Study On Novel Synthesis Of Key Intermediates Of Hydrocortisone From Phytosterols

Hydrocortisone(HC) is one of the largest varieties of hormone drugs in the production. Market capacity of HC is about 100t/a in the global, and increasing year by year. At present, 60% of steroid drugs in our country is still prepared from the starting material, diosgenin. The main problems existing in the traditional synthesis method of hydrocortisone are:(1) the exhaustion of dioscorea resources;(2) the treatment of chromium waste water and environmental pollution;(3) the high cost of iodination reaction;(4) the lower selectivity introduced β-OH into C11 using of microbial oxidation method.This thesis will uphold the concept of green chemistry using the plant sterol fermentation 4-AD(androst-4-ene-3, 17-dione) as the starting material to prepare HC. Because phytosterol mainly comes from the residues of refined vegetable oil, so this is a subject of comprehensive utilization of resources to synthetic steroid drugs, which has a significant meaning for social and economic. The intermediate of hydrocortisone, 17α, 21-dihydroxypregn-4-ene-3, 20-dione-17-valerate was synthesized by using addition, silicon etherification, cycloaddition-protiodesilylation and other reactions with 4-AD as the starting materials, which is the fermented product of phytosterol. The novel synthetic route has the following advantages:(1) the starting material is phytosterol which is resources comprehensive utilization and abundant;(2) the entire route does not use heavy metals and less pollution to the environment;(3) avoiding the iodination reaction can reduce the production cost in a certain extent;(4) the final product changed the C-11 steric hindrance, this can improve the selectivity introduced β-OH into C11 using of microbial oxidation method in theory;(5) the intermediates generated during the synthesis process, such as 17α, 21-dihydroxypregn-4-ene-3,20-dione-21-acetate, 17α, 21-dihydroxypregn-4-ene-3, 20-dione, can directly generate HC by microbial fermentation. This makes the synthetic route more flexible, which can have a good prospect for industrial applications. The main research contents of this thesis are following:The first part briefly described the theoretical and practical significance of phytosterol as the raw of steroid drugs, and in the same time, through the comparative study of the means of introducing dihydroxyacetone side chain on C17 and the existing route of synthesis of HC, the final synthetic route was determined。The second part mainly researched the possible reaction mechanism in each step of reactions. The optimum reaction conditions of all the reaction were inferred according to the effects of T, pH, H2 O, dosage and so on. The total yield was about 75% through the multi-step reaction. The purity of the final product is more than 96%.The third part summarized the thesis and described the prospect of the applications of this field.