A PROCESS FOR THE PREPARATION OF ROSUVASTATIN INVOLVING A TEMPO-MEDIATED •OXIDATION-STEP
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of provisional application Serial Number 60/587,653, filed July 13,2004, which is incorporated herein by reference.
FIELD OF THE INVENTION The present invention relates to processes for the preparation of rosuvastatin.
BACKGROUND OF THE INVENTION
Statins are currently the most therapeutically effective drugs available for reducing low-density h'poprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Thus, statins are used in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. A high level of LDL in the bloodstream has been linked to the formation of coronary lesions that obstruct the flow of blood and can rupture and promote thrombosis (Goodman and Oilman, The Pharmacological Basis of Therapeutics, page 879, 9th Ed. 1996).
Statins inhibit cholesterol biosynthesis in humans by competitively inhibiting the 3- hydroxy-3-methyl-glutaryl-coenzyme A ("HMG-CoA") reductase enzyme. HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Decreased production of cholesterol causes an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. Reduction in the LDL level in the bloodstream reduces the risk of coronary artery disease (J.A.M.A. 1984,251,351-74).
Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin, which are administered in their lactone form, as sodium salts or as calcium salts. Rosuvastatin calcium is disclosed in U.S. patent No. 5,260,440.
Rosuvastatin (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-rnethylsulfonylamino) pyrimidin-5-yl]-(3R, 5S)-dihydroxy-(E)-6-heptenoic acid) calcium is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shonogi, 8 Feb 1999 & 25 Feb 2000). Rosuvastatin is a superstatin,
which can lower LDL-cholesterol and triglycerides levels more effectively than first generation drugs. Rosuvastatin calcium has the following chemical formula:
Rosuvastatin calcium
Rosuvastatin calcium is marketed under the name CRESTOR® for treatment of a mammal such as a human. According to the maker of CRESTOR®, it is administered in a daily dose of from about 5 mg to about 40 mg. For patients requiring less aggressive LDL-C reductions or who have pre-disposing factors for myopathy, the 5 mg dose is recommended, while 10 mg dose is recommended for the average patient, 20 mg dose for patients with marked hyper-cholesterolemia and aggressive lipid targets (>190 mg/dL), and the 40 mg dose for patients who have not
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