Synthesis Study Of A Key Intermediate Of The HMG-CoA Reductase Inhibitors

The paper was focused on the synthesis of key intermediate for HMG-CoA reductase inhibitors which is a new type of hypolipidemic drugs--statin drugs developed from 1980s. These drugs have extreme efficacy with little side-effect, and won a dominant position in the hypolipidemic drugs market, meanwhile with the highest growth rate leapt to the forefront in the entire cardiovascular drugs market.Generally, statin drugs are synthesized by the clustering approaches, that is, firstly the main skeleton and hexanoate with double chiral hydroxy group are synthesized separately, and then the both react further to the final product. We study the synthesis of tert-butyl (3R,5S)-6-hydroxy-3,5-0-isopropylidene-3,5-dihydroxyhexanoate, which can conveniently convert to the intermediates of statin drugs.So far, various approaches can synthesize these crucial intermediates. However, all of these are unable to satisfy our demand of industrial statin-drug production. Base on the existing methods, we did some improvement and achieved two approaches. The main work of the first approach is to synthesize (S)-3-hydroxy-Y-butyrolactone and to get target compound by several subsequent reactions. The idea of the second one came from the asymmetric hydrogenized reduction obtaining the second chiral hydroxy under THP protection. But the protective group has obvious deficiencies, inducing unsatisfied yield and d.e. Herein, PMB was selected to protect ethyl (S)-4-benzyloxy- 3-hydroxybutyrate. After Claisen condensation and asymmetric hydrogenized reduction, and then PMB was deprotected by CAN. Finally the target compound was obtained through two more steps. The total yield and d.e of the latter approach is extraordinary satisfied. The latter approach, which is main work of this thesis, has been successfully completed and applied for patent protection.The two improved approaches are economic, environmentally friendly, simple and suit to be industrialized. Especially, the second approach obtains the target compound through twice asymmetric hydrogenized reductions, in which the proliferation of the chiral catalyst is great, enormously decreasing the cost of production.