A Study On The Synthesis Of Anti-asthma Drug Ciclesonide Of New-generation Adrenocortical Homone And Pivotal Intermediate For Inhilitor Of HMG-CoA Reductase (Statinr)

The first part of this paper was focused on the synthesis of Ciclesonide(trade name, Alveso). Ciclesonide is a new-generation inhaled nonhalagenated adrenocor-tical hormone with high anti-asthma property. In March of 2004, Australia gave first approval of Ciclesonide for the treatment of patients with asthma. Advantages of on-site activation include targeted activation in the lung, minimal system adverse effects and minimal orpharyngeal side effects, suggesting a superior therapeutic index.Firstly we synthesized the key intermediate 16a-hydroxyprednisolone from the start material prednisolone in six steps and the route reported by the bibliography was improved as follows: (ll|3)-hydroxy-21-acetoxy-l,4,16-pregnatriene-3,20-dione was dihydroxylated selectively at the 16α-position in 68% yield by the cooperation of O_sO₄ and NMO; and the optimal reaction condition was finally found to cleavage the cicle of compound (8); then by adding the PTC 18-Crown-6 into the reactants, lower temperature and increased yield is resulted in the reaction, one molecule of acetic acid is escaped from the compound (10); at last 16a-hydroxyprednisolone was obtained from the saponification of 21 -acetoxy-11β, 16α, 17-trihydroxy-1,4-pregnadiene-3,20-dione and the yield rise to 63% from 55% by the replacement of NaOH to K₂CO₃/ CH3OH. Secondly, three different methods was studied to synthesis the targeted molecule Ciclesonide from the above prepared key intermediate 16a-hydroxypredni-solone and finally found the optimal reaction condition to the compound (4)——4awas the main ingredient.In the second part, we carried our work on the synthesis of pivotal intermediates for inhibitor of the HMG-CoA reductase (Statins). Statin is a new-generation lipid-lowering medicines with reducing LDL-C and enhancing HDL-C developed in the eightieth of the 20th and the effect is the best by contrasting to others of the same types on market, exemplified by Pivavastatin and Rosuvastatin which have excellent spectrum activity.We focused on the preparation of the pivotal intermediate——t-Butyl (3R,5S)-6-oxo-3,5-O-isopropylidene-3,5-dihydroxyhexanoate. By comparing two different ways to synthesis the important intermediate from the start material (S)-malic acid or ethyl 4-chloroacetoacetate, the route from the later material was regarded as economic environmental and can be industrialized. And we optimized two synthetic routes and researched in detail. After pilot study, a technique was disvovered to separate syn-1,3-diol and anti-l,3-diol. In the end, we found that the coarse resultant aldehyde react with main body of statins without further purification, the experimental result was beyond compare.