DE1170949B - Process for the production of water-soluble gestagens - Google Patents

Description

Process for the production of water-soluble gestagens In the main patent 1 152 105 describes a process for the production of 17ca-hydroxyprogesterone hemisulphate described that in the form of its salts, especially its sodium salt, a good is an effective progestin with excellent real water solubility, which is used in the situation is shifted to the intravenous administrable solutions during the preparation of the progesterone previously indispensable solubilizer, the cause undesirable Side effects are to be avoided. Regarding the effectiveness, the oxytocin test be shown that by intravenous administration of 100 mg hydroxyprogesterone hemisulfate sodium in aqueous solution the abortion caused by oxytocin in pregnant rabbits Security is prevented.

In a further development of the main patent 1 152 105 it has now been found that not only the 17oc-hydroxyprogesterone hemisulphate sodium, but also its at least as strongly gestagenic descendants have the advantages mentioned, with these, moreover, an unexpectedly significant increase in effectiveness is achieved. This is shown in the oxytocin test on pregnant rabbits, for example the 17a-hemisulfate sodium salts of 19-nor-17a-hydroxyprogesterone and dl # 4.g-pregnatrien-17a-ol-3,20-dione definitely ten times and of 1,2a-methylene-44,8-pregnadien-17a-ol-3,20-dione three times more effective than 17ca-hydroxyprogesterone-17-hemisulphate sodium.

The colorless aqueous solutions that can be prepared according to the invention Substances can be kept well. So they point to about even after 3 hours of heating 100 ° C no discoloration or other types of decomposition.

Example 1 1.3 g of 17a-hydroxy-19-norprogesterone are dissolved in 10 ml of dry pyridine, and 0.6 g of pyridine-SO3 adduct is added. The reaction mixture is stirred for 24 hours at room temperature under argon or nitrogen, the pyridine-insoluble SO3 adduct going almost completely into solution. Then about 0.5 ml of water is added to the reaction solution and stirring is continued until it is completely dissolved. The solution is then introduced into 100 ml of absolute ether with stirring, the precipitate which occurs is filtered off with suction and washed with absolute ether. The precipitate is then dissolved in 15 ml of absolute methanol and the solution is adjusted to pA = 10 with 1N sodium methylate solution (glass electrode). After 16 hours of standing at room temperature, the precipitated inorganic salt is filtered off and the filtrate is concentrated in vacuo to about 10 ml. The concentrated solution is introduced into 50 ml of absolute ether: the precipitate is suctioned off and washed with absolute ether. The 17a-hydroxy-19-norprogesterone hemisulfate sodium obtained in this way can be recrystallized from a little methanol; the yield is at least 1.4 g (75% of theory); M.p. 152-155 ° C; [a] D = --- 63.7 ° (c = 1; methanol); E "= 15920.

The compound dissolves in water to an extent of 16 to 17 per cent. Example 2 4 g of 6a-methyl-17a-hydroxyprogesterone are dissolved in 20 ml of pyridine and with 2.4 g Pyridine-SO3 adduct (about 81%) was added with stirring at room temperature and Keep stirring until almost complete solution has occurred. After that will be 0.12 ml of distilled water is added to the reaction mixture and more is added Stirred for 2 hours. The reaction mixture is then stirred into 200 ml of ether, the precipitated product is suctioned off, washed with ether and dried in a desiccator. To convert the dry product into the sodium salt, it is dissolved in 40 ml of methanol and adjusted to px 10 with about 1 normal methanolic sodium methylate solution. After standing for about 16 hours, the reaction product is treated with decolorizing charcoal and sucked off. The filtrate is concentrated in vacuo to about 20 ml and then in 140 ml of ether poured in. The excreted 6a-methyl-17a-hydroxyprogesterone sulfate sodium is filtered off with suction, washed with ether and dried in vacuo over NaOH. Yield: about 68% of theory. By appropriate work-up of the mother liquor, the Yield can still be increased. The substance is strongly hygroscopic and decreases in spite of it Store over NaOH in a vacuum desiccator after about 1.5 ° / 0 humidity.

C "Hsl0sSNa: Calculated ... S 7.18%, Na 5.15%; found ... S 6.78%, Na 5.03 l) /,.

(converted to anhydrous substance).

The infrared spectrum shows the expected characteristic bands for the 20-keto group at 5.87 #L, for the 3-keto-d 4 grouping at 6.02 and 6.23 #t and for the -S03 grouping at 7.97 and 8.10 Example 3 2 g of dl # 4 # e-Pregnatrien-17x-ol-32,0-dione, manufactured according to USA patent 2962510, are slurried in 10 ml of absolute pyridine and added with 1.07 g of pyridine-SO3 adduct offset. This suspension is stirred for about 20 hours at room temperature until a clear solution is obtained. 0.055 ml of water are then added to the reaction product and the mixture is stirred for a further 6 hours. Thereafter, ether is added to the reaction mixture, the precipitated product is filtered off with suction and dried over phosphorus pentoxide. The dry product is then dissolved in absolute methanol and 1N sodium methylate solution is added until the pH value is 10. After standing for about 20 hours at room temperature, the pH dropping to about 9, the reaction solution is treated with activated charcoal, filtered, the filtrate is concentrated to about 10 ml and the precipitate obtained with ether is suctioned off and dried. 1.3 g of dl # 4,8-Pregnatrien-17_x-ol-3,20-dione-17-hemisulphate sodium with a melting point of 166 ° C. (decomposition) are obtained. Example 4 1 g of 1,2oc-methylene-44 # e-pregnadien-17a-ol-3,20-dione-17-acetate (shown in accordance with German Auslegeschrift 1,096,353) in 30 ml of boiling methanol are slowly mixed with a solution of 175 mg Sodium hydroxide in 0.2 ml of water and 2.5 ml of methanol are added. After 2 hours, the reaction mixture is stirred into ice water, the precipitate is filtered off with suction, dried and recrystallized from methanol. 400 mg of 1,2x-methylene-A4 # e-pregnadien-17a-ol-3,20-dione with a melting point of 242 to 245 ° C. are obtained, which is reacted with pyridine-SO3 adduct analogously to Example 13. 190 mg of 1,2 a-methylene-44 # e-pregnadien-17a-ol-3,20-dione-17-hemisulphate sodium with a melting point of 152 ° C. (decomposition) are obtained in this way.

For the production of the starting product described above Protection is not sought within the scope of the present invention.

Claims (2)

Claims: 1. Further development of the method according to the patent 1 152105 for the production of water-soluble gestagens by converting 17x-hydroxyprogesterone using methods known per se, in particular by the action of the pyridine-sulfur trioxide adduct, in its acidic sulfuric acid ester, which is then also known in Way into its physiologically acceptable salts, especially the sodium salt transferred, characterized in that instead of hydroxyprogesterone is known at least as strongly gestagenic descendants are used. 2. Procedure according to Claim 1, characterized in that 19-nor-17a-hydroxyprogesterone, 6x-methyl-17x-hydroxyprogesterone, dl # 4,8-Pregnatrien-17x-ol-3,20-dione or 1,2: x-Methylen-44 # ° -pregnaien-17x-ol-3,20-dione used as starting compounds.