DE926247C - Process for the preparation of pregnanes with at least one keto group in the 20-position and at least hydroxyl groups in the 16- and 17-position - Google Patents

Description

Process for the preparation of pregnanes with at least one keto group in the 20-position and at least hydroxyl groups in the 16- and It is known t (H @ elvetica Chimica Acta, B, d. Aq., 1941, p. 1127) that the diaoetate of a 2o-methyl , 15-pregnadien-3, 21-.diol@s, which possibly dias Diacetate of ao-methyl-d5, 1s-pregnadiene- 3, 21-diols, with osmium tetroxide to 3, 21-di- Acetate of a tetrol can be oxidized and possibly: 2o-Methylpregnen- (5) -tetrol- (3, 16, 17, 21) ist. If the constitutional formulas given are correct, the oxidation can be represented by the following reaction scheme It has now shown that @ anmitOsmi. tetroxyd 'as an oxidizing agent in good yield Pregnanderivate, which have a double division between carbon atoms 16 and 17 and a keto group contained in the 2o-position, can oxidize to the corresponding 16, 17-diol-2o, ones. A corresponding result was not to be expected, since the 16, 17-position double bond is conjugated with the double bond of the 20-position keto group and such a conjugation. Experience has shown that the double bond between the carbon atoms is often stabilized or something else: causes reaction digestion (cf. Fieser and Fieser, "Natural Products Related to Phenamthrene", 1949 p. 227, line 8 to ro, as well as Karret, "Origanic Chemistry", 1947, P. 58). As a result of this oxidation reaction, it is now possible to produce several hitherto unknown pregnen'16, 174iol-2o-ones in a simple manner, namely those at the same time. have a hydroxyl or keto group in the 3-position, such as d5-Pregnen-3, 16, 17-triol-2o-one and A4-Preignen-16, 17-diol-3, 2ö-di @ one.

Accordingly, the bowing invention relates to a method for the production of Pregnian-16, i7-diiol-2o-ones by oxidation of pregnane derivatives, which has a double bond between carbon atoms 16 and 17 and a keto group contained in the 2o position, with osmium tetTOxyd ,.

This makes it possible to create a number of connections in a simple way to produce the processes that are already known in. Pregnaniderivate with hormonal effects or can be converted into other steroid hormones.

Double bonds between two carbon atoms in the ring system, the are not conjugated to the double bond of a keto group will usually be attacked by osmium tetroxide. Solos. This can be avoided by getting them before the Protect oxidation with osmium tetroxide by bromination and then the bromine with a bromab ° splitting agents, e.g. B. Nabrium iodide or zinc dust, remove again.

The compound used as the starting material can, in addition to the 16, 17-piece double-endings, dune a cader contained several other double-endings, however, compounds with more than three in the ring system are difficult to establish, and moreover, if there are more than three double bonds, conjugations will often occur, which in the oxidation or in work-up .the resulting reaction mixture Cause complications.

The compound used as the starting material can also be used in addition to 2o-keto group contain other keto groups and one or more hydroxyl groups. If the last of them are attacked by osmum tetroxide, they must when you get them wishes to be protected by esterification.

Of the compounds produced by the process according to the invention the Pregnancy derivatives are of particular importance, as most of them: Horned tones, like Cortisone, Corticosterone, Progesterone and Testosterone, as well as many intermediates in the synthesis of other hormones a - double bond between carbon atoms in the Ring system included. The Me'hrza'hl the compounds that by the invention Process can be produced, were previously unknown, z. B. the following listed compounds: 16, 17-Dioxy-3, 2o-diketo-pregnapo'lyene, 3, 16, i7-Trioxy-2o-keto, - pregnapolyene, 3, 16, 17-trioxy-i i, 2o-d @ iketo-pregnapolyene, 3, 16, 17, 2 i-tetraoxy-2o-keto-pragnapodyene and 16, 17, 2i-trioxy-3,11,2o-tni'keto-pregnapolyene. Understood by pregnapolyenes one pregnane derivatives, which one or more @ double bonds between the carbon atoms included in the ring system.

The solvent used to dissolve the starting compound must be inert to osmium hydroxide. That is why you usually work expediently paints volatile, oxygen-containing, organic solvents, which did not contain hydroxyl groups, e.g. B. ether or acetone. Benzene is also in Can be used in many cases. During oxidation: As a rule, the following is formed: the osmic acid ester of a r6,17 diol. This. Is in the vast majority of cases in the above Solvents mentioned are insoluble or difficult to dissolve. To remove the osmium you put the. Osmiatester in a known manner, expediently by saponifying under reducing conditions, e.g. B. by treatment with a water soluble. Sulfite, such as nabrium sulfite, in an aqueous medium. The resulting sodium osmium stilfit crystallizes out and can be separated from the solution.

After oxidation with osmium tetroxide, it is removed. expediently the solvent by distillation, dissolves the. Residue: 1n a water-miscible organic solvent., Z. B. alcohol, and adds an aqueous solution of sodium sulfite. For complete decomposition of the osmic acid ester it is usually necessary to reflux the mixture for a few hours. Then the insoluble osmium compounds are separated and z. B. extracted by boiling with alcohol. @ The solutions are then combined and the solvent is distilled off. The aqueous solution is then treated with a water-immiscible organic solvent, e.g. B. chloroform, -ausschüttelt, the extract eritwäsisert, this solvent albdestif-liert and the residue from a solvent, z. B. methanol or acetone, um.knistallisiert. B, eiispie11 d5-Pregnen @ 3 ß, 16, 17-triol-2o-one 45 ls-Pze- gna., dien-3 ß-ol-2o-one,. whose 3-position hyd, roxyl = group by acetylation and its 5, 6-position Double bond through brominating against Oxy4alion is protected. The corresponding 5, 6-di`bromo- d1s-pregnen-3 ß-ol-2o-odi-aoetat can be as follows make: 3, oi5 g 45, 1s-pregnadien-3 ß-ol-2o-on- acetate are poured in roo ccm of anhydrous fish solves. A solution of 6 g is added to this solution dehydrated potassium acetate in 6o cam glacial acetic acid give;. After the mixture has cooled to 0 °, 30 cc of a bromine-glacial acetic acid solution containing 4.5 g of bromine per zoo cc are added dropwise and with stirring over the course of 9 hours. The solution is left to stand overnight at a low temperature, then diluted with ether and the acetic acid is removed by washing with water. around sodium carbonate solution. The ethereal solution is washed with water by blowing air, dried over dehydrated sodium sulfate and concentrated in vacuo, initially with warming and then at room temperature. After adding about 50 cc of methanol, the dibromide crystallizes out in needles on further concentration. After recrystallization, the product melts at IIg to 12o '. A smaller amount of a by-product with a higher melting point can also be obtained, but this has not been investigated further. The yield bends from 63 to 700/0 of theory; the bromine content is 30.r40 / 0 (calculated: 3o, g5%).

The absorption spectrum of the nm ultraviolet product showed that for a, ß-unsaturated ketones characteristic maximum at 237.5MY at one absorbance of E = 1oioo. According to: the literature shows dls-Pregnendion, (3, 2o) e (in maximum at 239 m, u with s = 980o. It is concluded: from this, the 16, 17-year-old Double bond was not brominated.

The oxidation! of the di-bromide and the debruration of the oxidation product This happens as follows: 2.66 g of dibromide become -in 1 g0 ccm of anhydrous ether solved. 1.44 g of osmium tetroxydi are added to this solution. After 4m! Al 24 hours When standing, the ether is abdesbil.lated and. the brown-black residue dissolved in 400 cc alcohol. This solution is crystallized with a solution of 30: g Sodium sulphate in: 400 CCM water and 7 g zinc dust are added, after which 3 to 4 hours .is boiled with stirring .and reflux cooling. Then the unresolved The remainder is inherited by filtration and boiled with alcohol. The solutions are combined to Removal of the alcohol concentrated in vacuo. And extracted with chloroform. This is distilled after drying and the residue is converted into methanol. The reaction product crystallizes in needles with a melting point of 233 ° to 235 °. To Another recrystallization melts the purified product at 239 to 24o °. Yield-: 34% of theory.

Analysis: Found C 72.32%, H 9.120 / a. Calculated C 72.38%, H 9.25 0/0. Be, isp-iel2 44-Pregnen-16, 17-diol-3, 2o-dnon To dissolve 2 g of dehydroprogesterone in 300 cc of ether, 1.63 g of osmium tetroxide are added, where: the osmium acid ester turns out to be a brownish yellow Precipitation is discarded. After standing 4 times for 24 hours, the ether is earth-distilled in vacuo and the residue is dissolved in a mixture of 150 cc alcohol and 20 cc water which contains 20 g of crystallized sodium sulfite. After boiling for 2 hours: the black precipitate is filtered off, boiled several times with alcohol and: the combined extracts are concentrated in vacuo. The concentrated solution is extracted by shaking with chloroform, this is earth-distilled and the glass-like residue is recrystallized from acetone. This gives about 0.48 g of crude product with a melting point of 215 to 217 °. A further recrystallization increases the melting point to 2i8 to 2i9.5 °. This product shows an absorption at 249 Ma with an extinction of 15 60 °, whereby it is shown that the hydroxylation on the carbon atoms 16 and 17 has taken place. Example 3 All. 1s-Pregnen-3, 16, 17-trioh-2o-one To dissolve 1.5 g of All, 16_pregniadien-3 ß-ol-2o-on-, a.cetat in 5o ccm of anhydrous ether, a solution of 3 g of dehydrated potassium acetate in 30 cc of glacial acetic acid, the solution cools to 0 °, and at this temperature, 15 cc of a bromine-glacial acetic acid solution, which contains 4.5 g of bromine per Zoo com, is added dropwise over the course of 6 hours. The mixture is then left to stand at 0 ° for 16 hours. After adding a further 50 cc of ether, the glacial acetic acid and potassium acetate are removed by washing with water, 1% strength sodium bicarbonate solution and finally again with water. The solution is then dried over anhydrous sodium sulfate and freed from the solvent in vacuo. The oily, crude 11, 12-dibromo-dl0-pregnen-3 ß-01-2o-on-3-acetate is dissolved in zoo ccm anhydrous ether, treated with 0.72 g Osmi: umtetroxyd and left to stand for 5 days at room temperature, a dark precipitate of osmium acid ester forms. The ether is then earth-distilled in vacuo, the black-brown residue is dissolved in 200 cc of alcohol and a solution of 15 g of sodium sulfite in 150 cc of water and 5 g of zinc dust are added. The Misehung is then 3 hours under stirring and RückfluBkühlung to saponification £ ung of osmium: s, äureesters, Biel extension of the two hydroxyl groups .an the Koh.lenstoffatomen: 16 and 17, waste cleavage of the bromine and recovery of the double bond, cooked, the dregs Erbfiltered, boiled with alcohol and, the combined filtrates largely concentrated in vacuo. The solution is then shaken out with 50 cc of chloroform, the chloroform extract is washed with water and evaporated to dryness. The oily residue does not crystallize. By dissolving the residue in 30 cc of chloroform, treating with 3 g of active charcoal and filtering off. the charcoal gives a solution which leaves about 0.7 g of a puffy mass on evaporation. The determination of the active hydrogen according to Z erewi, ti -noff showed the presence of three hydroxy groups. In the catalytic hydrogenation with Pt in glacial acetic acid, the 20-keto group and a hydrocarbon double bond are correspondingly absorbed twice hydrogen, so that the first compound is the all-pregnen-3, 16, r7-triol-2o -on represents.

Beispie14 As (9) -Pregnen-3, 5, 16, 17-tetrol-i i, 2o-dione To a solution of, ig 48 (9). 1s-Prebaden-3, 5-d`iol-i, 2o-diorn-3-acetate in 100 ccm of anhydrous ether are given 0.66 g of osmium tetroxide. The osmic acid ester gradually falls from this mixture as a brownish-yellow precipitate. After standing for 5 days, the ether is removed in vacuo and the residue is dissolved in 100 cc of alcohol. Then sodium sulfite is added in 10 ounces of water, the solution is boiled for 2 hours, and the black precipitate is filtered off. Sodium osmdum suIfit consists, and boils twice with 2o ccm of alcohol each time. The combined filtrates are largely concentrated in vacuo and extracted with chloroform. The chloro form extract is washed with water, ridden with anhydrous calcium, dried chloride and evaporated to dryness in vacuo. After treating the residue with chloroform and methanol. o; 31 g of an amorphous substance are obtained, the absorption maximum of which is at 253 m, u (E = 88oo). The determination of the more active hydrogen nasch Zerew: i tIrno ff produced four hydroxyl groups; the connection established is thus d $ (9) -Preg-nen-3, 5, 16, 17-tetrol-i i, 2o-dione.

Example5 45-Pregnen-3, 16, 17, 2i-tetrol-2o-one To a solution of 1.5 g 45.1s-Pregnadnenr 3, 2i-; di01-20-one-3, 21, acetate in i5o After cooling to 15 °, 0.57 g of bromine, which is dissolved in 75 cc of anhydrous ether, are added to anhydrous ether, and then, without separation of the 5,6-dibromide, 0.08 g of osmum tetroxide is added. After standing for 24 hours at 0 ° and then for 3 days at 20 °, a dark brown precipitate of osmic acid ester forms.

Thereafter, the ether is distilled off in vacuo and the residue dissolved in zoo cc alcohol; then one gives a solution of; 15 g sodium sulfite in zoo cc of water as much as 4 g of zinc dust. The misohung will then take 4 hours Stir, and reflux cooling boiled and filtered. The solid residue is carefully Washed out with alcohol, the combined filtrates freed from alcohol in vacuo; the solution with Tetr: ach'l.orkohlenr substance shaken out, the extract with water washed, dried and evaporated to dryness in vacuo. The oily residue is dissolved in alcohol and precipitated again by adding petroleum ether. To several. such. 0.6 g of an amorphous substance is obtained from precipitations. The product shows no absorption in the ultraviolet. So the 16, 17 double bond is no longer present after treatment with osmium tetroxide. A Zerewitinoff provision indicates four hydroxyl groups.

Beisp1e16 44-Pregnen-i6, 17, 2i-triol-3, ii, 2o-trdon To a solution of 2 g of 44.1s_pregnadien-2i-acetoxy-3, ii, 2o-trione in 300 cc of ether, 1.32 g of osmium tetroxide are added given ,. The osmic acid ester separates out as a brown precipitate. After standing for 5 days at room temperature, the ether is distilled off in vacuo and: the residue is dissolved in a mixture of: 250 cc alcohol and a solution of 20 g sodium sulfite in 200 cc water. The solution is refluxed for 3 hours, after which the sediment of sodium osmium sulfite is filtered off and extracted three times with boiling alcohol. The combined filtrates are concentrated in vacuo and the evaporated solution is extracted by shaking with chloroform. The chloroform solution is dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the residue from acetone melts the product at 2o6 to 2o8 °. Yield: 0.51 g; Absorption maximum at 240 with (E = 14,300), from which it can be seen that the hydroxylation on: the: carbon atoms 16 and. 17 took place. B ei, s pi e47 45, "_pregna-clien-3, 16, 17-tniol-2o-one To a solution of 1.5 g 45, 11. 16-pregnatrien-3-ol-2o-one - acetate 6 g of dehydrated potassium acetate in 6o cc of glacial acetic acid are added to 100 cc of anhydrous ether. After the mixture has cooled to 0 °, 3o cc of a bromine-glacial acetic acid solution containing 4.5 g of bromine per 100 cc is added dropwise.

The solution is left to stand for 18 hours at 0 °, after which the acetic acid by washing with water, 10% sodium bicarbonate solution and again with water Will get removed. After drying, the ether is distilled off in vacuo and the The residue was dissolved in 100 cc of anhydrous ether. To this solution -man i g osmium tetroxide, leave the mixture to stand for 5 days and then work up according to Example 3. After Recrystallization from methanol gives 0.42 g of 45 ° precnadiene-3; 16, 17-triol-2o-one with a melting point of 268 to 270 °.

Claims (1)

PATENT CLAIM: Process:, for the production of pregnans with at least a keto group in the 2o position and at least hydroxyl groups in the 16 and 1Z positions, characterized in that one Pregnane, which at least one double-handed between have carbon atoms 16 and 17 and at least one veto group in the 2o position, with Osmiu # mtetroxyd im; known to be oxidized.