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Processes for preparing calcium salt forms of statins

Inactive Publication Date: 2005-09-08
TEVA PHARMA IND LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The '460 patent does not disclose any methods for preparing the calcium salt of rosuvastatin.
The '930 patent and its related patents do not disclose preparing the calcium salt of any compound.
U.S. Pat. No. 6,335,449 does not disclose how to prepare the calcium salt or any other salt of pitavastatin.

Method used

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

Examples

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example 1

Preparation of Atorvastatin Calcium from a Dioxane Ester Derivative

[0072] In a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester (2.0 g) was suspended in an 80% aqueous solution of acetic acid (50 ml). The mixture was stirred at ambient temperature for about 20 hours until a clear solution was obtained. The clear solution was evaporated to dryness and the traces of acetic acid were removed by azeotropic distillation with toluene (3×50 ml) to obtain a powder.

[0073] The above obtained powder (200 mg, 0.32 10−3 mole) was dissolved in ethanol (8 ml), to which a saturated solution of calcium hydroxide (8 ml) containing tetrabutyl ammonium bromide (10 mg) was added. The mixture was stirred and heated at a temperature of about 45° C. for about 24 hours. Additional saturated solution of calcium hydroxide (4 ml) was added. After about 20 minutes of stirring at ambien...

example 2

Preparation of Atorvastatin Calcium from a Dioxane Ester Derivative

[0074] In a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester (10.0 g, 15.29 10−3 mmole) was suspended in an 80% aqueous solution of acetic acid (150 ml). The mixture was stirred at ambient temperature overnight until a clear solution was obtained. The clear solution was evaporated and the traces of acetic acid were removed by azeotropic distillation with toluene (3×100 ml) to obtain an oily product containing toluene.

[0075] The oily product was placed in a mixture of ethanol (100 ml) and water (20 ml). A mixture of calcium hydroxide (5.5 eq., 6.22 g, 84.0 10−3 mmole) and 5% (w / w of the dioxane ester derivative) tetrabutyl ammonium bromide (0.46 g) was added. The mixture was heated to a temperature of about 45° C. for about 3 hours until the reaction was completed. While the mixture was hot, ...

example 3

Preparation of Atorvastatin Lactone from a Dioxane Ester Derivative

[0076] To a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester (0.5 g, 0.76 10−3 mmole) was dissolved in a 1:1 mixture of trifluoroacetic-tetrahydrofuran (4 ml) in the presence of catalytic amount of water. The reaction mixture was stirred at ambient temperature for about 24 hours. The solution obtained was evaporated and the traces of trifluoroacetic were removed by azeotropic distillation with ether (3×100 ml). A white solid was obtained (0.3 g). Based on HPLC analysis, the white solid was a mixture of atorvastatin and atorvastatin lactone in the ratio of 40:60, respectively.

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Abstract

Processes for preparing a calcium salt of a statin from an ester derivative or protected ester derivative of the statin by using calcium hydroxide are provided. The ester or protected ester derivative is contacted with calcium hydroxide to obtain the calcium salt. Preferred statins are rosuvastatin, pitavastatin and atorvastatin, simvastatin and lovastatin. In processes beginning with a protected statin ester derivative, the protecting group is hydrolyzed during salt formation by contact with calcium hydroxide, or is contacted with an acid catalyst followed by contact with calcium hydroxide.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of provisional application Ser. No. 60 / 312,812, filed Aug. 16, 2001 and U.S. patent application Ser. No. 10 / 037,412, filed Oct. 24, 2001, which claims the benefit of provisional application Ser. No. 60 / 249,319, filed Nov. 16, 2000, all of which are incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates to processes for preparing calcium salt forms of statins. BACKGROUND OF THE INVENTION [0003] 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 rup...

Claims

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Application Information

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IPC IPC(8): A61KC07D207/34C07D209/24C07D213/55C07D215/14C07D239/42C07D309/30C07D405/06C07F
CPCC07D207/34C07D209/24C07D213/55C07D405/06C07D239/42C07D309/30C07D215/14Y02P20/55C07F3/04
Inventor NIDDAM-HILDESHEIM, VALERIELIFSHITZ-LIRON, REVITALLIDOR-HADAS, RAMI
Owner TEVA PHARMA IND LTD
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