How to prepare Cefditoren Pivoxil Dimer?

Cefditoren pivoxil is belong to cephalosporin drugs and is widely used for the treatment and prevention of various infectious diseases caused by pathogenic bacteria. Cefpodoxime proxetil is the third-generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria, especially against Streptococci, than other antibiotics for oral administration [1]. 

In new drug research and development process, the quality of the drug is to weigh a major criterion of drug quality, the matter of drug, the effect of amount is decided by drug itself first and toxic side effect, the i.e. validity of drug and safety. The active ingredient of drug and the effect of content are the important symbol of reflection pharmaceutical purity, and impurity present in drug directly influences drug may simultaneously cause.

For medicament research and development personnel, groundwork is not only that how to obtain the bulk pharmaceutical chemicals (API) of high quality, and send out synthesis technology efficient, and it is often more important that dopant species, source and the production for how controlling process contaminants in research bulk pharmaceutical chemicals.  

But the impurity reference substance currently used for cefditoren pivoxil quality control is mainly by thick from cefditoren pivoxil separation and extraction obtains in the product, and this method has complex steps, low yield and low purity and it will influence the accuracy of detection. With the propulsion that country works to drug agreement, impurity compound is determined. So Zhang Guiming and his team developed the preparation method of Cefditoren pivoxil dimer, which provides qualified reference substance to control the quality Cefditoren pivoxil. 

The preparation (scheme 1) starts from Cefditoren pivoxil (24.83g, 0.04mol), formalin (3.48g, mass fraction are 37%~40%) and sulfuric acid (0.12g, 1.2mmol), which is added in acetonitrile (125mL), and keeping the temperature 80℃ for 2.0h, then the reaction solution is cooled down to room temperature. The solution is added the mixture of purified water (100mL) and ethyl acetate (200mL) and keep stirring 10min after liquid separation. After being filtered, purified and recrystallized, the finished dimer was got with yield 87.6%.

Scheme 1 The synthesis of Cefditoren Pivoxil Dimer

Zhangying and his coworkers developed another method to cefditoren pivoxil dimer [3]. 

Scheme 2 The synthesis of Cefditoren Pivoxil Dimer

Scheme 2 shows the reaction mechanism. First, the cephem compounds (1) nucleophilic attack of the amino Vilsmeier reagent (1), to generate intermediate (3); another molecule cephem compound (I) followed by nucleophilic attack of the amino group resulting intermediate (3) to generate intermediate (5); and then the intermediate (5) dimethylamine off, to form the intermediate (6), the generates the desired products (7) by the transfer of hydrogen ions.

resources

[1] https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/cefditoren 

[2] Zhang Guiming etc., A kind of preparation method of Cefditoren pivoxil Cephalosporins dimer, CN 108727418a

[3] Zhangying etc., Preparation method of cephalosporin dimer compound, CN106543206A