A New Approach to the Total Synthesis of Rosuvastatin

Abstract

A new multi-step synthesis of the lipid-lowering agent rosuvastatin, involving two homogeneously catalyzed reaction steps, is described. The key building block, N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (2), was prepared by Pd-catalyzed formylation with CO/H 2 (1:1, 50 bar, phosphane ligand/substrate ratio of 1:10). Several alternative pathways for the preparation of 2 were also tested, but were found to be in-

Highly stereoselective hydrogenations—As key‐steps in the total synthesis of statins

“…39,40 The first part covers the asymmetric hydrogenation of ethyl 5,5-dimethoxy-3-oxopentanoate (17) to ethyl 3-hydroxy-5,5-dimethoxypentanoate (18) (Scheme 6). 41 From the retrosynthetic analysis depicted in Scheme 6 it follows that the chiral side chain of rosuvastatin acid A can be created by diastereoselective and chemoselective reduction of the keto group in structure B. The protected hydroxy ylide (R)-19 was postulated as a possible building block for the preparation of B, as long as the Wittig coupling reaction with the corresponding aldehyde could be performed and the HO-protecting group subsequently removed.…”

“…Wittig coupling of aldehyde 26 and ylide (R)-19 was performed under reflux in CH 3 CN over 14 h and gave the rosuvastatin precursor 27 in a yield of 70% (Scheme 11). 41 Removal of the tBuPh 2 Si protective group by treatment with aqueous HF in CH 3 CN and final exclusive diastereoselective reduction of the keto group with Et 2 B(OMe) and NaBH 4 in THF/MeOH at -788C, afforded rosuvastatin ethyl ester in 85% yield.…”

Highly Enantioselective Hydrogenation of Ethyl 5,5‐Dimethoxy‐3‐oxopentanoate and its Application for the Synthesis of a Statin Precursor

“…[28] The employment of ylide (R)-6 for the synthesis of rosuvastatin, as well as the synthesis of the requisite heterocyclic part, will be described in a subsequent publication. [29] …”

An Efficient Synthesis and In Vitro Antimicrobial Screening of 2-Cyanoimino -4-aryl-6-(1,1'-biphenyl-4-yl)-3,4-dihydro-1H-Pyrimidines

“…drugs Meridianins (Antitumor) 6 , Diaveridine (Antimicrobial) 7 , and Peroly-L-glutanin (Anemia-treatment) 8 . Although large number of functionalities with different position in 2-aminopyrimidines were reported, the N-substitution in amino moiety possess a divergent pharmacological activities like Rosuvastatin (Reduce cholesterol level) 9 , tyrosine kinease inhibitor Gleevec 10 etc.…”