Processes for preparing calcium salt forms of statins

Details Processes for preparing calcium salt forms of statins Processes for preparing calcium salt forms of statins

2002-08-16

2004-08-17

Solola, Taofiq (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C548S491000, C548S537000, C549S292000

Reexamination Certificate

active

06777552

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to processes for preparing calcium salt forms of statins.
BACKGROUND OF THE INVENTION
The class of drugs called statins are currently the most therapeutically effective drugs available for reducing low-density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease and 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 Gilman, 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. Lovastatin (disclosed in U.S. Pat. No. 4,231,938) and simvastatin (ZOCOR; disclosed in U.S. Pat. No. 4,444,784 and WO 00/53566) are administered in the lactone form. After absorption, the lactone ring is opened in the liver by chemical or enzymatic hydrolysis, and the active hydroxy acid is generated. Pravastatin (PRAVACHOL; disclosed in U.S. Pat. No. 4,346,227) is administered as the sodium salt. Fluvastatin (LESCOL; disclosed in U.S. Pat. No. 4,739,073) and cerivastatin (disclosed in U.S. Pat. No. 5,006,530 and 5,177,080), also administered as the sodium salt, are entirely synthetic compounds that are in part structurally distinct from the fungal derivatives of this class that contain a hexahydronaphthalene ring. Atorvastatin and two new “superstatins,” rosuvastatin and pitavastatin, are administered as calcium salts. The structural formulas of these statins are shown below.
Atorvastatin is the common chemical name for [R-(R
*
,R
*
)]-2-(4-fluorophenyl)-&bgr;&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. The free acid of atorvastatin is prone to lactonization. The systematic chemical name of atorvastatin lactone is (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. Atorvastatin and its corresponding racemic lactone are disclosed in U.S. Pat. No. 4,681,893.
The lactone form is disclosed in U.S. Pat. No. 5,273,995. In Examples 4 and 5 of the '995 patent, the lactone is prepared by dissolving 1,1-dimethylethyl (R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoate in tetrahydrofuran and triethyl borane, followed by the addition of t-butylcarboxylic acid. After cooling, methanol is added followed by sodium borohydride. The mixture is poured into an ice/hydrogen peroxide/water mixture. Trichloromethane is added and the mixture is partitioned. The organic layer is dried over magnesium sulfate, filtered, and the solvent is evaporated. The product is dissolved in tetrahydrofuran and methanol and added to a solution of sodium hydroxide. The mixture is concentrated to remove organic solvent, added to water, and extracted with diethyl ether. The aqueous layer is acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is dried with anhydrous magnesium sulfate, filtered, and the solvent evaporated. The residue is dissolved in toluene and concentrated. The product is recrystallized from ethyl acetate and hexane to produce the lactone.
The lactone can also be prepared according to the procedures disclosed in U.S. Pat. No. 5,003,080. For instance, in Example 2, Method A, cis-2-(4-Fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl-1H-pyrrole-1-heptanoic acid, methyl ester is treated with sodium hydroxide, and after dilution with water and separation, the remaining layer are washed with hexane and ethyl acetate followed by concentrated hydrochloric acid solution. Upon separation, the upper layer is washed with hydrochloric acid and concentrated. The residue is dissolved in toluene.
As disclosed in the '080 patent, the lactone can also be prepared by mixing (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (Example 2, Method B); (±)-(2&agr;,4&agr;,6&agr;) or (±)-(2&agr;,4&bgr;,6&bgr;)-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid (Example 2, Method C); (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid (Example 2, Method D); (±)-cis-(4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-2acetic acid (Example 2, Method E); or (±)-(2&agr;,4&agr;,6&agr;) or (±)-(2&agr;,4&bgr;,6&bgr;)-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid (Example 2, Method F and G) with (±)-4-fluoro-&agr;-[2-methyl-1-oxopropyl]-&ggr;-oxo-N,&bgr;-diphenylbenzenebutaneamide in dimethyl sulfoxide. After heating, the solution is poured into a mixture of diethyl ether and saturated ammonium chloride in water. After separation, the organic layer is washed with water and sodium hydroxide. The aqueous layer is acidified with dilute hydrochloric acid and extracted with ethyl acetate, to which hydrochloric acid is added, and the solution is concentrated. The residue is dissolved in toluene.
Another method of making the lactone, according to the '080 patent, includes mixing (+)-cis 1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (Example 2, Method H); (±)-(2&agr;,4&agr;,6&agr;) or (±)-(2&agr;,4&bgr;,6&bgr;)-1,1-dimethyl-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetate (Example 2, Method I); or (±)-cis-1,1-dimethylethyl (4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate (Example 2, Method J) with (±)4-fluoro-&agr;-[2-methyl-1-oxopropyl]-&ggr;-oxo-N,&bgr;-diphenylbenzene butaneamide in heptane:toluene (9:1). After heating, the solution is poured into a mixture of tetrahydrofuran and ammonium chloride in water. After separation, the organic layer is washed with brine, followed by the addition of hydrochloric acid. After stirring, sodium hydroxide is added to the organic layer. The reaction is stopped by adding a mixture of water and hexane. After separation, the aqueous layer is acidified with dilute hydrochloric acid, extracted with ethyl acetate, and concentrated. The residue is dissolved in toluene.
The lactone or the free acid may be used to prepare the pharmaceutically acceptable calcium salt, [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate. In animal models, atorvastatin calcium salt has been shown to lower plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver. Atorvastatin is marketed by PFIZER as the hemicalcium salt trihydrate under the trade name LIPITOR, as 10, 20, 40 and 80 mg tablets. Atorvastatin hemicalcium salt has the following structure:
The hemicalcium salt is disclosed in U.S. Pat. No. 5,273,995, which teaches that the calcium salt is obtained by crystallization from a brine solution resulting from the transposition of the sodium salt with calcium chloride and further purified by recrystallization from a 5:3 mixture of ethyl acetate and hexane.
U.S. Pat. No. 5,298,627, also discloses a process for making the hemicalcium salt. In Example 1 of this patent, (4R-cis)-1-[2-[6-[2-(

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