Synthesis Of Azithromycin

The isomeration of Erythromycin A 6,9-iminoether, which was synthesized from Erythromycin A(E) oxime has been studied. Two major isomer, Erythromycin A 6,9-iminoether and Erythromycin A 9,11-iminoether have been confirmed. The transformation of Erythromycin A 6,9-iminoether to Erythromycin A 9,11-iminoether has been achieved in dichloromethane. The crystal of Erythromycin A 9,11-iminoether has been obtained and the yield of the product is 17.5%, and the melting point is 191.1℃~192.5℃, the HPLC content is 77.31%.The Beckmann rearrangement reaction which using Erythromycin A(E) oxime and the salt of Erythromycin A(E) oxime as raw material in acetone-water mixing system has been studied. The volume ratio of acetone and water, the kinds of sulfonylation reagent and the dosage of sulfonylation reagent and the dosage of base and hydrochloric acid, the reaction time and the kinds of dealing with the reaction have been studied. And the most optimization reaction condition is: the molar ratio of Erythromycin A(E) oxime thiocyanate and Methanesulfonyl chloride is 1:2.86, the molar ratio of Erythromycin A(E) oxime thiocyanate and sodium bicarbonate is 1:4.5, the volume ratio of acetone and water is 1.45:1, the molar ration of diluted hydrochloric aid and the salt of Erythromycin A(E) oxime is 1:15; The reaction time is 3 hours and the reaction temperature is 0~5℃. The yield of Erythromycin A 6,9-iminoether is 82.86%, and the content of HPLC is 90.13% when reacting under these conditions.Three different kinds of method have been studied in the reduction of Erythromycin A 6,9-iminoether with potassium hydride. The effect of the acid to the reaction has been studied. And the most optimization condition is: the molar ratio of Erythromycin A 6,9-iminoether and potassium hydrid is 1:3, acidized with 20%sulphuric acid, the reaction temperature is 0~5℃, and the reaction time is 6.5 hours; The yield of the reaction is 98.65% when reacting under these conditions.The hydrolysis of 9-deoxo-9a-aza-9a-homoerythromycin A 11,12-hydrogen borate has been studied. The most optimization condition is: the ratio of the weight of 9-deoxo-9a-aza-9a-homoerythromycin A 11,12-hydrogen borate and the volume of water is 1:15, and the molar ratio of 9-deoxo-9a-aza-9a-homoerythromycin A 11,12-hydrogen borate and sobitol is 1:4, pH=2, the temperature is 10~15℃; The yield of the reaction is 82.45% and the content of HPLC is and 96.69% when reacting under these conditions.The hydrolysis of Azithromycin 11,12-hydrogen borate has been studied, and it is found that Azithromycin 11,12-hydrogen borate is difficult to hydrolyze than 9-deoxo-9a-aza-9a-homoerythromycin A 11,12-hydrogen borate.