DE1150076B - Process for the production of therapeutically effective 6ª ‡ -fluoromethyl steroids - Google Patents

Description

Process for the preparation of therapeutically effective 6a-fluoromethyl steroids The present invention relates to a process for the preparation of therapeutically effective 6a-fluoromethyl steroids of the general formula in which X is hydrogen or fluorine and R is hydrogen or the acetyl radical. The process according to the invention consists in that, according to methods known per se, a compound of the general formula hydrolyzed, optionally the 6a-fluoromethyl-1 1,17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione obtained acetylated, optionally introducing a 9a-fluorine substituent into the obtained 21-acetate and optionally the 21-position Acetoxy group of the obtained 6a-fluoromethyl-9a-fluoro-21-acetate hydrolyzed.

Possess the novel steroid compounds obtainable according to the invention pronounced anti-inflammatory, salt and water regulating, pituitary inhibiting, progestational, glucocorticoid and anti-anabolic properties with improved Ratio of therapeutic effectiveness to undesirable side reactions, such as Gastric and intestinal disorders, edema, etc., which are known to be of similar physiological effective steroids without a 6a fluoromethyl group. You own It is therefore used to treat inflammation of the skin, eyes, airways, and bones internal organs caused by bacteria or viruses, contact dermatitis, allergic phenomena or rheumatoid arthritis. You can do this in the usual way processed into ointments, creams, lotions, sprays, tablets, suspensions and solutions are, if necessary together with antibiotics, especially penicillins, neomycin, Tetracycline, chloromycetin and novobioein, as well as fungicidal agents such as griseofulvin.

The starting material for the process according to the invention is obtained in the following way: By treating 17a, 21-dihydroxy-4-pregnen-3,11,10-trione with formaldehyde in the presence of strong acids such as hydrochloric, perchloric, sulfuric acid and the like ., the corresponding 17: 20.20 21-bismethylenedioxy derivative is prepared. The obtained 17 20.20 : 21-bismethylenedioxy-4-pregnen-3,11 -dione is then enolacylated with an alkenylate in the presence of an acid catalyst, e.g. B. isopropenyl acetate in the presence of p-toluenesulfonic acid, or other enol acylating agents. The obtained 17: 20.20 : 21 - bismethylenedioxy - 3,5 - pregnadien-1 1-one-3-acylate is then hydrogenated with sodium borohydride or another suitable reducing agent and subsequently acylated again, whereupon a 17: 20.20 : 21-bismethylenedioxy-3fl, 11p-dihydroxy -5-pregnen-3-acylate is obtained. This is hydroxymethylated in the presence of a catalyst with carbon monoxide and hydrogen under excess pressure to 17: 20, 20 : 21-bismethylenedioxy-6a-hydroxymethyl-.3fl, lIß-dihydroxy-5a-pregnane-3-acylate and then with an organic sulfonyl halide, z . B. p-toluenesulfonyl chloride, converted to the corresponding tosyloxymethyl derivative. The tosyloxymethyl group is then treated with an alkali fluoride, e.g. B. anhydrous potassium fluoride, converted into a fluoromethyl group, and after alkali hydrolysis one obtains 17: 20, 20 : 21-bismethylenedioxy - 6a - fluoromethyl - 3ß, 11ß - dihydroxy-5a-pregnane. Then, according to Oppenauer, d. H. in a ketone such as acetone or cyclohexanone with an aluminum alcoholate, e.g. B. aluminum isopropoxide, whereupon 17: 20, 20 : 21-bismethylenedioxy - 6a - fluoromethyl -1 Iß - hydroxy-5a-pregnan-3-one is obtained. This goes in the dehydrogenation with selenium dioxide in the inventively used starting material, the 17: 20,20: 21-Bisiiiethylendioxy-6a-fluoriiiethyl- 11 beta-hydroxy-1,4-pregnadien-3-one, about. Protection is not sought for its production in the context of the present invention.

The following example illustrates the process according to the invention: Example a) 6a-fluoromethyl-ILß, 17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione 60% formic acid heated on a steam bath becomes nitrogen for 5 minutes by 10ccm directed. Then 60 mg of 17: 20, 20 : 21-bismethylenedioxy-6a-fluorineietliyl-II # -hydroxy-1,4-pregnadien-3-one ( temperature - 255 to 265 ° C.) are added to the hot formic acid, whereupon one further Heated for 15 minutes on the steam bath while passing in nitrogen. After cooling, the solution is poured into an ice-sodium bicarbonate mixture and the organic material is extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and the solvent is evaporated off. What remains is 57 mg of crystalline solid material, which are dissolved in 20 ml of methanol that has previously been treated with nitrogen for 20 minutes. An aqueous solution of potassium bicarbonate (100 mg in 10 ml of nitrogen treated water) is then added and the mixture is stirred at room temperature for about 48 hours. Then acetic acid is added up to pH 7 and the solvent is removed under vacuum. The organic material is extracted from the residue with methylene chloride and the extract is dried with sodium sulfate. After evaporation, 58 mg of crystalline material remain, which are dissolved in a mixture of methylene chloride and ethyl acetate and chromatographed on a column of 5.0 g of synthetic magnesium silicate that has previously been moistened with hexane hydrocarbons ("Skellysolve B"). From the eluates obtained with 30% acetone-hexane hydrocarbons, slightly colored crystals are obtained, which after recrystallization from acetone-hexane hydrocarbons 19 mg of 6a-fluoromethyl- 1 Iß, 17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione from Melting point 232 to 235'C result. Analysis for C22H29F05: Calculated ..... C 67.35, H 7.4, F 4.85; found ..... C 67.77, H 7.95, F 5.24.

b) 6a-fluoromethyl-ILß, 17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione-21 acetate 0.338 g 6a - fluoromethyl - 1 Iß, 17a, 21 - trihydroxy-1,4-pregnadiene- 3,20-dione are left to stand overnight in 10 ml of pyridine containing 2.5 ml of acetic anhydride. After 18 hours the reaction mixture is poured into an ice-sodium bicarbonate mixture and then extracted with ethyl acetate. The combined extracts are washed with water, dilute sulfuric acid and again with water until neutral and then dried over sodium sulfate. After removal of the solvent, a slightly colored, crystalline product is obtained which, after recrystallization from a mixture of acetone and hexane hydrocarbons, 248 mg of 6a-fluoromethyl- 11β, 17a, 21-trihydroxy-1,4-pregnadiene-3.20-dione-21 acetate with a melting point of 226 to 229 ° C. A purified product with a melting point of 231 to 233 ° C. is obtained by recrystallization from the same solvent mixture.

The infrared spectrum confirmed the assumed structure. Analysis for C- # 4H., 31F06: Calculated ..... C 66.36, H 7.14, F 4.38; found ..... C 66.23, H 7.34, F 4.8 1. c) 6ct-fluoromethyl-ILß, 17a, 21-trihydroxy-9a-fluoro-1,4-pregnadiene-3.20- dione-21-acetate A solution of 1.0 g of 6a-fluoroethyl- 11 fl, 1 7a, 21 -trihydroxy - 1,4 - pregnadiene -3.20- dione - 21 - acetate in 30 ml of pyridine is 0.6 g of N-bromoacetamide are added. After standing for 15 minutes at room temperature, the solution is cooled to 5 to 10 ° C and sulfur dioxide is passed onto the surface of the solution while shaking until acidified potassium iodide starch paper is no longer colored. The reaction mixture becomes warm during the sulfur dioxide treatment. The temperature is kept below 30 ° C. by external cooling and appropriate metering of the sulfur dioxide supply. Ice water is then added to the reaction mixture and the resulting precipitate is recrystallized from 6a-fluoromethyl-17a, 21-dihydroxy-1,4,9 (I1) -pregnatriene-3,20-dione-21-acetate from acetone-hexane hydrocarbons.

To a solution of 6.0 g of 6a-fluoromethyl-17a, 21 - dihydroxy - 1,4,9 (11) - pregnatrien - 3,20 - dione 21-acetate in 200m1 100M1 fuse Methylenehlorid and tert-butyl, a solution of 14m1 of 72% perchloric acid in 100 ml of water and then a solution of 2.5 g of N-bromoacetamide in 60 ml of tert. Given butyl alcohol. After the reaction mixture has been stirred for 15 minutes, a solution of 3 g of sodium sulfite in 150 ml of water is added and the reaction mixture is concentrated to a small volume under reduced pressure at 50.degree. It is then cooled in an ice bath and the same volume of water is added while stirring. After stirring for 1 hour, the precipitated product is filtered off and the filter cake made of 6a-fluoromethyl-1 Iß, 17a, 21 - trihydroxy -9a- bromo - 1,4 - pregnadiene-3,20-dione-21-acetate is washed with water and on the Air dried.

To a solution of 7, Og 6a-fluoromethyl-1 Eat, 1 7a, 21 - trihydroxy - 9a - bromo - 1,4 - pregnadiene-3,20-dione-21-acetate in 200m1 of acetone are added 7, Og potassium acetate. The suspension obtained is heated to boiling under reflux for 17 hours. It is then concentrated to a small volume on a steam bath under reduced pressure, diluted with water and extracted with methylene chloride. The methylene chloride extracts are combined, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is then redissolved in methylene chloride and chromatographed over synthetic magnesium silicate. The column is eluted with hexane hydrocarbons containing increasing proportions of acetone. The washed-out 6-fluoromethyl-9β, 11β-oxido-17a, 21-dihydroxy-1,4-pregnadiene-3,20-dione-21-acetate is freed from the solvent by evaporating the eluate.

To about 1.3g of hydrogen fluoride in a polyethylene bottle add 2.3m1 of tetrahydrofuran at -60'C and then a solution of 50Omg of 6a - fluoromethyl - 9j3.1 Iß - oxido - 17a, 21 - dihydroxy-4-pregnen-3.20- dione-21-acetate in 2m1 methylene chloride. The steroid solution is rinsed with another milliliter of methylene chloride. The light red solution is left to stand for about 1 hour at -30 ° C and then for about 18 hours at -i-5 ° C. It is then carefully mixed with excess, cold sodium bicarbonate solution and the organic material is extracted with methylene chloride. The combined extracts are washed with water, dried over anhydrous sodium sulfate and concentrated to a small volume. The solution is then chromatographed over synthetic magnesium silicate. Hexane hydrocarbons with increasing proportions of acetone are used to develop the column. The eluted 6a-fluoromethyl-1 1f3,17a, 21-trihydroxy-9a-fluoro-1,4-pregnadiene-3,20-dione-21-acetate is freed from the solvent by evaporation of the eluate fractions and purified by recrystallization from acetone-hexane hydrocarbons . F. = 215 to 217'C. Analysis for C ._ ", H3oF-, 06: Calculated ..... F 8.41, found ..... F 8.47. D) 6a-fluoromethyl-ILß, 17a, 21-trihydroxy-9a -fluoro-1,4-pregnadiene-3.20-dione 3g 6a-fluoromethyl-Ilfl, 17a, 21-trihydroxy-9a-fluoro-1,4-pregnadiene-3,20-dione-21-acetate are dissolved in 300 ml of methanol which has previously been freed from atmospheric oxygen by bubbling nitrogen through it (10 minutes). 25 ml of a likewise deoxygenated 5% aqueous solution of potassium bicarbonate are added to the solution. This mixture is left to stand for 5 hours at room temperature under nitrogen and then neutralized with The mixture is then concentrated to about a third of its volume on a water bath at 60 ° C. under reduced pressure, mixed with water and cooled. 4-pregnen-3,20-dione is collected on a filter, washed with water and dried.

Claims (1)

PATENT CLAIM: Process for the production of therapeutically effective 6a-fluoromethyl steroids of the general formula in which X is hydrogen or fluorine and R is hydrogen or the acetyl radical, characterized in that a compound of the general formula is obtained by methods known per se hydrolyzed, optionally the 6a - fluoromethyl -11, 17a, 21 - trihydroxy - 1,4 - pregnadiene-3,20-dione obtained acetylated, optionally introducing a 9a-fluorine substituent into the 21-acetate obtained and optionally the 21-position Acetoxy group of the obtained 6a-fluoromethyl-9a-fluoro-21-acetate hydrolyzed.