DE1130443B - Process for the production of modification products of the 17ª ‡ -hydroxyprogesterone ester - Google Patents

Description

Process for the preparation of modification products of the 17α-hydroxyprogesterone ester In the main patent application Sch 24493 IVb / 12 o is the production of modification products the 17a-Hydroxyprogesteronester described, which differs from the latter by introduction an additional carbon-carbon double bond in the 6-position. These modification products turned out to be, especially when administered orally, the 17a-hydroxyprogesterone esters in terms of strength and duration of the progestative Significantly superior in effectiveness. The esters of the aliphatic are preferred according to the invention and cyclic carboxylic acids having 1 to 10 carbon atoms.

It has now been found that the corresponding esters of 17a-hydroxy-19-norprogesterone by introducing an additional carbon-carbon double bond in the 6 position can achieve a very similar increase in effectiveness as in the esters of 17x-hydroxyprogesterone.

The preparation of the new esters of J 6-17a-hydroxy-19-norprogesterone happens in complete analogy to the procedure of the main patent application according to an known methods of steroid chemistry, in particular by esterification of the hitherto not yet described, but also available in a manner known per se free 46-17a-hydroxyprogesterone with the same carboxylic acid esters as in the Main patent application, preferably in the form of reactive derivatives of these acids, like the acid anhydrides and acid halides, or by transesterification in the usual way Way of working. It is of course completely analogous to the procedure for the main patent application also possible to start from esters of such 17a-hydroxy-20-keto-19-norpregnane, the one in the molecule already has a carbon - carbon emanating from carbon atom 5 -Double bond (44,45 or here also A5 (10 »and in the 3-position an oxygen-containing Group (oxo or hydroxyl group) carry, and in these starting materials the additional 4 6 double bond by way of z. B. to introduce dehydration in a manner known per se. As a dehydrating agent for the introduction of the 46 double bond, for example Quinone or brownstone can be used. If necessary, the ß, γ-unsaturated 3-hydroxyl grouping then in a likewise known manner into the a, ß-unsaturated 3-ketone grouping converted.

Example 1 4 6-17a-Hydroxy-19-norprogesterone-17-acetate 2 g of 17a-Hydroxy-19-norprogesterone are dissolved in 600 ccm of n-amyl alcohol and after adding 3.0 g of chloranil for 4 hours refluxed under nitrogen. The amyl alcohol is distilled off in vacuo, the residue taken up in ether and the solution several times with weakly alkaline Sodium dithionite solution, then with n / 10 sodium hydroxide solution and finally with water neutral washed. After drying over sodium sulfate, the solution is concentrated and the residue dissolved in methanol and purified over activated charcoal. When concentrating the methanolic Solution precipitates the 46-17a-hydroxy-19-norprogesterone. UV: Egg. = 24800.

560 mg of 4 6-17a-hydroxy-19-norprogesterone are dissolved in 25 cc of acetic anhydride dissolved and after adding 700 mg of p-toluenesulfonic acid monohydrate at 37 ° C. for 8 hours ditched.

The excess acetic anhydride is poured into the solution pyridine-containing ice water decomposes, the precipitate that forms in the process is sucked off, washed neutral and dried.

600 mg of the crude product obtained are dissolved in 60 ccm of methanol, 0.6 cc of concentrated hydrochloric acid is added and the mixture is blown for 10 minutes under nitrogen 60 ° C heated. For work-up, it is diluted with water and extracted with ether. The ether extracts are washed neutral with water, dried and concentrated. Recrystallize A6-17oc-hydroxy-19-norprogesterone-17-acetate is obtained from isopropyl ether. UV: a284 = 25900.

Example 2 d g-17a-Hydroxy-19-norprogesterone-17-formate In a mixture of 17 cc acetic anhydride and 45 cc 95 ° / jger formic acid, which has been at 0 'C for 6 hours, 300 mg d e-17a Dissolved hydroxy-19-norprogesterone and, after adding 380 mg of p-toluenesulfonic acid monohydrate, allowed to stand for 16 hours at room temperature.

The solution is introduced into pyridine-containing ice water, which in this case the precipitate which separates out is filtered off with suction, washed until neutral and dried. To recrystallization from isopropyl ether gives the dB-17a-hydroxy-19-norprogesterone-17-formate. UV: a283 = 24,600. Example 3 d e-17a-Hydroxy-19-norprogesterone-17-acetate 5 g of 17x-hydroxy-19-norprogesterone are dissolved in 500 ml of acetic anhydride and in the presence of 6.6 g of p-toluenesulfonic acid Stirred at 37 ° C. under argon for 3 hours. The reaction mixture is then poured into 15 liters of ice water, the 11 pyridine is added, stirred in. After about 2 hours, the obtained Sucked off precipitate, washed neutral and dried at room temperature. That crude 17a-hydroxy-19-norprogesterone-3-enol-17-diacetate obtained with a yield of 5.6 g melts at 212 to 217 ° C.

2.5 g of the crude enol diacetate in 12.5 ml of glacial acetic acid and 7.5 ml of collidine slurried. With good stirring and under nitrogen, at about 10 ° C 10 ml of a 10 ° / jgen bromine-glacial acetic acid solution was added dropwise, the addition in the Measures is taken as discoloration of the bromine occurs. The reaction product is used for working up after the addition of bromine into a slurry of 100 g of sodium bicarbonate in 100 Stir in ml of water and extract several times with ether. The combined ether extracts are washed neutral with water and in vacuo under nitrogen to a residual volume concentrated by about 100 ml. This residual solution is converted into a slurry of 5 g of lithium carbonate and added 5 g of lithium bromide in 80 ml of dimethylformamide. The ether then becomes ahdistilled and the residue heated to about 100 ° C under nitrogen for 16 hours. The cooled reaction product is then in 15 times the amount of acetic acid Ice water is stirred in and the resulting precipitate is filtered off with suction, neutral washed and dried.

The crude product thus obtained is dissolved in 200 ml of methanol and in Presence of 2 ml of concentrated hydrochloric acid for 15 minutes under nitrogen on the Steam bath heated. For work-up, the solution is then diluted with water and extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed neutral. After drying the ethyl acetate solution with sodium sulfate the filtered solution concentrated to dryness. The residue will eventually recrystallized from ethyl acetate, d e-17a-hydroxy-19-norprogesterone-17-acetate obtained from melting point 232 to 234 ° C.

Claims (1)

PATENT CLAIM: modification of the process for the preparation of derivative products of the 17a-Hydroxyprogesteronester enhanced particularly at peroral administration progesterone-like activity by the synthesis of d e-17a-Hydroxyprogesteronestern according to conventional methods of steroid chemistry according to patent application Sch 24493 IVb / 12 o, characterized in that corresponding 19-norsteroids are used as starting compounds.