Study On The Processes Of Representative Macrolides Azithromycin And Its Key Intermediates

Azithromycin is a second generation erythromycin macrolide antibiotics,it’s very useful in the infection area.And its structure reformations play the very important role for research and development next generation erythromycin macrolide antibiotics.Altrough the preparation of azithromycin had been studied for many years,and the drug has been manufactured in our country,but there were many problems for the process of preparation of azithromycin which need to improve further.On the base of the route of synthesis of azithromycin which reported in litertures,we design a route of synthesis of azithromycin,which erythromycin thiocyanate used as starting material by oximation,Beckmann rearrangement,catalytic hydrogenation and methylation with many advantages of lower material cost,operation simple and higher yield. In process of the oximation of erythromycin thiocyanate,The effect of solvent,base and reaction temperature on the oximation reaction of erythromycin thiocyanate had been investigated.The optimum reaction conditions were found as following:the methanol used as reaction solvent, the ammonium hydrocarbonate was used as base in order to control pH=6.5,the reaction temperature is at 70℃,the reaction time is 24 h. Under above selected conditions,the yield of erythromycin A oxime is 83.7～86.4%.The effect of reaction temperature,reaction time,the amount of TsCl on the Beckmann rearrangement of erythromycin A oxime in order to prepared erythromycin A 6,9-iminoether had been investigated.The experimental results showed the optimum Beckmann rearrangement reaction conditions were found as following:the molar ratio of TsCl to erythromycin A oxime is 1.4,the reaction temperature is at 5℃,the reaction time is 2 h.Under above selected conditions,the yield and assay of erythromycin A 6,9-iminoether are 95.7～96.5%and 92.1～92.8% respectively.The effect of the kind and amount of catalyst,the amount of acetic acid,reaction temperature,reaction press and reaction time on catalytic hydrogenation of erythromycin A 6,9-iminoether had b -een investigated.The optimum reaction conditions were found as following:the amount of 5%Pt/C catalyst ia 10%on the basis of erythromycin A 6,9-iminoether,the mixture solvent which the rati -o of acetic acid to water is 3:87 is used as reaction solvent,reac -tion temperature is 27℃,reaction press is 1.20 MPa,reaction tim -e is 24 h.Under above selected conditions,the conversion of ery -thromycin A 6,9-iminoether is 100%.The selectivity of 9-deoxo-9 a-aza-9a- homoerythromycin A is about 92%.The effect of reaction solvent and the molar ratio of 9-deoxo-9a-aza-9a- homoerythromycin A,formaldehyde to formic acid on synthesis of azithromycin had been investigated.The optimum reaction conditions were found as following:CHCl₃ is used as reaction solvent,the molar ratio of 9-deoxo-9a-aza-9a- homoerythromycin A, formaldehyde to formic acid is 1:1.2:2.0.Under above selected conditions,the yield of azithromycin is about 88.4%.