The Synthesis Of 6α-Methylprednisolone By Chemical Reaction And Microbial Biotransformation

6α-Methylprednisolone and its derivatives which have high anti-immunity activity belong to the adrenal cortex hormone. They are widely used in the replant of viscera, the anti-immunity reaction and the shock after surgery. 6α-Methylprednisolone was also one of the most important clinical pharmaceuticals for SARS (Severe Acute Respiratory Syndrome) due to its special effect on the anti-immunity system. At present the productivity and technology of 6α-Methylprednisolone synthesis is still in the low level in domestic market and can not satisfy the demanding requirement. As a result the price of 6α-Methylprednisolone is up to 25000 RMB/kg which blocks the wide application of 6α-Methylprednisolone. So it is quite urgent to explore a novel synthesis technique for 6a-Methylprednisolone with high yield.An integrated synthesis route for 6a-Methylprednisolone was developed which combined the chemical reaction and microbial bioconversion. The 6α-Methylprednisolone was prepared by a series of steps beginning with Cortisone acetate including the synthesis of 3-enol ether, the mannich reaction, the synthesis of 6α-methyl, the 1-en-dehydrogenation and the transformation of 11 β-hydroxy steroid. The product which was obtained was proved to be 6α-Methylprednisolone by HPLC, FTIR and NMR. The yield and purity of 6a-Methylprednisolone is 36.7% and 97.8% respectively. The synthesis of 6a-Methylprednisolone has high position specificity and high conversion which can be applied into the preparation of other important steroids.Meanwhile, the 1 -en-dehydrogenation of 6a-methyl cortisone by Arthrobacter simplex was investigated. The transformation technique was explored and the optimization method of genetic algorithm was used to obtain the compositions of the fermentation medium. Furthermore, the dehydrogenation transformation was carried out in the 3.7L fermentor which resulted in high conversion rate.Based upon the experimental results, the kinetic characteristics of the 1-en-dehydrogenation of 6a-methyl cortisone by Arthrobacter simplex were investigated. The effects of concentrations of biomass, substrate and product on the conversion process of dehydrogenation were considered. As a result, a noncompetitive inhibitory model was proposed to describe the dehydrogenation process, and the parameters of the kinetic equation were calculated.