Oxidation process for preparing 3-formyl-cephem derivatives
AssigneeBasilea Pharmaceutica International AG
InventorIvan Joseph Maria Vervest
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Abstract
The present invention relates to an improved process for oxidizing 3-hydroxy-methyl-cephem derivatives to the corresponding 3-formyl-cephem derivatives. In particular this oxidation process is for the preparation of 7-[2-(5-amino-[1,2,4]thia-diazol-3-yl)-2-hydroxyimino-acetylamino]-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid derivatives of formula (I) using a combination of a hypervalent iodine oxidizing agent of the type 10-I-3 such as bis(acetoxy)iodo-benzene (BAIB) and a catalyst such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). These compounds of formula (I) are intermediates in the synthesis of ceftobiprole.
Claims10
A process for the preparation of ceftobiprole in form of its water-soluble prodrug ceftobiprole medocaril, comprising the steps of:
- (1) preparing 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxy-imino-acetylamino]-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid derivative of formula (I):
- wherein R1 is a hydroxy protecting group and R2 is a carboxylic acid protecting group, with a process, which comprises oxidizing a compound of formula (II)
- with a combination of a hypervalent iodine oxidizing agent of the type 10-I-3 and a catalyst selected from 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy and 4-(acetylamino)- 2,2,6,6-tetramethyl-1-piperidinyloxy in a solvent selected from the group consisting of dichloromethane, a mixture of dichloromethane and tetrahydrofurane and a mixture of dichloromethane and acetonitrile;
- and
- (2) synthesizing said ceftobiprole medocaril from said compound of formula (I).
A process for the preparation of ceftobiprole, comprising the steps of:
- (1) preparing a 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxy-imino-acetylamino]-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid derivative of formula (I):
- wherein R1 is a hydroxy protecting group and R2 is a carboxylic acid protecting group, with a process, which comprises oxidizing a compound of formula (II)
- with a combination of a hypervalent iodine oxidizing agent of the type 10-I-3 and a catalyst selected from 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy and 4-(acetylamino)- 2,2,6,6-tetramethyl-l-piperidinyloxy in a solvent selected from the group consisting of dichloromethane, a mixture of dichloromethane and tetrahydrofurane and a mixture of dichloromethane and acetonitrile;
- and
- (2) synthesizing said ceftobiprole from said compound of formula (I).
Dependencies are inferred from the claim text.