Lowering Drug Atorvastatin The Ting Calcium Synthesis

Atorvastatin is a new generation of HMG-CoA reductase inhibitors (blood lipid lowering agent of statins class). Not only cholesterol but also triglyceride(TG) can be lowered by the agent and it is more effective than other statins such as simvastatin, pravastatin, fluvastatin and lovastatin .With a daily oral dose of 10 mg/d LDL-C can be lowered by 40%; with a 20~40mg/d daily dose TG can be lowered by 30%, and the event of coronary heart disease and its mortality can also be decreased .This paper is a study about the synthesis of atorvastatin. There are two strategy,one is liner synthesis and the other is convergent synthesis. The convergent is more practical. The synthesis of 4-Fluro- α -[2-methyl-l-oxopropyl]- Y -oxo-N, β -diphenylbenzenebutaneamide(mother nucleus) and (4R,6R) 1,1 -dimethylethyl-6-(2-aminoethyl)-2,2-dimethyI-1,3-dioxane-4-acetate(side chain) is reviewed in detail. The convenient routes start from malonic acid to mother nucleus and from L-malic acid to side chain.The mechanism and optimization of every step has been discussed. With the fully functionalized,stereochemically pure side chain and the fully substituted mother nucleus in hand.they are reacted under Paal-Knorr's condensation.Deprotection and formation of the hemi-calcium salt produced atorvastatin calcium in high-yielding and commercially viable manner. From malonic acid the overall yield of atorvastatin calcium is 9.35% .(7.56% of reference)In the course of the synthesis of the mother nucleus ,the amount of N-ehtylthiazolium catalyst is cut down. The total yield of the mother nucleus is 16.4%,which is correspond to 16.8% of the reference.In order to improve stability of acylated meldrum's acid (AST-2), hydrolyzing it to 4-methyl-3-carbonyl butyrate sodium salt as a solid is studied.In the course of the synthesis of the side chain , the L-malic acid dimethyl ester is reducted to (S)-3,4-dihydroxybutane acid methyl ester with the use of self-made borane-dimethyl sulfide,followed by sulfonylation and cyan displacement, then the key intermediate (R)-4-cyano-3-hydroxybutane acid methyl ester is obtained. Lithium diisopropylamine and methoxydiethylborane ,which are used in the reactions of the side chain, are very expensive and can not be produced in our country.These two reagents are synthesized and used directly in our reactions. In order to control optical purity, (4S,6R)-1,1 -dimethylethyl-6-cyanomethyl-2 , 2-dimethyl-l,3-dioxane-4-acetate (the isomer of ATS-8) is synthesized.With the prove ofHPLC-MS ,the synthesized ATS-8's optical purity is highly ,and there is no epimeric isomer after recrystallization. The total yield of side chain is improved from 50.2% of the reference to 57.5% of experiment.In the condensation reaction the ratio of mother nucler to side chain is decreased from 1:1.3 to 1 :l,and the total yield is increased from 45% of the reference to 57%.Atorvastatin calcium has been confirmed by element analysis, MS, NMR,IR,TGA and water analysis ,rotation and 'H-NMR are in accord with the reference.