DE713193C - Process for the preparation of polyketones of the cyclopentanopolyhydrophenanthrene series - Google Patents

Description

Process for the preparation of polyketones of the cyclopentanopolyhydrophenanthrene series The invention relates to a process for the preparation of ketones from acids of the formula wherein R is an unsaturated cyclopentanopolyhydrophenanthrene radical.

So far, these ketones have only been accessible by extensive means. They were converted from the acids mentioned through their esters Grignard's reagent is obtained in tertiary alcohols, which are then extracted after dehydration were subjected to an oxidation process.

It has now been found that the ketones can be prepared in a particularly simple reaction sequence if the abovementioned acids are subjected to the C urtius degradation (cf., for example, Gattermann-Wieland, Praxis des organic chemists, p. 147 [1933] C urtius: Ber XXIII, 3029 [I 89o]; Ber. XXVII, 779 [z894]; Nägeli: Helv. Chim. Acta XV, 6o and XVI, 349; J. v. Braun Ber. LXIV, 2860) and the amines obtained in this way converted oxidatively into the corresponding ketones. The new process has proven to be particularly advantageous in the sterols series. For example, in 3-oxy- or 3-acyloxybisnorcholenic acid, the side chain can be converted into the associated ketone by the new process by first converting 3-acetoxybisnorcholenic acid into the associated azide via its chloride and the latter into the corresponding amine. The amino group can be eliminated either by means of oxidants, such as hypochlorite, whereby the -CH-NH, group changes into the C 0 group, or by means of HN 02 into the. transfer appropriate alcohol. The pregnendial (3, 2o-monoacetate- [3]) obtained in the latter way can be converted into the associated diketone dibromide and this into the unsaturated diketone after saponification of the acetyl group with protection of the double bond, for example with bromine.

This can be done with the same or similar success by saponifying of 3-acetoxyternorcholenylamine- (2o) obtained 3-oxyternorcholenylamine - (= o) to 3-Oxoternorcholenylamin- (2o), for example with temporary protection of Double bond, oxidize and in the so obtained3 = oxoternozcholenylamine- (2o) die -CHNH, - Gruppe.:iii convert a carbonyl group.

The compounds obtainable by the new process are said to be Find therapeutics or to represent new drugs use.

The method described here leads in comparison to the known Process to significantly better yields and is also easier to use without Experimental or technical difficulties in feasible chemical methods.

Examples i. 16 g of acetoxybisnorcholenic acid are heated in 200 cc of dry benzene with 48 g of thionyl chloride for 2 hours, the reaction solution is evaporated in vacuo and the residue is immediately taken up in 100 cc of acetone. A solution of 5.75 g of sodium azide in 16 cc of water is slowly added to the acetone solution, which is cooled to 0 °. The desired azide flocculates. The reaction solution is left to itself at -15 ° for 1/2 hour, then the azide is quickly suctioned off and washed with cold acetone.

The azide is taken up in 200 cc of dry toluene and treated with sodium sulfate shaken at -5 °. The solution is then filtered and slowly warmed. At 4o ° the N-splitting begins, which reaches its climax at 8o °. The solution is, still heated to boiling, whereby the elimination of nitrogen is ended. The reaction solution is concentrated in vacuo and the residue is recrystallized from petroleum ether. Yield of isocyanate: 12 g = 67%, calculated on acetoxybisnorcholenic acid.

6- isoxyanate are dissolved in 15o cc of ether and 15o cc of benzene and the solution is stirred intensively for 30 minutes with zoo g of 60% sulfuric acid, which has previously been cooled to 0 °. The reaction solution is then poured into water, the amine sulfate is thrown off and the amine is set free with alcoholic potassium hydroxide solution. The alkaline solution is extracted with ether and, after the ethereal solution has dried, the amine is precipitated as acetate with a few drops of glacial acetic acid. Yield 5.01 9 = 77 °%, calculated on the isocyanate.

6 g of Acetoxyternorcholenylamins are dissolved in 1.51 ether and the solution was sharply dried over potassium hydroxide. Then the solution is filtered, a little anhydrous sodium sulfate was added and the mixture was cooled to -10 °. so one leaves the calculated amount of the essential solution of H O Cl, which is also on -15 'is cooled, pour in slowly. At the beginning something hydrochloric separates Acetoxyternorcholenvlamin. After adding the calculated amount of hypochlorous Acid is the reaction of the solution, which was initially strongly basic, neutral. It will about 59 cc of an ethereal solution of H O Cl is used for this purpose, which is 14.8 cc mg of hypochlorous acid. The reaction solution is filtered immediately and im Evaporated in vacuo. A residue of 5.4 g remains, which is the corresponding Represents chloryl compound. The residue is oily, but crystallizes when rubbed. It is rubbed in with q.o ccm of 10% alcoholic potassium hydroxide solution, the separation immediately taking place of potassium chloride begins and ammonia is split off. After 24 hours it is Reaction ended. It may be possible to heat the process to speed up the process. The reaction solution is now poured into water acidified with sulfuric acid and after heating the Mixture etherified on the steam bath. The residue of the ether contains 3.5 g of the desired ketone compound.

The incidental result of the reaction of the amine with hypochlorous acid and the above-mentioned hydrochloric acid acetoxyternorcholenylamine is recovered. The precipitation is suspended in water, the amine is set free with alkali and the alkaline one Solution etherified. After adding a few drops of glacial acetic acid to the dry essential Solution, the acetate of 3 Acetoxyternorcliolenylamin precipitates. Yield 0.6 g.

-2. 56.6 g of acetoxy bisnorcholenic acid are dissolved in 450 cc of dry benzene heated with 150 g of thionyl chloride for 2 hours, the reaction solution is evaporated in vacuo and the residue was immediately taken up in 315 cc of acetone. To the acetone solution, -the on o ° is cooled, a solution of 18.2 g of sodium azide is left with constant stirring slowly pour into 44 ccm of water. The desired azide flocculates. The reaction solution is left to itself further at -15- '1/2 hour, then the azide quickly Aspirated and washed with cold acetone.

The azide is now taken up in 600 ccm of dry toluene and mixed with Sodium sulfate shaken at -50 °. The solution is then filtered and slowly warmed up. At: 4o ° the N splitting begins, which reaches its peak at 8o °. The solution is heated to boiling, with the cleavage is terminated by N. The reaction solution is concentrated in vacuo and the residue from petroleum ether. crystallized. Yield of the corresponding isocyanate: 35.2 g; 4 g are still obtained from 'the mother liquor.

6 g of isocyanate are dissolved in 15o cc of ether and 15o cc of benzene and the solution with zoo g 60% sulfuric acid, which has previously been cooled to 0 °, 3o Stirred intensely for minutes. The reaction solution is then poured into water that Amine sulfate is thrown off and the amine is set free with alcoholic lye. The alkaline solution is extracted with ether and, after drying, the ethereal solution the amine is precipitated as acetate with a few drops of glacial acetic acid. Yield: 6.4 g of amine acetate; 42 g of amine acetate are obtained from 39.2 g of isocyanate.

13.4 g of the 3-acetoxyternorcholetlylamine are dissolved in 1.5 liters of ether and the solution is sharply dried over potassium hydroxide. The solution is then filtered, some anhydrous sodium sulfate is added and the mixture is cooled to -15 °. 270 cc of an ethereal solution of hypochlorous acid, which contains 1.96 g of HOCI and is also cooled to -15 °, is now allowed to flow in slowly with shaking. The solution, which initially reacted strongly basic, is now completely neutral. The reaction solution is immediately evaporated in vacuo; the residue, which has crystallized well, is the corresponding Chlorylverbin @ dung of the amine, which is obtained almost quantitatively.

It is made with 465 ccm of absolute alcohol and an alcoholate solution, which consists of 8.8 g of sodium and igo ccm of alcohol abs. is prepared, included and 4.5 Heated for minutes on the water bath. After that, the reaction solution that makes up the sodium chloride has already deposited, poured into: water, the colloidal Mixture acidified with sulfuric acid and left to itself. In these times the desired pregnenol- (3) -one- (2o) has deposited as a white compound .. The mixture is etherified, the residue of the ethereal solution, which is solid and is obtained crystallized, distilled in a high vacuum between 18o to 2io ° and o, oi mm. The distillate, which solidifies as a pure white product, can still be redissolved from methanol will. Yield 8 g, melting point 187 to igo °.

3. An ethereal solution of 0.8 g of 3-acetoxyternorcholenylamine is mixed with 30 cc of an ice-cold solution of HN 02 prepared from ig Na N02 + 0.5 g of glacial acetic acid. shakes. It immediately flocculates the amine nitrite that is thrown off. The amine nitrite is well stable and durable in the air.

. . . To oxidize the amino group, the amine nitrite is suspended in a solution of HN 02 which has been prepared from 70 cc of alcohol, 8 cc of 2 n-acetic acid, 20 cc of water and 1.6 g of Na N 02 and has been cooled to 0 ° . Then the mixture is slowly heated on the steam bath; at 50 ° the amine nitrite is dissolved, at 55 to 60 ° the N evolution begins, which ends after 1 hour (temperature last 75 °). The solution is then mixed with water and the mixture is extracted with ether. The residue of the ether is 0.56 g. It is crystallized, nitrogen-free, rustic and consists primarily of two substances. For separation, the residue is refluxed for 30 minutes in 15 cc of 10% strength alcoholic potassium hydroxide solution and the solution is then poured into ice-cold water acidified with dilute sulfuric acid. The mixture is extracted with ether and the ethereal solution is dried. The residue of the ether contains the alcohol to be expected in the reaction with nitrite and the hydrocarbon formed by the simultaneous elimination of water.

The whole thing is now dissolved in a little ethyl acetate and mixed with a lot of petroleum ether. The alcohol mentioned in the example precipitates out in good crystalline form. Yield 250 mg. For better cleaning, the alcohol is expediently distilled in a high vacuum. It goes over between 170 and 22o ° at 0.02 mm. The crystallized distillate is redissolved from ethyl acetate. The substance has a melting point of 178 to 179 ' and has the formula C21H3402. Oxidation of the body protected by bromination with chromic acid and removal of the bromine produces the ketone C21 Hso 02, which is identical to progesterone. The vinegar ester and petroleum ether solutions contain the second substance, which shows values that correspond to the formula C21 H32 O. It is obtained in well crystallized needles by recrystallization from aqueous alcohol. It has a melting point of i2o °.

4. A bromine solution containing 0.67 g of bromine in 30 cc of glacial acetic acid is added to a solution of 1580 mg of 3-oxyternorcholenylamine acetate (decomposition point 245 to 2q.7 °) in 100 cc of glacial acetic acid; slowly added dropwise and then a solution of. 0.84 g of chromic acid in 10 cc. of 10% glacial acetic acid was added. A thick precipitate separates out, which goes back into solution after adding 4 ccm of water. The oxidation solution is now stored for 24 hours at room temperature, then zinc dust is added to the solution and, after standing for 2 hours, it is evaporated in vacuo at .45 °, the residue is moistened several times with methanol and again concentrated in vacuo to the brittle. The dry residue is left to stand in 100 cc of methanol with strong acid for 20 hours, then heated to a gentle boil for 45 minutes, and the hot solution is filtered. The filtrate is concentrated in vacuo, the residue is taken up in water, the aqueous solution is made alkaline with sodium carbonate and thoroughly extracted with ether. The residue of the dry ethereal solution contains ig of 3-oxoternorcholenylamine, which crystallizes after trituration with ether and is expediently further processed immediately. One gram of this oxoamine is reacted with an ethereal solution of hypochlorous acid as described in Example 2. 22.8 ccm of an ethereal solution of hypochlorous acid containing 0.00735 HOCO per ccm is required. The reaction solution is then concentrated in vacuo, the residue is poured over with a sodium methylate solution, which has been prepared from ig sodium and 70 cc of absolute methyl alcohol, and kept at a low boil for 45 minutes. The reaction solution is then poured into water containing sulfuric acid and left to stand for a day. It is then hardened, fermented, the residue of the ethereal solution heated in 50 cc alcohol and 2 cc -2 normal sulfuric acid for 40 minutes. The solution is then concentrated in vacuo, mixed with water and extracted with ether. * The residue of the ethereal solution, which makes up around -6oo mg, is now distilled in a high vacuum at 0.1 mm and 150 to 200 ° and the yellowish distillate is then recrystallized from aqueous alcohol. Up to 220 mg of pure progesterone with a melting point of 120 to i29 ° are obtained.

Claims (1)

PATENT CLAIMS: i. Process for the preparation of ketones of the cyclopentanopolyhydrophenantbren series, characterized in that compounds of the formula in which R denotes an unsaturated cyclopentanopolyhydrophenanthrene radical, subject to C urtius degradation and the amines obtained in this way, optionally after conversion of the amino group in the 20-position, oxidized into the hydroxyl group with the aid of nitrous acid. Embodiment of the process according to Claim i, characterized in that any double bond present in the hydroaromatic radical is protected in a manner known per se by introducing removable substituents.