DE1048915B - Process for the preparation of 6-methyl-9ª ‡, 21-difluoro-11ª ‰, 17ª ‡ -dioxy-1,4-pregnadiene-3,20-dione and its 11-keto analogues - Google Patents

Description

Process for the preparation of 6-methyl-9a, 21-difluoro-11 P, 17a-dioxy-1,4-pregnadiene-3,20-dione and its 11-keto analogs The subject matter of the invention is a process for the preparation of 6-methyl -9a, 21-difluoro-lIß, 17a-dioxy-1,4-pregnadiene-3,20-dione and its 11-keto analogues.

The method according to the invention is carried out according to the following scheme: where the reaction sequence of the process steps known per se can also be changed in the following manner: In the above formulas, X denotes a halogen with an atomic weight of 33 to 80, P denotes the methyl radical or another hydrocarbon radical and Ac denotes the acyl radical of an organic carboxylic acid with preferably 1 to 8 carbon atoms. Instead of the methyl group, there can also be another hydrocarbon group in the 6-position.

The 6-methyl-9a, 21-difluoro-liß, 17a-dioxy-1,4-pregnadiene-3,20-dione which can be prepared according to the invention and its 11- keto analogues represent new compounds which have valuable therapeutic properties. In particular, their glucocorticoid effect is many times stronger than that of hydrocortisone and cortisole, as can be seen from the results of comparative tests given below, in which the values determined are related to the effectiveness of hydrocortisone assumed with 1. 9,21-difluoro-liß, 6 a-methyl-9 a'21- 17a-dioxy-1,4-preg-difluor-llß, 17a- nadiene-3,20-dione dioxy-1,4-pregna- diene-3,20-dione Liver glycogen deposit .... 6.5 46.8 Granuloma test ... 5.5 35.5 The new compounds according to the invention, which can also contain a hydrocarbon group other than the methyl group in the 6-position, also do not act as a salt; reserved and have pronounced diuretic properties. Due to their strong anti-inflammatory effect, they are suitable for the treatment of joint inflammation, especially in cases in which chronic congestive heart defects, nephrotic syndromes and other circulatory disorders occur at the same time. The steroid derivatives that can be prepared according to the invention can be administered orally in conjunction with customary carriers and diluents. In the form of ointments, lotions, jellies, creams, suppositories, bougies, aqueous suspensions, etc., they are also suitable for topical application, in particular for inflammation of the skin and eyes. Antibiotics and sulfonamides can be added to increase their effectiveness.

According to the process according to the invention, 1-De-'hydro-6-methyl-hydrocortisone- (6-methyl-ILß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione) is treated with a halide of a sulfonic acid, such as Methane, ethane, propane, benzene, p-toluene, α- or ß-naphthalenesulfonic acid, implemented. It is preferable to work in solution, e.g. B. in pyridine, benzene or toluene, at a temperature between -10 and + 30'C. The reaction time is generally from 30 minutes to 6 or 8 hours. The 6-methyl-11fl, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-21-sulfonate obtained can be precipitated or extracted by known methods and then immediately treated with sodium or potassium iodide in a dialkyl ketone solution, e.g. B. in Ac # clay solution, be treated, using an excess of iodide (3 to 20 moles of iodide per mole of steroid) expediently. After brief heating under reflux, the reaction mixture formed is steamed by switching off the solvent removed. The obtained 6-methyl-ILß, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione is without prior purification in a suitable solvent such as acetonitrile, hexane, heptane, benzene or tert-butyl alcohol, dissolved and advantageously reacted with the exclusion of light and with stirring with silver fluoride. It is expedient to use beer for a 500 μg aqueous silver fluoride solution. The reaction can be carried out between 10 and about 75 ° C. Since this creates a molecular compound with silver fluoride, at least 2 lUol silver fluoride per mole steroid are required for the reaction. To achieve higher yields, an excess of 10 to 15% over this amount is advantageous.

This is done by evaporating the solvent and extracting the crude 6-methyl-11ß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione product obtained with a suitable solvent can be according to conventional methods, z. B. by repeated extraction, recrystallization or chromatographically, further getting cleaned.

The 21-fluoride can also, as will be shown later, by direct reaction of the 21-sulfonate with potassium fluoride. The dehydration of the obtained 6-M # ethyl-Ilß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione with known agents, such as phosphorus oxychloride, hydrochloric acid, sulfuric acid or acetic acid, thionyl chloride or by the pyrolytic route, gives 6-methyl-21-fluoro-1 7a-oxy-1,4,9 (I1) -pregnatriene-3,20-dione.

The dehydration can also be carried out in an advantageous manner by reacting the 11β-oxy compound with an N-halide or N-haloimide in the presence of an organic base and treating the 11-hypohalite formed as an intermediate with dry sulfur dioxide in an organic base, whereby to increase the yield is worked with the exclusion of water. The reaction time is usually 5 minutes to 3 hours, depending on the temperature used. The sulfur dioxide used for the reaction can be used as such in gaseous or liquid form or in situ. The 6-methyl-17a-oxy-21-fluoro-1,4,9 (I1) -pregnatrieii-3,20-dione formed is converted from the reaction mixture by conventional methods, e.g. D. by introducing the mixture into excess water, extraction with a water-immiscible solvent and evaporation of the solvent, and can then be further purified if necessary.

The 6-methyl-17a-oxy-21-fluoro-1,4,9 (11) -pregnatriene-3,20-dione obtained is then converted to 6-methyl-9a- halogen-ILß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione converted. The hypohalous acid can be formed in situ from an N-halo amide or imide. The reaction, which is advantageously carried out in an organic solvent, is usually carried out between 15 and 50 ° C. The reaction time is between 4 to 5 minutes and 1 hour. After the reaction time has elapsed, the excess subbalanced acid is destroyed by adding sodium sulphite or other sulphites or hydrosulites.

The resulting 6-methyl-9a-halogen-ILß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione is made from the reaction mixture by adding an excess of water and extraction with organic solvents or filtering off the precipitated compounds isolated. It can be recrystallized from organic solvents.

The oxidation of 6-methyl-9a-halogen-ILß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione with chromic acid gives the pharmaceutically active 6-methyl-9a-halogen-17a-oxy-21-fluoro-1,4-pregnadiene-3,11,20-trione.

To produce the 9a-fluoro compound, 6-methyl-9a-halogen-11ß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione is used heated in solution with a weak base. The 6-methyl-9β, llp-oxido-17a-oxy-21-fluoro-1,4-pregnadiene-3,20-dione formed is made by diluting with excess water and filtering or extracting of the precipitated crystalline product with water-immiscible solvents obtained from the reaction mixture.

The 6-methyl-9p, llß-oxido-17a-oxy-21-fluoro-1,4-pregnadiene-3,20-dione obtained is then reacted with hydrofluoric acid. Suitable solvents for this are, for. B. methylene chloride, tetrahydrofuran, ethylene dicloride, chloroform or carbon tetrachloride. The reaction is expediently carried out with stirring at temperatures between 20 and 30 ° C. if methylene chloride is used as the solvent, and at lower temperatures (0 to 80 ° C.) if tetrahydrofuran is used. If methylene chloride is used, aqueous (480%) hydrofluoric acid is generally used, and liquid hydrogen fluoride for tetrahydrofuran. The reaction time is 1 to 24 hours. After the reaction has ended, the mixture is poured into water and neutralized with a dilute base such as sodium bicarbonate or potassium bicarbonate. An excess of strong alkalis can also be used. The reaction mixture is then extracted with a water-immiscible solvent such as methylene chloride, the organic layer separated, washed with water, dried and evaporated, whereupon crude 6-methyl-9a, 21-difluoro-11ß, 17a-dioxy-1 , 4-pregnadiene-3,20-dione, which can be purified by recrystallization or cbroma-tographically.

The treatment of 6-methyl-9a, 21-difl-uor-llß, 17a-dioxy-1,4-pregnadier) -3,20-dione with z. B. Chromic acid hydride or an AH <: alicb-romat in solution, e.g. B. acetic acid, at a temperature between 0 and 40 ' C gives the corresponding 6-methyl-9a, 21-difluoro-17a-oxy-1,4-pregnadiene-3,11,20-ti-ioi).

The modified reaction sequence includes the same process steps, only here is the introduction of the 9a fluorine atom before that of the 21 fluorine atom. The starting material for this reaction sequence is a 21-ester of 1-dehydro-6-methylhydrocortisone, z. B. the acetate, propionate, butyrate, pentanoate, hexanoate, benzoate, phenyl acetate Od. The like. That easily by reacting 1-dehydro-6-methylhydrocortisone with a Acid chloride, an acid bromide or an acid anhydride of a carboxylic acid in P # ridin can be produced.

It is dehydrated to 6-methyl-17-oxy-21-acyl-oxy-1,4,9, (11) -pregnatriene-3,20-dione according to the formula shown in column 3. In a manner analogous to that described above, this is converted into methyl-9a-fluoro-11ß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione via the 9α-halogen compound and the corresponding 9β, 11β-epoxide -21-acylate (XIV) converted, which is hydrolyzed with a base, preferably under nitrogen, to the free triol.

The 6-Mc, # thyl-9a-fluoro-11ß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione obtained is then converted into the desired via the 21-sulfonate and the corresponding 21-iodine compound 6-methyl-9a, 21-difluoro-11ß, 17a-dioxy-1,4-pregnadiene-3,20-dione converted. The introduction of the 21-position fluorine atom can also by direct reaction of the 21-sulfonate with Potassium fluoride.

The following examples explain the process according to the invention, the individual stages of which represent measures known per se. Example 1 a) 6a-methyl-Ilfl, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-21-m-, thanesulfonate (1-dehydro-6a-methylhydrocortisone-21-methanesulfonate) of 164mg ( 0.437 mlillimol) 1-dehydro-6a-methylhydrocortisone (G. B. Spero and coworkers, J. Am. Chem. Soc., Vol. 78, 1956, p. 6213) and 1 cc of pyridine were prepared. It was cooled to 0 ° C and then treated with a cooled solution of 75 mg methanesulfonyloride in 0.5 cem pyridine. It was then left to stand at 0 to 5 ° C. for 2 hours. Then ice and hydrochloric acid which was sufficiently diluted to neutralize the pyridine were added and the mixture obtained was extracted three times with 25 cc of methylene chloride each time. The extracts were combined, washed with cold sodium bicarbonate solution and then with water, then dried over anhydrous sodium sulfate and under reduced pressure to give crystalline 6a-methyl-Ilfl, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-21 evaporated methanesulfonate.

b) 6a-Methyl-Ilfl, 17a-dioxy-21-iodo-1,4-pregnadien-3,20-dione The crystalline 21-methanesulfonate was dissolved in 15 cc of acetone, with a solution of sodium iodide in 5 cc 20Omg, acetone added and heated under reflux and stirring for 15 minutes. The reaction mixture was then evaporated to dryness under reduced pressure. 6a -.% Iethyl-1 1fl, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione were obtained.

c) 6a-methyl-11ß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione. By heating to the boiling point, a solution of 1 g of 6a-methyl-11ß, 17a-dioxy-21- iodine-1,4-pregnadieD-3,20-dione in 150 cc of acetonitrile (commercial grade). After cooling to 40 ° C., the solution was protected from light and 0.8 cem of a 500 μg aqueous silver fluoride solution was added with stirring. The solution turned cloudy and turned brown. With continued stirring, a further 40 to 45 ° C. were then added at intervals of 1 hour, ten times 0.7 cc of silver fluoride solution. The mixture was then heated and stirred for a further 2 hours. The brown reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure from a bath at a temperature of 50 ° C. The brown residue was extracted twice thoroughly with 100 cc of warm methylene chloride each time , the methylene chloride extracts were concentrated to about 100 cc and chromatographed over 50 g of synthetic magnesium silicate. There were collected the following fractions of 200 CCIN: Fractions solvent 1 to 5 ........... .... hexangeniisch acetone 93: 7 6 to 28 ............... hexanes-acetone 90: 10 29 .................... acetone Fractions 18 to 25 were combined and evaporated, whereupon 470 mg of crystals were obtained which, after recrystallization from acetone-hexane hydrocarbons, 343 mg of 6a-methyl-Ilfl, 17a-dioxy-21-fluoro-1,4-pregnadiene-3.20 -dione with a melting point of 216 to 222 ° C. Analysis-. For C "H" 0, F calcd ..... C 70.18, H 7.76, F 5.05; found ..... C 70.43, H 7.91, F 3.78. d) 6a-methyl-17a-oxy-21-fluoro-1,4-pregnadiene-3,11,20-trione A mixture of 0.3 g of 6a-methyl-Ilfl, 17a-dioxy-21-fl- nor-1,4-pregnadiene-3,20-dione, 100 mg chromic anhydride, 10 cem glacial acetic acid and 0.5 cc water. This mixture was kept at room temperature with stirring for 8 hours. It was then added to 50 cc of ice water and neutralized with dilute sodium hydroxide. The resulting precipitate was collected on a filter and recrystallized three times from ethyl acetate and hexane hydrocarbons to give 6a-methyl-17a-oxy-21-fluoro-1,4-pregnadiene-3,11,20-trione.

Instead of the 1-dehydro-6α-methylhydrocortisone in Example 1, a, the corresponding 6β-epilnere can also be used. If approximately neutral conditions are maintained in the subsequent reaction stages, 6fl-methyl-ILß, 17a-dioxy # 21-fluoro-1,4-pregnadiene-3,20-dione can be isolated from the reaction mixture of Example 1. When treated with an acid or base in an organic solvent such as ethanol at room temperature, this converts into the corresponding 6a-epimer.

e) 6a-methyl-17a-oxy-21-fluoro-1,4,9 (11) -pregnatriene-3,20-dione A mixture of 1 g of 6a-methyl-ILß, 17a-dioxy-21-fluoro-1 , 4-pregnadiene-3,20-dione, 650 mg of N-bromoacetamide and 6 cc of pyridine were stirred for 30 minutes with exclusion of light, then cooled in an ice-water bath and sulfur dioxide was passed onto the surface of the mixture with stirring until the potassium iodide starch paper sample was negative. Then 50 cc of water were added and the mixture was kept at about 5 ° C. for 30 minutes. The precipitated white solid was filtered off, washed with water and dried in vacuo. After recrystallization from acetone, about 0.7 g of 6a-methyl-17a-oxy-21-fluoro-1,4,9 (I1) -pregnatriene-3,20-dione was obtained.

f) 6a-Methyl-9a-bromo-ILß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione A solution of 0.5 g 6a-methyl-17a-oxy-21-Iluor-1 , 4.9 (I1) -pregnatriene-3,20-dione in 20 cc of methylene chloride, a solution of 1 cc mrde 71 0 /, perchloric acid in 0 cc of water and 200 mg of N-bromoacetamide was added in 50 cc ert.-butyl alcohol. This mixture was kept at room temperature for 5 minutes and then mixed with a solution of 0.3 g sodium sulfite in 12 cc water. The resulting mixture was distilled at reduced pressure until the remaining solution became cloudy. The product was precipitated from this by adding 100 cc of an ice-water mixture. The white crystalline precipitate was filtered off, washed with water, dried and recrystallized from a mixture of acetone and hexane hydrocarbons. g) 6a-methyl-9p, llp-oxido-17a-o.xy-21-fluoro-1,4-pregnadiene-3,20-dione A mixture of 0.45 g of 6a-methyl-9a-bromo-llß, 17a-di-) xy-21-fluoro-1,4-pregnadiene-3,20-dione, 0.45 g of anhydrous potassium acetate and 20 cc of acetone were refluxed for 5 hours. It was then cooled, the reaction mixture was poured into water and extracted with ethylene chloride. The methylene chloride extract was dried and poured onto a column of 25 g synthetic magnesium silicate. The column was developed with flexan hydrocarbons containing increasing amounts of A. acetone. The eluate containing hexane hydrocarbons 100 /, acetone contained 5α-methyl-9β, 11β-oxido-17a-o-xy-21-fluoro-1,4-pregnadiene-3,20-dione.

, i) 6a-methyl-9a, 21-difluoro-11ß, 17a-dioxy-1,4-pregnadiene-3,20-dione 1 g 6a-methyl-9ß, llß-oxido-17a-oxy-21-fluoro- 1,4-pre-, crnadieD-3,20-dione was dissolved in 50 cc of methylene chloride. Then 5 ccra 480 / jge hydrofluoric acid and 0.5 cc 710 / # ge perchloric acid were added. The mixture was stirred vigorously for 6 hours at room temperature and then poured into excess cold, aqueous 50% sodium bicarbonate solution. The methylene chloride layer was separated, dried over anhydrous sodium sulfate and then poured onto a column of 100 g of synthetic magnesium silicate. The column #v was developed with hexane hydrocarbons and acetone. The fractions containing 100 % acetone contained the desired product. It was recrystallized from acetone and hexane hydrocarbons, whereby pure 6a-methyl-9a, 21-difluoro-ILß, 17a-dioxy-1,4-pregnadie-n-3,20-dione with a melting point of 262 to 274 ° C ( with decomposition) and an optical rotation in acetone of [a] D = +71 '.

Analysis: For C "H" 0, F, calculated ..... F 9.63; found ..... F 9.80.

It can according to known methods, for. B. with chromic anhydride in acetic acid can be converted into the corresponding 11-keto compound. In the above-described The reaction sequence can of course also be 11p, 17a, 21-trioxy-1,4-pregnaclien-3,20-diones as starting materials are used which have a different hydrocarbon radical than the 6-position Contain methyl group.

Example 2 a) 6a-Miethyl-17a, 21-dioxy-1,4,9 (11) -pregnatriene-3,20-dione-21-acetate A solution of 530 mg 6a-methyl-11ß, 17a, 21-trio -xy-1,4-pregnadiene-3,20-dione-21-acetate (1-dehydro-6a-methylhydrocortisone-21-acetate) in 5 cc of pyridine, 225 mg of N-bromoacetamide were added to nitrogen. The mixture was then left to stand under nitrogen at room temperature for 30 minutes and then cooled to 10 to 15 ° C. Sulfur dioxide was then passed onto the surface of the solution, while shaking, until it did not produce any coloration when the iodine starch paper was acidified. Heat developed during the sulfur dioxide treatment. The temperature was therefore kept below 30 ° C. by external cooling and changing the speed of the sulfur dioxide feed line. The reaction mixture was then left to stand for 15 minutes at room temperature and then poured into 30 cc of ice water. The resulting rubbery precipitate was extracted with 50 cc of ether. The ether extract was washed with 50% hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness, whereupon 371 mg of residue were obtained. After recrystallization from acetone-hexane hydrocarbons, this gave 318 mg of 6a-methyl-17a, 21-ffioxy-1,4,9 (I1) -pregnatriene-3,20-dione-21-acetate with a melting point of 188 to 191.5 C. b) 6a-methyl-9a-bromo-ILß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-21-acetate (1-dehydro-6a-methyl-9a-bromohydrocortisone-21 acetate) A solution of 332 mg of 6a-methyl-17a, 21-dioxy-1,4,9 (I1) -pregnatriene-3,20-dione-21-acetate in 5 cc of methylene chloride and 9.9 cc of tert-butyl alcohol resulted in a solution of 0 83 ccm of 720% perchloric acid in 5.8 cc of water and then a solution of 14-9 mg of N-bromoacetan-iide in 2.5 cc of tert-butyl alcohol was added. The reaction mixture was stirred for 15 minutes, then added to a solution of 142 mg of sodium sulfite in 7 cc of water and cc concentrated under reduced pressure at about 60 'C to about 25th At this point crystallization started. The concentrate was cooled in an ice bath while stirring, and 35 cc of water was added. After stirring for 20 minutes, the crystalline product was filtered off, the crystals were washed with water and air-dried, whereupon 406 mg of 6a-methyl-9a-brora-Ilfl, 17a, 21-trioxy-1,4-pregnadiene-3, 20-dione-21-acetate (1-dehydro-6a-methyl-9a-bromohydrocortisone-21-acetate) with a melting point of 173 to 177 ° C. (with decomposition) was obtained. c) 6a-methyl-9p, llß-oxido-17a, 21-dioxy-1,4-pregnadiene-3,20-clione-21-acetate A solution of 406 mg 6a-Metlivl-9a-brora-Ilp, 17a, 21-trio, xy-1,4-pregnadieii-3,20-dione-21-acetate in 15 cc of acetone were added 406 mg of potassium acetate. The resulting suspension was refluxed for 18 hours. It was then concentrated to 5 cc on a water bath, after which 10 cc of water were added. As a result, the potassium acetate formed went into solution and the steroid product crystallized out. It was filtered off and recrystallized from acetone, whereupon two batches totaling 232 mg of 6a-methyl-9a, 11ß-oxido-17a, 21-dioxy-1,4-pregnadiene-3,20-dione-21-acetate with a melting point of 255 to 263 'C would be obtained.

d) 6a-methyl-9a-fluoro-ILß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-21-acetate (1-dehydro-6a-methyl-9a-fluorohydsocortisone-21-acetate) A solution of 230 mg of 6a-methyl-9fl,13-oxido-17a, 21-dioxy-1,4-pregnadiene-3,20-dione-21-acetate in 5 cem methylene chloride gave 1.2 cc of a 480 igen Hydrogen fluoride solution added. The two-phase mixture was stirred for 20 hours, then diluted with 15 cc of methylene chloride and carefully added to 40 cc of water containing 4 g of sodium bicarbonate. The excess hydrogen fluoride was neutralized by shaking, whereupon the methylene chloride was separated off and the aqueous phase was extracted with further methylene chloride. The combined methylene chloride extracts (about 75 cc) were dried over anhydrous sodium sulfate, diluted with 25 cc of ether and chromatographed over 20 g of synthetic magnesium silicate. The column was eluted in the following manner: Table I. Fraction no solvent 1 methylene chloride ether (100 ccm) (3: 1) 2 to 6 hexane hydrocarbons Ge 40 cem) + 12 1> /, acetone 7 to 16 hexane hydrocarbons (40 ccm each) -i 150 /, acetone 17 to 21 4exane hydrocarbons (40 cc each) + 20 0 /, acetone 22 to 26 hexane hydrocarbons (40 ccm each) + 25 % acetone 27 to 30 hexane hydrocarbons (40 cem each) + 50 "/, acetone Fractions 2 to 13 inclusive, which contained a total of 140 mg of dissolved substance, were combined and evaporated. The residue obtained was from acetone-Hexankohlenwa # - erstoffen and recrystallized from methylene chloride, followed by 89 mg ß 6 a-methyl-9a-fluoro- 11, 17a, 21 -trioxy- 1,4-pregnadiene -3,20 - dione -21-acetate (1-dehydro-6a-niethyl-9a-fluorohydrocortisone-21-acetate) with a melting point of 233 to 237 ° C. was obtained. The ultraviolet absorption gave the following values: A 238.5 m # t; af, 41- = 15,325. Infrared absorption in Nujol mineral oil found hydroxyl: 3430 cm- '; 21-acetoxy-20-keto: 1735, 1717 cm- '; conjugated 3-keto group: 1658 cm- '; AI, 4 double bonds: 1615, 1610 cm--; Acetate CO bond: 1270, 1239 cm- '.

The oxidation of the compound obtained with chromic anhydride in acetic acid gives 6a-.Uethyl-9a-fluoro-17a, 21 - dioxy 1,4 - pregnadiene - 3,11,20 - trione -21 - acetate (1 Dehvdro-6a-rnethyl -9a-fluorocortisone-21-acetate).

If the corresponding 6β-epimer is used instead of the 1-dehydro-6a-methyl-hydrocortisone-21-acetate given in Example 2, a, then at the end of the reaction sequence 6P-methyl-9a-fluoro-11, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-2l-acetate and its 11-keto analogs. e) 6a-methyl-9a-fluoro-llß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione A solution of 1.028 g 6a-methyl-9a-fluoro-llß, 17a, 21-trioxy- 1,4-pregnadiene-3,20-dione-21-acetate in 100 cc of methanol, through which nitrogen had been bubbled for 10 minutes, was a solution of 1.028 g of potassium bicarbonate in 5 cc of water, which had also been treated with nitrogen, added. The resulting cloudy solution was stirred for 16 hours at room temperature (about 25 ° C.) and then acidified with 0.6 cc of acetic acid in 30 cc of water. The reaction mixture was then concentrated to 20 cc under reduced pressure at 60.degree. A jelly-like mass formed, which was extracted three times with 100 cc of ethyl acetate each time. The combined extracts were washed with dilute sodium bicarbonate solution and water, then dried and evaporated to dryness, whereupon 0.898 g of 6a-methyl-9a-fluoro-ILß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione were obtained , which after recrystallization from acetone had a melting point of 248 to 255'C (with decomposition) and an optical rotation in dioxane of Ea] D = + 93 ' .

Analysis: Calculated for C "H" 0, F -. C67.33, H7.55, F4.84; found ...... C67.48, 117.61, FS, 02.

f) 6a-methyl-9a-fluoro-IIP, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-21-methanesulfonate A solution of 20 mg 6a-methyl-9a cooled to 0 to 5'C fluoro-ILß, 17a, 21-trio-xy-1,4-pregnadiene-320-dione in 10ccm pyridine, 0.2ccm methane; aionyl chloride was added. The reaction mixture was cooled to 6 ° C. for 17 hours and then introduced into 40 ccni of cold, 5% strength aqueous hydrochloric acid. The precipitated methanesulfonate was filtered off, washed with water and dried, whereupon 0.195 g of crude 6a-methyl-9a-fluoro-Ilfl, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione-21-methanesulfonate with a Melting point of 205 to 220'C (with decomposition) obtained.

g # 6a-methyl-9a-fluoro-11ß, 17a, 21-trioxy-21-iodo-1,4-pregnadiene-3,20-dione 150 mg crude 6a-methyl-9a-fluoro-liß, 17a, 21-trioxy- 1,4-pregnadiene-3,20-dione-21-methausulfonate was dissolved in 15 cc of acetone and treated with a solution of 0.5 g of sodium iodide in 5 cc of acetone. The mixture was refluxed with stirring for 15 minutes. The temperature was then reduced and the mixture was concentrated to one third of its volume under reduced pressure. Ice and water were then added, the precipitated product was filtered off and washed with water and dried, whereupon crude 6a-methyl-9a-fl-aor-left, 17a-dioxy-21-iodo-1,4-pregnadiene-3.20 -dion received. h) 6a-.Methyl-9a, 21-difluoro-11ß, 17a-dioxy-1,4-pregnadiene-3,20-dione. A solution of 0.1 g of 6a-methyl-9a-fluoro was obtained by heating to the boiling point -Ilß, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione made in 15 cc acetonitrile. After cooling to 40 ° C., the solution was protected from light and 0.1 ccm of a 500% aqueous silver fluoride solution was added with stirring. Stirring was continued for 1 hour at about 40.degree. C., then a further 0.1 ccm of silver fluoride solution was added, the mixture was stirred for 1 hour and another 0.1 ccm of silver fluoride solution was added. The mixture was then heated for a further 2 hours while stirring.

The brownish mixture obtained was filtered through a pad of diatomaceous earth and the filtrate was evaporated under reduced pressure on a bath at 50 ° C. The brown residue was extracted three times with 10 cc of warm methylene chloride each time, the extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to about 8 cc. These were filtered, evaporated and recrystallized three times from methanol and water, whereupon 6a-methyl-9a, 21-difl-uor-11 ß, 17a-dioxy-1,4-pregnadiene-3,20-dione with a melting point of 26 -9 to 270'C (with decomposition) received.

i) 6a-methyl-9a, 21-difluoro-ILß, 17a-dioxy-1,4-pregnadiene-3,20-dione from 6a-methyl-9a-fluoro-llß, 17a-21-trioxy-1,4- pregnadiene-3,20-dione-21-methanesulfonate To a solution of 145 mg of 6a-methyl-9a-fluoro-1 ß i, 17 a, 21-trioxy-1,4-pregnadien-3,20-dione-21 Methanesulfonate in 4ccm dimethylsulfoxide was added to 120 mg potassium fluoride. The resulting suspension was stirred and heated on a water bath for 16 hours. The mixture was cooled, 30 cc of water was added, the crude solid was separated off, washed with water and dried. The aqueous phase was extracted with methylene chloride and the extract was washed with water and dried. The solid was dissolved in 1 cc of acetone and added to the methyl euchloride solution. The combined solutions were chromatographed over 10 g of anhydrous synthetic magnesium silicate, the following fractions of 20 ccm each being collected: Table II Solvent fraction No. 1 to 5 hexane hydrocarbons-acetone (10 6 to 10 hexane hydrocarbons-acetone (12,5010) 11 to 15 hexane hydrocarbons-acetone (15 0 /,) 16 to 20 hexane hydrocarbons-acetone (20 o / yr 21 to 22 acetone Fractions 9 to 15 were combined and evaporated to give 54 mg of residue. After recrystallization of the residue from acetone-hexane hydrocarbons, 46 mg of 6a-methyl-9a, 21-difluoro-Ilfl, 17a-dioxy-1,4-pregnadiene-3,20-dione were obtained, which after recrystallization from acetone at 262 to 274'C (with decomposition) melted.

Of course, in this reaction sequence also 17a 21 - dioxy - 1,4,9 (11) - pregnatrien - be used dione 21-acylates, which in the 6-position a different hydrocarbon radical as the Meth - 3.20: yl included.

Claims (1)

Claim: for the preparation of 6-methyl-9a, 21-difluoro-ILSS, 17a-dioxy-1,4-pregnadiene-3,20-dione Following a procedure and, in the 1 1-Ketoanalogen characterized in that, in manner known per se 1- Dehydro-6-methylhydro- cortisone with an organic sulfonyl halide sets, the obtained organic 21-sulfonate with a Treated alkali metal iodide in AcetoD solution, the 6-methyl-ILß, 17a-dioxy-21-iodine-1,4-pregna- diene-3,20-dione with silver: fluoride converts the obtained 6 - methyl llß, 17a dioxy-21 -fluoro-1,4-pregnadiene- 3,20-dione dehydrated, the 6-methyl-17a obtained oxy-21-fluoro-1, -1,9 (11) -pregnatriene-3,20-dione with a under halide acid converts, the obtained 6-ale- thyl-9a-halogen-Ilß, 17a-dio, xy-21-fluoro-1,4-preg.na- Treated diene-3,20-dione with a weak base and the obtained 6--1 #, ethyl-9,11-oxido-17a-oxy-21- fluoro-1,4-pregnadiene-3,20-dione with hydrogen fluoride cleaves and optionally the 6-methyl- 9a, 21-difluoro-ILß, 17a-dio.xy-1,4-pregnadiene-3,20-dione treated with oxidizing agents, or that one in known manner 1-dehydro-6-methylhydrocortisone acylated, the obtained 6-Miethyl-hydrocortisone-21-acy- lat dehydrated, the 6-methyl-17a, 21-di- oxy-1,4,9 (11) -pregnatriene-3,20-dione-21-acylate with a hypohalous acid converts the obtained 6-methyl-9a-halogen-Ilß, 17a, 21-trio, xy-1,4-pregna- diene 3,20-dione-21-acylate with a weak alkali treated, the obtained 6-iMethyl-9ß, llß-oxido- 17a, 21-dioxy-1,4-pre, -nadiene-3,20-dione-21-acylate with Converts hydrogen fluoride, the ester obtained hydro- lysed, the obtained 6-methyl-9a-fluoro-llß, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione with an organ Niche sulfonyl halide converts the obtained 21-sulfonate reacts with an alkali metal iodide and the obtained 21-dead connection with an over- shot of silver fluoride or the 21-sulfonate reacts directly with potassium fluoride. Publications Considered: Act. Chem. Scand., 9, 587 (1955); Journ. Amer. Chem. Soc., 78, 2658 (1956).