Studies On Asymmetric Synthesis Of Atorvastatin Calcium And Its Relative Reactions

Atorvastatin calcium, a3-hydroxy-3-methyl-glutaryl coenzymeA (HMG-CoA) reductase inhibitor, has been the most widely used and one of the best-selling drugs for the treatment of hypercholesterolemia due to its efficiency, safety, and long-term benefits. To date, a lot of synthetic methods and strategies have been reported. However, several drawbacks such as long multistep preparation sequences as well as the harsh reaction condition make the problem of industrial synthesis of atorvastatin calcium unresolved. In this thesis, a short and cyanide-free synthetic route has been achieved, laying the foundation for the further industrial research.In chapter1, the significant advancement of atorvastatin calcium utilizing different strategies including chiral pool synthesis, chiral auxiliary method, asymmetric catalysis, and chemoenzymatic processes over the past30years is described.In chapter2, a novel and5-step asymmetric synthesis of atorvastatin calcium (1) was accomplished in40%overall yield through the key intermediate7by employing a Ti(O-i-Pr)4-Schiff base complex promoted asymmetric aldol reaction as the key technique. The enantiomeric purity of1was determined to be>99%ee which was up to the quality standards of the European Pharmacopoeia after recrystallization. Meanwhile, a set of novel Schiff base chiral ligands was designed and synthesized utilizing (1S,2S)-2-amino-l-(4-nitrophenyl)-1,3-propanediol, an unwanted-product in the industrial production of chloramphenicol as starting material, reducing the cost of the ligands. Moreover, the preparation of1-amino-3,3-diethoxypropane in62%overall yield from commercially available acrolein avoided the highly toxic cyanide in the traditional synthesis of atorvastatin calcium. The novel route is characterized by cheap and readily available reagents, short preparation sequences and mild conditions, making it practical for large-scale preparation.