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Process for preparing rosuvastatin

A technology of rosuvastatin and alkyl, applied in the field of preparation of HMG-CoA reductase inhibitors, achieving the effect of high yield and purity

Inactive Publication Date: 2011-12-14
新梅斯托克尔卡・托瓦纳・兹德拉维尔公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] It has been found that the prior art processes for the preparation of rosuvastatin have various drawbacks such as the need for protecting groups or the need for multiple reaction steps

Method used

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  • Process for preparing rosuvastatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0239] a.) tert-butyl 2-[(4R,6S)-6-(iodomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (V)

[0240] To toluene (11.5 mL) was added tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl- 1,3-Dioxan-4-yl]acetate (1 g, 3.84 mmol), imidazole (0.523 g, 7.68 mmol) and triphenylphosphine (2.01 g, 7.78 mmol) and cooled on ice. With stirring, iodine (1.46 g, 5.80 mmol) was added in several portions. After further stirring on ice for several minutes, stirring was continued at room temperature for 2.5 h. The white precipitate formed was removed by filtration and the filtrate was evaporated to dryness to afford 1.295 g (91%) of the title compound as a yellow oil. IR: 2978, 1727, 1380, 1368, 1261, 1203, 1158, 951, 844.

[0241] b.) tert-butyl 2-{(4R, 6S)-6-[(triphenylphosphonium)-methyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl Ester iodide (IV)

[0242] In a nitrogen atmosphere at reflux temperature, tert-butyl 2-[(4R,6S)-6-(iodomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]ethane Ester (1.61 g, 4.35...

Embodiment 1-2

[0244] a.) tert-butyl 2-{(4R,6S)-6-[(tert-butyldiphenylsilyloxy)methyl]-2,2-dimethyl-1,3-dioxane- 4-yl]acetate

[0245] Tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (20mmol, 5.20 g) was dissolved in dichloromethane (12 mL), imidazole (1.852 g) was added, and the mixture was cooled on ice. Tert-butyldiphenylchlorosilane (6.24 mL) was added with stirring. After stirring on ice for another 15 min, stirring was continued at room temperature for 20 min. The formed precipitate was removed by filtration, and the filtrate was successively washed with 5% aqueous HCl, 5% NaHCO 3 Aqueous solution and water wash. Anhydrous Na for organic phase 2 SO 4 Drying, filtration and evaporation of the solvent gave 9.689 g (97%) of the title compound as an oily residue. IR: 2931, 2858, 1730, 1368, 1152, 1113, 702. 1 H-NMR (CDCl 3 ): δ=1.05(s, 9H, tBu), 1.20(dd, 1H, J=24.31, 11.70Hz), 1.35(s, 3H), 1.43(s, 3H), 1.45(s, 9H), 1.69( ddd, 1H, J=12.75, 2.48Hz), 2.3...

Embodiment 1-3

[0262] (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl}-(3R,5S)-3 , 5-dihydroxy-hept-6-enoic acid sodium salt (rosuvastatin-Na, IA-Na)

[0263] Rosuvastatin (200 mmol) was dissolved in ethanol (1347 mL) generally according to the procedure disclosed in EP 0 521 471 . 0.1M NaOH (1672 mL) was added slowly with stirring and cooling. After the addition of NaOH was complete, stirring was continued for 1 h at room temperature. The solvent was evaporated under reduced pressure and the oily residue was treated with ether (400 mL). Precipitated crystals of rosuvastatin sodium salt were filtered off. Optionally, if no crystals formed, the ether was distilled off and crystals gradually formed from the resulting foamed oil. IR: 3421, 2968, 1605, 1546, 1510, 1381, 1155, 963, 834, 775, 519.

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PUM

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Abstract

The invention relates to a process for the preparation of a HMG - CoA reductase inhibitor such as rosuvastatin, as well as intermediates useful in such process. The invention also relates to salts of HMG-CoA reductase inhibitors and processes for preparing same as well as processes for preparing pharmaceutically acceptable salts of HMG-CoA reductase inhibitors.

Description

technical field [0001] The present invention relates to processes for the preparation of HMG-CoA reductase inhibitors such as rosuvastatin or pharmaceutically acceptable salts and solvates thereof and intermediates useful in such processes. The present invention also relates to salts of HMG-CoA reductase inhibitors and methods of preparing the salts as well as methods of preparing pharmaceutically acceptable salts of HMG-CoA reductase inhibitors. Background technique [0002] The following compound of formula IA is rosuvastatin, whose chemical name is (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino ]-pyrimidin-5-yl}-(3R,5S)-3,5-dihydroxy-hept-6-enoic acid [0003] [0004] Rosuvastatin and its sodium and calcium salts are disclosed in EP 0521 471 A1 as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which can be used in the treatment of Hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. [0005] WO 00 / 49014 A1 di...

Claims

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Application Information

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IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor P·本基奇D·贝夫克R·莱纳西奇S·祖潘契奇A·瓦伊斯D·亚克谢
Owner 新梅斯托克尔卡・托瓦纳・兹德拉维尔公司
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