Refining of fluvastatin sodium intermediate and preparation method of fluvastatin sodium

A technology of fluvastatin sodium and a refining method, which is applied in the field of compound refining, can solve the problems of no impurity removal, low purity of fluvastatin sodium, and low product purity, and achieve the goal of improving purity, improving product quality, and high purity Effect

Inactive Publication Date: 2008-07-09
HUIZHOU XINLITAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The purity of the obtained product is not high, without further impurity removal, a large amount of impurities are brought into the subsequent process, and it is difficult to refine and remove, resulting in the lower purity of the prepared fluvastatin sodium

Method used

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  • Refining of fluvastatin sodium intermediate and preparation method of fluvastatin sodium

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Experimental program
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Embodiment 1

[0044] Inside the reactor, nitrogen gas was added, anhydrous tetrahydrofuran was added, and stirred. Add 1.7 g NaH and stir for 5 minutes. The temperature was lowered to below 0°C, and 4.6 mL of methyl acetoacetate solution was slowly added dropwise. After the dropwise addition, stirring was continued below 0°C for 1 hour. Slowly add 27.5mL of n-butyllithium / n-hexane solution dropwise, stir and react at 0~5°C for half an hour, add 8g of (E)-3-[3-(4-fluorophenyl)-1-(1-methylethane base)-1H-indol-2-yl]-2-propenal / 150mL THF solution, then add a saturated ammonium chloride hydrochloric acid mixed solution, fully stir for 20 minutes, carry out liquid separation, and wash the organic layer twice with saturated saline, Dry over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure to obtain an orange translucent oil (hereinafter referred to as "orange oil").

[0045] Dissolve 9 g of the above orange oil in 12 mL of ethyl acetate,...

Embodiment 2

[0047]Dissolve 9 g of orange oil in 54 mL of isopropanol, heat to dissolve, add 54 mL of n-heptane, stir for 2 hours, filter, and dry in vacuo at 45°C to obtain 7.5 g of yellow solid (E)-7-[3-(4-fluorobenzene yl)-1-(1-methylethyl)-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoic acid methyl ester. Mp: 98~100°C, HPLC: 98.7%.

Embodiment 3

[0049] Dissolve 9g of orange oil in 18mL of methanol, heat to dissolve, add 63mL of n-hexane, stir at room temperature for 2 hours, filter, and dry under vacuum at 45°C to obtain 6.7g of yellow solid (E)-7-[3-(4-fluorophenyl) - 1-(1-methylethyl)-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoic acid methyl ester. Mp: 99~100.5°C, HPLC: 99.3%.

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Abstract

The invention provides a refining process of intermediate I (E)-7-[3-(4-fluorophenyl)-1-(1-methyl ethyl)-1H-indole-2-radicial]-5-hydroxy-3-oxygen-6-heptene methyl acetate. The invention refines fluvastatin sodium intermediate I through adopting acetic acid ethyl ester and hexane solvent system, which increases the purity of product which is refined, and simultaneously avoids the inference of impurities for subsequent preparation fluvastatin sodium. Simultaneously, the invention further provides a preparation process of fluvastatin sodium which contains the intermediate refining steps.

Description

Technical field: [0001] The present invention relates to a method for refining a compound, especially (E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]- A method for refining 5-hydroxy-3-oxo-6-heptenoic acid methyl ester (I) and a method for preparing fluvastatin sodium. Background technique: [0002] Compound (E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptyl Methyl enoate (hereinafter referred to as fluvastatin sodium intermediate I) is a commonly used intermediate for the preparation of fluvastatin sodium. The compound is usually composed of (E)-3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenal (II) and Prepared from methyl acetoacetate. [0003] [0004] A known preparation method is disclosed in US4739073 example 5 step 5. The process uses (E)-3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenal and methyl acetoacetate , NaH, and n-butyllithium reaction, the reaction product was soaked in n-p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/24
Inventor 付鑫祥
Owner HUIZHOU XINLITAI PHARMA
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