo, methyl groups,
• c) converting crystalline salts (IA) into Cefixime (I).

Cefixime crystalline salts with alkyl- or arylsulfonic acids of formula (IA)

• wherein
• n is an integer ranging from 0 to 3,
• R is a C1-C6 straight or branched chain;
• or a benzene or naphthalene ring.