DE1119858B - Process for the production of 3-position oxygen-free í-19-norsteroids - Google Patents

Description

Process for the production of 3-position oxygen-free d4-19 norsteroids The invention relates to a process for the production of 3-position oxygen-free d4A9 norsteroid by converting a d4-3-keto-19-norsteroid with a monovalent one or divalent mercaptan in a manner known per se, whereupon the obtained d4-3 thioketal steroid with an alkali metal in the presence of liquid ammonia reduced.

The compounds prepared according to the invention and processes for their Manufacture are already in the Dutch patents 89 813 and 89 818 and in the USA: Patent 2,878,267.

The present method results in contrast to and compared to the previous known method for the production of 19-norsteroids, which in the 3-position none Have oxygen function, much higher yields. The yield in the present Process is generally between 80 and 90 °, / o. As starting compounds d4-3-keto-19-norsteroids can generally be used for the present process. Assuming steroids of the 19-norandrostan- or 19-norpregnan series, you get one after the process biologically active end products. As examples of important Starting compounds may be mentioned, inter alia: d4-3-keto-17-hydroxy-19-norandrostene; d4-3,17-diketo-19-norandrosten; d 4-3-keto-17-hydroxy-17a-vinyl-19-norandrostene ; d4-3-keto-17-hydroxy-17ac-methyl-19-norandrostene; d4-3,11,17-triketo-19-norandrosten ; d4-3-keto-11,17-dihydroxy-17cx-methyl-19-norandrosten; d4-3,20-diketo-19-norpregnen ; d4-3,20-diketo-21-hydroxy-19-norpregnen; 44-3,20-diketo-11 ß, 17a, 21-trihydroxy-19-norpregnen: d4-3,20-diketo-11β, 21-dihydroxy-19-norpregnen; d4-3,20-diketo-17a-hydroxy-19-norpregnen; d4-3,20-diketo-17a, 21-dihydroxy-19-norpregnen; d4-3,11,20-triketo-17a, 21-dihydroxy-19-norpregnen and functional derivatives of these compounds.

The thioketalization of the keto group in position 3 can after a the known methods can be carried out, e.g. B. by condensation of a corresponding d4-3 keto steroid with a monovalent or divalent mercaptan in the presence zinc chloride or hydrochloric acid and a dehydrating agent such as sodium sulfate. It is also possible to obtain the desired 3-thioketals by an exchange reaction or by reacting a monovalent or divalent mercaptan in the presence of p-toluenesulfonic acid and to prepare a water-immiscible organic solvent, wherein the water formed in the reaction is removed. There is another possibility in that the 3-ketosteroid, preferably dissolved in glacial acetic acid, with the relevant Mercaptan in the presence of a Lewis acid, preferably boron trifluoride or boron trifluoride etherate, to react.

The 3-keto group is preferably by means of a divalent mercaptan, z. B. ethanedithiol, propanedithiol or butanedithiol, in a cyclic thioketal convicted. However, open-chain thioketals can also be used as intermediates be used in the present process, e.g. B. those connections that are derived from ethyl mercaptan, propyl mercaptan, thiophenol or benzyl mercaptan.

The d4-19-nor-3-thioketal steroid produced in this way becomes then treated with an alkali metal in the presence of liquid ammonia, the 3-thioketal steroid being reduced and a d4-19 norsteroid which is oxygen-free in the 3-position is obtained.

From theoretical considerations one should expect that the most stable Position of a double bond present in ring A in 19-norsteroids with oxygen free 3-position lies between the carbon atoms 5 and 10. In the method according to the invention It was therefore surprising that in the starting compounds between the carbon atoms 4 and 5 existing double bond is retained in this position after the thioketal group is split off.

The reduction of the substituent in position 3 is carried out by treatment the starting compound, dissolved in a suitable solvent, with an alkali metal in the presence of liquid ammonia. As a solvent, for. B. aliphatic Ethers, such as dimethyl ether, methyl ethyl ether or diethyl ether and dioxane or tetrahydrofuran, be used.

The alkali metal used for this reaction can e.g. B. Lithium, Be sodium or potassium; it was found beneficial to use sodium.

If the 3-thioketal steroid to be reduced contains one or more reducible ones Carbonyl groups, these are converted into hydroxyl groups during the reduction, which are again converted into keto groups by oxidation in a manner known per se can be.

The following examples explain the process according to the invention. Example 1 A solution of 0.7 g ethanedithiol and 0.7 ml boron trifluoride becomes a Solution of 1.95 g of d4-3-keto-17ß-hydroxy-19-norandrostene in 6 ml of glacial acetic acid at 20 ° C given. The mixture is stirred for 15 minutes and then poured into water. The resulting Precipitation is filtered off with suction and dried over sodium sulfate. The precipitation is made from methanol recrystallized.

The 3 -, # ethylene thioketal of d4-3-keto-17a-hydroxy-19-norandrostens melts at 150 ° C.

To a mixture of 1 g of this compound, 5 ml of ether and 30 ml of liquid Ammonia, 1 g of small sodium chips are added. The blue colored solution will Stirred for 15 minutes at -35 ° C, then anhydrous ethanol is added until the blue color has disappeared. The ammonia is then distilled off and the Extracted residue with ether. The ether extract is evaporated to dryness and the residue recrystallized several times from acetone-ether. The A 4-17β-hydroxy-19-norandrosten is obtained with a m.p. of 98'C.

The d 4-3-keto-17ß-hydroxy-17a-methyl-19-norandrosten was in a corresponding manner with methyl mercaptan and boron trifluoride etherate into the corresponding 3-methylene hemi-ketal and then converted with lithium in liquid ammonia to d4-17ß-hydroxy-17a-methyl-19-norandrosten, M.p. 147 to 150 ° C, reduced. Likewise, the d4-3-ketollß, 17ß-dihydroxy-17oc-vinyl-19-norandrosten thioketalized with butanedithioi in position 3 and then with sodium in liquid Ammonia reduced to d4-11ß, 17ß-dihydroxy-17oc-vinyl-19-norandrosten. This connection exhibits characteristic bands at 2.79, 6.04, 11.15 and 12.38 #t in the IR spectrum on.

Example 2 A mixture of 0.95 g of d 4-3,20-diketo-19-norpregnane, 1.0 g propanedithiol, 45 ml anhydrous benzene and 30 mg p-toluenesulfonic acid is 2 Boiled under reflux for hours and the water formed in the reaction was separated off. The benzene solution is then cooled with sodium bicarbonate solution and water washed, dried and evaporated to dryness. The residue becomes from a Recrystallized mixture of acetone and methanol. The 3-propylenebioketal is obtained of the d4-3,20-diketo-19-norpregnens.

7u a mixture of 0.5 g of this compound in 8 ml of ether and 20 ml of liquid ammonia 0.18 g of small lithium chips are added, then the Solution stirred for 2 hours at -35'C and then with absolute ethanol up to Disappearance of the blue color thins. Then the ammonia is evaporated, the The residue is diluted with water and the solution is extracted with ether. The ether extract is washed with water, dried over sodium sulfate and evaporated to dryness. After recrystallization from methanol and then from petroleum ether, this is obtained d4-20-hydroxy-19-norpregnen; M.p. 93 to 94'C; [ocv] - + - 41'C (chloroform).

0.5 g of this compound are dissolved in 25 ml of acetone and added dropwise with stirring at O 'C with chromic acid solution. The chromic acid solution was prepared by dissolving 70 g of chromium trioxide in 100 ml of water and 55 ml of concentrated sulfuric acid and then making up to 250 ml with water. The chromic acid solution is added dropwise until the color is constant yellow. The reaction mixture is then evaporated almost completely to dryness under reduced pressure, the residue is then taken up in water, the aqueous mixture is extracted with chloroform, the chloroform layer is separated off, washed neutral with dilute sulfuric acid, then with cold dilute sodium hydroxide solution and then with water. After the solvent has evaporated, the d 4-20-keto-19-norpregnene is obtained; 113-114 ° C; [a] b -} - 146 ° C (chloroform).

In a corresponding way, the d4-3,20-diketo-21-hydroxy-19-norpregnene Boiled under reflux for 3 hours with propanedithiol in the presence of p-toluenesulfonic acid and converted into the corresponding 3-propylenethioketal. The reduction of this connection in a manner analogous to that described in this example and the subsequent oxidation the obtained 20-hydroxy compound with chromium trioxide gave the d 4-20-keto-21-hydroxy-19-norpregnene. The 21-acetate of this compound melts at 156 to 158 ° C; [a] v + 141'C (chloroform).

The d4-3,11,20-triketo-17a, 21-dihydroxy-19-norpregnated in the same way converted with butanedithiol into the corresponding 3-butylenethioketal and then with Sodium in liquid ammonia to d 4-11-keto-17a, 20ß, 21-trihydroxy-19-norpregnen reduced. This compound shows characteristic bands in the IR spectrum at 2.80, 5.88 and 12.38 #t.

The acylation of this compound with acetic anhydride and the subsequent Oxidation with chromic acid solution and saponification with sodium hydroxide solution to the above in The manner described in this example gave the d 4-11,20-diketo-17a, 21-dihydroxy-19-norpregnene. This compound has characteristic bands at 2.95, 5.86 and in the IR spectrum 12.38. on.

Example 3 An ice-cold mixture of 0.75g d 4-3-keto-17ßhydroxy-17a-ethyl-19-norandrosten, 1 g zinc chloride and 1 g of anhydrous sodium sulfate is mixed with 2 ml Benzyl mercaptan added.

The mixture is left to stand at room temperature for 3 days and thereafter undressed with ether. The ethereal solution is evaporated to dryness and the Recrystallized residue from ethanol-benzene. The 3-dibenzyl mercaptal is obtained of d 4-3-keto-17ß-hydroxy-17a-ethyl-19-norandrostens.

0.5 g of this compound are dissolved in 5 ml of ether and 35 ml of liquid ammonia dissolved and then mixed with 0.5 g of small sodium chips. The mixture will Stirred for 30 minutes and then excess sodium by adding 20 ml of methanol destroyed. The ammonia is evaporated and the ethereal solution, as in the example 2 described, worked up. The d4-17ß-hydroxy-17a-ethyl-19-norandrostene is obtained from m.p. 76 to 78 ° C.

In an analogous manner, the d 4m3-keto-17ß-hydroxy-17a-vinyl-19-norandrosten was converted via the 3-diphenyl mercaptal into the d4-17ß-hydroxy-17x-vinyl-19-norandrosten of melting point 78 to 79'C and that j4 -3-keto-17β-hydroxy-17a-propyl-19-norandrosteno via the 3-diethyl mercaptal into d 4-17β-hydroxy-17a-propyl-19-norandrostene with a melting point of 98.5 to 99.5 ° C converted. Example 4 A mixture of 0.95 g of j4 -3-keto-17ß-hydroxy-17oc-butyl-19-norandrostene and 1 ml of ethanedithiol is heated on a water bath for 2 hours and then treated with 1 ml of boron trifluoride etherate. After 15 minutes, the mixture is diluted with 5 ml of acetic acid and the precipitate formed is filtered off with suction and washed with methanol. The 3-ethylenethioketal of A4 -3-keto-17ß-hydroxy-17ca-butyl-19-norandrostens is obtained. 1 g of small sodium chips are added to 1 g of this compound in 5 ml of ether and 35 ml of liquid ammonia. The solution is stirred for 20 minutes and then absolute ethanol is added until the blue color disappears. The ammonia is then distilled off and the residue is extracted with ether. The ether extract is evaporated to dryness and then the residue is recrystallized from a mixture of acetone and ether. The d4-17ß-hydroxy-17a-butyl-19-norandrostene melts at 98 to 100 ° C.

The d4-3,20-diketo-17oc-hydroxy-19-norpregnen was carried out in an analogous manner converted via the 3-propylenethioketal into the d 4-17a, 20ß-dihydroxy-19-norpregnen. This compound becomes the corresponding in the manner described in Example 2 20-keto compound oxidized; this compound has a melting point of 147 to 149'C.

Claims (3)

PATENT CLAIMS: 1. Process for the production of 3-position oxygen-free d 4-19-norsteroids, characterized in that one d 4-3-keto-19-norsteroid converted in a manner known per se into its 3-thioketal, whereupon this compound is used reduced with an alkali metal in the presence of liquid ammonia and optionally Hydroxyl groups formed during the reduction according to methods known per se re-oxidized. 2. The method according to claim 1, characterized in that the Converted starting compound into a cyclic 3-thioketal. 3. The method according to claim 1 or 2, characterized in that the alkali metal used is sodium.