Study On The Synthesis Of Clarithromycin

Clarithromycin is one of the 14-membered macrolide antibiotics,which has inhibitory effects on gram-positive bacteria,some gram-negati-ve bacteria,some anaerobic bacteria and some mycoplasma,and is widely used in clinical treatment because of its superior antibacterial properties.The synthesis of clarithromycin involves many steps,involving many intermediates,and there have been many synthetic routes since it came out.However,most of the synthesis routes have not been industrialized.The purpose of this article is to improve the industrial production process of clarithromycin.Therefore,the ether silication method,which is currently available for industrial production,was selected for the study of clarithromycin synthesis.At present,the industrial production of clarithromycin mainly uses the traditional stirred tank reactor.Due to its large volume,it is easy to cause the problem of uneven mixing between materials,thus affecting the mass transfer and heat transfer effect of the reaction,and ultimately reducing the yield of the product.In view of the shortcomings of the kettle reactor,this paper introduces a new type of reactor—high gravity reactor to study the synthesis process of clarithromycin.First,determine the optimal process conditions for synthesis in the stirred tank reactor,and then optimize the synthesis process by connecting the high gravity reactor in series on the basis of the conditions.The main research conclusions are as follows:(1)Explored the optimum technological conditions of clarithromyc-in synthesis in stirred tank reactor.Etherification reaction:the ratio of erythromycin A oxime to solvent dichloromethane is 1:10(g/m L),the molar ratio of erythromycin oxime to 2-ethoxypropene to pyridine hydrochloride is 1:2.6:1.5,the stirring speed is 250 rpm,the reaction took place at 20 degrees celsius for 30 minutes,under these conditions,the yield of etherification reaction product is 92.61%;Silanization reaction:the ratio of etherified substance to solvent dichloromethane is1:10(g/m L),the molar ratio of etherified compound to trimethylchlorosilane to imidazole is 1:2.4:3.5,the stirring speed is 250rpm,the reaction took place at 25 degrees celsius for 30 minutes,under these conditions,the yield of silylation reaction product is 96.44%;Deprotection reaction:the ratio of methylation to anhydrous ethanol to deionized water is 1:6.25:6.25(g/m L/m L),the molar ratio of methylate to sodium bisulfite is 1:10,and the reaction system p H is 4.5,the reaction took place at 80 degrees celsius for 3 hours,under these conditions,the yield of deprotection reaction is 85.92%.(2)On the basis of the best process conditions of the above stirred tank experiment,explored the better process conditions of applying the high gravity reactor(Rotating packed bed,RPB)to etherification and silylation reactions.Etherification reaction:the RPB speed is 600 rpm,the material circulation volume is 160 m L/min,the reaction temperature is 18℃and the cycling time is 15 minutes,under these conditions,the yield of etherification reaction is 94.99%.Silylation reaction:the RPB speed is 700 rpm,the material circulation volume is 160 m L/min,the cycling time is 10 minutes,the reaction temperature is 25℃,and the molar ratio of etherification to imidazole is 1:3,under these conditions,the yield of silylation reaction is 93.76%.(3)Conducted the kinetic experiments,and the kinetic equation of etherification reaction during the synthesis of clarithromycin is (-dC_A)/(dt)=89.×10~5exp((-4380.30)/T)·CA·CB。...