DE1198358B - Process for the preparation of 3beta-hydroxy-16beta-methyl-20-oxo-5alpha-pregnane or 3-lower-alkanoyloxy compounds - Google Patents

Description

Process for the production of 3ß-hydroxy-16ß-methyl-20-oxo-5a-pregnane or its 3-lower-alkanoyloxy compounds The present invention relates to a process for the production of 3ß-hydroxy-16ß-methyl-20-oxo-5a -pregnan or its 3-lower alkanoyloxy compounds, which is characterized in that 3ß-hydroxy-20-oxo-16ß- (y-oxymethylvaleroyloxy) -5a-pregnan-16a-acetic acid or its corresponding 3-acylates with a basic substance treated in an aqueous or anhydrous organic solvent, the resulting 3ß-hydroxy-16e-methyl-5a, 16e, 17e-androsta- [16,17-2 ', 3'] - pyran-4 ', 6'-dione from the acidic fraction of the reaction mixture isolated, optionally acylated in a known manner, then decarboxylated with an acidic substance and, if necessary. the 3ß-hydroxy-16-methyl-16.20-dioxo-16.17-seco-5a-pregnane or the 3ß, 16e-dihydroxy-16e-methyl-20-oxo-5a, 17a-pregnane or its obtained as an intermediate corresponding 3-acylates are subjected to a further treatment with an acidic substance and the 3β-hydroxy-16-methyl-20-oxo-5a-16 (17) -pregnene obtained or its corresponding 3-acylates are hydrogenated in a manner known per se. wherein R and R 'are each hydrogen or a lower alkanoyl group, e.g. B. acetyl, propionyl, butyryl. Valeryl, is; R "represents hydrogen or an The conversions in the present inventive process are illustrated by the following formulas: lower alkyl group, e.g., methyl, ethyl. Propyl, butyl, and the wavy line (j) represents an indefinite configuration. R and R Can be converted from hydrogen to a lower alkanoyl group or vice versa by processes known per se, in order to facilitate the process used in each case for the isolation or purification.

The chemical structure of the compound according to formula II is has not yet been confirmed which structure that of the formula II 'can also assume. In the present description, however, the connection is tentatively represented by the Formula II illustrates. The method according to the invention is based on these findings built up.

It is known that naturally occurring cryptogenin can be found in the [3-Oxo-20-oxy-1,4,17 (20) -pregnatrien-16-ylidene] -acetic acid-lactone by means of a Series of reaction stages can be converted, the latter compound possesses physiological activities (U.S. Patent 3,043,834). In the course of this Conversion gave the 3ß-oxy-20-oxo-5a-16 (17) -pregnen-16-acetic acid as an intermediate with a low yield. It has now been established that this low yield of said intermediate by the expiration of Side reactions is caused.

The aim of the present invention is thus to provide a useful method to provide a compound that was originally a by-product (see US Pat. No. 3,043,834) and is now an important intermediate in the synthesis of a well-known physiologically active steroid, betamethasone (9a-fluoro-16ß-methylprednisolone), has proven (O 1 i v e t o and coworkers, J. At the. Chem. Soc., 80, 4431 [1958]).

3ß-Hydroxy-20-oxo-16ß- (γ-hydroxymethylvaleroyloxy) are used as the starting material for the present invention - 5a - pregnan -16a - acetic acid or its derivatives of formula 1, which are derived from the Obtaining cryptogenin according to a known method (U.S. Patent 3,043,834) can be.

The conversion of the steroidal acetic acid I into the steroidal lactone II is accomplished by treating the former with a basic substance such as an alkali metal hydroxide, e.g. B. sodium hydroxide, potassium hydroxide. with an alkali metal alcoholate, e.g. B. sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, with an alkali metal bicarbonate, for. B. sodium bicarbonate, potassium bicarbonate, or an alkali metal acetate, e.g. B. sodium acetate, potassium acetate, in a suitable aqueous or anhydrous organic solvent medium, e.g. B. methanol, ethanol, benzene, toluene, acetic acid. In general, the use of a strongly basic substance is preferred for the purpose of easy isolation of the steroidal lactone II produced from the reaction mixture, including the inevitable by-product. The reaction can be carried out at a temperature lower than about 30 ° C, but the higher temperature, usually the reflux temperature, is preferred in view of obtaining the steroidal lactone II in a relatively high yield. Usually the reaction can be completed in about 30 minutes to about 10 hours, the lower temperature necessarily requiring longer reaction times. In a short response time, e.g. B. within 10 minutes, the steroidal lactone II can hardly be obtained, even if the reaction temperature is so high. The reaction product is usually a mixture of the steroidal lactone II with 3ß-hydroxy-20-oxo-5a-16 (17) -pregnen-16-acetic acid and / or (3ß, 20-dihydroxy-5a -17 (20) - pregnen - 16 - ylidene) - acetic acid lactone; the latter two compounds can be illustrated by the following formulas: The co-formation of one or both of these two connections is inevitable. However, these by-products can be removed from the reaction mixture by a simple method such as extraction, recrystallization and chromatography. For example, the reaction mixture is diluted with water and then washed with a suitable water-immiscible organic solvent, e.g. B. dichloromethane, chloroform, carbon tetrachloride, shaken in neutral or in an alkaline medium, the steroidal lactone II and the compound of formula A retained in the aqueous layer, while the compound of formula B is removed by the organic solvent layer. The separation of the steroid lactone 11 from a mixture with the compound A can be carried out by using the difference in their solubilities in a suitable organic solvent. For example, the mixture of the same is treated with acetone, the steroidal lactone II first crystallizing out and the compound A then being obtained from the mother liquor. In general, the elimination of the compound B from the reaction mixture is easier than that of the compound A. Accordingly, it is recommended to carry out the reaction using a strong basic substance and at a higher temperature, usually under reflux, for a relatively longer reaction time, so that the Co-formation of the connection A can be suppressed.

The steroidal lactone II produced in this way is subjected to decarboxylation and provides the pregnen III. The decarboxylation can be carried out by treating the steroidal lactone II with an acidic substance, e.g. Sulfuric acid, hydrochloric acid, acetic acid, in a suitable water-miscible organic solvent medium, e.g. B. tetrahydrofuran, dioxane, heated to reflux. Usually this reaction takes 1 to 3 hours. A shorter reaction time usually leads to the formation of one or both of the compounds listed below: in which formulas R has the same meaning as given above. However, these by-products can easily be converted into Pregnen III by repeating the treatment with an acidic substance, as mentioned above.

The resulting Pregnen III is conventional in itself Kind reduces and delivers the Pregnan IV. For example, the catalytic reduction des Pregnens III in the presence of palladium-carbon or platinum dioxide in a suitable organic solvent medium, e.g. B. methanol, ethanol. Ethyl acetate carried out and gives the Pregnan IV.

The steroidal lactone 1I has considerable anti-DOCA (deoxycorticosteronaceta *) activity. For example, it leads to a complete inhibition of the effect caused by 10 µg of DOCA if the same is administered to rats at a dose of 1 mg. The steroidal Lactone II is thus a useful * anti-DOCA agent.

Example 1 3β-Hydroxy-16e-methyl-5a, 16e, 17e-androsta- [16,17-2'.3 '] pyran-4'.6'-dione (1I: R = H) 3β-Acetoxy-20-oxo-16β- (γ-acetoxymethylvaleroyl = oxy) -5a-pregnane-16a-acetic acid methyl ester (1.004 g) is added to the ethanolic solution of sodium ethylate, made from 400 mg of metallic sodium and 4m1 of anhydrous ethanol, added, after which the resultant Solution is refluxed for one hour on a water bath. Thereafter the reaction mixture is poured into water and shaken with chloroform. To Acidifying the aqueous layer with dilute hydrochloric acid it becomes with Shaken chloroform. The chloroform layer is washed with water and dried and the solvent evaporated under reduced pressure. The residue will be off Methanol crystallizes and gives II (R = H) in a yield of 24.10 / 0. F. = 263 to 265'C (decomposition). [a] ö +115.0 t2 ° (in ethanol. c = 1.012).

Analysis for C231310 ,: Calculated ... C 73.76, H 9J5-, found ... C 73.86, H 9.30. Amax: 251 m # L (e: 9250). When adding one Drops of N / 10 NaOH dmax 278 m # t (e: 17 850). YNuxol (cm- '): 3240, 1678, 1658, 1620. 3ß-Hydroxy-1.6-methyl-20-oxo-5a-16 (17) -pregnen (III: R = H) and its 3-acetate (III: R = CHLCO A solution consisting of 1,000 g of II (R = H ) in a mixture of 143 ml of dioxane and 61 ml of 20% sulfuric acid is refluxed for 11/2 hours. The reaction takes place with the formation of carbon dioxide gas, which can be detected by passing through an aqueous solution of barium hydroxide After washing the ether layer with water, then with dilute aqueous sodium carbonate solution and again with water, the same is dried over anhydrous sodium sulfate. The solvent is then evaporated off and the residue crystallizes from a mixture of ether and petroleum ether; these crystals are recrystallized again from the same solvent and give III (R = H) in a 44.80% yield. F. = 183.5 to 185 ° C; [a] ö -11 : E 2 ° (in ethanol, c = 0.989).

Analysis for C2213402: Calculated. . . C 79.95, H 10.37; found ... C 80.20, H 10.47. Y maxol (cm- '): 3410, 1634, 1600. y max (C111-1) 3612, 3440, 1652, 1600. @, mSaX ° ethanol: 252 mi. (£: 9500). III (R = H) is mixed with acetic anhydride and pyridine and left to stand at room temperature overnight. By crystallizing this reaction product from a mixture of ether and petroleum ether, one arrives at III (R = CH3CO). F. = 173 to 174 ° C. [a] ED -22.7 ± 2 ° (in chloroform, c = 1.043).

Analysis for C24Hm03: Calculated ... C 77.37, H 9.74; found ... C 77.36, H 9.76. Ymaxof (cm- '); 1729, 1652, 1597.ymeX L '(.m-1): 1723, 1652, 1601. m # aX # ethanol: 252.5 mp. (e: 9700). 3ß-Hydroxy-16ß-methyl-20-oxo-5a-pregnane (IV: R = H) and its 3-acetate (IV: R = CH3C0-) A solution consisting of 200 mg III (R = CH3C0) in 50 ml of methanol is shaken with 200 mg of palladium-carbon in a stream of hydrogen for 5 hours. The catalyst is then filtered off and the filtrate is evaporated, whereupon crude crystals precipitate, which, recrystallized from methanol, give 168 mg IV (R = CH3CO -). M.p. = 148 to 149'C; [a] ö5 -! - 33.3 t2 ° (in ethanol, c = 0.980). ymaxo ' (cm- '): 1730, 1711, ymäc'- (cm- '): 1725, ymax (cm- '): 1733.1710. i msaX ° ethanol 290 m # L (e: 39). IV (R = CH3C0) is hydrolyzed with alkali and yields IV (R = H).

Example 2 3β-Hydroxy-16e-methyl-5a, 16e, 17e-androsta = [16,17-2 ', 3'] pyran-4 ', 6'-dione (1I: R = H) 3β-Acetoxy-20-oxo-16β- (γ-acetoxymethylvaleroyloxy) -5a-pregnane-16a-acetic acid methyl ester (1.011 g) becomes a solution of 410 mg of potassium hydroxide in 2 ml Water and 12 ml of methanol were added, after which the resulting solution was added over 1 hour is stirred at 0 to 5 ° C. The resulting mixture is poured into water, acidified with dilute hydrochloric acid and shaken with chloroform. The chloroform layer is washed with water and dried, and the solvent evaporated under reduced pressure. After adding to the residue a solution of 2.0 g of potassium bicarbonate in 20 ml of 800 / Qigem methanol is the solution thus obtained during Heated to reflux on a water bath for 2 hours. The reaction mixture is then treated as described in Example 1 and provides 1I (R = H) in one yield of 23.6%.

3ß-acetoxy-16-methyl-20-oxo-5a-16 (I7) -pregnen (III: R = CH3C0), 3ß-acetoxy-16-methyl-16,20-dioxo-16,17-seco-5a- pregnane (C: R = CH3C0), 3β, 16e-dihydroxy-16e-methyl-20-oxo-5a, l7a-pregnane (D; R = H) and its 3-acetate (D: R = CH3C0-) a solution consisting of 500 mg II (R = H) in a mixture of 71 ml of dioxane and 31 ml of 200% sulfuric acid is heated at reflux for 11 minutes. The reaction mixture is then poured into water and shaken with ether. The ether extract is washed in sequence with water, aqueous sodium carbonate solution and water and dried over anhydrous sodium sulfate. After evaporation of the solvent, 478 mg of a residue is obtained which, after standing overnight at room temperature, ie at 15 to 20 ° C., with 1 ml of acetic anhydride and 5 ml of pyridine, gives 509 mg of a crude acetylated substance. This acetylated substance is chromatographed on 15 g of clay. The eluate with petroleum ether is crystallized from a mixture of ether and petroleum ether and yields 81 mg III (R = CH3CQ). 'The eluates with petroleum ether and a mixture' of petroleum ether and benzene, in a ratio of 8: 2 to 7: 3, are crystallized from a mixture of ether and petroleum ether and yield 91 mg of C (R = CH3C0). M.p. = 138 to 139 ° C; [a] 21 -I-17.5 @ 2 ° (in chloroform, c = 1.037).

Analysis for C24H3s03: Calculated ... C 73.80, H 9.81; found ... C 73.83, H 9.78. 172U, 1 "113, 1700. (cm- '): 1732, 1714, 1693. (cm-1) The eluates with a mixture of petroleum ether and benzene, in the ratio of 6: 4 to 1: 1, of benzene and a mixture of benzene and ether, in the ratio of 8: 2, are crystallized from a mixture of ether and petroleum ether and give 81 mg of D (R = CH3C0-). M.p. = 188 to 190 ° C. [a] 22-1 -40.5 ± 2 ° (in chloroform, c = 1.011). Analysis for C24H3s03: Berec $ net .... C 73; 8Q, H 9.81; found ... C 73.57, H 9.85. y maz ol (cm- '): 3595, 1722, 1704. y mHX l3 (cm-1) 3626, 1723, 1710. D (R = CH3C0) is treated with potassium carbonate in a mixture of methanol and water at room temperature and yields D (R = H). F. = 241.5 to 243 ° C. [«] 21s -34.3 ± 2 ° (in ethanol, c = 1.072).

Analysis for C223603: Calculated ... C 75.81, H 10.41; found ... C 75.96, H 10.64. ymäX ° '(cm-1): 3390, 1691. C (R = CH, 9CO) is refluxed for 20 minutes in a mixture of dioxane and sulfuric acid. The resulting substance is acetylated with pyridine and acetic anhydride. The reaction product obtained in this way is chromatographed and gives D (R = CH3C0) and III (R = CH3C0).

D (R = CH`3C0) is in a mixture of dioxane and sulfuric acid heated for one hour and gives III (R = CH3C0).

3ß-Hydroxy-16ß-methyl-20-oxo-5a-pregnane (IV: R = H) and its 3-acetate (IV: R = CH3C0 III (R = CH3C0) is mixed with palladium-carbon in a hydrogen stream shaken for 5 hours. The product is recrystallized with methanol and yields IV (R = CH3C0).

IV (R = CH3C0) is treated as described in Example 1 and provides IV (R = H).

Claims (1)

Claim: Process for the production of 3ß-hydroxy-16ß-methyl-20-oxo-5a-pregnane or its 3-lower alkanoates, characterized in that 3ß-hydroxy-20-oxo-16ß- (γ-hydroxymethylvaleroyloxy) - 5a- pregnan-16a - acetic acid or its corresponding 3-acylates with a basic one Substance treated in an aqueous or anhydrous organic solvent, the 3β-hydroxy 16e-methyl-5a, 16e, 17e-androsta [16,17-2 ', 3'] pyran-4 ', 6'-dione obtained isolated from the acidic fraction of the reaction mixture, optionally in a known manner Way acylated, then decarboxylated with an acidic substance and, if necessary, the 3ß-hydroxy-16-methyl-16.20 obtained as an intermediate - dioxo -16,1'7 - seco - 5a - pregnan or the 3ß, 16e - dihydroxy - 16e - methyl - 20 - oxo-5a, 17a-pregnane or their 3-lower alkanoates undergo further treatment with subjected to an acidic substance, and the resulting 3ß-hydroxy-16-methyl-20-oxo-5a-16 (17) -pregnen or its corresponding 3-acylates are hydrogenated in a manner known per se.