- A diastereoselective synthesis of 7α-nitromethyl steroid derivative and its use for an efficient synthesis of eplerenone
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A novel and efficient method of stereoselectively introducing α-nitromethyl group to C-7 position of 11α-hydroxyl canrenone 4 was described. In addition, this method was successfully applied in a total synthesis of Eplerenone 8. The route was characteristic of simple operation, moderate reaction conditions with 5 steps and 55% total yield, at the same time, without any expensive or toxic reagent in use.
- Zhang, Bin,Chen, Hongli,Tang, Huanyu,Feng, Huijin,Li, Yuanchao
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- Synthesis and physicochemical characterization of the process-related impurities of eplerenone, an antihypertensive drug
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Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra). The new process-related impurities were identified and fully characterized as the corresponding (7β,11α,17α)-11-hydroxy- and (7α,11β,17α) -9,11-dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11α-hydroxy-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7α,17α)-9(11)-enester 7, including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H- and 13C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone related substances 12a and 13, were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone.
- Dams, Iwona,Bia?ońska, Agata,Cmoch, Piotr,Krupa, Ma?gorzata,Pietraszek, Anita,Ostaszewska, Anna,Chodyński, Micha?
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- Preparation method of eplerenone with high efficiency and low pollution
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The invention discloses a preparation method of eplerenone with high efficiency and low pollution, and belongs to the technical field of preparation and processing of steroid hormone drugs. The methodcomprises the steps: by taking a compound I, namely delta 9,11-canrenone, as an initial raw material, carrying out 7-furyl addition, furyl ring opening and lactonization cyclization reaction to obtain 5,7-lactone, and carrying out ring opening methylation and 9,11-double bond epoxidation reaction to obtain the eplerenone. According to the method, raw materials and reagents are cheap and easy to obtain, and the method has extremely high market competitiveness in equipment investment and production cost; reagents used in the method are low in environmental pollution, and particularly cyano-containing high-toxicity compounds are not used, so that the method is greener and more environment-friendly; the production process is easy to control, high in yield, low in cost and suitable for industrial production.
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- Method for synthesizing 7a-methyl formate-9(11)-encanrenone
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The invention discloses a method for synthesizing 7a-methyl formate-9(11)-encanrenone. The method comprises the following steps: reacting 9(11)-encanrenone used as a raw material with 2-methylfuran atfirst, performing ring opening by using dibromohydantoin, rearranging, ozonizing, adding a metal reducing agent to methanol or a mixed solution of methanol and other solvent, and performing reducingesterification to directly obtain the 7a-methyl formate-9(11)-encanrenone. The method has the advantages of operation step simplification, high yield, simplicity in operation, few three wastes, and suitableness for industrial production.
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- A steroid compound derivative having, its preparation process and its use in the preparation of Eplerenone
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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.
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- Process for the preparation of Eplerenone
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The invention belongs to the medical field, and particularly relates to a preparation method of eplerenone. The preparation method comprises the following steps: in the presence of phosphorous pentachloride and boron trihalide, performing dehydration reaction on 17alpha-pregn-4-ene-7alpha,21-dicarboxylic acid-11alpha,17beta-dihydroxy-3-oxo-gamma-lactone-7-methyl ester used as an initial raw material to obtain 17alpha-pregn-4,9(11)-diene-7alpha,21-dicarboxylic acid-17beta-hydroxyl-3-oxo-gamma-lactone and 7-methyl ester; and performing epoxidation reaction on the 17alpha-pregn-4,9(11)-diene-7alpha,21-dicarboxylic acid-17beta-hydroxyl-3-oxo-gamma-lactone and 7-methyl ester to obtain the eplerenone. The preparation method has specificity, and reduces generation of foreign matters; the obtained product is favorable in quality and high in yield, and the product purity is up to 99.5% or above; and the preparation method has the advantages of accessible raw materials, simple operation and mild reaction conditions, and is easy to implement industrial production.
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Paragraph 0056; 0057; 0058; 0059
(2016/10/17)
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- A chemobiological synthesis of eplerenone
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This paper will describe an approach to the synthesis of eplerenone, which is being marketed for the treatment of hypertension. The synthesis begins with DHEA available from wild yams and uses a combination of microbiological and chemical transformations to build eplerenone. Georg Thieme Verlag Stuttgart.
- Wuts, Peter G. M.,Anderson, Andrew M.,Ashford, Scott W.,Goble, Michael P.,White, Michael J.,Beck, Doris,Gilbert, Ivan,Hrab
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p. 418 - 422
(2008/09/17)
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- IMPROVED PROCESS FOR THE PREPARATION OF 9,11 EPOXY STEROIDS
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Processes are described for epoxidation reactions. In particular, the process comprises the conversion of a steroid substrate having an olefinic unsaturation in the steroid nucleus to a structure comprising a 9,11-epoxy substituent by reaction of the substrate with a peroxide compound in the presence of a peroxide activator. The epoxidation processes described are conducted at relatively low hydrogen peroxide to steroid substrate ratio. Several optional process modifications are described.
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Page/Page column 32-39
(2008/06/13)
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- Processes for preparing C-7 substituted steroids
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This invention relates to processes for the preparation of novel 7-carboxy substituted steroid compounds of Formula I,
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Page/Page column 5-6; 13
(2008/06/13)
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- Processes for preparation of 3-keto-7alpha-alkoxycarbonyl-delta-4,5- steroids and intermediates useful therein
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Multiple novel reaction schemes, novel process steps and novel intermediates are provided for the synthesis of epoxymexrenone and other compounds of Formula I wherein:-A-A- represents the group -CHR4-CHR5- or -CR4=CR5- R3, R4 and R5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, varyloxy;R1 represents an alpha-oriented lower alkoxycarbonyl or hydroxyalkyl radical;-B-B- represents the group -CHR6-CHR7- or an alpha- or beta- oriented group: where R6 and R7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; andR8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R8 and R9 together comprise a carbocyclic or heterocyclic ring structure, or R8 or R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring.
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- Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
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Multiple reaction schemes, process steps and intermediates are provided for the synthesis of epoxymexrenone, useful as a diuretic, and other 9,11-epoxy-steroids.
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- Steroidal, aldosterone antagonists: Increased selectivity of 9α,11-epoxy derivatives
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In the search for aldosterone antagonists with an optimal activity profile, twelve 9α,11-epoxy-steroids were prepared and compared with their 9α,11α-unsubstituted analogues in terms of steroid receptor binding in vitro and electrolyte excretion in vivo. Substitution of the parent structures by an epoxy group at positions 9α,11 resulted in marginal effects on mineralocorticoid receptor binding and electrolyte excretion, but greatly reduced androgen and gestagen receptor binding. This finding is reflected in the largely lacking unwanted anti-androgenic and gestagenic side effects in animal models of the three most interesting 9α,11-epoxy-spirolactones 4(CGP 33033), 18(CGP 29245), and 25(CGP 30083).
- Grob,Boillaz,Schmidlin,Wehrli,Wieland,Fuhrer,Rihs,Joss,De Gasparo,Haenni,Ramjoue,Whitebread,Kalvoda
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p. 566 - 585
(2007/10/03)
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