Preparation Process Of Rifamycin S Through Heterogeneous Oxidation

As a precursor for the synthesis of rifamycins,rifamycin S can be prepared by oxidizing rifamycin SV.At present,the industrial preparation method of rifamycin S is homogeneous oxidation of SV in water-based system.However,due to the poor solubility of rifamycin SV in water,the titer of fermentation broth is very low.And there are many impurities in the fermentation broth,which cause many side reactions and lower space-time-yield of rifamycin S in the oxidation process.Additionally,chloride ion(Cl-)in the reaction solution can result in equipment corrosion during the extraction process,which will increase difficulties for the production process.To solve the above problems,the preparation process of rifamycin S by taking rifamycin SV as the raw materials were systematically studied.And a new oxidation process combining reaction with separation was put forward in this paper.Then,heterogeneous reaction-mass transfer process was investivated,which would provide a theoretical guidance for the control and optimization of process.Besides,the semi-batch and continuous reaction processes were explored to find an economical and suitable production method for industrial production.Firstly,the process of preparing rifamycin S by heterogeneous oxidation and the suitable oxidant were determined.Taking butyl acetate/water two-phase system as the reaction solvent,the effects of several oxidants(such as H2O2,CH3COOOH,NaNO2,NaClO)on the rifamycin SV heterogeneous oxidation process and the corresponding oxidation mechanism were investigated.While reaction condition was mild and the reaction time was shorter taking NaCIO as an oxidant.Due to its strong electron-acquisition ability,there were no chain reaction,less side reaction as well as highest selectivity and yield of product,thus it was a suitable oxidant.Secondly,by measuring and calculating the mass transfer coefficient and diffusion coefficient of rifamycin SV in the aqueous phase,as well as rate constant of the pseudo-homogeneous reaction,the number of Hatian Ha)under diferent conditions was obtained.The results showed that Ha was greater than 3 within the temperature range from 278.15 K to 308.15 K,that is,heterogeneous oxidation of rifamycin SV was a fast reaction that controlled by mass transfer-reaction.Then,the macroscopic reaction rate equation was established based on the double membrane theory,meanwhile the theoretical value agreed well with the experimental value.In addition,the process conditions of preparation of rifamycin S were optimized by heterogeneous oxidation in semi-batch reaction.The results showed that the yield,selectivity and the space-time-yield of rifamycin S were 89.02%,92.42%and 139.60 g/(L�h)respectively under the conditions of NaCIO concentration 0.32 mol/L,NaClO/SV molar ratio 1.41,reaction temperature 30 ?,stirring rate 300 rpm,pH 12.3 and reaction time 12 min.Compared with the traditional technology,the yield and selectivity increased by 3.61%and 6.74%respectively under the same conditions,and the space-time-yield increased by 122.85 g/(L�h).Finally,a preliminary study on the preparation of rifamycin S was carried out by heterogeneous oxidation in a microtubular reactor.The results showed that the conversion of rifamycin SV,the yield and selectivity of rifamycin S were 74.60%?68.46%?91.78%respectively,and the space-time-yield was 1642.31 g/(L�h)under the conditions of NaCIO concentration 0.20 mol/L,NaClO/SV molar ratio 1.38,reaction temperature 30 ?,and residence time 47 s.The residence time was shorter and the space-time-yield was higher.Besides,the reaction process was easier to control or magnify and the continuous production was easier,which possessed the prospects for industrial development.