CH331998A - Process for the preparation of 3-keto-oxysteroids - Google Patents

Description

  

  Process for the production of 3. keto-oxysteroids Das sehweiz. U.S. Patent No. 322242 relates to a process for the preparation of new enamine derivatives of 3-keto steroids which is characterized by reacting a 3-keto steroid with a secondary amine.



  The conversion of 3-keto steroids into the I: namine derivatives is a valuable method for blocking the 3-keto group; the 3-keto group can be regenerated easily and with high yield by simple hydrolysis after further conversions have been carried out in the steroid molecule.



  The subject of the present patent is a process for the production of 3-Ket.o-oxysteroids, which is characterized in that one 3-keto-steroids, which contain at least one further carbonyl group in the molecule, by reaction with a secondary amine, preferably pyrrolidine, converts into the corresponding 3-dnamine derivatives, in which the free carbonyl groups are reduced to Ilydroxylgruppen, preferably with lithium-aluminum hydroxide,

      and in the enamine derivatives thus obtained, the 3-keto group is restored by hydrolysis.



  If lithium aluminum hydride is used as the reducing agent, the restoration of the 3-keto group usually takes place simultaneously with the decomposition of the complex compound formed during the reduction.

      For example, the physiologically active hormone testosterone can be produced from 4-androstene-3,17-dione via the enamine derivative by converting the 4-androstene-3,17-dione into the 3- (N-pyrrolidyl) -3,5-androstadien-17- converted and in the ketone protected in this way, the 17-keto group is reduced to the 17-oxy group.

   If the 3-keto group is then regenerated in 3- (N-pyrrolidyl) -3,5-androstadien-17-ol, 4-androsten-17-ol-3-one, i.e. testosterone, is obtained. When using 3-keto steroids with additional keto groups at any other point in the molecule, one can proceed in the same way.



  The starting materials can in the core further substituents such. B. oxy, acyloxy, carbalkoxy groups, etc., carry, which are located on one or more of the carbon atoms of the core, z. B. in position 7, 11, 12, 17 or other positions can be. In addition, the nucleus can form double bonds. These double bonds can be isolated or conjugated and can also be conjugated to the carbonylsaiierstoffatom in the 3-position.

   If a 4 (5) double bond is present, the 4 (5) double bond shifts to the 5 (6) position during the reaction. In the 17-position of the core there may be a side chain, e.g. B. such as occurs in natural steroids, such as in the sterols, bile acids and pregnanes, or one obtained from such by substitution or partial degradation.



  Examples of such ketosteroids which can be used as starting materials are, for example, sterols such as cholestane-3,6-dione, 11-keto-progesterone, pregnane-3,20-dione, pregnane-3,11,20-trione, cortisone , 21-acyloxy-17aoxy-pregnane-3,11,20-trione, androstane-3,17-dione, 4-androstene-3,17-dione.



  The enamine derivatives are preferably obtained by heating the 3-keto-steroid with the secondary amine in an organic solvent with continuous removal of the water formed during the reaction. The water can be distilled by azeotropic De or by means of a basic, inorganic, water-binding compound, such as potassium carbonate, calcium or barium oxide and the like.

   Such enamines are formed at temperatures between about 25 and about 150 ° C., preferably between 40 and 110 ° C., expediently at the reflux temperature of the reaction mixture, but always below the decomposition temperature of the end product, i.e. of the enamine. The reaction time varies depending on the reactivity of the amine and the reaction temperature. A reaction time of from 30 minutes to 20 hours is usually advantageous in the preferred temperature range.

   The preferred amount of secondary amine is 4 moles of amine per mole of steroid; but you can generally with. Amounts of about 1-20 moles of amine or more will work. Suitable solvents are diethyl ether, tetrahydrofuran, an excess of the amine, benzene, xylene, toluene, pentane, ilexamine and the like.



  An acid catalyst such as p-toluenesulfonic acid, naphthalenesulfonic acid, sulfuric acid and the like can be added to promote the reaction and increase the yield, with p-toluenesulfonic acid being usually preferred. Sometimes, especially when the amine is hard to react, you can work in a bomb using pressure.

      As secondary amines, dialkylamines such as diethylamine, dipropylamine, di-butylamine, dihexylamine, dioctylamine and di-dodecylamine can be used; Cycloalkylamirie, such as Diey clohexylamine and the like;

       Cyclic amines such as piperidine, pyrrolidine, tetrahydroehinoline, oxazolidine (tetrahydrooxazole), chlorophyllur and the like; Aralkylalkylamines such as N-methyl-1-benzylamine, N-aryl-benzylamine and the like; substituted dialkylamines such as diethanolamine and the like;

   and arylalkylamines such as. Use N-141ethyl-aniline, N-3-ethyl-toluidine, N-methyl-anisidine, and the like.



  <I> Example. </I> a) A solution of 8.58 g (0.3 mol) 4-androstene-3,17-dione and 10.02 cm3 (0.12 mol) pyrrolidine in 150 em3 benzene is dissolved in a flask with a reef-flow bucket and water catcher heated vigorously for 3 hours on the re-flow while stirring, after which time the theoretical amount of water has been collected.

   The solution is then evaporated to dryness in vacuo and the yellow, crystalline residue is triturated with 50 cm3 of methanol. After cooling for six hours at 4 C, it is filtered, washed with 23 cubic meters of cold methanol and dried.

   The yield of 3- (N-pyrrolidyl) -3,5-androstadien-17-one is 9.15 g (90 / o). b) A solution of 3.8 g (0.10 111o1) lithium aluminum hydride in 1600 em3 anhydrous ether is placed in a Soxhlet flask, and 6.09 g (0.018) hol) 3- (N) are placed in the extraction cartridge -Pyrrolidyl) -3,

  5-androstadien-17-one. Then it is heated to reflux. The condensed returning vapors dissolve the steroid and bring it into the flask, where the reduction takes place. After 45 minutes, all steroid is dissolved. The mixture is cooled, carefully decomposed by adding 10 cm3 of water and extracted with benzene. The benzene solution is dried and evaporated.

    5.25 g (86 "/ m) of crude 3- (N-pyrrolidyl) -3,5-androstadien-17ss-ol are obtained. A sample recrystallized from methylene chloride-methanol gives yellow needles with a melting point of 133 to 137 C: Analysis: / oa calculated for Cz3H35ON: N 4.13 found:

   N 4.07 e) A solution of 4.25 g of 3- (N-pyrrolidyl) -3,5-androstadien-17ss-ol (prepared as described under b), 7.5 g -, atrium acetate, 8 cin3 Water and 2 cubic meters of concentrated hydrochloric acid in 150 cubic meters of methanol - is refluxed:; Cooked for hours. The solution is then diluted with 200 cubic meters of water, cooled and the precipitated testosterone is filtered off. The latter is with.

   Washed water and get.rock- i) et. The yield is 2.04 g (73%); Melting point 149-150 C).



       Same as in the previous one. For example, starting from other 3-keto-steroids with additional carbonyl groups, one can arrive at the corresponding 3-keto-oxysteroids, which can already be physiologically active steroid hormones or can be converted into active compounds.

   For example, from 3- (N-pyrrolidyl) -3,5-androstadiene-11,17-dione and from 3- (N-pyrroliclyl) -3,5-pregnadien-lla-ol-20-one by reducing with lithium aluminum hydride or other reducing agents and restoring the 3-keto group by acidic droolysis of the 11 ', - Oxv-testosterone or

   the 11a, 20- I) ioxy -4-pregnen-3-one.

 

Claims (1)

PATENT CLAIM Process for the production of 3-keto-oxy- steroids, characterized in that 3-keto-steroids, which contain at least one further carbonyl group, by reaction with. secondary amines are converted into the corresponding -enamine derivatives, in which the a <B> 2 </B> free carbonyl groups are reduced to hydroxyl groups. and in the 3-enamine derivatives of the oxysteroids obtained in this way, the 3-keto group is restored by hydrolysis. SUBClaims 1. Method according to patent claim, characterized in that the reduction is carried out with lithite aluminum hydride. 2. The method according to claim, characterized in that 4-androstene-3,17-dione is converted with a secondary amine into the corresponding 3-enamine derivative, this to the 3-enamine derivative of 3,5-androstate-1. 7-ol is reduced and the latter is hydrolyzed to testosterone. 3. Process according to dependent claim 2, characterized in that the secondary amine used is pvrrolidine.