Study On The Synthesis Process For The Key Intermediates Of Rosuvastatin

Rosuvastatin is a competitive inhibitor of hydroxymethyl-acetyl-Co A reductase,which can reduce cholesterol levels in the body.The therapeutic effect of rosuvastatin on lowering blood fat and cholesterol is significantly better than that of statins currently on the market,and it also has the advantages of long action time,less interaction with other drugs,and high safety.Rosuvastatin has achieved good market results after being listed and is known as "super statin".According to literature reports,(4R-cis)-6-carbaldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester and 4-(4-fluorophenyl)-6-isopropyl-2-(Nmethyl-N-methanesulfonylamino)pyrimidine-5-carbaldehyde is a key intermediate in the synthesis of rosuvastatin,which corresponds to two different reverse synthetic ideas Realized industrial production.There are some reported deficiencies in the synthesis process of these two intermediates,such as low yield,long reaction time,and dimethyl sulfide emission in the reaction.Therefore,in view of the above two intermediates,it is of great research significance and wide application value to develop a high-efficiency synthetic method with high yield and environmental friendliness.The main research contents of this article are as follows:(1)First,the selection of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methylN-methanesulfonamido)]-pyrimidine-5-methanol as the raw material was selected.The synthesis process improvement and optimization of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-pyrimidine-5-carbaldehyde by sexual oxidation reaction is about to be traditional The chemical oxidant oxidation reaction was improved to an air oxidation reaction involving TEMPO free radicals.In order to improve the catalytic efficiency,by adopting an improved method of catalyst derivatization,the catalyst of the oxidation system can still maintain a high catalytic activity after being effectively cycled for 5 times.Compared with the existing process,the yield of this route is basically the same,and the discharge of dimethyl sulfide is avoided to the greatest extent,and the separation and purification of the product and the catalytic system is more convenient and suitable for industrial applications.(2)On the other hand,the substitution of(4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester with acetate was studied 1.Synthesis and optimization of(4R-cis)-6-formaldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester by hydrolysis and selective oxidation reaction.In the acetate substitution reaction step,by using imidazole ionic liquid catalysis,the existing process conditions were optimized to reduce the reaction time from the original 24 hours to within 3 hours,and the reaction yield was increased from 75% to 83%.Secondly,in the selective oxidation reaction step,the traditional Swern selective oxidation reaction was improved to an air oxidation system involving diamine ligands,avoiding dimethyl sulfide emissions,and further improved compared with the TEMPO/air oxidation system Air's ability to oxidize aliphatic alcohols.After further investigation on the key factors affecting the reaction in the above steps,the optimal reaction conditions were determined,and the target product with higher purity was obtained,with a total route yield of 62%.Compared with the original process,this method has fast reaction rate,high yield,relatively environment-friendly,and has great industrial application value.The research of the paper makes the key intermediate of rosuvastatin 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-pyrimidine-5-carbaldehyde and(4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester synthesis route has a more valuable choice,also for Ruishu The commercial production of vastatin plays a good role in promoting.