US3597453A - Mineralocorticoidal 3-ethers - Google Patents

Mineralocorticoidal 3-ethers Download PDF

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US3597453A
US3597453A US781269A US3597453DA US3597453A US 3597453 A US3597453 A US 3597453A US 781269 A US781269 A US 781269A US 3597453D A US3597453D A US 3597453DA US 3597453 A US3597453 A US 3597453A
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acid
hydroxy
compounds
pregnen
methoxy
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Klaus Irmscher
Gerhard Cimbollek
Hans Guenther Kraft
Herbert Halpaap
Juergen Harting
Hans-Jochen Schliep
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Merck KGaA
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E Merck AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • R is lower alkyl or cyclo alkyl
  • R and R represent hydrogen or together a double bond
  • R is a free or esterified hydroxy group
  • This invention relates to steroids, and in particular to those exhibiting mineralocorticoidal activity.
  • An object of this invention is to provide steroids having a high index of mineralocorticoidal to glucocorticoidal activities.
  • Another object is to provide novel steroids, processes for their preparation, and intermediates for such processes.
  • compositions and methods of administration for effecting mineralocorticoidal activities include pharmaceutical compositions and methods of administration for effecting mineralocorticoidal activities.
  • R and R represent hydrogen or together a double bond
  • R represents a free or esterified hydroxy group, as well as ester salts of the acidic or basic 21-esters thereof.
  • the compounds of Formula I are valuable drugs, and, in particular, can be administered to animals without danger for combating Addisons disease and hypotonia.
  • the compounds exhibit a blood pressure elevating activity.
  • a 3-hydroxy-steroid of Formula II CH R4 wherein R to R, have the above-indicated meanings, or a derivative of such a 3-hydroxy-steroid reactively esterified in the 3-position, can be reacted with an alcohol of the formula R OH or with a reactive derivative of such an alcohol;
  • R to R have the above-indicated meanings, and can be reacted with zinc in aqueous acetic acid to remove the 17oc-OH group;
  • a functionally modified 20-ketoand/or 21-R group in a steroid otherwise corresponding to Formula I can be liberated by solvolysis, preferably by acidic or alkaline hydroylsis, or by hydrogenolysis;
  • an acidic or basic 21-ester can be converted into the ester salt thereof;
  • a double bond present in the 4(5)-position can be catalytically hydrogenated.
  • R represents alkyl groups advantageously of 1-10, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and furthermore also sec.-butyl, tert.-butyl, n-amyl, isoamyl, nhexyl, n-octyl, and n-decyl; or cycloalkyl groups of especially 3-7, preferably 5 or 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • R represents a free or esterified hydroxy group.
  • the acid residues are those derived from saturated or unsaturated aliphatic or cycloaliphatic, aromatic or heterocyclic carboxylic acids of respectively l-18 carbon atoms in total, examples including, but not limited to:
  • valeric acids such as n-valeric acid or trimethylacetic acid
  • caproic acids such as B-trimethylpropionic acid or diethylacetic acid
  • the enanthic, caprylic, pelargonic, capric or undecylic acids the undecylenic acids, the lauric, myristic, palmitic or stearic acids, oleic acid, cyclopropy1-, cyclobutyl-, cyclopentyland cyclohexyl-carboxylic acids, cyclopropyl-methylcarboxylic acid, cyclobutylmethylcarboxylic acid, cyclopentylethylcarboxylic acid, cyclohexylethylcarboxylic acid, the cyclopentyl-, cyclohexylethylcarboxylic acid, the cyclopentyl-, cyclohexylethylcarboxylic acid, the cyclopentyl-,
  • phenylacetic acid or 3-phenylpropionic acid benzoic acid, phenoxyalkanoic acids, such as phenoxyacetic acid, as well as halocarboxylic acids, such as chloroacetic acid, p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid, ether acids, such as 4-tert.-butylphenoxyacetic acid, 3-phenoxypropionic acid, 4-phenoxybutyric acid, heterocyclic acids, such as furan-Z-carboxylic acid, 5-tert.-butylfuran-2-carboxylic acid, S-bromofuran-Z-carboxylic acid, nicotinic acid or isonicotinic acid, fi-ketocarboxylic acids, e.g. acetoacetic acid, propionylacetic acid, butyrylacetic acid or capronoylacetic acid, or amino acids, such as diethylaminoacetic acid or aspartic acid.
  • residues of sulfonic, phosphoric, sulfuric or hydrohalic acids can also be used.
  • esters containing a group which imparts water-solubility to the compound such as a hydroxyl, carboxyl or amino group, since they can be employed for the preparation of aqueous solutions.
  • esters are derived from dicarboxylic acids of preferably 2-10 carbon atoms, examples of such acids including, but not limited to: oxalic, succinic, maleic, glutaric, dimethylglutaric, pimelic, acetonedicarboxylic, acetylenedicarboxylic, phthalic, tetrahydrophthalic, hexahydrophthalic, endomethylenetetrahydrophthalic, endomethylenehexahydrophthalic, endoxyhexahydrophthalic or endoxytetrahydrophthalic acid, camphoric acid, cyclopropanedicarboxylic acid, cyclobutanedicarboxylic acid, diglycolic acid, ethylenebisglycolic acid, polyethylenebisglycolic acid, poly
  • Additional acids include amino-, alkylaminoor dialkylaminocarboxylic acids, and polybasic inorganic acids, such as sulfuric or phosphoric acids.
  • the corresponding esters can be produced, including, but not limited to, for example: oxalates, succinates, maleates or the acid addition salts of aminocarboxylic acid esters, e.g. the esters of aspartic acid or diethylaminoacetic acid.
  • Typical ester salts of the acidic 21-esters e.g. the sulfuric and phosphoric acid esters and the 2l-mono-esters of dibasic carboxylic acids are, in particular, the alkali salts, preferably the salts of alkali metals, particularly the sodium salts; the ammonium salts; and the ethanolammonium, diethanolamrnonium and triethanolammonium salts.
  • Characteristic ester salts of the basic 21-esters are the acid addition salts, especially the hydrohalogenides, e.g. the hydrochlorides and hydrobromides of 21-(aminocarboxylic acid)-esters.
  • starting compounds of Formula II are, in particular, those wherein the optionally esterified hydroxy group in the 3-position is more reactive than the hydroxy or ester group in the 21-position.
  • suitable starting compounds include, but are not limited to: 3ocand 3fl-chloro-2l-hydroxy-5aand Sfl-pregnan-ZO- one, 311- and 3p-bromo-21-hydroXy-5otand Sflregnan- 20-one and the corresponding 3-sulfonic acid esters, e.g.
  • Alcohols of the formula R OH suitable for the etherification are preferably methanol and ethanol, but, of course, all other species of R OH can also be used, e.g. propanol, isopropanol, butanol, isobutanol, cyclopropan01, cyclobutanol, cyclopentanol, cyclohexanol and cycloheptanol.
  • Reactive derivatives of these alcohols are the corresponding chlorides, bromide, iodides, sulfates and sulfonic acid esters, particularly the esters of methanesulfonic, benzenesulfonic and p-toluenesulfonic acid, such as, e.g. methyl chloride, methyl bromide and methyl iodide, dimethyl sulfate, methylmethanesulfonate, -benzenesulfonate and -p-toluenesulfonate.
  • Reactive derivatives along the lines of the present invention are also the corresponding diazoalkanes, e.g. diazomethane and diazoethane.
  • the sodium compound of a S-hydroxy-steroid of Formula II can also be made to react with methyl iodide, methyl bromide or with the methyl ester of a sulfonic acid.
  • the re action is normally conducted in the presence of an additional inert solvent, suitable solvents in this connection being, for instance, hydrocarbons, such as hexane, benzene, toluene; or ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane.
  • suitable solvents in this connection being, for instance, hydrocarbons, such as hexane, benzene, toluene; or ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane.
  • the reaction is conducted at temperatures preferably between C. and the boiling point of the solvent employed.
  • the reaction times range generally between 1 and 48 hours.
  • Another method resides in reacting a compound of Formula II containing a free 3-hydroxy-group with a diazoalkane, such as diazomethane, in the presence of a Lewis acid, such as aluminum chloride or boron trifluoride.
  • a Lewis acid such as aluminum chloride or boron trifluoride.
  • Suitable solvent are especially ethers, such as the ones enumerated above.
  • the starting compounds of Formula II are obtainable, for example, by reducing the 3-keto-group of the desoxycorticosterone (optionally after first etherifying or esterifying the 2l-hydroxy-group and/or blocking the -ketogroup) selectively to a mixture of the 3aand 3B-hydroxy compounds, with the aid of a suitable reducing agent, such as lithium-tri-tert.-butoxyaluminum hydride or sodium borohydride.
  • a suitable reducing agent such as lithium-tri-tert.-butoxyaluminum hydride or sodium borohydride.
  • the resulting mixture is separated, if desired (for example, by chromatography), and any protective groups present can then be cleaved, for example, by alkaline or acidic hydrolysis.
  • the mixture (or the individual epimers) can be converted with thionyl chloride or phosphorus pentachloride into the 3m and BB-chloro-compounds; with phosphorus pentabromide or triphenylphosphine dibromide into the 304- and 3,8bromo-compounds; or with the corresponding sulfonic acid chlorides into the B-methanesulfonates, 3-benzenesulfonates and 3-p-toluenesulfonates.
  • the corresponding derivatives saturated in the 4-position are obtainable by catalytic heydrogenation of the unsaturated starting compounds or the intermediate products thereof.
  • the hydrogenated intermediates can then be converted into the above-mentioned saturated starting materials in analogous reaction sequences.
  • the starting substances of the saturated series can also be produced by selectively reducing pregnane-3,20-dione into a mixture of cand 3B-hydroxypregnan-ZO-one, acetoxylating this mixture in the 2-position, and optionally halogenating same in the 3-position, as described above, or reacting same with a sulfonic acid chloride, as likewise set forth in the foregoing.
  • the compounds of Formula I can also be produced by reductively removing the 17u-hydroxy-group in steroids of Formula III, by treating the latter with zinc in aqueous acetic acid.
  • a large excess of zinc dust is employed, and the reaction mixture is heated for /2 to 4 hours in boiling 50% acetic acid.
  • Suitable starting materials are, for example, 3ocand 3,B-methoxy-, -ethoxy-, -propoxy-, -cyclopentyloxyand cyclohexyloxyl7a, 21- dihydroxy-4-pregnen-20-one, as well as the corresponding 6 5aand SB-pregnane derivatives saturated in the 4(5)- position.
  • These starting compounds can be produced from cortexolone (Reichstein substance S), the dismethylenedioxy derivative of which is reduced with a complex metal hydride, e.g. sodium borohydride, to a mixture of the epimeric 3-hydroxy compounds.
  • a complex metal hydride e.g. sodium borohydride
  • an etherification in the 3-position is conducted.
  • a separation of the 3-epimers and/or, if desired a hydrogenation of the 4(5)-double bond, can be conducted at various stages.
  • Another process for obtaining the products of Formula I comprises converting a functionally modified ZO-ketogroup in a steroid otherwise corresponding to Formula I into a free 20-keto-group by solvolysis, preferably by acidic or alkaline hydrolysis.
  • the functionally modified 20-keto-group is preferably present as the ethylene ketal or the semicarbazone.
  • Additional suitable functional derivatives are other ketals, e.g. the dimethyl, diethyl, and propylene ketals, as well as hemithioketals (ethylene-, propylene-, dimethyland diethylhemithioketals), thioketals (ethylene, pr0pylene-, dimethyland diethylthioketals), enol ethers, thioenol ethers, cyanohydrins, oximes, phenylhydrazones and Girard derivatives (for example, the Girard-T derivative).
  • the solvolysis of the above-mentioned 20 keto-deriva tives is conducted in the conventional manner described in the literature.
  • the ketals are preferably split by treatment with dilute acids.
  • Suitable acids are, for example, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, p-toluenesulfonic acid, oxalic acid, acetic acid, as Well as Lewis acids, such as boron trifluoride etherate.
  • an inert solvent such as methanol, ethanol, acetone, dioxane, ether, tetrahydrofuran, benzene, chloroform or methylene chloride or mixtures of these solvents, optionally with the addition of water.
  • Acetic acid can simultaneously serve as the reactant and the solvent.
  • the splitting takes place readily at room temperature, but it is also possible to conduct the process at temperatures up to the boiling point of the solvent employed, if splitting of the ether group in the 3-position is avoided, which latter measure does not entail any difficulties.
  • the reaction is terminated after a few minutes up to after 24 hours.
  • Thioketals and thioenol ethers are suitably split by treatment with mercury chloride/cadmium carbonate at room temperature or under heating, preferably in aqueous acetone, but also by hydrolysis with dilute hydrochloric acid or sulfuric acid. Hemithioketals are split by employing the same acids, with mercury chloride or with Raney nickel, e.g. in acetic acid in the presence of sodium acetate. Also semicarbazones, oximes, phenylhydrazones and Girards T derivatives can be split in an acidic medium, but the cyanohydrin is split with bases, such as methanolic potassium methylate or pyridine.
  • the splitting operation in the presence of a carbonyl compound, which, in turn, reacts with the liberated reactant With the formation of the corresponding derivative.
  • the semicarbazone is converted into the free keto compound in a particularly advantageous manner by treatment with pyruvic acid.
  • This reaction is conducted, for example, in aqueous dioxane or aqueous acetic acid at room temperature or, more suitably, at elevated temperatures up to the boiling point of the solvent.
  • the ZO-keto-derivatives to be employed as the starting materials can be obtained, for instance, from desoxycorticosterone, the latter being first partially functionalized in the 20-position, e.g. ketalized.
  • the thus-obtained derivative is thereafter reduced in the 3-position, optionally after first separating the isomers and by-products; the reduction process is preferably conducted with a complex metal hydride, such as lithium aluminum hydride or sodium borohydride.
  • Saturated starting. substances are produced by catalytically hydrogenating the 4(5)-double bond.
  • the ethers of the general Formula I can also be obtained by converting a functionally modified 2'1-R -group in a steroid otherwise corresponding to Formula I into an R -group by solvolysis.
  • 21-hydroxy-steroids of Formula I can be liberated from the 21-esters or 21-ethers thereof.
  • Characteristic starting steroids are those wherein the 21-hydroxy-group is present in the form of a readily splittable ester, for example, as the acetate or benzoate, or a readily splittable ether. In the last-mentioned case, the 21-ether-group must be more easily splittable than the ether group in the 3-position.
  • 21-ethers suitable for this purpose are the benzyl, diphenylmethyl (benzhydryl), triphenylmethyl and tetrahydropyranyl ethers.
  • suitable starting substances are the following, for example: 3a and 3fi-methoxy-2l-acetoxy-5otand -55- pregnan-ZO-one, 3aand 3B-methoxy-2l-benzoyloxy-5aand -5,8-pregnan-20-one, 3aand -methoxy-21-benzyloxy-5aand Sfl-pregnan-ZO-one, 341- and 3,8-methoxy-2ltriphenylmethoxy-5uand -5fl-pregnan-20-one, as well as the corresponding 4(5)-dehydro-derivatives, e.g.
  • the Ill-esters are preferably converted into the free 21- hydroxy-compounds by alkaline or also by acidic hydrolysis.
  • suitable solvents are lower alcohols, such as methanol, ethanol, or isopropanol, or mixtures thereof with water.
  • the saponification is generally conducted at temperatures between room temperature and the boiling point of the solvent, the reaction times ranging between 1 and 48 hours.
  • An acidic saponification of the 21-ester-group can be accomplished with the aid of mineral acids, such as hydrochloric or sulfuric acid; however, owing to the vulnerability of the ether group in the 3-position, alkaline saponification is preferred.
  • the splitting of the 21-ester-groups is preferably conducted in an acidic medium; in this connection, the conditions must be selected so that the ether group in the 3- position is not affected.
  • this is normally possible without difiiculties.
  • the triphenylmethyl (trityl) ether, tetrahydropyranyl ether, tert.-butyl ether and methoxymethyl ether are split in an organic solvent with the addition of a mineral acid.
  • 21-ethers such as 21-benzyl ether, 21-benzhydryl ether and 21-trityl ether can also be split by catalytic hydrogenation.
  • Suitable catalysts are, for example, noble metal, nickel and cobalt catalysts.
  • the noble metal catalysts can be employed in the form of supported catalysts, such as, for example, palladium on charcoal, calcium carbonate or strontium carbonate; as oxide catalysts, such as platinum oxide, for instance; or as finely divided metal catalysts.
  • Nickel and cobalt catalysts are suitably employed as Raney metals, and nickel is also used supported on kieselguhr or pumice; palladium (5-10%) on charcoal is preferred.
  • the hydrogenation can be conducted at room temperature and under normal pressure, or also at elevated temperature and/ or under elevated pressure.
  • the process is conducted at pressures between 1 and 100 atmospheres and at temperatures between and +150 C.
  • the reaction is carried out in the presence of a solvent, e.g. methanol, ethanol, isopropanol, tert.-butanol, dioxane, glacial acetic acid, tetrahydrofuran or Water, the preferred solvent being ethyl acetate.
  • a solvent e.g. methanol, ethanol, isopropanol, tert.-butanol, dioxane, glacial acetic acid, tetrahydrofuran or Water, the preferred solvent being ethyl acetate.
  • a mineral acid is advisable, for example, hydrochloric or sulfuric acid.
  • 21-halosteroids which otherwise correspond to Formula I can be converted into the corresponding 2l-acylates by reaction with an alkali salt of a fatty acid.
  • the acetoxy compounds corresponding to Formula I can be obtained, for example, by treating the 21-bromides with anhydrous potassium acetate in acetone. The reaction requires temperatures ranging preferably from room temperature to the boiling point of the solvent and is terminated after 1 to 48 hours.
  • esterification agents are all those acids or the derivatives thereof suitable for esterification which yield physiologically compatible esters; for example, the above-listed acids or the derivatives thereof suitable for esterification can be employed in this connection.
  • esterification agents the halogenides and anhydrides of the above-mentioned acids can be employed, for example.
  • the lower alkyl esters thereof are suitable.
  • the esterification is normally conducted in the presence of an organic base, such as pyridine. Whereas the base can also serve as the solvent, an additional inert solvent can also be employed.
  • the esterification is generally conducted at temperatures between room temperature and the boiling point of the solvent employed and lasts normally between /2 and 12 hours.
  • the 2l-hydroxy-steroid to be esterified is dissolved in an excess of another ester of that acid with which the steroid is to be esterified (in order to produce 21-acetoxy-steroids, for example, in ethyl acetate); as the catalyst, a small amount of a strong base is utilized, such as sodium methylate or potassium tert.- butylate.
  • a strong base such as sodium methylate or potassium tert.- butylate.
  • the reaction is preferably conducted with the aid of sulfamic acid.
  • the corresponding sulfuric acid esters are obtained, which can be converted into the sodium salts with pyridine and 12% aqueous sodium hydroxide solution.
  • a double bond in the 4(5)-position present in the compounds of Formula I can be catalytically hydrogenated, if desired.
  • the hydrogenation is conducted under the above-described conditions.
  • a group which can be hydrogenolyzed in the 21-position eg. a benzyloxy or trityloxy group
  • R represents alkyl of 1-4 carbon atoms or cycloalkyl of 3-7 carbon atoms
  • R is hydroxy or O-acyl wherein acyl is the residue of a carboxylic acid of up to 11 carbon atoms, or a phosphoric or sulfuric acid residue;
  • R and R represent hydrogen
  • R and R represent hydrogen
  • R and R represent a 4(5)-double bond
  • R and R have the same meanings as in subgenerlc group (F) compounds wherein:
  • R has the same meaning as in subgeneric group (A) and R is methyl or ethyl;
  • R and R have the previously indicated meanings;
  • R represents methyl or ethyl;
  • R represents hydroxyl or acetoxy.
  • Carrier substances can be such organic or inorganic substances suitable for parenteral, enteral, or topical application, and which, of course, do not delete riously react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, benzyl alcohol, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol, etc.
  • solutions preferably oily or aqueous solutions, as well as suspensions, emulsions or implants.
  • Ampoules are convenient unit dosages.
  • tablets or dragees which are also characterized by talc and/or a carbohydrate carrier or binder or the like, the cabohydrate carrier being preferably lactose and/or corn starch and/ or potato starch.
  • a syrup or the like can also be used wherein a sweetened vehicle is employed.
  • viscous to semisolid forms are used such as liniments, salves or creames, which are, if desired, sterilized, or mixed With auxiliary agents, such as preservatives, stabilizers, or Wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.
  • auxiliary agents such as preservatives, stabilizers, or Wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.
  • the substances of this invention are generally administered to animals, including, but not limited to, mammals and avians, e.g. cattle, cats, dogs, and poultry.
  • a daily dosage of the compounds of Formula I comprises about 0.1-100, preferably 1-10 mg. together with 1-5000 mg. of pharmaceutically acceptable carriers and/or excipients.
  • the dose can be administered all at once or as divided dosages throughout the day.
  • the mg./ kg. ratio is preferably about 0.001 to 1 mg. to kg. of body weight.
  • Oral administration is preferred, the compounds of Formula I being particularly valuable in the treatment of patients who cannot tolerate the glucocorticoidal side efiects.
  • EXAMPLE 1 (a) 100 mg. of 304,2l-dihydroxyl-pregnen-ZO-oneimono-p-toluenesulfonate is allowed to stand in 5 ml. of methanol in the presence of 10 mg. of p-toluenesulfonic acid for 24 hours. Then, 5 ml. of water is added, the reaction mixture is extracted several times with ether, the ether extracts are Washed with water, dried over sodium sulfate, evaporated, and the residue is chromatographed in chloroform on silica gel. 3or-m6thOXY-21-hYdfOXY-4- pregnen-ZO-one, M.P. 143-145" C. is obtained.
  • the starting material is obtained by selective reduction of the 3-keto-group of desoxycorticosterone with sodium borohyride in isopropanol; separation of the thus-obtained 304- and S/E-hydroxy-steroids by chromatography; and reaction of the 3a-isomer with p-toluenesulfonyl chloride/ pyridine.
  • EXAMPLE 2 100 mg. of Son-methoxy-17a,2l-dihydroxyl-pregnen- 20 one is dissolved in 5 ml. of acetic acid, mixed with 5 ml. of water and 1 g. of zinc dust and refluxed for minutes. The mixture is filtered, and the Zinc is washed with methanol. The filtrate is mixed with ice, almost neutralized with 3 N sodium hydroxide solution and extracted several times with ether. The ether extracts are washed with water, dried over sodium sulfate, evaporated, and the thus-obtained crude product is purified by chromatographing same in chloroform on silica gel. 30:- methoxy-Zl-hydroxy-4-pregnen-20-one, M.P. l43145 C., is produced.
  • the starting material is obtained by converting Cor texolon into the bismethylenedioxy derivative (M.P. 255257 C.), reduction with lithium aluminum hydride to produce the 3-hydroxy-compound, M.P. 153155 C., removing the bismethylenedioxy group by hydrolysis, tosylation in the 3-position, methanolysis and chromatographic separation of the thus-obtained 3aand 3,8-1nethoxy-epimers.
  • EXAMPLE 3 (a) 2.6 g. of 20,20-ethylenedioxy-4-pregnene-3[3,21-diol is dissolved, together with 230 mg. of p-toluenesulfonic acid, in 1.3 l. of methanol and allowed to stand at room temperature for 8 hours. Thereafter, the reaction solution is poured into 1.3 l. of Water, extracted several times with ether, the ether extracts washed with water, dried over sodium sulfate and concentrated by evaporation. The residue (1.7 g.) is dissolved in 15 ml. of chloroform and separated by layer chromatography on three plates coated with silica gel of a length of cm. There are obtained 3 B methoxy 21-hydroxy-4-pregnen-20-one, M .P. 101-103 C. and 3a-methoxy-21--hydroxy-4-pregnen-20- one, M.P. 143l45 C.
  • the starting material is produced as follows:
  • EXAMPLE 4 (a) 300 mg. of the 21-trityl ether of 3[5'-methoxy-21- hydroxy-4-pregnen-20-one is dissolved in ml. of 95% acetic acid and 10 ml. of glacial acetic acid and allowed to stand at 30 C. for 7 hours. The acetic acid is removed under reduced pressure and replaced by benzene. The solution is chromatographed on silica gel in order to remove the concomitantly produced triphenylcarbinol. By elution with chloroform and subsequent concentration, 3 ,B-methoxy-Z1-hydroxy-4-pregnen-ZO-one, M.P. l01-103 C., is obtained.
  • the starting material is produced as follows:
  • EXAMPLE 5 250 mg. of 35,21-dihydroxy-4-pregnen-20-one is dissolved in 130 ml. of methanol and allowed to stand at room temperature for 10 hours with 23 mg. of p-toluenesulfonic acid. The reaction mixture is poured into 200 ml. of Water, extracted with ether, the ether solution Washed with water, dried over sodium sulfate and evaporated. A mixture of 3,8-methoxy-21hydroxy-4-pregnen-20-one and 3ot-methoxy-21-hydroxy 4 pregnen-ZO-one is obtained Which is separated by chromatography as described in Example 3.
  • the starting material is produced from 20,20-ethylenedioxy-4pregnene3fi,2l-diol with 20% aqueous-ethanolic oxalic acid solution.
  • EXAMPLE 6 575 mg. of 35 methoxy 21 triphenylmethOXy-Sapregnan-ZO-one is dissolved in 60 ml. of ethyl acetate and hydrogenated at room temperature after the addition of 350 mg. of 5% palladium-charcoal. The catalyst is fi1 tered off, and the filtrate is evaporated, thus obtaining 3B-methoxy-21-hydroxy-5a-pregnan-20-one.
  • 21-hydroxy- 50c pregnane-3,20-dione is converted into the 2l-tritylether and selectively reduced in the 3-position with tritert.-butoxylithiumaluminum hydride to 3 ,8 hydroxy-2ltrityloxy-5a-pregnan 20 one; etherification with methanol/p-toluenesulfonic acid results in 3,8-methoxy-21-trityloxy-5ot-pregnan-20-one.
  • EXAMPLE 7 388 mg. of 2l-acetoxy-35-methoxy-4-pregnen-20-one is dissolved in 12 ml. of methanol, mixed with a solution of 93 mg. of sodium bicarbonate in 2 ml. of water and boiled for 10 minutes. The mixture is poured into ml. of water and extracted with chloroform. The combined chloroform extracts are dried over sodium sulfate and evaporated; the thus-obtained 3,8-methoxy-2l-hydroxy-4-pregnen-20-one is recrystallized from methanol, M.P. 101 103 C.
  • the 2l-acetate of ll-desoxycorticosterone is ketalized selectively in the 20-position with ethylene glycol; the ZO-ketal is reduced in the 3-position with sodium borohydride in methanol, and the thus-produced 21-acetoxy-20,20-ethylenedioxy- 4-pregnen-3fl-ol is simultaneously deketalized in the 20-positi0n and etherified in the 3-position with methanol/ p-toluenesulfonic acid.
  • the mixture of 3u-methoxy-21- acetoxy-4-pregnen-20-one and 3,8-methoxy-21-acetoxy-4- pregnen-20-one obtained in this manner is separated by chromatography.
  • EXAMPLE A Tablets Each tablet contains:
  • EXAMPLE C Solution for injection A solution of 2 g. of 3a-methoxy-21-hydroxy-4-pregnen- 20-one in 998 ml. of sesame oil is prepared and filled into ampoules in such a manner that each ampoule contains 2 mg. of said sodium salt.
  • R is lower alkyl or cycloalkyl of 3-7 carbon atoms
  • R and R each represent hydrogen or together a double bond
  • R is hydroxy or O-acyl wherein acyl is the residue of a carboxylic acid of up to 11 carbon atoms, or a phosphoric or sulfuric acid residue.
  • R and R represent hydrogen.
  • R and R together represent a double bond 4(5).
  • R is methyl or ethyl.
  • R represents methyl or ethyl
  • R represents hydroXyl or acetoxy.
  • a member as defined in claim 1 wherein said member is 3a-methoxy-21-hydroxy-4-pregnene-20-one.
  • a member as defined by claim 1 wherein said member is 3fi-methoXy-2l-hydroxy-4-pregnene-20-one.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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US781269A 1967-12-13 1968-12-04 Mineralocorticoidal 3-ethers Expired - Lifetime US3597453A (en)

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ES361360A1 (es) 1970-08-16
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FR8163M (de) 1970-08-24
BE725269A (de) 1969-06-11

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