Synthesis And Characterization Of Pitavastatin Calcium

Pitavastatin calcium, as a kind of 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors, has been used in clinic for the treatment of hyperlipoidemia, which was registered in Japan in november 1999 and peformed clinical experimentⅡin America. It has been listed in 18 kinds of the greatest sales potential of new drugs in the world, which not only with advantages of other statin drugs, but also with the shorter onset time, lower dosage, smaller side effects, better tolerance, better market prospects. Some experts have predicted that both pitavastatin calcium and rosuvastatin will become two major drugs that leading statin drug market in the next few years.At present, the main problems of developing pitavastatin calcium are: its complex structure, the difficulty of the synthesis and the high cost of the synthesis, and its industrialization technology has not been found in the domestic market. Therefore, it is necessary to develop synthesis process with high efficiency, low pollution and low cost.On the basis of references, the main synthesis methods of pitavastatin calcium are as follows: optical resolution, chiral reagents and other methods. The defect of chiral reagents is the great difficulty in the synthesis of side chains; expensive reagents used in other ways resulted in the high cost; the process of optical resolution was used in this paper because of strong controllability and ease operation.In order to ensure the quality of the final product, the Z-isomer impurity of starting material by HPLC was studied and controlled. The results show that the E-isomer of the raw materials in light (UV) radiation was turned into the unstable Z-isomer, with higher energy, but transfomed into the E-isomer with thermodynamic stability by heating (condensed into a solid process).The effects of system solvent, raw materials molar ratio, recrystallization solvent and chiral separation reagent on reaction results were investigated. The optimized process conditions were as follows: Intermediate 3 was prepared via the reaction of starting material 3-(2'-cyclopropyl-4 '-(4 "- fluorophenyl)-quinoline 3'-yl) - acrolein with ethyl acetoacetate under sodium hydride / butyl lithium catalysis; under the conditions of tetrahydrofuran-methanol as solvent, the ratio of materials: Intermediate 3: diethyl methoxy-B: sodium borohydride = 1:1.25:1.34, temperature: -70℃, the intermediate 4 was prepared in 98.0% yield; Double salts 6 was formed after the intermediate 4 were hydrolyzed in an aqueous NaOH solution and then splited by D-(+)-a-methyl benzylamine. When the ratio of materials: Intermediate 4: D (+)-a-methyl benzylamine=1:1.25, ethanol and methyl isobutyl ketone as crystallization reagent, the yield of double salts 6 is as high as 29.2 %; finally pitavastatin calcium was synthesized in one step by salt formation with sodium hydroxide and calcium chloride.The structures of the target compound were characterized and analysed by 1H-NMR and IR, the results showed that its structure is in line with sample pitavastatin calcium.