Study On Synthesis Of High Purity Atorvastatin Calcium

The chemical name of Atorvastatin calcium is(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate trihydrate,which is a novel tissue-selective inhibition of the synthesis of 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-GoA).It can reduce the level of low-density lipoprotein cholesterol in the blood circulation and inhibit the synthesis of cholesterol in the plasma,thereby achieving the effect of reducing blood lipids.Compared to the other statins,atorvastatin calcium has a stronger hypolipidemic effect,a longer duration of action,a rapid onset of action,safety,and high efficacy.This prompt atorvastatin calcium become a best-selling drug for the treatment of cerebrovascular diseases.At the same time,the optimization of this drug has also become a research hotspot to scientific researchers.On the basis of studying a large amount of literature,the first chapter of this paper briefly describes the current pathogenesis of cardiovascular and cerebrovascular diseases and the research status of lipid-lowering drugs,and compares the existing synthesis routes of atorvastatin calcium.It is finally determined that the atorvastatin calcium key intermediate L1 is prepared by the Paal-Knorr method,followed by hydrolysis to deprotect it and then salified to obtain atorvastatin calcium.In addition,this section also provides an overview of the raw materials,key intermediates,and major impurities in this synthesis method.The second chapter of this article is a pilot study of the synthesis of high-purity atorvastatin calcium,which consists of three parts: 1.During the process of studying the purification method of ATS-9,it is determined that the method of forming a salt with pivalic acid and then deacidification,it can increase the content of ATS-9 from 97.92% to 99.90% and its yield is 97.01%.2.It is found that ATS-9 pivalate salt is more stable than ATS-9 during the study of refined ATS-9 and easier to purify.Therefore,the reaction of ATS-9 and M4 in the original process is changed to the reaction of ATS-9 pivalate and M4.In response to this change,a large number of experimental conditions are explored,and the best catalyst triethylamine is found which break through the original process.Catalyst dosage is 1% of M4 mass,which greatly shorten the reaction time.According to the optimized experimental conditions,the refined product of L1 can reach 96.76% and the yield is 80.40%.According to L1 crude: isopropyl alcohol: distilled water =2 : 0.25 : 1(quality ratio)the L1 purity obtained by refining is 99.88% and the yield is 94.20%.3.The experimental process of preparing atorvastatin calcium by acid hydrolysis of L1 to deprotect it into salt is optimized,and the best purification method of atorvastatin calcium is found.In the condition of methanol: tetrahydrofuran: water: atorvastatin calcium crude = 12 : 3 : 20 : 1,the content of the atorvastatin calcium can be refined from 98.67% to 99.98% and the yield is 98.50%.Total yield from ATS-9 to atorvastatin calcium products is 60.82%.The third chapter of this paper is to enlarge the small test process of the second chapter from 10g-100g-500 g.Based on the 10 g process parameters,the parameters of the 100 g reaction process are selected and optimized.rocess parameters of 100 g are finally determined,the amount of solvent in L1 is from the original methanol: distilled water: ethyl acetate: L1 quality =8 : 8.5 : 10.2 : 1 optimization is 7 : 7.5 : 9 :1,and the optimal refining method of atorvastatin calcium is performed in the original condition: methanol: tetrahydrofuran: water: atorvastatin calcium crude = 12 : 3 : 20 : 1 optimizes to 10 : 2.5 : 16.7 : 1.The content of the atorvastatin calcium product is 99.98%.Total yield from ATS-9 to atorvastatin calcium products is 65.0%.On the basis of the 100 g process parameters,the process is scaled up to 500 g,and three batches of experiments are performed to verify that the final 100 g process parameters are determined as the pilot plant experimental parameters.The experimental results of this paper are mainly the product content data which are measured by gas chromatography and high performance liquid chromatography.