DE1176651B - Process for the preparation of 20, 20-bis-hydroxymethyl-3-keto-1, 4-pregnadienes or esters thereof - Google Patents

Description

Process for the preparation of 20,20-bis-hydroxymethyl-3-keto-1,4-pregnadienes or esters thereof. The invention relates to a process for the preparation of new 20,20-bis-hydroxymethyl-3-keto-41.4-pregnadienes or of esters of the same, those of the general formula I where R1 = H2 or O, R2 and R3 each signify H or an acyl or nitric acid residue.

There have already been processes for the preparation of 20, 20 bis-hydroxymethylpregnane compounds with saturated ring A or with a 4 (5) double bond proposed, which show a vasodilatory effect on the coronary vessels.

It has now been found that the novel produced according to the invention 20,20-bis-hydroxymethyl-3-keto-41,4-pregnadienes and corresponding esters containing a Have system of two conjugated double bonds in ring A, also one show considerable vasodilatory effectiveness on the coronary vessels.

To prove the superiority of the process products over the usual ones Compounds used to treat angina have been pharmacological Comparative tests carried out with trinitroglycerin and papaverine, which give have that the effective limit concentration of 3,11-diketo-20,20-bis-nitratomethyl-1,4-pregnadiene in the Langendorfl test (Arch. f. ges. Physiol., Vol. 61, 1895, p. 291) 0.001 to 0.005 y / ccm and is therefore much lower than that of trinitroglycerin (1 y / ccm) and papaverine (10 y / ccm). In addition, the said process product opposes the two comparison substances have a stronger corona effect. For 3-keto-20,20-bis-acetoxymethyl - 41.4 - pregnadiene and 3 - keto - 20.20 - bishydroxymethyl-A1.4-pregnadiene the effective limit concentration in the same test is 0.005 y / ccm. In acute toxicity testing in mice the 3,11-diketo-20,20-bis-nitratomethyl-41.4-pregnadiene was found in Concentrations up to 100 mg / kg body weight, injected subcutaneously, are considered non-toxic. The inventive method for the preparation of the compounds of the general Formula 1 consists of a 3 - keto - 20.20 in a known manner - bis - hydroxymethyl - pregnane, whose primary hydroxyl groups were in the 20-position before have been blocked by acylation, brominated in the 2- and 4-positions, from the dibrominated Compound splits off hydrogen bromide, the primary hydroxyl groups of the obtained 3-keto-20,20-bis-acyloxymethyl-d1.4-pregnadiens, if necessary by alkaline Saponification releases and the obtained 3 - keto - 20.20 - bis - hydroxymethyl - 41, 4 - pregnadiene optionally in the corresponding 20,20-diester of an organic Carboxylic acid or converted into the corresponding 20,20-dinitrate.

There is a preferred embodiment of the method according to the invention in that the starting compound is 3,11-diketo-20,20-bis-acetoxymethyl-pregnane used, which carries out the bromination with a solution of bromine in acetic acid and hydrogen bromide by the action of the salt pair lithium bromide-lithium carbonate in dimethylformamide splits off. The following examples and the reaction scheme illustrate the method according to the invention.

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

Example 1 Dinitrate of 3,11-diketo-20,20-bis-hydroxymethyl-.41,4-pregnadiene A. 2,4-Dibromo-3,11-diketo-20,20-bisacetoxymethyl-5 @ -pregnane (III, R1 = O, R2 = -COCH3) 2 g of 3,11-diketo-20, 20-bis-acetoxymethyl are added to 20 cc of acetic acid - 5/5 - pregnane (1I), then add about 0.2 cc of acetyl chloride while stirring at 20 to 22 ° C and then immediately add 10 cc of a solution in the course of about 10 minutes of bromine in acetic acid (14 to 14.2 g Br °.! o). The reaction mixture is then poured in 300 cc of a mixture of water and ice.

The crystals obtained are filtered off, washed with water and dried. 2.649 g of the abovementioned compound III are obtained; Br = 26.60.10 (theoretical 25.89%). The crystals are insoluble in water.

The compound has not yet been described in the literature.

The starting compound 1I was according to the in the patent application L 38189 IV b / 12 o (German Auslegeschrift 1 173 092) Esterification of the hydroxymethyl groups of 3.11 - diketo - 20.20 - bis - hydroxymethylpregnane made with acetic acid.

B. 3,11-Diketo-20,20-bis-acetoxymethyld 1, 4-pregnadiene (IV, R1 = O, R # -; - = R3 = -COCH3) Add 1.1 g of lithium bromide to 18 ccm of dimethylformamide, then heated to 80 ° C. while stirring and bubbling nitrogen through, and 1.1 g of lithium carbonate and then 2.640 g of the compound III obtained were added. The mixture is then heated with stirring and under nitrogen for about 17 to 18 hours at 95 to 100 ° C., then cooled to 20 to 25 ° C. and the reaction mixture is slowly poured into 180 cc of a mixture of water and ice and 3.5 cc of acetic acid. The precipitate is filtered off with suction, washed with water and dried.

The crude product is purified by treating it with boiling isopropyl ether triturated and then chromatographed on silica gel, using methylene chloride, which contains 6 to 8% acetone. eluted. The eluates are evaporated, then with hot Isopropyl ether resumed and left to stand one night at room temperature. The crystals obtained are filtered off, washed with isopropyl ether and with 80'C dried.

0.935 g of the abovementioned compound IV from F. (on the Block) = 141 to 142'C; t = 15 200 at 239 m # t.

The compound is soluble in chloroform, slightly soluble in ether and Isopropyl ether and insoluble in water. The connection has been in the literature so far not described.

C. 3,11-Di keto-20,20-bis-hydroxymethyl-11A-pregnadiene (V. R, = O).

0.900 g of the compound IV obtained is added to 22 cc of 95% oiges Ethanol and 2.7 cc of water. The solution is obtained for 15 minutes while bubbling through of nitrogen at 20 to 22 ° C and then 0.9 ccm of sodium hydroxide solution is added. The reaction mixture is kept at about 20 to 22 ° C. under nitrogen for 3 hours. Then neutralized by adding acetic acid and pouring into 300 ccm of a mixture of water and Ice cream. The precipitate formed is filtered off with suction, washed with water and dried.

The crude product is purified by refluxing in a Mixture of ethyl acetate and ethanol, filter on the heat and crystallize at 0 to -, - 5-C.

The yield is 0.440 g (V. R, - = O) from F. - 202 to 203-C.

The compound is soluble in chloroform, slightly soluble in ether and Ethyl acetate and insoluble in water.

The compound has not yet been described in the literature.

D. Dinitrate of 3.11-diketo-20,20-bishydroxymethyl-.1 1 - 1-pregnadiene (I, R, = O, R2 and R3 = NO-) Add 6.2 ccm to --15 to -20 ' C slowly chilled acetic anhydride with 1.52 ccm of fuming nitric acid and then add 0.420 g of compound V (R1 == O), dissolved in 6.2 ccm of chloroform, in 2 to 3 minutes.

The reaction mixture is stirred and under for about 20 minutes Bubbling nitrogen through maintained at -10 to -15'- C and then slowly in 75 ccm of a mixture of water and ice poured. Then you separate the resulting Precipitate and the liquid extracted several times with methylene chloride. the organic phases are combined, one after the other with water, 2% sodium bicarbonate solution and washed again with water until the washing waters are neutral and then over Dried magnesium sulfate. The solvent is distilled off in vacuo and poured then the residue in 25 cc of ice water; then stirred for 1 hour. The dinitrate I (R1 = O) crystallizes out. The crystals are filtered off with suction, washed with water and dried at 20'-C.

The crude product is redissolved and refluxed in ethanol the solution filtered in the heat; it is allowed to crystallize in the refrigerator.

Further purification is done in the same way under treatment executed with animal charcoal.

0.24 g of compound 1 (R, - = O) with a temperature of --- 152 to 153 ° C. is obtained. [<x] = _ = 106 '± 3 (c == 0.5% in chloroform).

The compound is soluble in chloroform, soluble in heat Ethanol. sparingly soluble in ether and insoluble in water. Analysis: C2aII3oN20s; Molecular Weight = 462.49. Calculated ... C 59.72, H 6.53, N 6.05%; Found ... C 59.9, H 6.7, N 6.3%.

UV spectrum: 7.max (in ethanol) 238 mu, F = 14,900. The compound has not yet been described in the literature.

Example 2 3-Keto-20,20-bis-nitratomethyl-d 1,4-pregnadiene A. 2,4-Dibromo-3-keto-20,20-bisacetoxymethyl-5β-pregnane (III, R1 = H2, R2 = R2 = -COCH3) 3.625 g of 3-keto-20,20-bis-acetoxymethyl-5β-pregnane are dissolved (II) in 50 ccm of acetic acid and then treated with 2 drops of hydrogen bromide and 14.6 ccm of a solution of 11.154 g of bromine in enough acetic acid that the volume is 50 ccm. The bromination occurs in 20 minutes at room temperature; man pour the reaction mixture into 700 cc of a mixture of water and ice; one stirs 30 minutes, sucks off the precipitate and dries it. This gives 5.85 g of the compound III given above. This crude product is used for the following Procedural stage.

B. 3-Keto-20,20-bis-acetoxymethyl-I 1,4-pregnadiene (IV, R1 = H2, R2 = R3 = -COCH3) 5.85 g of the compound III obtained are added to a mixture of 3.2 g LiBr, 2.9 g Li2COa and 40 ccm dimethylformamide. The mixture is heated to 100 ° C. for 16 hours, cooled and poured into 400 cc of a mixture of water and ice and 8 cc of acetic acid; the mixture is stirred for 1/2 hour. The precipitate is then filtered off with suction, washed with water and dried; the residue is dissolved in benzene and purified by chromatography by adsorbing the substance on 200 g of magnesium silicate and eluting with benzene containing 3% methanol; the benzene fractions are combined and evaporated to dryness. The dry residue is recrystallized from ether and isopropyl ether; 2 g of crystalline compound IV (R1 = H2; R2 = R3 = -COCH3) with a melting point of 117 to 119 ° C. are thus obtained. For analysis, 254 mg of this compound IV are recrystallized from 12 cc of isopropyl ether by dissolving in the heat and cooling. The pure compound has a temperature of 118 to 119 ° C and [a] 211 _ + 25.4 ° (c = 1% in chloroform). The compound is soluble in benzene and chloroform, slightly soluble in ether and insoluble in water.

Analysis: C27H3805; Molecular Weight = 442.50. Calculated ... C 73.27, H 8.64%; found ... C 73.3, H 8.5%. UV spectrum: 245 mt., E = 15,800 (ethanol).

C. 3-Keto-20,20-bis-hydroxymethyl-41,4-pregnadiene (V, R1 = H2) Man are 1.1 g of the compound IV obtained in a mixture of 22 ccm of methanol, 3.3 ccm of water and 1.1 ccm of sodium hydroxide solution. Then left for 2 hours at room temperature stand, treated with 1.1 ccm of acetic acid, filtered off the precipitate and gives slowly add 25 cc of water to the solution, and the compound V crystallizes. Man sucks them up, washes them with water and dries them. This gives 818 mg of compound V (R1 = H2) from F. = 170.5 ° C. The yield is 92%. Crystallized for analysis to 310 mg of this compound V by dissolving the substance in 15 cc of ethyl acetate dissolves in the heat, concentrates to 7 cc, cools with ice and sucks off the precipitate. This gives 240 mg of compound V with a temperature of 170.5 ° C and [a] ö = +21 '(c = 1% in chloroform). The compound is soluble in alcohol and chloroform, slightly soluble in ethyl acetate and insoluble in water and ether.

Analysis: C23H3403; Molecular weight = 358.50. Calculated ... C 77.05, H 9.56%; found ... C 71.1, H 9.5%.

D. 3-Keto-20,20-bis-nitratomethyl-41,4-pregnadiene (I, R1 = H2, R2 and R3 = NO2) 359 mg of the compound V obtained (R1 = H2) are added at -15.degree into a mixture of 3.6 cc acetic anhydride and 0.9 cc nitric acid (48 ° B8) prepared at -15 ° C. The mixture is allowed to stand at -10 ° C. for 20 minutes, the resulting solution is then poured into 35 cc of a mixture of water and ice, stirred for 30 minutes, the crystallized compound I is extracted with methylene chloride, the methylene chloride phase is separated off, washed with water and then with 10% sodium bicarbonate solution and finally again with water, dry over sodium sulfate and evaporate to dryness. The residue is recrystallized from 8 cc of alcohol and 1 cc of methylene chloride, filtered, the solution is concentrated until crystallization, cooled to ice temperature, filtered off with suction and dried. 300 mg of recrystallized compound I (R1 = H2) with a temperature of 139 ° C. and [a] δ = + 25.6 ° (c = 1) / o in chloroform) are thus obtained. The compound is soluble in chloroform, sparingly soluble in alcohol and insoluble in water.

Analysis: Cz3H3207N2; Molecular Weight = 448.50. Calculated ... C 61.59, H 7.19, N 6.25%; Found ... C 61.5, H 7.1, N 6.2%.

The starting compound 3-keto-20,20-bis-acetoxymethyl-5ß-pregnane (II) is prepared as follows. 3.625 g of 3-keto-20,20-bis-hydroxymethyl-5β-pregnane are dissolved in 22 cc of pyridine, then mixed with 11 cc of acetic anhydride, stirred for 2 hours at room temperature, pour the resulting solution into 250 ccm of a mixture Water and ice, stir for 1/2 hour and extract the precipitate with ethyl acetate; the ethyl acetate solution is washed with water, normal hydrochloric acid, water, 10% strength Sodium bicarbonate solution and finally again with water; it is dried over sodium sulfate and evaporates to dryness; so one obtains the amorphous compound II with theoretical Yield.

Example 3 3-Keto-20,20-bis-acetoxymethyl-41,4-pregnadiene One dissolves 0.500 g of the 3-keto-20,20-bis-hydroxymethyl-d1,4-pregnadiene obtained according to Example 2, C) (V, R1 = H2) in 7 ccm of pyridine, then the solution is cooled to + 5 ° C and stirred dropwise 2 cc acetic anhydride. The mixture is stirred for a further 2 hours. Then pour the reaction mixture in 100 cc of ice water, whereupon the diacetate precipitates. Man Let the mixture stand for 1 hour and then stir it 3 times with 20 cc of chloroform each time. The chloroform layers are decanted with water, dilute hydrochloric acid and washed again with water until neutral and then dried. You narrow them Chloroform solution to dryness. The residue is heated with 10 cc of alcohol recorded. On cooling to ice temperature, the 3-keto-20,20-bis-acetoxymethyl-J1.-1-pregnadiene crystallizes. The compound is filtered off and 0.490 g of substance with a F. = 118 bis is obtained 119 ° C.

Claims (4)

Claims: 1. Process for the preparation of 20,20-bis-hydroxymethyl-3-keto-1,4-pregnadienes or esters thereof, which have the general formula where R1 = H2 or O, R2 and 12.3 each signify H or an acyl or nitric acid residue, characterized in that bromine is converted into the 2- and 4-positions of a corresponding 3-keto in a manner known per se -20,20-bishydroxymethyl-pregnans, whose primary hydroxyl groups in the 20-position have been protected beforehand by acylation, splits off hydrogen bromide from the dibrominated compound, optionally the primary hydroxyl groups of the 3-keto-20,20-bis-acyloxymethyl- A1,4-pregnadiene is released by alkaline saponification and the 3-keto-20,20-bis-hydroxymethyl-41,4-pregnadiene obtained is optionally converted into the corresponding 20.20-diester of an organic carboxylic acid or into the corresponding 20.20-dinitrate. 2. Method according to claim], characterized in that the starting compound is 3,11-diketo-20,20-bis-acetoxymethyl-pregnane used. 3. Process according to claims 1 and 2, characterized in that the bromination is carried out with a solution of bromine in acetic acid. 4. Procedure according to claims 1 to 3, characterized in that the splitting off of hydrogen bromide using the salt pair lithium bromide-lithium carbonate in dimethylformamide. References considered: Bull. Soc. Chim. France, 1958, p. 366; Chemical Reports, Vol. 91 (1958), pp. 799-801.