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Novel method for preparing rosuvastatin, intermediate compounds useful for preparing same, and method for preparing same

A compound and reaction technology, applied in the field of preparation of medicinal rosuvastatin, can solve the problems of low purity and low yield

Inactive Publication Date: 2012-05-16
CHONG KUN DONG CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, since currently known methods for the preparation of the hemi-calcium salt of rosuvastatin exhibit low yields and low purity, there is an ongoing interest in developing alternative methods for the preparation of pharmaceutically acceptable salts of rosuvastatin. need

Method used

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  • Novel method for preparing rosuvastatin, intermediate compounds useful for preparing same, and method for preparing same
  • Novel method for preparing rosuvastatin, intermediate compounds useful for preparing same, and method for preparing same
  • Novel method for preparing rosuvastatin, intermediate compounds useful for preparing same, and method for preparing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Embodiment 1: Preparation of 6-chloro-5-hydroxyl-3-oxohexanoic acid (2-methyl-1-phenylpropan-2-yl) ester (7a) prepare

[0102]

[0103] Lithium bis(trimethylsilyl)amide (190.8 g) was dissolved in tetrahydrofuran (1400 ml) in the main reaction vessel before cooling to -75°C and flushing with nitrogen. (2-Methyl-1-phenylpropan-2-yl) acetate (219.2 g) was charged to a separate reaction vessel and dissolved by adding tetrahydrofuran (300 ml), and the solution was gradually was added dropwise to the main reaction vessel, followed by stirring for 1 hour. (S)-Ethyl 4-chloro-3-hydroxybutyrate (50 g) was added and dissolved in tetrahydrofuran (50 ml), and the resulting solution was gradually added dropwise to the main reaction vessel over 20 minutes, after which Stir for 5 hours. Thereafter, acetic acid (124 ml) was gradually added dropwise thereto, and the temperature was gradually raised to 0°C. Ethyl acetate (1500 ml) and purified water (1500 ml) were added thereto, ...

Embodiment 2

[0105] Embodiment 2: Preparation of 6-bromo-5-hydroxyl-3-oxohexanoic acid (2-methyl-1-phenylpropan-2-yl) ester (7b) prepare

[0106]

[0107] In the same manner as in Example 1, except that ethyl (S)-4-bromo-3-hydroxybutyrate (50 g) was used instead of ethyl (S)-4-chloro-3-hydroxybutyrate (50 g) Go through the process. The crude title compound (290.0 g) was obtained. A part of the crude compound was purified by a silica gel column (ethyl acetate:n-hexane=3:7 (v / v)) to obtain the following NMR data.

[0108] 1 H-NMR (400MHz, CDCl 3 )δ7.35-7.20 (m, 5H), 4.40-4.36 (m, 1H), 3.69-3.65 (m, 2H), 3.43 (s, 2H), 3.02 (m, 1H), 2.81-2.77 (m, 2H), 2.00(s, 2H), 1.50-1.46(m, 6H)

Embodiment 3

[0109] Example 3: (3R,5S)-6-Chloro-3,5-dihydroxy-hexanoic acid (2-methyl-1-phenylpropan-2-yl) ester (8a) preparation of

[0110]

[0111] The crude compound 6-chloro-5-hydroxy-3-oxohexanoic acid (2-methyl-1-phenylpropan-2-yl) ester (7a, 298g) prepared in Example 1 was dissolved in tetrahydrofuran (2000ml ) and methanol (1000ml) in a mixed solvent, and the solution was cooled to -75°C. At the same temperature, methoxydiethylborane (78.8 ml) was gradually added dropwise to the solution over 20 minutes, followed by stirring for 40 minutes. Thereafter, sodium borohydride (25.0 g) was added in 5 portions, followed by stirring for 5 hours, and acetic acid (96 ml) was gradually added dropwise thereto. The mixture was warmed to room temperature and kept there. Ethyl acetate (1800 ml) and 3% aqueous hydrogen peroxide solution (1500 ml) were charged into the reaction zone, followed by stirring for 30 minutes and extraction. The aqueous layer was back extracted with ethyl aceta...

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Abstract

The present invention relates to novel intermediate compounds used in preparing Rosuvastatin or the pharmaceutically acceptable salts thereof, to a method for preparing same, and to a method for preparing Rosuvastatin or the pharmaceutically acceptable salts thereof from the intermediates. The preparation method of the present invention has the effect of providing Rosuvastatin hemi-calcium salts with an excellent yield rate.

Description

technical field [0001] The present invention relates to a new intermediate compound used in the preparation of rosuvastatin (rosuvastatin) or a pharmaceutically acceptable salt thereof, a method for preparing the new intermediate compound, and a method for preparing a pharmaceutically acceptable compound from the new intermediate Rosuvastatin method. Background technique [0002] A drug exhibiting a cholesterol-lowering effect by a mechanism of inhibiting the activity of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) is generally called "statin". Among them, examples of the earliest first-generation compounds developed include simvastatin, lovastatin, and pravastatin as fermentation products, and examples of second-generation compounds include Synthetic drugs atorvastatin, fluvastatin, rosuvastatin and pitavastatin. [0003] Among these, rosuvastatin calcium has the structural formula given below and is sold under the trademark CRESTOR TM On the mark...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42A61K31/505A61P3/06
CPCC07D405/06C07C69/716C07D239/42C07D405/12C07D417/12C07C67/31C07D317/30C07C67/343C07C69/675A61P3/06A61K31/505
Inventor 李洪雨朴大钟刘忠烈南东赫柳昊亨金东珍
Owner CHONG KUN DONG CORP
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