Studies On Asymmetric Synthesis Of Side Chain Of Rosuvastatin And Related Reactions

Rosuvastatin calcium (Crestor(?)), calcium salt of bis[(E)-7-[4-(4-fluorophenyl)-6-isoProPyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoie acid], is a totally synthesized single enantiomer, belonging to the new generation of statins pharmaceuticals. Because of its safety, efficiency and other excellent characteristics, it is also called "super statin". The present commercial production of rosuvastatin side chain has many disadvantages, for example, it uses highly toxic sodium cyanide and explosive methoxy diethyl boron. Focusing on those deficiencies, this thesis describes a novel environmentally friendly route for preparing rosuvastatin side chain. The key technique in this approach is applying HWE reaction to prolong carbon chain and intramolecular Michael addition reaction to creat the (3R)-stereochemistry of side chain. This work provides an important base for further optimization of industrial production for rosuvastatin side chain.In chapter 1, methods for preparing chiral side chain 1.1 and its intermediates have been overall reviewed since the first statin drug (Lovastatin) was developed by Merck in 1987, which could be divided into five categories:chiral auxiliary method, chiral pool method, asymmetric catalysis, asymmetric enzymatic catalysis and chiral resolution method.In chapter 2, a new route for the synthesis of chiral side chain of rosuvastatin calcium was described. The key intermediate 2.11 was obtained through this method starting from (R)-epichlorohydrin and then applying HWE reaction and Michael addition reaction as key techniques via six steps. Since it uses inexpensive and commercially available raw material and avoids highly toxic sodium cyanide and explosive methoxy diethyl boron, this new route could be considered as a promising industrial method.