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Preparation method of eplerenone and intermediate thereof

A technology of acetone and compounds, which is applied in the field of medicine and can solve the problems of high price and the like

Active Publication Date: 2013-04-10
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, many domestic patents have also done related reports (CN101121652, CN1724557, CN1749266). The key part of the synthesis is the construction of the methyl carboxylate structural unit concentrated in the C-7 position α configuration, but these methods need to use Highly toxic cyanide reagent, and expensive DIBAH reagent is used for cyano conversion; or noble metals, such as palladium acetate, etc., are needed when introducing C-7α-position carbonyl; or ozone and low temperature (-78°C) are needed ) and other harsh conditions

Method used

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  • Preparation method of eplerenone and intermediate thereof
  • Preparation method of eplerenone and intermediate thereof
  • Preparation method of eplerenone and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Embodiment 1: the preparation of compound shown in formula 3 (R 1 = methylsulfonyl)

[0111]

[0112] The compound shown in Formula 2 (5.800g, 0.0163mol) and triethylamine (2.29ml, 0.0163mol) were dissolved in 55ml of dichloromethane, cooled to 0°C in an ice-water bath, and methylsulfonate was added dropwise at this temperature Acyl chloride (1.26ml, 0.0180mol) was recrystallized from acetone / dichloromethane to obtain the compound represented by formula 3 (colorless transparent crystals), with a yield of 99%.

[0113] mp: 188~190℃;

[0114] 1 H NMR (300MHz, CDCl 3 )δ6.16(dd, J=9.7, 2.2Hz, 1H), 6.00(d, J=9.7Hz, 1H), 5.71(s, 1H), 5.15(td, J=10.4, 4.9Hz, 1H), 3.02(s, 3H), 1.28(s, 3H), 1.09(s, 3H)

[0115] 13 C NMR (300MHz, CDCl 3 )δ 199.05, 176.00, 161.20, 137.06, 129.09, 125.53, 94.30, 77.80, 53.40, 46.43, 46.41, 40.84, 40.20, 37.60, 36.67, 35.40, 34.78, 34.23, 17, 30.957, 5.3, 22.5

Embodiment 2

[0116] Embodiment 2: the preparation of compound shown in formula 4

[0117]

[0118] Potassium formate (6.655g, 0.079mol), formic acid (150ml), and acetic anhydride (7.48ml, 0.079mol) were mixed at room temperature and heated to 80°C for 12 hours. After that, the compound represented by formula 3 (34.329g, 0.079mol) was added, and the temperature was raised to 100°C to react for 3 hours. After most of the solvent was spin-dried under reduced pressure, dichloromethane and water were added for extraction, and the organic layers were combined, and the organic layers were successively washed with saturated NaHCO 3 Washed three times with aqueous solution, water, and saturated brine, and separated by column chromatography to obtain the compound described in Formula 4 (white yellowish solid powder), with a yield of 90%.

[0119] 1 H NMR (300MHz, CDCl 3 )δ6.16(dd, J=9.86, 2.19Hz, 1H), 6.09(dd, J=9.65, 1.31Hz, 1H), 5.69(s, 1H), 5.55-5.48(m, 1H), 1.30(s , 3H), 0.99 (s, 3H).

[...

Embodiment 3

[0121] Embodiment 3: directly prepare the compound shown in formula 4 by the compound shown in formula 2

[0122]

[0123] At -50°C, compound 2 (116mg, 0.33mmol), tetrahydrofuran (20ml), dimethyl sulfoxide (39mg, 0.33mmol) and NaCl (20mg, 0.33mmol) were sequentially added, stirred thoroughly and gradually warmed to room temperature, Water (20 ml) was added to terminate the reaction, and extracted with ethyl acetate to obtain 89 mg of the compound represented by formula 4, with a yield of 80%.

[0124] 1 H NMR (300MHz, CDCl 3 )δ6.16(dd, J=9.86, 2.19Hz, 1H), 6.09(dd, J=9.65, 1.31Hz, 1H), 5.69(s, 1H), 5.55-5.48(m, 1H), 1.30(s , 3H), 0.99 (s, 3H).

[0125] 13 C NMR (300MHz, CDCl 3 )δ199.065,176.36,161.827,140.325,137.854,127.257,123.895,118.501,94.794,44.276,43.962,38.835,38.538,35.212,34.024,32.878,32.023,31.174,29.075,24.354,22.877,14.318。

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Abstract

The invention provides an important intermediate compound used for preparing eplerenone: 5alpha-oxygen-7alpha-methylene-17beta-hydroxy-3-oxo-17alpha-pregn-9(11)-alkene-21-carboxylic acid-gamma-lactone (shown in a formula 6) and 9alpha, 11alpha-epoxy-5alpha-oxygen-7alpha-methylene-17beta-hydroxy-3-oxo-17alpha-pregn-21-carboxylic acid-gamma-lactone (shown in a formula 10), a method for preparing the intermediate compound and an application.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to an important intermediate compound 5α-oxygen-7α-methylene-17β-hydroxyl-3-oxo-17α-pregna-9(11)-ene for preparing eplerenone -21-carboxylic acid-γ-lactone (as shown in formula 6) and 9α, 11α-epoxy-5α-oxygen-7α-methylene-17β-hydroxy-3-oxo-17α-pregna-21 -Carboxylic acid-γ-lactone (as shown in formula 10), and the preparation method and use of these intermediates. Background technique [0002] Eplerenone, whose structure is shown in the following formula 1, was prepared by Ciba-GeigyAg in Switzerland in 1984, and was approved for marketing by the US FDA in 2002. [0003] [0004] Eplerenone is mainly used to treat essential hypertension and heart failure after myocardial infarction, and it is also the first selective aldosterone receptor blocker approved for marketing. Metabolized by CYP4503A4 in the body, the half-life is 4-6 hours. Eplerenone may be used to improve survival in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00
Inventor 李援朝张斌王均良王友富冯慧瑾
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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