DEC0009455MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: June 4, 1θ54. Announced August 2, 1956

GERMAN PATENT OFFICE

The invention relates to the preparation of 20-ketopregnans which have an oxy- or in the 2i-position Acetoxy, in the 16-position a free or an esterified or etherified oxy group, in the 3-position a free one Contain keto group and a double bond in the 4, (5) -position. These 20-ketopregnans are especially valuable because they have the effects of previously unknown adrenal cortical hormones. You can therefore find use as a remedy.

It is known per se, compounds of the adrenal cortex hormone series by introducing an acyloxy group into the 21-position of 20-ketopregrianes, which are unsubstituted in the 16-position with metal acylates or to prepare aryl iodosoacylates. The Process according to the invention is now characterized in that lead tetraacetate is in the 21-position unsubstituted 20-ketopregnane, which in the 3-position is a free or functionally modified hydroxyl or have a keto group and a free, esterified or etherified hydroxyl group in the 16-position leaves, in compounds obtained in this way having a free oxy group or a functional modified oxy or keto group in the 3-position, this group into a free one by known methods Keto group converted into the compounds saturated in the 4 (5) position in a manner known per se

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Introduces 4 (5) double bond and, if desired, functionally modified oxy groups in i6- and 2i-position partially or completely free puts.

The 4 "pregnen-3, 2O-dione-i6,2i-diols or their functional ones Derivatives have interesting pharmacological properties. In particular, exhibit the i6a-oxy-deoxycorticosterone and the i6 / S-acetoxy-i7aoxy-deoxycorticosterone acetate an outspoken

ίο on the adrenal cortex hormone effect, which differs in the type of effect from similar compounds unsubstituted in the i6-position and sometimes even exceeds them. So z. B. iöa-oxy-deoxycorticosterone according to a method of determination for water-sodium and potassium retention, which is a modification of the test given by Kazawa for sodium retention, with regard to water and sodium retention on a very similar behavior as deoxycorticosterone; compared to the potassium excretion, however, it shows a completely different behavior, in that the increased potassium excretion is again reduced with increasing doses. The x6ß, 17a-dioxy-deoxycorticosterone-16, 21-diacetate has a similar effect to an even greater extent. Furthermore, z. B. the i6 / 5, I7a-Dioxydesoxycorticosteron-16, 21-diacetate to the I7a-Oxydesoxycorticosteron (Reichstein's substance S) also with respect to the intensity of action by z. B. a visible effect occurs with the former at a dosage of 5 to 10 γ , whereas with the latter such an effect can only be determined after administration of 100 to 400 γ .

Further substituents can be present in the starting materials, namely free or functional modified hydroxyl or keto groups, e.g. B. a free or functionally modified hydroxyl group in the 17-position and / or a free or functionally modified hydroxyl group or keto group in II position. Furthermore, double bonds can be present be, so z. B. starting from carbon atom 5.

Ester groups are particularly suitable as esterified or etherified hydroxyl groups in the 16-position with the residues of acetic acid, trimethyl acetic acid, propionic acid, 4-methyl-5-acyloxyvaleric acids, Benzoic acid, carbonic acid monobenzyl ester, carbonic acid monodiphenylmethyl ester, methanesulfonic acid or p-toluenesulfonic acid and ether groups, e.g. alkoxy, such as methoxy or propyloxy groups, aryloxy, such as phenyloxy or tolyloxy groups, aralkoxy, such as benzyloxy, p-methylbenzyloxy, diphenylmethoxy or triphenylmethoxy groups, or those with heterocyclic radicals, such as the dihydropyranyl radical.

To react with lead tetraacetate, the compounds mentioned are dissolved or suspended in solvents. The solvent used is in particular acetic acid, often with the addition of acetic anhydride and optionally a further inert solvent or diluent, such as hexane, heptane, benzene or toluene. In general, temperatures around 70 ^{0 are used} . To avoid the reaction, which often also occurs in the 17-position, however, it is possible to work at significantly lower temperatures, if appropriate in the presence of small amounts of catalysts, such as acids or boron trifluoride.

The conversion of the reaction products of the starting materials mentioned with lead tetraacetate in the physiologically active compounds are carried out according to known methods. In particular, a Acyloxy group in 3-position by the mild action of alkaline, acidic or esterifying agents, for example by hydrogen carbonate solution or dilute mineral acids.

In the after 'the inventive method obtained process products which carry a free 3-position hydroxyl group, these in per se known, way by dehydrating agents, such as chromic acid in glacial acetic acid, chromium salts in an acidic Medium, chromium trioxide-pyridine complex, permanganates, metal alcoholates or phenolates in ketones, N-bromoacetamide, for example in dioxane-water or pyridine-tert-butanol, hypohalites, heating with metals or metal oxides, such as copper oxide, convert into a keto group. A double bond in 5, 6-position can be temporarily removed by attachment from halogen or hydrogen halide or by converting the corresponding steroids into 3,5-cyclosteroids (cf. HeIv. Chim. Acte, Vol. 34, 19.51, p. 1682) protection. According to the process, it is then converted directly or indirectly into a 4 (5) double bond in a known manner transformed.

iö-acyloxy groups in unsubstituted 17-position Compounds, like the free substituents in this position, can in the hydrolysis can easily be cleaved to form a double bond. Aralkoxy, e.g. B. benzyloxy groups, and corresponding Carbonic acid esters can usually be obtained by careful hydrogenation, e.g. B. in the presence of a Palladium-calcium carbonate catalyst, cleave. You are therefore with advantage z. B. used in 16 position, to the here particularly easily occurring cleavage of the substituent with the formation of a Avoid double bonds.

The process products are separated off and purified in the usual way, for example by recrystallization, Chromatography, e.g. B. after the continuous process, by distribution between not miscible solvents, for example by the countercurrent process, or by sublimation.

The following examples illustrate the invention Proceedings. The temperatures are given in degrees Celsius.

Protection is not sought for the production of the starting materials in the context of the present invention.

. example 1

For a solution of 1 part by weight of 4-Pregnen-16 / ?, i7a-diol-3, 20-dione-i6-acetate in 50 parts by volume Glacial acetic acid is added to 0.9 parts by weight of lead tetraacetate, heated gently until the lead tetraacetate has been used up and pour in ice water. The suspension is taken up in ethyl acetate, the solution with dilute ice-cold sodium bicarbonate solution and water, washed, dried and evaporated in vacuo, Obtained by chromatography on aluminum oxide

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the 4-pregnene-i6 / 3, 17α, 2i-triol-3, 2O-dione-i6, 21-diacetate from the mp = 167 to 168 °; [α] = + 99 ° (in Chloroform).

To saponify the acetate groups, 0.26 part by weight of this compound is dissolved in 0.6 part by volume of methanol and a methylate solution composed of 0.03 part by weight of sodium and 2.2 parts by volume of methanol is added. After 3 minutes, 1 part by volume of a mixture of equal parts by volume of water and methanol is added and, after a further 3 minutes, acidified with 0.1 part by volume of glacial acetic acid. The reaction mixture is then concentrated in vacuo, mixed with 20 parts by volume of water and extracted with chloroform. From the chloroform extract, which has been washed with water, sodium carbonate solution and water and dried, 0.18 parts by weight of crystals are obtained after evaporation of the solvent with the addition of acetone. Recrystallization from acetone and isopropyl ether to win a Trioxyverbindung mp = 225-227 ^0;

[a] ₀ = + ιοί ⁰ (in chloroform-ethanol).

The starting material used above can advantageously be obtained as follows:

3 parts by weight of 16, i7a-Oxido-4-pregnen-3, 20-dione are dissolved in 60 parts by volume of glacial acetic acid and mixed with

• 35 6 parts by volume of a mixture of 10 parts by volume of glacial acetic acid and 2.5 parts by volume of concentrated sulfuric acid are added. After 8 hours, the strongly red, fluorescent solution is poured into 350 parts by volume of ice water and extracted with benzene; the benzene extracts are washed with water, sodium bicarbonate solution and water, dried and evaporated. 1.83 parts by weight of crude 4-pregnene-τββ, i7a-diol-3, 2o-dione-i6-acetate are obtained from the oily yellow residue by crystallization from a mixture of benzene and hexane. After recrystallization from benzene-hexane and from acetone, the pure compound is obtained with a melting point of 183 to 184 ^° ; [α] % = + 10 ° (in chloroform), which has a strong absorption maximum (ε = 16,600) in the ultraviolet spectrum at 242 m / i.

To saponify the acetoxy group, 0.5 part by weight of this compound is used in 15 parts by volume Dissolved methanol, with a solution of 0.15 parts by weight of potassium carbonate in 5 parts by volume of water. sets and left to stand for 25 hours at room temperature. After acidification with 0.2 parts by volume Glacial acetic acid, the reaction mixture is concentrated to 5 to 7 parts by volume, and 70 parts by volume of water are added and the precipitate sucked off. The received

.50 crude product is taken up in a moist state in chloroform, with 1N sodium carbonate solution and Washed water, dried and evaporated. From the 0.41 parts by weight of solid crude product obtained is obtained by crystallization from a mixture

.55 of hexane and acetone a pure dioxy compound from F. = 217 to 219 ⁰ ; [α] + 92% = ⁰ (in chloroform). The compound has a strong absorption maximum (s = 16 150) in the ultraviolet spectrum at 239 ταμ.

Example 2

13 parts by weight of lead tetraacetate are added to a solution of 10 parts by weight of 5-pregnen-3 (3, i6a-diol-2O-one-3-formate-i6-acetate in 500 parts by volume of a glacial acetic anhydride mixture (4: 1) until the lead tetraacetate is consumed and then poured into ice water. The suspension is extracted with ether-chloroform (4: 1), the ether-chloroform solution is then washed with dilute ice-cold potassium carbonate solution and water, dried and evaporated in vacuo recrystallized from ether - pentane, the 5-pregnen-3/3, 16a, 2i-triol-2O-one-3-formate-16a, 21-diacetate from F. = 180 to 182 ⁰ and the specific rotation [a] ² J = -24 ° (in chloroform) This compound reduces alkaline silver diammine solution rapidly and strongly.

A solution of 1 part by weight 5 - Pregnen - 3/3, 16a, 2i-triol-2O-one-3-formate-16a, 21-diacetate in 50 parts by volume A solution of 0.5 parts by weight of potassium bicarbonate in 5 parts by volume is added to dioxane at 15 ° Water and let stand 10 minutes. The solution is then neutralized with dilute acetic acid and strongly concentrated in vacuo. The residue is dissolved in ethyl acetate and the ethyl acetate solution is washed with. dilute potassium bicarbonate solution and water, dry and evaporate them. By recrystallizing the Residue from ether or ether - pentane, one obtains the pure 5-pregnene ~ 3 / ?, i6ct, 2i-triol-2O-one-i6, 21-diacetate from F / = 157 to 159.5 °.

To protect the 5 (6) double bond, 1 part by weight of 5-pregnen-3/3, 16a, 2i-triol-2o-one-16, 21-diacetate is dissolved in 20 parts by volume of carbon tetrachloride and a solution is slowly added to the solution 0.4 parts by weight of bromine in 5 parts by volume of carbon tetrachloride. The excess bromine is then removed in vacuo. A solution of 0.18 parts by weight of chromium trioxide in 95 parts by volume of glacial acetic acid and 5 parts by volume of water is then added to the solution of the dibromide at 20 ° and the mixture is left to stand for 10 hours at 20 °. The excess chromic acid is decomposed with a little sodium bisulfite solution and strongly concentrated in vacuo. The suspension obtained is extracted with ethyl acetate, the ethyl acetate solution is washed with dilute hydrochloric acid, dilute potassium bicarbonate solution and water while cooling with ice, and it is dried and evaporated. The residue is then dissolved in 40 parts by volume of acetone, mixed with a solution of chromium (2) chloride (prepared from 9 parts by weight of chromium (3) chloride) and left to stand for 20 minutes at 20 °. The reaction solution is mixed with water, the acetone is evaporated in vacuo, the residue is taken up in ether, the ethereal solution is washed with water, dried and evaporated. The crude product obtained in this way is chromatographed on 30 parts by weight of alkali-free aluminum oxide. The fractions eluted with benzene and ether are combined and evaporated in vacuo. The residue is crystallized from acetone-petroleum ether mixtures to yield the 4-pregnene-i6a, 2i-diol-3, 2O-dione i6, 21-diacetate, mp = 150.5 to 153 ^0; [α] " = + 113 ° (in ethanol). This compound reduces silver diammine solution rapidly and strongly and shows strong ultraviolet absorption at 240 ταμ (ε max. = 16,400 in alcohol).

The two acetoxy groups can be hydrolyzed as follows: An enriched active choline

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esterase fraction is mixed with 100 parts by volume of a sterile dilute aqueous sodium acetate solution. With good stirring is then between 30 to 37 ^0, a solution of 1 part by weight of 4-pregnene-5 '16a, 21-CÜ0I-3, 2O-dione i6, 21-diacetate in a little acetone and some toluene were added. The resulting suspension is stirred for 2 to 3 days at the same temperature, it is then extracted with ethyl acetate, the extract is washed with dilute hydrochloric acid, dilute potassium bicarbonate solution and water, dried and evaporated in vacuo. The residue is chromatographed on 30 parts by weight of silica gel and, after redissolving from acetone and methanol, 4-pregnen-16a, 2i-diol-3, 20-dione of F. = 203 to 205 ⁰ ; [α] I «= - | - 114.5 ° (in ethanol); λ max. 241 ταμ, ε = i6 300 (in ethanol).

For the monoacetylation, 1 part by weight of 4 "pregnen-i6a, 2i-diol-3, 20-dione is dissolved in acetone, benzene is added and the mixture is evaporated in vacuo. The compound thus dried is dissolved in 15 parts by volume of dry pyridine, and 3.9 parts by volume are added a io% by weight acetic anhydride solution in dry benzene added and allowed 20 hours at 20 ⁰ are The reaction solution is then admixed with a little water and evaporated in vacuo at 35 ° The residue is taken up in ether-chloroform.. (4: 1), washed the solution in the cold with dilute hydrochloric acid, dilute sodium bicarbonate solution and water, dry it and evaporate it. For purification, the residue is dissolved in benzene and chromatographed on 30 parts by weight of alkali-free aluminum oxide. Somewhat unchanged 4 3 win -Pregnen-i6a, 2i-diol ^J, dion-20. from the other Essigestereluaten separating the 4-pregnene i6a, 2i-diol-3, 2O-dion-2i-acetate from. For methanol-ether recrystallized in Pri smen from F. = 207 to 209 ⁰ .

The 5-Pregnen-3 / ?, i6a-diol-2O-on-3-formate-i6-acetate used as starting material can be z. B. from 5-pregnen-3 / ?, i6a-diol-2O-one-3-formate-16-phenyl acetate by hydrogenation in the presence of a palladium-carbon catalyst in ethanol solution and subsequent acetylation of the hydrogenation product with acetic anhydride and pyridine at 20 °.

Claims (2)

PATENT CLAIMS: 1. A process for the preparation of 4-position unsaturated pregnan-i6-ol-3,20-diones which carry a free or acetylated oxy group in the 21-position and in which the 16-position oxy group can also be esterified or etherified, thereby in that in 21-position are unsubstituted in the 3-position by an oxygen-containing group substituted 20-Ketopregnane that in 16-position a free, esterified or possess etherified oxy group obtained, in a known W ^e i ^{se w} ith lead tetraacetate is reacted, in the Compounds, provided they contain a free oxy group or a functionally modified oxy or keto group in the 3-position, this group is converted into a free keto group by known methods, into the compounds obtained, provided they are saturated in the 4 (5) position, introduces a 4 (5) double bond in a known manner and, if desired, functionally modified oxy groups in the 16- and 21-positions in a known manner partially or completely in Fr unit sets. 2. The method according to claim 1, characterized in that that one 20-ketopregnane, which in i6cc- or i6 / 3-position is a free, esterified or have etherified oxy group, used as starting materials. © 609 577/491 7. 56