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Method for preparing spirolactone key intermediate epoxide

A technology of bulk epoxy and spironolactone, which is applied in the field of drug synthesis, can solve problems such as high price of strong organic bases, troubles in environmental protection work, difficult removal of filtrate, etc., and achieve the effects of reducing power costs, reducing energy consumption, and being easy to recycle

Pending Publication Date: 2021-10-29
TIANJIN JINJIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This reaction not only requires strict anhydrous reaction conditions, but also the price of the strong organic base used is relatively high. What is more unfavorable is that the solvent used to dissolve the strong organic base is dimethyl sulfoxide with very good water solubility, and its boiling point is high. It is difficult to remove in the filtrate, and it will also produce strong toxicity to microorganisms, resulting in the waste water produced cannot be treated by biochemical methods, which brings great troubles to environmental protection work.

Method used

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  • Method for preparing spirolactone key intermediate epoxide
  • Method for preparing spirolactone key intermediate epoxide
  • Method for preparing spirolactone key intermediate epoxide

Examples

Experimental program
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Effect test

Embodiment 1

[0019] A method for preparing spironolactone key intermediate epoxy, comprising the following steps: 20g of ether compound I is dissolved in 100ml of dichloromethane, 2ml of 1-butyl-3-methylimidazolium tetrafluoroborate, 20g of Trimethylsulfonium bromide, 100ml of sodium hydroxide solution with a mass fraction of 20%, stirred and reacted at 40°C for 5 hours, separated the water layer, and concentrated the organic phase to a small volume under normal pressure (the amount of solvent is about 50-60ml), cooling, 0 It was kept at -10°C for 2 hours, and 17.8 g of solid was obtained by filtration. After testing: the melting point of the obtained product is 104-106° C. (literature value 105° C.), the molar yield is 85.21%, the NMR test confirms that it is epoxy compound II, and the HPLC test shows that its purity is 99.2%.

Embodiment 2

[0021] A method for preparing spironolactone key intermediate epoxy, comprising the following steps: 20g of ether compound I is dissolved in 400ml of toluene, 20ml of 1-methyl-3-methylimidazolium tetrafluoroborate, 20g of brominated Trimethylsulfonium, 30ml of potassium hydroxide solution with a mass fraction of 30%, stirred and reacted at 20°C for 5 hours, separated the water layer, and concentrated the organic phase under reduced pressure (absolute pressure not greater than 0.02MP, temperature less than 80°C) to a small volume (The amount of solvent is about 50-60ml), lower the temperature, keep warm at 0-10°C for 2 hours, and filter to obtain 18.2g of solid. After testing: the melting point of the obtained product is 104-105°C (literature value 105°C), the molar yield is 87.12%, the NMR detection is determined to be epoxy II, and the HPLC detection has a purity of 99.0%.

Embodiment 3

[0023] A method for preparing spironolactone key intermediate epoxy, comprising the following steps: 20g of ether compound I is dissolved in 200ml of methyl tetrahydrofuran, and 30ml of 1-methyl-3-ethylimidazole tetrafluoroborate, 20g Trimethylsulfonium bromide, 200ml of 50% mass fraction of sodium hydroxide solution, stirred and reacted at 10°C for 5 hours, separated the water layer, and concentrated the organic phase under reduced pressure (absolute pressure not greater than 0.02MP, temperature less than 60°C) to Small volume (solvent amount about 50-60ml), lower the temperature, keep warm at 0-10°C for 2 hours, lower the temperature, and filter to obtain 18.1g of solid. After detection: the melting point of the obtained product is 105-106° C. (literature value 105° C.), the molar yield is 86.64%, and the NMR detection is determined to be epoxy compound II, and the HPLC detection has a purity of 99.3%.

[0024] The part characteristic hydrogen data of embodiment 1-3 gained p...

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Abstract

The invention provides a method for preparing a key intermediate epoxide of spirolactone, which comprises the following operation steps: dissolving etherate (I) in an organic solvent, adding ionic liquid, trimethyl sulfonium bromide and inorganic alkali liquor, reacting at 10-40 DEG C while stirring to prepare epoxide (II), wherein the ionic liquid is any one of 1-butyl-3-methylimidazolium tetrafluoroborate, 1-methyl-3-methylimidazolium tetrafluoroborate, 1-methyl-3-ethylimidazolium tetrafluoroborate or 1-ethyl-3-ethylimidazolium tetrafluoroborate. The reaction route is as follows: a low-cost inorganic strong base is used for replacing a high-cost organic strong base, the ionic liquid is used for replacing the dimethyl sulfoxide difficult to post-treat, the reaction is finally completed under the simple and easily available conditions, the cost is low, the energy consumption is small, and the environmental pollution is small.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to a method for preparing spironolactone key intermediate epoxy. Background technique [0002] Spironolactone, whose chemical name is 7α-acetylthio-17-one-hydroxy-3-oxo-17α-pregn-4-ene-2l-carboxylate-γ-lactone, is a specific aldosterone antagonist. For edema diseases, treatment of congestive edema, liver cirrhosis ascites, renal edema, etc., can also be used for adjuvant treatment of hypertension, can be used as the prevention of hypokalemia, combined with thiazide diuretics, enhance diuretic effect and Prevent hypokalemia. In the prior art, the mainstream process for producing canrenone and spironolactone is the technical solution disclosed in patent DE2404946: using androstenedione as raw material, after etherification, Corey epoxidation, dehydrogenation, lactone cyclization, and decarboxylation Canrenone (the following structural formula 6) is obtained, and can...

Claims

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Application Information

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IPC IPC(8): C07J21/00
CPCC07J21/00Y02P20/54
Inventor 邵范武只永润
Owner TIANJIN JINJIN PHARMA
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