DE1155776B - Process for the preparation of 19-nor-5, 7, 9 (10) -Pregnatrienes - Google Patents

Description

Process for the production of 19-nor-5,7,9 (10) -Pregnatrienes The invention relates to a process for the production of 19-nor-5,7,9 (10) -Pregnatrienes of the general formula in which R is a hydrogen atom or an acyl radical, especially an acyl radical derived from a lower aliphatic carboxylic acid having 1 to 6 carbon atoms, e.g. B. from acetic acid, propionic acid or butyric acid, or from an aryl carboxylic acid, e.g. B. of benzoic acid. The substances that can be prepared according to the invention can be converted into physiologically active steroids, e.g. B. in compounds of the equilenin series, by aromatization of ring A, ie by dehydration of ring A in the presence of palladium or platinum and degradation of the Cl, side chain (by enol acetylation and subsequent ozonolysis) or vice versa. The compounds of the general formula obtainable by the process according to the invention are derived from compounds of the general formula in which R is a hydrogen atom or an acyl radical and X is either the radical (where R1 is an aliphatic, an aralkyl or an aromatic radical and R2 is an aliphatic or an aralkyl group, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic radical), or the radical is - OR3 (where R #, is an acyl group ), manufactured.

The starting compounds of the formula II can be prepared from aldehydes of the formula can be prepared by converting the aldehyde group into an enamine or enol derivative. The conversion can be carried out either by reaction with a secondary cyclic or noncychian amine to form an enamine or by formation of an enol acylate, e.g. B. by reacting the aldehyde compound with acetic anhydride and an alkali metal acetate or by reaction with acetic anhydride in a suitable solvent such as toluene, in the presence of a sulfonic acid.

In the process according to the invention, the enamine or enol derivative is obtained in the cold by methods known per se, with the formation of the desired C "side chain oxidized. When using an enamine as starting material (which is preferably in an organic solvent such as benzene. where the formed water z. B. has been removed by azeotropic distillation and for Shortening the reaction time, a strong acid catalyst may be added It should be noted that these enamines are not very stable and should therefore preferably not crystallize before oxidation.

The enamine oxidation can be carried out in three ways: a) Ozonolysis in an organic solvent such as ether or chloroform-acetic acid, preferably at low temperatures, e.g. B. -30 to 0 ° C, and subsequent reduction of the ozonide, z. B. with zinc and an acid such as acetic acid, or by catalytic hydrogenation. Ozonolysis must be carefully controlled as the reaction is not defined End point and because the aromatic ring will be attacked if you use it for too long going on. The optimal ozone introduction rate and the required The total amount of ozone can be determined beforehand by means of samples. The course of the reaction can be followed by observing suitable optical properties by aliquots of the ozonolysis reaction mixture taken and z. B. with zinc and Acetic acid can be reduced; the characteristic keto band (maximum 1710 cm- ') and the characteristic aromatic band (maximum 810 cm-1) are for this purpose suitable optical properties.

b) Oxidation with an alkali metal dichromate in a liquid aliphatic Carboxylic acid such as acetic acid. According to this method, for. B. from the corresponding Enamine obtained in 49% yield 3ß-acetoxy-19-norpregnatrien-5,7,9 (10) -one- (2), although some evidence suggested that the aromatic ring was attacked became.

c) Oxidation with a chromium trioxide tertiary amine complex. That is the preferred of the three methods as they generally give the best yields. So were z. B. from the corresponding enamine when using a chromium trioxide-pyridine complex as an oxidizing agent up to 75% yields of 3ß-acetoxy-19-norpregnatrien-5,7,9 (10) -one- (20) obtain. In this process, the 3-hydroxy-enamine can interestingly for 3-hydroxyketone- (20) (formula I, R = H) are oxidized. The 3-hydroxy group is in contrast to the corresponding compounds without an aromatic ring B, generally not oxidized at the same time.

There is a preferred embodiment of the method according to the invention So in the use of an enamine as a starting material, which is with a chromium trioxide tertiary amine complex is oxidized.

When using an enol acylate as starting material, the process according to the method Oxidation expediently by ozonolysis, observing the precautionary measures mentioned under a) performed.

The following examples explain the process according to the invention. All temperatures are given in degrees Celsius. Example 1 3β-Acetoxy-19-norpregnatriene-5,7,9 (10) -one- (20) Crude 3β-acetoxy-20-acetoxymethylene-19-norpregnatriene-5,7,9 (10) prepared from 2 g Aldehyde as described below was dissolved in chloroform-acetic acid solution (50:50 V / V, 60 ml) and ozonated with 101 / hour oxygen (0.0375 g O 3 per liter, 0.65 mol) at 0 ° under vigorous Stir ozonated for about 28 minutes. The solution was left to stand for 5 minutes at 0 °, then zinc powder (washed with acid) was added and the suspension was stirred for 30 minutes. The solution was tested with potassium iodide starch paper acidified with dilute hydrochloric acid and gave no color. The suspension was filtered, washed with chloroform and the filtrate was poured into water. The mixture was extracted with methylene chloride. The methylene chloride extract was washed with water, sodium hydrogen carbonate solution and again with water, filtered and evaporated to dryness to give a gummy product: 1.96 g, [ac] δ '= -3-12 ° (c = 0.58 in CHCl3 ). This product was refluxed with Girard reagent P (2 g) in ethanol (20 ml) containing 10% v / v glacial acetic acid for 1 hour, cooled to room temperature and poured into sodium hydrogen carbonate solution. The aqueous solution was extracted with ether and acidified to pH 1 with concentrated hydrochloric acid. After 15 minutes the mixture was extracted with ether. The ethereal solution was washed with water, sodium hydrogen carbonate solution and again with water, dried over magnesium sulphate, filtered and evaporated to dryness. Crystallization of the residue from aqueous alcohol gave the 20-ketone (320 mg) with a melting point of 109 ° to 112 °, [a] n = -3-46 ° (c = 0.46 in CHCl3). A second batch (28 mg) had m.p. 110-116 °. The first part was recrystallized from alcohol and yielded 235 mg, melting point 114 to 116 °, [: x] n = + 51.5 ° (c = 0.36 in CHCl3).

The starting compound was prepared by adding 2 g of 3β-acetoxy-19-norpregnatriene-5,7,9 (10) aldehyde (20) in toluene (54 ml) containing acetic anhydride (5.2 ml) and sulfosalicylic acid dihydrate (80 mg) , dissolved and the mixture refluxed for 12 hours. In the last 6 hours, 18 ml of distillate was removed. The mixture was cooled to room temperature and poured onto ice, shaken occasionally for 30 minutes, and extracted with ether. The ether extract was washed with water, ice-cold 5 ° / jger sodium hydroxide solution and again with water, dried over sodium sulfate, filtered and evaporated to dryness, the crude enol acetate being obtained as a gummy mass, [cX] n = -30.7 ° (c = 0.48 in CHC3j). Example 2 3β-Acetoxy-19-norpregnatriene-5,7,9 (10) -one- (20) 3β-acetoxy-20 -piperidinomethylene -19-norpregnatriene-5,7,9 (10) (3 g) in dry ether (60 ml) was added 18 minutes ozonized oxygen (41 1 per hour; 0.0408 g 03 per liter, 1.47 mol) at -35 °. The temperature of the solution was then allowed to rise to 0 ° and acetic acid (20 ml) was added. Zinc dust was then gradually added until starch iodide paper indicated the absence of ozonide. The zinc dust was filtered off through kieselguhr and the filtrate was washed three times with water and then twice with 2 normal aqueous sodium carbonate solution. Further washing with water, drying and evaporation gave 2.23 g of crude ketone. This product was refluxed in 30 ml of ethanol for 1 hour with Girard reagent P (2.0 g) and acetic acid (3 ml). The cooled reaction solution was poured into aqueous sodium hydrogen carbonate solution and extracted with ether. The aqueous fraction was acidified to pH 1 with hydrochloric acid and extracted with ether. Evaporation of the extract and crystallization of the residue from aqueous ethanol gave the 20-ketone (1.42 g) with a melting point of 109 °, [OCID = -E-45 ° (c = 0.9 in CHCl3). Further recrystallization from aqueous ethanol gave a substance of melting point 111 to 112 °, [OCID = -I-49 ° (c = 1.0 in CHCl3).

To prepare the starting compound, 3ß-acetoxy-19-norpregnatriene-5,7,9 (10) -aldehyde- (20) (13.3 g), piperidine (5.3 ml) and toluene-p-sulfonic acid (0.4 g) in benzene (200 ml) Heated under a nitrogen atmosphere on the reflux condenser for 1 hour. A "Dean & Stark apparatus" was created (see. Practical Organic Chemistry, 3rd Edition, p. 429) incorporated to during the Reaction to remove water formed.

The solution volume was then reduced in vacuo and methanol was added. Evaporation continued until enamine crystals settled. The mixture was cooled and the solid substance (10.11 g) filtered off, washed with methanol and dried.

Recrystallization of a sample from acetone gave 3β-acetoxy-20-piperidinornethylen-19-norpregnatriene-5,7,9 (10), mp = 129-132 °, [a] D = -42 ° (c = 1.0 in CHC13). (Found: C 79.9; H 9.3; N 3.1. Calculated for C "H" 02N: C 79.8; H 9.3; N 3.3 l) /,).

The starting compound could also be prepared as follows: 3ß-acetoxy-19 - norpregnatriene - 5,7,9 (10) - aldehyde- (20x) (1.7 g) was dissolved in benzene (30 ml, reagent grade) which contained piperidine (purified, 0.67 ml) under nitrogen for 3.5 hours, using a "Dean & Stark apparatus" to remove water, refluxed. The reaction mixture was then evaporated to dryness in vacuo and the pale, straw-colored, partially crystalline residue (2.06 g) obtained was triturated with cold methanol and filtered off: 1.63 g (80 ° / 0), melting point 115 ° to 119 °. Recrystallization three times from acetone gave an analytically pure sample of 3ß-acetoxy-20-piperidinomethylene-19-norpregnatriene-5,7,9 (10) with a melting point of 126 to 128 °, [x] D = -36 ° (c = 1, 6 in CHCl 3); (Found: C 79.7; H 9.3; N 3.3 ° / o; calcd for C "H" O, N: C 79.8; H 9.25; N 3.3 ° / o).

Example 3 3ß-acetoxy- 20 - piperidinomethylene -19 - norpregnatriene-5,7,9 (10) (1 g) in benzene (8 ml) was added to a stirred solution of Sodium dichromate dihydrate (1.5 g) and acetic acid (7.5 ml) in benzene (5 ml) at 0 ° added. The mixture was then stirred at 0 ° for a further hour and then another 2 hours at room temperature. After cooling, it slowly became methanol (7 ml) added over the course of 10 minutes and stirring at 0 ° for a further 30 minutes continued. Water was added and the mixture extracted with ether. Of the The extract was washed with 2N sodium carbonate solution, dried and evaporated in vacuo. The residue (0.79l g) was with Girard reagent P, as described in Example 2, and gave the corresponding 20-ketone (0.5 g).

Recrystallization from aqueous alcohol gave 3β-acetoxy-19-norpregnatriene-5.7, 9 (10) -one- (20) (0.4 g), mp 112 °, [a] D = '-, 53.5 ° (c = 11.0 in CHCl3). Example 4 Finely powdered chromic acid (4.45 g) was added to pyridine (55 ml) at 0 ° under nitrogen over the course of 15 minutes with stirring. A solution of 3β-acetoxy-20-piperidinomethylene-19-norpregnatriene-5,7,9 (10) (5.45 g) in pyridine (55 ml) was added over the course of 5 minutes, and the mixture was stirred at 0 ° for a further 4 hours and then left to stand at room temperature overnight. Benzene was added and the mixture filtered through diatomaceous earth and then through an alumina column (60 g) using benzene as the eluent. Evaporation of the eluate in vacuo gave 4.81 g of substance which was treated with Girard reagent P as in Example 2. Recrystallization from aqueous ethanol gave the ketone (3.24 g) with a melting point of 112 ° to 113 °, [OCID = -E-49.6 ° (c. = 1.0 in CHCl3). Further recrystallization from ethanol gave 3ß-acetoxy-19-norpregnatrien-5,7,9 (10) -one- (20) of m.p. 113.5-114.5 °, [OCID = -E-52 ° (c = 1.0 in CHCl3); (found: C 77.5; H 8.2 ° / 0; calcd for C, H2303: C 77.6; H 8.3 ° / o). Example 5 3β-Hydroxy-20-piperidinomethylene-19-norpregnatriene-5,7,9 (10) (4.0 g), prepared as described below, was treated with chromic acid and pyridine as in Example 4. The Girard P separation gave 1.87 g of substance which, after crystallization from ether, was 3β-hydroxy-19-norpregnatrien-5,7,9 (10) -one (20) (1.14 g), m.p. 150 °, [OCID = -E-56.8 ° (c = 1.0 in CHCl3).

To prepare the starting compound, 3ß-hydroxy-19-norpregnatriene-5,7,9 (10) -aldehyde- (20) (8.1 g) with piperidine and toluene-p-sulfonic acid, as in the preparation of the starting compound of Example 2 described, treated. The product (4.19 g) had the melting point 122 °, [x] D = -49.5 ° (c = 1.1 in CHCl3).

For the preparation of the starting compounds used according to the process Protection is not sought within the scope of the present invention.

Claims (7)

PATENT CLAIMS: 1. Process for the production of 19-nor-5,7,9 (10) -Pregnatrienes of the general formula I in which R is a hydrogen atom or an acyl radical, characterized in that a compound of the general formula A in which R is a hydrogen atom or an acyl radical and X is either the radical (where R1 is an aliphatic, an aralkyl or an aromatic radical and R2 is an aliphatic or an aralkyl group, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic radical), or the radical is - OR3 (where R3 is an acyl group), oxidized in the cold by methods known per se. 2. The method according to claim 1, characterized in that the oxidation using ozonated oxygen in the presence of an organic solvent executes and reduces the ozonide obtained with zinc and acetic acid. 3. Procedure according to claim 2, characterized in that the organic solvent used is ether or a mixture of chloroform and acetic acid is used. 4. The method according to claim 2 and 3, characterized in that the oxidation is carried out at -40 to 0 ° C. 5. The method according to claim 1, characterized. that group X is the remainder and the oxidation is carried out using a chromium trioxide tertiary amine complex. 6. The method according to claim 5, characterized in that as tertiary amine pyridine used. 7. The method according to claim 1, characterized in that R is an acyl radical and the group X is the radical and the oxidation is carried out using an alkali metal dichromate in a liquid aliphatic carboxylic acid. Publications considered: Journ. At the. Chem. Soc. 69: 1957f1 (1947); Vol. 72 (1950), p. 2617fI :; Vol. 74 (1952), p. 3627fI :; Vol. 75 (1953), pp. 1918fI :, and Vol. 77 (1955), pp. 1212fI: