A New Approach to the Total Synthesis of Rosuvastatin

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/H2 (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 inferior. Rosuvastatin precursor 1 was assembled by Wittig coupling of aldehyde 2 and ylide (R)-3, derived from a Ru-catalyzed asymmetric hydrogenation. The second stereogenic center was finally created by stereoselective reduction with Et2BOMe and NaBH4 to afford rosuvastatin ethyl ester. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

[1]  A. Börner,et al.  Highly Enantioselective Hydrogenation of Ethyl 5,5‐Dimethoxy‐3‐oxopentanoate and its Application for the Synthesis of a Statin Precursor , 2008 .

[2]  A. Börner,et al.  Synthesis of the Chiral Side Chain of Statins – Lactone versus Lactol Pathway , 2006 .

[3]  A. Börner,et al.  Synthesis and Highly Stereoselective Hydrogenation of the Statin Precursor Ethyl (5S)‐5,6‐Isopropylidenedioxy‐3‐oxohexanoate , 2006 .

[4]  Michael Böhm,et al.  Statins in the Treatment of Chronic Heart Failure: A Systematic Review , 2006, PLoS medicine.

[5]  W. Insull.  Treatment of hypercholesterolemia in patients with the metabolic syndrome: how do various statins compare? , 2006, Nature Clinical Practice Cardiovascular Medicine.

[6]  K. Rossen,et al.  A general and efficient method for the formylation of aryl and heteroaryl bromides. , 2005, Angewandte Chemie.

[7]  A. Olsson,et al.  Rosuvastatin is cost-effective compared with atorvastatin in reaching cholesterol goals. , 2005, International journal of cardiology.

[8]  N. Culhane,et al.  Rosuvastatin for the Treatment of Hypercholesterolemia , 2005, Pharmacotherapy.

[9]  J. Mckenney.  Efficacy and safety of rosuvastatin in treatment of dyslipidemia. , 2005, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[10]  B. Roth,et al.  Contemporary Drug Synthesis: Li/Drug Synthesis , 2004 .

[11]  Z. Ciunik,et al.  Synthesis, X‐ray Crystallographic and 1H NMR Spectroscopic Structural Studies on Cobalt(II) Complexes of Homoscorpionate, Heteroscorpionates and Chiral Tris(pyrazolyl)borates Obtained from 5(3)‐Isopropyl‐3(5)‐phenylpyrazole and 3,5‐Dimethylpyrazole , 2003 .

[12]  S. Roberts,et al.  A route to the structure proposed for puetuberosanol and approaches to the natural products marshrin and phebalosin , 2003 .

[13]  K. Hirai,et al.  Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors. , 1997, Bioorganic & medicinal chemistry.

[14]  T. Konoike,et al.  Practical Synthesis of Chiral Synthons for the Preparation of HMG-CoA Reductase Inhibitors , 1994 .

[15]  T. Horaguchi,et al.  Exploratory study on photoinduced single electron transfer reactions of .alpha.,.beta.-epoxy ketones with amines , 1991 .

[16]  O. Repič,et al.  Improved Synthesis of Fluoroalkyl and Fluoroaryl Substituted 2-Aminopyrimidines , 1990 .

[17]  M. Wilson,et al.  Inhibitors of cholesterol biosynthesis. 2. 1,3,5-trisubstituted [2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. , 1990, Journal of medicinal chemistry.

[18]  M. Jovanovic.  Iodination of some diazines and diazine N-oxides , 1984 .

[19]  Karl Schermanz,et al.  Dihydropyrimidines and related structures. I: N2-substituted 2-pyrimidinamines and dihydro-2-pyrimidinamines by reaction of phenylbutenones and monosubstituted guanidines , 1984 .

[20]  S. Pine,et al.  Formic acid-formaldehyde methylation of amines , 1971 .

[21]  D. Lyman,et al.  Acylation. I. The Mechanisms of Enol Ester and 1,3-Diketone Formation in the Reaction of Ketone—Enol Systems with Acyl Halides , 1966 .