Studies On The Synthetic Process For Atorvastatin Calcium

Rencently, cardiovascular and cerebrovascular disease has become the leading cause of human death causes. Statins could inhibit 3- hydroxy- 3- methyl glutaric acyl coenzyme A(HMG-CoA) reductase and play an important role of reducing blood fat. Atorvastatin calcium, as the outstanding drug of statins, has a flexible time of taking medicine, high activity and low side effects, and many other advantages, and thus is widely researched. Furtheremore, it is not only used in mixed hyperlipidemia, hypercholesterolemia, but also can prevent coronary heart disease, stroke and unstable angina, and can reduce the cardio-cerebrovascular disease mortality etc.A brief review on cardiovascular and cerebrovascular disease in the points of the actualities, pathogenesis and development of the therapeutic medicine was given. This article focuses on the research background of atorvastatin calcium and the recent research progress of synthesis. And its synthetic process is also described in detail.According to the reference literatures at home and abroad, the synthesis methods of atorvastatin calcium were summarized in this paper, including linear synthesis and convergent synthesis. In this paper a review was made on them, the three main synthetic routes were summed up, and the synthesis process were studied. Liner synthesis mainly includes phenethylamine resolution method, diastereoselective Aldol reaction, Olefin metathesis reaction and metal complex catalytic asymmetric reduction method and so on. Convergent synthesis is divided into the side chain synthesis, main ring synthesis and condensation reaction between them. There are many methods to synthesize side chain and main ring respectively. In terms of industrialization, convergent synthesis has much greater advantages. Through literature investigation, we select a simple and efficient synthetic route of easily realizing industrialized production, that is, the convergent synthesis of target product, which not only overcomes the shortcoming of low yield caused by tedious reaction steps in the linear synthesis, but also increases the total yield. This paper discussed the reaction mechanism, improved and optimized the reaction conditions. In addition, we also synthesized the main ring and side chains, and then got the condensation product L1 through a Paal-Knorr reaction between them. Finally we got the target product atorvastatin calcium with much higher total yield than reported in the literature through deprotection, saponification and the process of changing into calcium salt.The synthetic process of the important intermediate 2-(2-(4-fluorophenyl)-2-ox-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide(main ring) and condensation compound L1 were researched and a novel synthetic route was designed. The structure of intermediates of every reaction step and final products had been confirmed by HPLC-MS data, 1H-NMR and 13C-NMR spectroscopy. The improved process has the advantages of cheaper raw materials, easier operation, higher yield and better product, and is quite suitable for industrialized production.