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Method for preparing rosuvastatin calcium

A technology for rosuvastatin and compounds, which is applied in the field of pharmaceutical preparation, can solve the problems of expensive reagents, harsh reaction conditions and the like, and achieves the effects of stable yield, easy operation and low price

Active Publication Date: 2013-07-17
ZHEJIANG JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This series of methods has the disadvantages that the reagents used are relatively expensive and the reaction conditions are relatively harsh.

Method used

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  • Method for preparing rosuvastatin calcium
  • Method for preparing rosuvastatin calcium
  • Method for preparing rosuvastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] (R,E)-3-(tert-butyl-dimethyl-silyloxy)-7-(2-chloro-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5 Preparation of -yl)-5-oxo-6-heptenoic acid methyl ester (compound 2).

[0025] Reaction formula:

[0026]

[0027] Steps:

[0028] Add 20 grams of compound 1, 58 grams of phosphorus ylide reagent and 500 mL of anhydrous acetonitrile to a 1L single-necked bottle, and heat to reflux for 20 hours. The reaction is complete as monitored by TLC. The solvent is removed by rotary evaporation in a water bath at 30 ° C. The residue is washed twice with 20 mL of petroleum After washing with ether, 28.8 g of the compound was obtained, which was directly used in the next reaction with a yield of 74.95%.

[0029] 1 HNMR (300MHz, CDCl 3 ): δ0.01 (6H, d), 0.78 (6H, s), 1.26 (6H, dd, J = 6.69Hz), 2.47 (2H, m), 2.74 (2H, dd, J = 6.02Hz), 3.3 (1H, m), 3.65 (3H, s), 4.58 (1H, m), 6.19 (1H, dd, J=16.42Hz), 7.11 (2H, m), 7.56 (3H, m).

[0030] MS (ESI) m / z: 535 (M+H), 557 (M+Na).

Embodiment 2

[0032] (R,E)-7-(2-Chloro-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl)-3-hydroxy-5-oxo-6-heptenoic acid Preparation of methyl ester (compound 3).

[0033] Reaction formula:

[0034]

[0035] Steps:

[0036] In a 500mL single-necked bottle, add 18g of the compound of formula 2, 30mL of tetrahydrofuran, 90mL of glacial acetic acid and 30mL of water, and heat to 40°C for 24 hours. TLC monitors that the reaction is complete. Extract three times with 150ml of ethyl acetate, combine the oil layers, and wash with water. Monitored by TLC, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated in a water bath at 30°C to remove the solvent to obtain 13.45 g of compound 3, which can be directly used in the next reaction with a yield of 95%.

[0037] 1 HNMR (300MHz, CDCl 3 ): δ1.29 (6H, dd, J = 6.7Hz), 2.52 (2H, dd, J = 6.32Hz), 2.72 (2H, m), 3.34 (1H, m), 3.7 (3H, s), 4.46 (1H, m), 6.20 (1H, dd, J=16.42Hz), 7.09-7.15 (2H, m), 7.53-7.60 (3H, m)...

Embodiment 3

[0039] (3R,5S,E)-7-(2-Chloro-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl)-3,5-dihydroxy-6-heptenoic acid Preparation of methyl ester (compound 4).

[0040] Reaction formula:

[0041]

[0042] Steps:

[0043] In a 2000mL three-neck flask, under argon protection, add 24.2g of the compound of formula 3, 650mL of anhydrous tetrahydrofuran, 170mL of anhydrous methanol, cool to -50°C, add 12.2g of 50% diethylmethoxyboron reagent, and react for 0.5 hour, add 2.67 g of sodium borohydride, control the temperature at -40°C--60°C for 3 hours, TLC monitors that the reaction is complete, add 33mL of glacial acetic acid to quench the reaction, adjust the pH value to about 8 with saturated aqueous sodium carbonate solution, 240 ml Ethyl acetate was extracted three times, the oil layers were combined, washed with water, monitored by TLC, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation in a water bath at 30°C ...

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Abstract

The invention provides a preparation method of rosuvastatin calcium. The method comprises the following steps: carrying out condensation reaction on 4-(4-fluorophenyl)-6-isopropyl-2 chloropyrimidine-5-formaldehyde and (3R)-tertiary butyl dimethylsiloxo-5-oxo-6-triphenyl phosphaalkene hexanoate; and then removing a silylether protecting group of hydroxyl, carrying out stereoselectivity reduction, reacting with 2,2-dimethoxy propane, condensing with N-methyl methane sulfonamide, removing propylidene protection, hydrolyzing an ester group, salifying and carrying out other steps, so as to obtain the rosuvastatin calcium. According to the preparation method, the yield is stable, and the price of reagents is cheap; and the method is easy to operate and is beneficial to industrial production.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a preparation method of rosuvastatin calcium. Background technique [0002] The chemical name of rosuvastatin calcium is: (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl Calcium sulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoate. The chemical structural formula is: [0003] [0004] Rosuvastatin was successfully developed by Shionogi Company of Japan (Osaka Shionogi Company), and was transferred to AstraZeneca Company for development and marketed worldwide. Rosuvastatin has been widely used as a prescription drug for blood lipid regulation due to its satisfactory clinical results in terms of efficacy and safety. [0005] The preparation process of rosuvastatin calcium has been reported in numerous documents and patents, such as the method reported in the document (Bioorganic & MedicinalChemistry.vol.5.NO.2.pp.437-444.1997,), the important intermediate 4- ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42
CPCY02P20/55
Inventor 徐锋黄悦王光强张凯毅洪赟飞龚汉芳金彩芬
Owner ZHEJIANG JINGXIN PHARMA
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