DE956954C - Process for the preparation of pregnane-16-01-3, 20-dione unsaturated in the 4-position - Google Patents

Description

Process for the preparation of 4-position unsaturated pregnan-16-ol-3, 20-dione The invention relates to the preparation of 2o-ketopregnanes which in the 2i-position an oxy- or acetoxy-, in the i6-position a free or an esterified one or etherified oxy group, in the 3-position a free keto group and a double bond contained in 4, (5) position. These 2o-ketopregnans are especially valuable because they have the effect of previously unknown adrenal cortical hormones. They can therefore be used as a remedy.

It is known per se, compounds of the adrenal cortex hormone series by introducing an acyloxy group in the 2i-position of 2o-ketopregnanes, the are unsubstituted in the i6-position, with metal acylates or aryl iodosoacylates. The process according to the invention is characterized in that lead tetraacetate is used to 2o-ketopregnanes which are unsubstituted in the 2i-position and which have a free one in the 3-position or functionally modified hydroxyl or keto group and a free, have esterified or etherified hydroxyl group, can act in on this Compounds obtained in a manner that have a free oxy group or a functionally modified one Oxy or keto group in 3-position converts this group into one by known methods Free keto group converted into the compounds saturated in the 4 (5) position in a known way Introduces 4 (5) double bond and, if desired, functionally modified oxy groups in the 16- and 2i-positions partially or completely sets free.

The 4-pregnen-3, 2o-dione-16, 2i-diols and their functional derivatives have interesting pharmacological properties. In particular, exhibit the i6a-oxy-deoxycorticosterone and the 16β-acetoxy-17aoxy-deoxycorticosterone acetate has a pronounced adrenal cortical hormone effect which are unsubstituted in the nature of the action of similar ones in the i6-position Connections deviates and sometimes exceeds them. So z. B. 16a-oxy-deoxycorticosterone according to a determination method for water-sodium and potassium retention, which a modification of the test given by K a z aw a for sodium retention shows similar behavior with regard to water and sodium retention like deoxycorticosterone on; however, compared to the excretion of potassium it shows completely different behavior in that with increasing doses the increased potassium excretion is again reduced. It exhibits a similar effect to an even greater extent the 16ß, 17a-dioxy-deoxycorticosterone-16, 2i-diacetate. Furthermore, z. B. that i6ß, i7a-Dioxydesoxycorticosterone-i6, 2i-diacetate the i7a-Oxydesoxycorticosterone (Reichstein's Substance S) is also superior in terms of intensity of action by z. B. a visible effect in the former with a dosage of 5 to io y occurs, whereas in the case of the latter, such an effect only occurs when ioo to 400 y can be determined.

Further substituents can be present in the starting materials, namely free or functionally modified hydroxyl or keto groups, e.g. B. a free or functionally modified hydroxyl group in the i7-position and / or or a free or functionally modified hydroxyl group or keto group in ii position. Furthermore, double bonds may be present, e.g. B. starting from Carbon atom 5.

Come as esterified or etherified hydroxyl groups in the i6-position especially considering ester groups with the residues of acetic acid, trimethyl acetic acid, Propionic acid, 4-methyl-5-acyloxyvaleric acids, benzoic acid, carbonic acid monobenzyl ester, Carbonic acid monodiphenyl ethyl ester, methanesulfonic acid or p-toluenesulfonic acid and Ether groups, e.g. B. 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.

The compounds mentioned are used for reaction with lead tetraacetate dissolved or suspended in solvents. The solvent used is in particular Acetic acid, often with the addition of acetic anhydride. and possibly one more inert solvents or diluents such as hexane, heptane, benzene or toluene. In general, temperatures around 70 ° are used. To avoid the. often partially but one can also react in the i7-position with much deeper ones 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 is known according to Methods executed. In particular, an acyloxy group in the 3-position can be mildly Exposure to alkaline, acidic or esterifying agents, for example hydrogen carbonate solution or dilute mineral acids, are hydrolyzed.

In the according to the invention. Process products obtained, which carry a free 3-position hydroxyl group, this can be known per se Way by dehydrating agents, such as chromic acid in glacial acetic acid, chromium salts in one acidic agents, 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, into one Convert keto group. A double bond in the 5, 6-position can be temporarily by addition of halogen or hydrogen halide or by transferring the corresponding steroids in 3, 5-cyclosteroids (cf. Helv. Chim. Acte, Vol. 34, 1951, S. 1682) .. It is then directly or in accordance with the procedure in a known manner indirectly converted into a 4 (5) double bond.

i6-acyloxy groups in compounds unsubstituted in i7-position can as well as the free substituents in this position during hydrolysis can easily be cleaved to form a double bond. Aralkoxy, e.g. B. benzyloxy groups, and the corresponding carbonic acid esters can usually be obtained by careful hydrogenation, z. B. in the presence of a palladium-calcium carbonate catalyst, split. you will be therefore with advantage z. B. used in i6 position to make this particularly easy occurring cleavage of the substituent with the formation of a double bond avoid.

The process products are separated and purified in the usual way, for example by recrystallization, chromatography, e.g. B. according to the continuous process, by distribution between immiscible solvents, for example after the Countercurrent process, or by sublimation.

The following examples explain the process according to the invention. The temperatures are given in degrees Celsius.

For the production of the starting materials, this is given in the context of the present Invention Protection not sought. Example i For a solution of i part by weight of 4-Pregnancy, 17a-diol-3, 2o-dione-i6-acetate in 50 parts by volume of glacial acetic acid is added to 0.9 parts by weight Lead tetraacetate, heat gently until the lead tetraacetate is 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 in vacuo evaporated. Obtained by chromatography on aluminum oxide one that 4-Pregnen-16ß, 17a, 2i-triol-3, 2o-dione-16, 21-acetate from m.p. = 167 to 168 °; [a] = + g9 ° (in chloroform).

To saponify the acetate groups, 0.26 parts by weight of this compound are dissolved in 0.6 parts by volume of methanol and a methylate solution of 0.03 parts by weight of sodium and 2.2 parts by volume of methanol is added. After 3 minutes, one 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, after evaporation of the solvent, o.18 parts by weight of crystals are obtained after adding acetone. Recrystallization from acetone and isopropyl ether gives a trioxy compound with a melting point of 225 to 227 °; [a] D = + 10 ° (in chloroform-ethanol).

The starting material used above can advantageously be obtained as follows: 3 parts by weight of 16, 17a-oxido-4-pregnen-3, 2o-dione are dissolved in 60 parts by volume of glacial acetic acid and with 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 offset. 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-pregneni6ß, 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 °; [a] D = - @ - 1O1 ° (in chloroform), which has a strong absorption maximum (s = 16,6oo) in the ultraviolet spectrum at 242 mA.

To saponify the acetoxy group, 0.5 part by weight of this compound is dissolved in 15 parts by volume of methanol, mixed with a solution of 0.15 part by weight of potassium carbonate in 5 parts by volume of water and left to stand for 25 hours at room temperature. After acidification with 0.2 parts by volume of glacial acetic acid, the reaction mixture is concentrated to 5 to 7 parts by volume, 70 parts by volume of water are added and the precipitate is filtered off with suction. The crude product obtained is taken up in chloroform in the moist state, washed with sodium carbonate solution and water, dried and evaporated. A pure dioxy compound with a melting point of 217 to 219 ° is obtained from the 0.41 parts by weight of solid crude product obtained by crystallization from a mixture of hexane and acetone; [a] D = + 92 ° (in chloroform). The compound has a strong absorption maximum (s = 1615o) in the ultraviolet spectrum at 239 mg.

EXAMPLE 2 To a solution of 10 parts by weight of 5-pregnen-3β, 16a-diol-2o-one-3-formate-16-acetate in 50 parts by volume of a glacial acetic anhydride mixture (4: 1) are added '13 parts by weight of lead tetraacetate, heat gently until the lead tetraacetate is used up and then pour 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. The residue is recrystallized from ether-pentane, the 5-pregnene-3ß, 16a, 2i-triol-2o-one-3-formate-16a, 2i-diacetate from mp = 180 to 182 ° and the specific rotation [a ] ö = -24 ° (in chloroform). This compound rapidly and strongly reduces alkaline silver diammine solution.

A solution of 1 part by weight of 5-pregnen-3β, 16a, 2i-triol-2o-one-3-formate-16a, 2i-diacetate in 50 parts by volume of dioxane is mixed with a solution of 0.5 part by weight of potassium bicarbonate in 5 at 15 ° Parts by volume of water and let stand for 10 minutes. The solution is then neutralized with dilute acetic acid and concentrated strongly in vacuo. The residue is dissolved in ethyl acetate, the ethyl acetate solution is washed with dilute potassium bicarbonate solution and water, dried and evaporated. By recrystallizing the residue from ether or ether-pentane, pure 5-pregnene-3β, 16a, 2i-triol-2o-one-16, 2i-diacetate with a melting point of 157 to 159.5 'is obtained.

To protect the 5 (6) double bond, 1 part by weight of 5-pregnen-3ß, 16a, 2i-triol-2o-one-16, zi-diacetate is dissolved in 2o parts by volume of carbon tetrachloride and a solution of 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 g 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 off in vacuo, take the residue up in t ether, the ethereal solution 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 and the 4-pregnene-16a, 2i-diol-3, 2o-dione-16, 2i-diacetate is obtained with a melting point of 150.5 to 153 °; [a] ö = -j- = 13 ° (in ethanol). This compound reduces silver diammine solution rapidly and strongly and shows strong ultraviolet absorption at 240 μl (smax. = 16,4oo in alcohol).

The two acetoxy groups can be hydrolyzed as follows: 100 parts by volume of a sterile dilute aqueous sodium acetate solution are added to an enriched active cholinesterase fraction. A solution of 1 part by weight of 4-pregneni6a, 2i-diol-3, 2o-dione-16, 2i-diacetate in a little acetone and a little toluene is then added at between 30 ° and 37 ° with thorough stirring. 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, the evaporated ether-ethyl acetate and ethyl acetate eluates give the 4-pregneni6a, 2i-diol-3, 2o-dione with a temperature of 2o3 to 2o5 °; Cal u = -f- 1i4.5 ° (in ethanol); Amax. 241 mu, s = 16,300 (in ethanol).

For monoacetylation, 1 part by weight of 4-pregnene-16a, 2i-diol-3, 2o-dione is dissolved in acetone, benzene is added and the mixture is evaporated in vacuo. The compound dried in this way is dissolved in 15 parts by volume of dry pyridine, 3.9 parts by volume of a 10% strength acetic anhydride solution in dry benzene are added and the mixture is left to stand at 20 ° for 20 hours. The reaction solution is then mixed with a little water and evaporated in vacuo at 35 °. The residue is taken up in ether-chloroform (4: i), the solution is washed in the cold with dilute hydrochloric acid, dilute sodium bicarbonate solution and water, dried and evaporated. For purification, the residue is dissolved in benzene and chromatographed on 3o parts by weight of alkali-free aluminum oxide. Somewhat unchanged 4-pregnen-16a, 2i-diol-3, 2o-dione can be obtained from the evaporated ether-ethyl acetate eluates. The 4-pregnene-16a, 2i-diol-3, 2o-dione-2i-acetate is separated off from the other ethyl acetate eluates. From methanol-ether it crystallizes in prisms with a temperature of 207 to 209 °.

The 5-pregnen-3ß, 16a-diol-2o-one-3-formate-16-acetate used as starting material can z. B. from the 5-Pregnen-3ß, i6a-diol-2o-one-3-formiati6-phenyl acetate through Hydrogenation in the presence of a palladium-carbon catalyst in ethanol solution and subsequent acetylation of the hydrogenation product with acetic anhydride and pyridine win at 2o °.

Claims (2)

PATENT CLAIMS: i. Process for the preparation of pregnan-i6-ol-3, 2o-diones which are unsaturated in the 4-position and which have a free or acetylated oxy group in the 2i-position and in which the oxy group in the 16 position can also be esterified or etherified, characterized in that that in the 2i-position unsubstituted 2o-ketopregnanes which are substituted in the 3-position by an oxygen-containing group and which have a free, esterified or etherified oxy group in the i6-position, are reacted in a known manner with lead tetraacetate in the compounds obtained, provided they are 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, in the compounds obtained, if they are saturated in the 4 (5) position, a 4 (5) in a known manner ) introduces double bond and, if desired, functionally modified oxy groups in 16- and 2i-positions in a known manner partially or completely in freedom puts. 2. The method according to claim i, characterized in that that 2o-ketopregnanes, which are free in the 16a or 16ß-position, are esterified or etherified oxy group, used as starting materials.