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Canrenone derivative steroid compound, preparation method and application in eplerenone preparation thereof

A technology of eplerenone and compounds, applied in the field of preparation of eplerenone, can solve the problems of high price, cumbersome operation steps, poor stereoselectivity, etc., and achieve easy scale-up production, high application value, and mild reaction conditions Effect

Active Publication Date: 2013-05-08
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

Also have many domestic patent disclosures to do relevant reports (CN101121652, CN1724557 and CN1749266) in recent years, the key part of synthesis all is to concentrate on the construction of the methyl carboxylate structural unit of C-7 position α configuration, but needs to use in these methods To highly toxic cyanide reagents, such as sodium cyanide, cyanoacetone or diethylcyanoaluminum; at the same time, expensive DIBAH reagent is used for cyano conversion; or noble metals are required when introducing C-7α-position carbonyl , such as palladium acetate, etc.; or the stereoselectivity is not good; or harsh reaction conditions and cumbersome operation steps such as oxidation of the furan ring with ozone are required at low temperature (-46°C)

Method used

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  • Canrenone derivative steroid compound, preparation method and application in eplerenone preparation thereof
  • Canrenone derivative steroid compound, preparation method and application in eplerenone preparation thereof
  • Canrenone derivative steroid compound, preparation method and application in eplerenone preparation thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1: the preparation of the compound shown in formula 2

[0065]

[0066] Add compound (20g, 56mmol) shown in formula 1, quaternary ammonium salt (6mmol) (see Table 1), nitromethane (60ml, 112mmol) in the two-neck bottle that is connected with calcium chloride drying tube and air condenser and 190ml N,N-dimethylformamide (DMF), after the dissolution is complete, the temperature is raised to 90-100°C, and K is added while stirring. 2 CO 3 (78g, 565mmol), kept fully stirred, and reacted at this temperature for 48 hours. When the reaction was terminated, the temperature was lowered first, and after the temperature was completely lowered to room temperature, it was filtered with diatomaceous earth, and the filter cake was washed with dichloromethane (100ml×3), and the dichloromethane layers were combined. A little 10% (w / w) dilute hydrochloric acid was added to adjust the pH value of the organic layer to 6. Spin all the solvents under reduced pressure first t...

Embodiment 2

[0078] Embodiment 2: the preparation of the compound shown in formula 4

[0079]

[0080] 1) The compound represented by Formula 2 (5 g, 0.012 mol) was dissolved in 40 ml of N,N-dimethylformamide (DMF), and then the temperature was raised to 45°C. Add acetic acid (2.9ml, 0.051mol) to this solution, after fully stirring, add NaNO in batches within 30min 2 (2.484g, 0.036mol), after adding NaNO 2Finally, let it react for one hour, then mix acetic acid (2.9ml, 0.051mol) and 3ml DMF, and then add it dropwise to the above reaction solution. After complete dripping, it takes about 4 hours, TLC The raw materials were analyzed to disappear completely, and then the temperature was lowered to 0° C., then saturated sodium sulfite solution (54 ml, 0.089 mol) was added to quench the reaction, and then the temperature was raised to room temperature, and the reaction was completely terminated overnight. After the reaction was completely terminated, all the solvents were spin-dried under ...

Embodiment 3

[0087] Embodiment 3: Preparation of the compound shown in formula 6 (R=methylsulfonyl)

[0088]

[0089] 1) At 0°C, the compound (4g, 9.6mmol) shown in formula 4 was dissolved in 54ml of dichloromethane solution, and then methanesulfonyl chloride (1.4ml, 17mmol) was added, followed by triethylamine ( 4.65ml, 31mmol) and 2ml of dichloromethane were mixed, and then added dropwise to the above reaction solution. After the dropwise addition was complete, the temperature was raised to room temperature and reacted for 3 hours. TLC detected that when the compound shown in formula 4 disappeared completely, the reaction was complete. completely. All the solvents were spin-dried to obtain the crude product of the compound represented by formula 5-1 as a white solid (reddish), which was directly used in the next step.

[0090] 2) Add acetic anhydride (1.8ml) dropwise to a solution of potassium formate (1.3g, 0.015mol) in formic acid (3.6ml) under nitrogen protection at room temperatu...

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Abstract

The invention relates to a canrenone derivative steroid compound, a preparation method and an application in the medicine field, and particularly relates to 7alpha-nitro methyl-11alpha,17beta-dihydroxy-3-oxo-17alpha-pregna-4-ene-21-carboxylic acid-gamma-lactone (a compound shown in formula 2), a preparation method and an application in eplerenone preparation. The key steps of the invention are that nitromethane is used as a nucleophilic reagent; the alpha-nitro methyl group is introduced to the C-7 position stereoselectively so as to further construct a carboxylic acid methyl ester structure with a C-7alpha position configuration of eplerenone; the method of the invention has the characteristics of short steps, mild conditions, and low cost.

Description

technical field [0001] The present invention relates to a canrenone derivative steroid compound, its preparation method and its use in the field of medicine, in particular to 7α-nitromethyl-11α, 17β-dihydroxy-3-oxo -17α-pregn-4-ene-21-carboxylic acid-γ-lactone (compound shown in formula 2), its preparation method and its use in the preparation of eplerenone (compound shown in formula 7) use. Background technique [0002] Eplerenone is a new type of aldosterone antagonist with selective characteristics. It can directly bind with aldosterone to inhibit its action. Eplerenone, whose structure is shown in the following formula 7, was prepared by Ciba-Geigy Ag in Switzerland in 1984, and was approved for marketing by the US FDA in 2002. [0003] [0004] Eplerenone is a drug 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. It is metabolized by CY...

Claims

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Application Information

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IPC IPC(8): C07J21/00C07J71/00
Inventor 李援朝张斌王友富王均良陈红莉冯慧瑾
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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