β-lactam production

A process for the production of a compound of formula

• in free form, in the form of a solvate, in a salt form or in the form of a solvate of an ester or a salt,
• wherein X is unsubstituted or substituted alkyl, or unsubstituted or substituted alkenyl, said substituted alkyl or alkenyl substituted by alkoxy, heterocyclythio, heterocyclylcarbonylthio, alkylcarbonyloxy or heterocyclyl, and R1 is unsubstituted alkyl, or alkyl substituted by carboxyl, and RE is hydrogen or RE denotes together with the COO— group to which RE is attached an ester of a pharmaceutically acceptable salt, comprising either
• a) reacting a compound of formula
• wherein Y is halogen, X and R1 are as defined above and R′E is trialkylsilyl or denotes together with the COO— group to which R′E is attached an ester, with a compound of formula
• wherein R′ is hydrogen or trialkylsilyl and R″ is trialkylsilyl to obtain a compound of formula
• wherein X, R1, R′ and R′E are as defined above, and, optionally desilylating a compound of formula VI to obtain a compound of formula I;
• or a′) desilylating a compound of formula II, wherein Y, X, and R1 are as defined above and R′E is trialkylsilyl, and reacting a desilylated compound of formula II with thiorea in a solvent system containing organic solvent and water, to obtain a compound of formula I in free form, and thereafter optionally converting the compound of formula I to the salt form.

A process for the production of ceftriaxone in the form of a disodium salt comprising reacting a compound of formula II

• wherein Y is halogen, R1 is CH3, R′E is trialkylsilyl, and X is a group of formula
• wherein R′″ is trialkylsilyl, with a compound of formula V, wherein R′ is hydrogen or trialkylsilyl and R′″ is trialkylsilyl, to obtain a compound of formula VI, wherein R′E is trialkylsilyl;
• and R1 is CH3, is hydrogen or trialkylsilyl and X is a group of formula
• wherein R′″ is as defined above;
• and
• i) reacting the reaction mixture obtained with water/organic solvent which is miscible with water and a base;
• and with water/organic solvent which is able to form a two-phase system with water;
• ii) adjusting the pH of the mixture obtained to about 6.5;
• iii) separating off the organic solvent from the two-phase system obtained;
• iv) adjusting the pH of the aqueous phase obtained to a pH of about 3;
• v) filtrating off the precipitate formed;
• vi) suspending the precipitate obtained in a mixture of water and organic solvent which is miscible with water;
• vii) adjusting the pH of the mixture obtained to about 6.5;
• and
• viii) isolating ceftriaxone in the form of a disodium salt.