Method for preparing and refining eplerenone

A technique of refining eplerenone, which is applied in the field of preparation of pharmaceutical compounds, can solve problems such as low overall yield, potential safety hazards, and many steps, and achieve the effects of shortening reaction time, saving production costs, and shortening the production cycle

Inactive Publication Date: 2015-01-07
JIANGSU SINOBIOPHARMA
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0014] This route first constructs the 7-position branched chain. During the construction of the branched chain, the highly toxic hydrocyanic acid is used, which brings a lot of potential safety hazards to R&D and production; during the construction of the 7-position aldehyde group The reagent DIBAL is used, which is expensive and dangerous, which is not conducive to industrial mass production
Oxygen atom transfer reagent trichloroacetonitrile is used in the process of 9,11-ene oxidation. Trichloroacetonitrile is very exothermic in this reaction, and too obvious exothermic reaction system with hydrogen peroxide participation may cause serious problems. Large potential safety hazard; moreover, the route has many steps and leads to low overall yield, which is unfavorable for industrialized production

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  • Method for preparing and refining eplerenone
  • Method for preparing and refining eplerenone
  • Method for preparing and refining eplerenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of eplerenone crude product

[0042] Add 450 g of 9,11-enyl ester, 180.4 g of dipotassium hydrogen phosphate trihydrate, 366.8 g of trichloroacetamide, and 2700 ml of dichloromethane in sequence in a 5 L reaction flask at room temperature, and start stirring. Under the protection of nitrogen, start to add 30% hydrogen peroxide solution (15.8mol) dropwise, and control the temperature at 20-25°C. After the dropwise addition, stir the reaction at room temperature for 5h, and monitor the raw material (enyl ester) ≤ 0.1% in the liquid phase. Let stand, separate layers, extract the aqueous phase with 2700ml of dichloromethane again, combine the organic phases, and wash with 2700ml of 3% sodium bisulfite solution, 2700ml of 10% sodium carbonate solution, and 2700ml of saturated saline once, Dry over anhydrous sodium sulfate and concentrate to dryness to obtain 445.0 g of crude eplerenone with a molar yield of 95% and an HPLC purity of 98.3%. (See...

Embodiment 2

[0045] Embodiment 2: the preparation of eplerenone crude product

[0046]Add 20g of 9,11-enyl ester, 40.75g of trichloroacetamide, 8.0g of dipotassium hydrogen phosphate trihydrate, and 120ml of dichloromethane into a 500ml three-necked flask in sequence, start stirring, and cool down to 0-5°C under nitrogen protection. 108 ml of 30% hydrogen peroxide solution (0.75 mol) was added dropwise at a temperature of 0-5° C., and the reaction was carried out at a temperature of 20-25° C. for 4-6 hours after the addition was completed. The liquid phase shows that the raw material (enyl ester) ≤ 2.0%, let stand, separate layers, extract the water phase with 120ml of dichloromethane again, combine the organic phase, wash once with 120ml of 3% sodium bisulfite solution, and wash once with 10% sodium carbonate Wash once with 120 ml of the solution, once with 120 ml of saturated saline, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain 18.2 g of crude eplerenone, Y=94....

Embodiment 3

[0047] Embodiment 3: the preparation of eplerenone high-quality goods

[0048] The crude product obtained in Example 1 was transferred to a 5L glass reaction bottle, 4228ml of 2-butanone was added, the temperature was raised to reflux to dissolve the liquid, the heating was stopped, and the reaction was naturally lowered to room temperature and stirred for 4-8h for crystallization. After filtering, the filter cake was washed with an appropriate amount of 2-butanone, and dried to obtain 400 g of eplerenone fine product, with a refined yield of 90% and a liquid phase purity of 99.9%. (See figure 2 )

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Abstract

The invention discloses a method for preparing and refining eplerenone. The method for preparing and refining eplerenone comprises the following steps: taking 9,11-alkenyl ester to react at 0-30 DEG C in the presence of potassium hydrogen phosphate trihydrate, trichloroacetamide and hydrogen peroxide so as to prepare an eplerenone crude product; carrying out re-crystallization by 2-butanone to obtain an eplerenone fine product with a purity of greater than 99.9%. The method is simple to operate; poisonous and harmful trichloroacetonitrile is not used; the use amount of hydrogen peroxide is greatly reduced; the production period is greatly shortened; the yield and purity of products are greatly improved; the method is suitable for industrial application.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical compounds, in particular to a method for preparing and refining eplerenone. Background technique [0002] There are about ten methods for the synthesis of eplerenone reported in the literature (reference Drugs of the Future1999,24(5):488-501), but the main route is also to synthesize the eplerenone precursor (9,11-enyl ester) followed by epoxidation to obtain eplerenone. We now list the different precursors used for the synthesis of eplerenone and the methods of the different reagents used as follows: [0003] method one: [0004] [0005] The literature (Study on the synthesis process of aldosterone receptor antagonist eplerenone, Wang Xianlian) introduced that the selectivity of the oxygen atom transfer reagent trichloroacetonitrile used in this reaction is not good, and it has oxidative properties for the 4 and 5 ethylenic bonds at the same time, which leads to new Increase im...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00
CPCC07J71/0015
Inventor 黄乐群王磊熊远红薛焰
Owner JIANGSU SINOBIOPHARMA
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