| Pitavastatin calcium is(+)-monocalcium bis ?(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate},which is a new statin HMG-CoA reductase inhibitors to treat cardiovascular disease.There were many ways to synthesize Pitavastatin calcium,but chiral center and its yield were mianly poor.In the existing synthetic routes,there were several deficiencies such as high cost,low yield,and tough experimental conditions.To solve these problems,we develop a suitable synthetic route.In our way 2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylic acid methyl ester(12)was used as raw material,with the reduction reaction,substitution reaction,Wittig reaction,dehydroxylation protection and ester hydrolysis.We succeeded to synthesize pitavastatin calcium with a total yield of 28.9%.Compared with the existing routes,our route showed advantages in industrial production with raw material easy to get,the price cheaper,the requirement of equipment and operation lower,and process convenient.The main results of the study are as follows:(1)The first step was reduction reaction.2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylic acid methyl ester(12)as raw material was reduced into alcohol hydroxyl under the reduction system of ZnC12/KBH4 The structure of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-methanol(13)was determined by 1HNMR,LC-MS and melting point.The HPLC analysis method of compound(13)was also set up.The influence of raw material ratio,temperature and reaction time was investigated.The purity of compounds(13)was around 99.0%with yield 65.4%more than literature data 63%.The highlight of the step was that the residue was recrystallized for twice with more products withdrawed.(2)The second step was the substitution reaction.With the alcoholic hydroxyl of compound(13)substituted by the bromine 3-(bromomethyl)-2-cyclopropy-4-(4'-fluorophenyl)quinoline(30)was preparation.Based on the study of reaction temperature,material ratio and post-processing,the purity of compound(30)was more than 99%with the yield 89.7%.The unreported mixed solvent of hexane and ethanol was used as recrystallization solvent,which can avoid the ethers impurity generated by compound(13)and ethanol and the product can be better decolorization.(3)The third step reaction is that compound(30)reacted with triphenylphosphine to[2-Cyclopropyl-4-(4-fluorophenyl)-quinolin-3-ylmethyl]-triphenyl-Phosphonium bromido(34).Compound(34)as hydrocarbon triphenyl phosphate salt could be got rid of a-H into phosphorus ylide under the effect of the base with stronger nucleophilicity.Phosphorus ylide reacted with the aldehyde ketone by wittig reaction was used to the preparation of alkene compounds which was difficult to synthesize by the general method.The optimization conditions of temperature and ratio of reactants were studied with yield 96.4%.(4)The fourth step was wittig reaction,which is the key steps for the synthesis of pitavastatin calcium.With anhydrous K2CO3,chiral aldehyde tert-Butyl(4R-cis)-6-formaldehydel-2,2-dimethyl-1,3-dioxane-4-acetate(29)reacted with compound(34)to alkene compound(32).The optimization conditions of reaction time,reaction temperature,ratio of reactants and post-processing were studied with yield 67.9%.In this step reaction,potassium carbonate was the first reported as a catalyst,which was,milder and avoided danger reagents such as sodium hydride and n-butyl lithium with lower cost of raw materials and easlier post-processing.(5)Compound(32)can synthesize pitavastatin calcium by dehydroxylation protection,ester hydrolysis,alkali neutralization and calcification.In this step,trifluoroacetic acid was replaced by hydrochloric acid showing cheaper and esay to get.In recrystallization of pitavastatin calcium we found that the optimal volume ratio of isopropyl alcohol and water was 1/2 with yield 75.4%and the HPLC purity 99.91%.Finally,the product structure was verified with 1HNMR,LC-MS and Elemental Analysis... |
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