NO123831B - - Google Patents

Description

Process for the production of new cortisone derivatives with high glucocorticoid activity.

The present invention relates to a process for the production of the new compounds 1-dehydro-6-methyl-9a-fluoro-hydrocortisone and 21-acylates of this compound.

The method according to the invention and the compounds involved in it can be illustrated by the reaction scheme below:

In these formulas, R denotes the acyl group in an organic carboxylic acid, preferably a hydrocarbon-carbonic acid, which contains from and including 1 to 12 carbon atoms.

As can be seen from this reaction scheme, the method according to the invention treats 6-methyl-9β, 11β-oxido-17a, 21-dihydroxy-1,4-pregnadiene-3,20-dione-21-acylate which is represented by the formula I with hydrogen fluoride or substances that split off hydrogen fluoride, whereby the physiologically active fluorine derivative 6-methyl-9a-fluoro-11(3,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione is obtained -21-acylate or the free triol 1-dehydro-6-methyl-9a-fluorohydrocortisone-21-acylate represented by formula II. Hydrolysis of this compound II with a base yields the free alcohol 6-methyl-9a -fluoro-17a, 21-dihydroxy-1,4-pregnadiene-3,11,20-trione (1-dehydro-6-methyl-9a-fluorocortisone).

With the help of the present invention, a method for the production of the new adrenocortical hormones 1-dehydro-6-methyl-9a-fluoro-hydrocortisone and the 21-esters of this compound, particularly in the 6a-epimeric form, is thus obtained. Intermediate products in this method are e.g. 6-methyl-17a,21-dihydroxy-1,4,9(11)-pregnatriene-3,20-dione-21-acylate, 6-methyl-9(11)-oxylo-17ct,21-dihydroxy-1, 4-pregnadiene-3,20-dione-21-acylate, the 9α-chloro- and 9α-bromo-6-methyl-lip,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione-21-acylates and the free alcohols thereof.

The new compound 1-dehydro-6-methyl-9a-fluoro hydrocortisone and the 21-esters, especially the 6a-epimers, thereof, are very active adrenal-cortical hormones with a glucocorticoid effect that is greater than this effect in known cortisone derivatives and greater than the effect of the natural hormones.

The table below lists the glucocorticoid (liver glycogen depot) effect of the mentioned new compounds in comparison with this effect of some known similar compounds. In the first column of the table is indicated the literature where the compounds are described, in the second column the compound's chemical constitution, and in the third column the glucocorticoid effect expressed according to a scale based on this effect of hydrocortisone, since the effect of hydrocortisone is set -- 1.

It appears from this table that substituted hydrocortisones with a stronger glucocorticoid effect than that of the hydrocortisone itself have probably been produced in the past, but that the achieved increase in this effect of the products from the previous methods is far below that observed for products from the method according to the present invention. As for J. Am. Chem. Soc. Vol. 75, 2273 (1953) it may be added that the authors (Fried et al) in the same article state that 9a-chlorocortisone acetate was found to have an activity corresponding to 3.5 times that of cortisone acetate, i.e. the increase is min -dre than for the corresponding hydrocortisone compound.

In addition, said compound has a very strong anti-inflammatory effect. They are advantageous in preparations for parenteral and local application and can be given orally in the form of

tablets in which they are combined with bin-

diluents and carriers such as polyethylene glycol with a molecular weight of 4,000 to 6,000, lactose, sucrose and the like.

Particularly advantageous for this purpose are 1-dehydro-6α-methyl-9α-fluorohydrocortisone and esters of this compound.

For local application, the compounds can be introduced into ointments, liniments, gels, creams, suppositories, "bougies", aqueous suspensions and the like. Instead of 1-dehydro-6α-methyl-9α-fluorohydrocortisone or 1-dehydro-6α-methyl-9α-fluorocortisone, the 6(3-epimers of this compound can be used in therapeutically equivalent amounts.

The starting material for the method according to the present invention is the 1-dehydro-6a-methyl-hydrocortisone ester, as will be described in the following during the preparation of preparations 1-14. Instead of 1-dehydro-6α-methylhydrocortisone, the 6|3-epimer can be used, whereby the corresponding 1-dehydro-6β-methyl-9α-fluorohydrocortisone and 1-dehydro-6(3-methyl-9α-fluorocortisone are obtained.

According to the invention, 6-methyl-9|3,11(3,oxydo-17a,21-dihydroxy-1,4-pregnadiene-3,20-dione-21-acylate is reacted with hydrogen fluoride. Solvents for this reaction can be used methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride. Of these, methylene chloride is preferred. The reaction is carried out at room temperature (20-30° C), preferably with stirring. The reaction time is from 1 to 24 hours, while a period of from 1 to 12 hours is in generality is sufficient. After the reaction is complete, the mixture is poured into water and neutralized with a dilute base such as sodium bicarbonate, potassium bicarbonate, or the like. An excess of strong bases may also be used. The reaction mixture is then extracted with a water-immiscible solvent such as methylene chloride The organic layer is separated from the aqueous mixture, washed with water, dried and evaporated, whereby 6-methyl-9a-fluoro-1l|3,17a,21-trihydroxy-1,4-pregnadiene is obtained as a crude product -3,20-dione-21-acylate This r The product can be purified by crystallization or chromatography.

The 6-methyl-9a-fluoro-11(5,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione-21-esters obtained by this method can be hydrolysed, whereby they give 6-methyl -9a-fluoro-lip,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione which is also called 1-dehydro-6-methyl-9a-fluorohydrocortisone.

In the following, preparations 1-13 indicate the preparation of starting materials used in the method according to the invention.

Preparation 1

5a, 6a- oxido- llfi, 1 7a, 21 - trihydroxy- allopregnane- 3, 20- dione-3, 20, bis-( ethylene- ketal)

A solution of 0.901 g of lip,17α,21-trihydroxy-5-pregnene-3,20-dione-3,20-bis-(ethylene ketal) in 18 ml of chloroform was added to a solution of 331 ml of perbenzoic acid in 5.19 ml of chloroform. The resulting solution was left in a refrigerator (approx. 4° C) for 24 hours and then at room temperature for a further 72 hours. The solution was then washed with a 5% solution of sodium bicarbonate in water, dried over anhydrous sodium sulfate and evaporated to dryness, whereby 1.031 g of crude product was obtained. Recrystallization from acetone gave 431 mg of material with m.p. 230-247° C. After evaporation to dryness, the mother liquor was dissolved in methylene chloride and chromatographed on 25 g of washed aluminum oxide. The column was washed with three fractions each consisting of methylene chloride plus 5, 10, 15, 20, 25 and 50 percent acetone, acetone, and acetone plus 5 percent methanol. The eluate with acetone plus 5% methanol gave 279 mg of a high melting product. The high melting product, 5α,6α-oxido-lip,17α,21-trihydroxy-allopregna-3,20-dione-3,20-bis-(ethylene ketal) was recrystallized three times from acetone and methanol, giving main a pure product with m.p. 263—268° C. Other eluate fractions with lower melting points contained the 5a, 6a-isomers of this compound.

In the same way as stated under pre-<p>arat 1, other 5a,6a-oxido-lip,17a,21-trihydroxy-allopregnan-3,20-dione-3,20-bis-(alkylene ketals) can be prepared by reaction between organic peracids such as performic acid, peracetic acid, perbenzoic acid, monoperphthalic acid and the like and hydrocortisone diketals in which the ketol group is formed by allowing the steroid-3,20-dione to react with ethylene, propylene, 1,2-1 . The 2,4, 3,5 positions. When carrying out the method according to the present invention, it is preferred to use starting materials with ethylene ketal groups as these ketals are generally easier to produce with high yield than ketals which are produced by allowing 3,20-diketo compounds to react with higher alkanediols.

Preparation 2

5a, llfi, l 7a, 21- tetrahydroxy-6- methyl- allopregnane- 3, 20- dione- 3, 20-bis-( ethylene- ketal)

A solution of 1.115 g of 5α,6α-oxido-lip,17α,21-trihydroxyallopregna-3,20-dione-3,20-bis-(ethylene ketal) in 165 ml of tetrahydrofuran (which has been dried by distillation over lithium aluminum hydride) was added dropwise to a solution of 95 ml of methyl magnesium bromide in ether (at a concentration of 4 g per 1000 g). 575 ml of benzene was added to the resulting mixture, and the reaction mixture was then heated with stirring and reflux for 26 hours. After cooling, the reaction mixture was then poured into 700 ml of ice-cooled, saturated ammonium chloride solution, the mixture was stirred for 30 minutes and the benzene layer separated from the aqueous layer. The aqueous phase was extracted with three 200 ml portions of ethyl acetate and the extracts mixed with the benzene layer. The combined benzene and ethyl acetate extracts were then washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 1.314 of crude product. After trituration of this crude product with ether, 1.064 g of crystalline substance with m.p. 221—230° C. Recrystallization of this substance gave 5α,lip,17α,21-tetrahydroxy-6β-methyl-allopregna-3,20-dione-3;20-bis-(ethylene ketal) with m.p. . 228—233° C, and optical rotation [a]n of —11° in chloroform. Found by elemental analysis: C 64.29

pst.; H 8.69 per cent.

Calculated for C.,,H42Os: C 64.7 per cent.;

H 8.77 percent."

Preparation 3

5a, llfi, l 7a, 21 - tetrahydroxy- 6fi- methyl-allopregnane- 3, 20-dione

A solution containing 468 mg of 5α,11(3,17α,21-tetrahydroxy-6β-methylallopregna-3,20-dione-3,20-bis-(ethylene ketal), 38 ml of methanol and 7.7 ml of 2 N sulfuric acid. This solution was heated under reflux for 30 minutes, and then neutralized with 5% sodium bicarbonate solution (about 100 ml). The solution was then evaporated under reduced pressure at 55° C. to a volume of about 35 ml On cooling, a substance crystallized out which was separated from the solution by filtration. This substance was recrystallized from a mixture of acetone and Skellysolve B-hexanes, whereby a pro-analysis portion 5a, lip, 17a,21-tetrahydroxy-6p was obtained -methylallopregnan-3,20-dione with melting point 240-244° C (decomposition) and optical rotation [a]0 + 40° in dioxane.

Found by elemental analysis: C 66.84

pst.; H 8.86 percent Calculated for C„H340,.: C 66.98 percent;

H 8.69 percent."

Preparation 4

6a- methylhydrocortisone

A stream of nitrogen was bubbled through a solution of 429 mg of 5α,lip,17α,21-tetrahydroxy-6β-methylallopregna-3,20-dione in 100 mL of denatured absolute alcohol over a period of 10 minutes. The solution was then added to 4.3 ml of 0.1 N sodium hydroxy solution which had likewise been treated with nitrogen. The mixture was allowed to stand in a nitrogen atmosphere for 18 hours, after which it was acidified with acetic acid and evaporated to dryness at 55° C. and reduced pressure. The residue weighed 417 mg and was recrystallized from a mixture of acetone and Skellysolve B hexanes, whereby in two portions 249 mg of 6a-methylhydrocortisone was obtained which melted between 184 and 194° C. A sample for analysis was prepared. This melted at 203-208° C and consisted of 6a-methylhydrocortisone.

Found by elemental analysis: C 70.32

pst.; H 8.50 per cent.

Calculated for C,,Hr)Or,: C 70.18 per cent.;

H 8.57 percent."

The mother liquors contained, in addition to 6α-methylhydrocortisone, significant amounts of 6β-methylhydrocortisone which can be isolated by recrystallization, paper chromatography, counter-current methods and other methods known in the art.

In the esterification of 6α-methylhydrocortisone with acetic anhydride in pyridine at

room temperature gave 6α-methylhydrocortisone-21-acetate with m.p. 213—214° C. Found by elemental analysis: C 68.60

pst.; H 8.41 per cent.

Calculated for C.4H.40H: C 68.80 percent;

H 8.19 percent."

Preparation 5

6^- methylhydrocortisone

A solution was prepared containing 27.5 g of 5α,lip,17α,21-tetrahydroxy-6β-methylallopregna-3,20-dione in 6500 ml of ethanol which had been denatured with methanol. The solution was deoxygenated by bubbling oxygen-free nitrogen through it for 15 minutes. The solution was then added to a 0.1 N NaOH solution (235 ml) which was also deoxygenated. The mixture was allowed to stand at room temperature (approx. 22-24° C) in a nitrogen atmosphere for 20 hours, after which it was acidified with 14 ml of acetic acid. The acidic solution thus obtained was evaporated at approx. 50-60° C in vacuum. The residue obtained was dissolved in 200 ml of ethyl acetate and 200 ml of water, the aqueous layer separated from the organic layer and discarded. The organic layer was washed with 350 ml of 5% aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate, after which it was evaporated to a volume of 180 ml. After cooling the 180 ml solution in a refrigerator (to approx. 5° C), the solution was filtered, whereby 11.9 g of material was obtained. This material was redissolved in 500 ml of ethyl acetate, the ethyl acetate solution evaporated to a volume of 150 ml and cooled as indicated above, whereby 6.15 g of 6p-methylhydrocortisone with m.p. 220— 223° C.

By recrystallization a further three times from ethyl acetate of 6(3-methylhydrocortisone in the form of crude product, a pro-analyser portion of 6|3-methylhydrocortisone was obtained with m.p. 223-227° C, optical rotation [a]n = +105 ° in acetone, absorption in the ultraviolet region of the spectrum

95 percent in ethanol

243 (x; aM = 14,500.

max.

Found by elemental analysis: C 70.54

pst.; H 8.91 per cent.

Calculated for C^H^O.-: C 70.17 per cent.;

H 8.57 percent."

Preparation 6

l- dehydro- 6a- methylhydrocortisone ( 6n- methyl- ll$, 17a- 21- trihydroxy- l, 4-

b pregnadiene-3, 20-dione)

6 ml portions in 250 ml Erlenmeyer flasks, of a medium containing 1 per cent glucose, 2 per cent grain casting liquid (60 per cent, solids) and tap water were adjusted to a pH value of 4.9. The medium was sterilized for 45 min. at a pressure of 1.05 kg/cm2 and inoculated with a 1-2 day culture of Sep-tomyxaaffinis A.T.C.C. 6737. The Erlenmeyer flasks were shaken at room temperature, i.e. at approx. 24° C, for a period of 3 days. At the end of this period, the whole, i.e. 600 ml, was used as an inoculation medium for 10 1 of the same glucose-grain casting liquid medium which also contained 10 ml of an anti-foaming agent (a mixture of tallow oil ("lard oil") and octadeca- nol. The culture container was placed in a water bath, its temperature set at 28° C. It was stirred with an agitator speed of 300 revolutions per minute and aerated (0.5 1 air per 10 liters of medium). After 17 hours of incubation good growth had developed, and the acidity had risen to a pH value of 6.7. 2 g of 6a-methylhydrocortisone and 1 g of 3-ketobisnor-4-cholen-22-al dissolved in 115 ml were then added dimethylformamide, and the incubation was carried out at

same temperature and with the same aeration for 24 hours (final pH value 7.9). The mycelium (weight 56 g in the dry state) was filtered off, and the steroid material was extracted with methylene chloride, the extracts evaporated to dryness and the residue obtained chromatographed in a column of synthetic magnesium silicate (Florisil). The column was packed with 200 g of Florisil and eluted with five 400 ml portions of methylene chloride, mixtures of Skellysolve B and acetone in the ratios 9:1, 8:2, 7:3 and 1:1, as well as methanol. The fraction eluted with the mixture of Skellysolve B and acetone in the ratio 7:3 gave a product weighing 1.545 g and, by recrystallization from acetone in three portions, gave 928 mg of product with m.p. 210—235° C. A sample prepared for analysis melted at 245—247° C. The rotatability [a]i, was +83° in dioxane.

Found by elemental analysis: C 70.53

pst.; H 7.54 per cent.

Calculated for C.,,H.l(,0,: C 70.53 per cent.;

H 7.94 percent."

One

243, f. = 14.875

max.

Absorption in the infrared region of the spectrum, suspended in "Nujol" mineral oil:

Instead of fermentative dehydration, 1-dehydro-6a-methylhydrocortisone or esters of this compound can be obtained by dehydration of 6a-methylhydrocortisone or esters of the same with selenium dioxide as shown below under Preparation 7.

Preparation 7

1- dehydro- 6a- methyl hydrocortisone acetate

A mixture of 70 mg of 6α-methylhydrocortisone acetate in 4.5 ml of t-butyl alcohol, 0.45 ml of acetic acid and 24 mg of selenium dioxide was heated to 75° C. for 24 hours with stirring. A further 24 mg portion of selenium dioxide was then added, reheated to 75° C and the stirring continued. The mixture was then cooled, filtered to remove the selenium dioxide, and the filtrate evaporated. Paper chromatography showed that the residue contained 50-55 percent 1-dehydro-6a-methylhydrocortisone acetate which can be isolated from the residue by recrystallization and chromatography.

Adsorption in the infrared region of the spectrum with the compound suspended in "Nu-j ol" mineral oil:

Preparation 8 1 - dehydro-6n-methylhydrocortisone By proceeding in the manner shown under preparation 6, fermentation with Sep-tomyxa affinis in a nutrient medium with crude lip,21-dihydroxy-4,17(20)-pregnadiene-3 -on as promoter 6β-methylhydrocortisone the compound 1-dehydro-6β-methylhydrocortisone.

Preparation 9

1- dehydro- 6a- methyl hydrocortisone acetate

A mixture of 1-dehydro-6a-methylhydrocortisone was prepared in 5 ml of pyridine and 5 ml of acetic anhydride. The mixture was kept at room temperature (22-24° C) for a period of 6 hours and then kept in 100 ml of ice water. The aqueous mixture thus obtained was extracted with three 25 ml portions of methylene chloride. The methylene chloride extracts were combined, washed, dried over sodium sulfate and evaporated. The residue thus obtained was recrystallized three times from a mixture of acetone and "Skellysolve B" hexanes, whereby pure 1-dehydro-6a-methylhydrocortisone-21-acetate (6-methyl-lip,17a-dihydroxy-21-acetoxy -1,4-pregnadiene-3,20-dione).

Preparation 10

The method indicated under preparation 9 was used during treatment in pyridine solution, whereby: a) 1-dehydro-6a-methylhydrocortisone with propionic anhydride gave 1-dehydro-6a-methylhydrocortisone-21-propionate. b) 1-dehydro-6α-methylhydrocortisone with butyric anhydride gave 1-dehydro-6α-methylhydrocortisone-21-butyrate. c) 1-dehydro-6α-methylhydrocortisone with valeric anhydride gave 1-dehydro-6α-methylhydrocortisone-21-valerate. d) 1-dehydro-6α-methylhydrocortisone with hexanoyl bromide gave 1-dehydro-6α-methylhydrocortisone-21-hexanoate. e) 1-dehydro-6a-methylhydrocortisone with octanoyl chloride gave 1-dehydro-6a-methyl-1hydrocortisone-21-octanoate. f) 1-dehydro-6α-methylhydrocortisone with benzoyl chloride gave 1-dehydro-6α-methylhydrocortisone-21-benzoate. g) 1-dehydro-6α-methylhydrocortisone with phenylacetyl chloride gave 1-dehydro-6α-methylhydrocortisone-21-phenylacetate.

Preparation 11

6a- methyl- 17a- 21- dihydroxy-l, 4, 9 (11) -

pregnatriene-3, 20-dione-21-acetate

A solution of 550 mg of 6α-methyl-lip, 17α,21-trihydroxy-1,4-pregnadiene-3,20-dione-21-acetate (1-dehydro-6α-methylhydrocortisone-21-acetate) in 15 ml of pyridine was in a nitrogen atmosphere added 225 mg of N-bromoacetamide. After standing in a nitrogen atmosphere at room temperature for 30 minutes, the reaction solution was cooled to 10-15° C, and sulfur dioxide gas was passed over the surface of the solution while shaking until the solution did not stain acidified iodine starch paper. During the introduction of sulfur dioxide gas, the reaction mixture became hot. The temperature was kept below 30° C by cooling from the outside and by varying the conductivity of sulfur dioxide. After standing at room temperature for 15 minutes, the reaction mixture was poured into 30 ml of ice water and the gummy precipitate obtained was extracted with 50 ml of ether. The ether extract was washed with 5% hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness, whereby 371 mg of material was obtained. This material was recrystallized from a mixture of acetone and "Skellysolve B" hexanes, whereby 318 mg of 6α-methyl-17α,21-dihydroxy-1,4,9(11)-pregnatriene-3,20-dione-21 was obtained -acetate with melting point 188-191.5° C.

Preparation 12

6a- methyl- 9a- bromo- llfi, 17a, 21-trihydroxy- 1, 4- pregnadiene- 3, 20- dione-21- acetate (l- dehydro- 6a- methyl- 9a- bromo-hydrocortisone- 21 - acetate)

A solution of 332 mg of 6α-methyl-17α,21-dihydroxy-1,4,9(11)-pregnatriene-3,20-dione-21-acetate in 5 ml of methylene chloride and 9.9 ml of t-butyl alcohol was added a solution of 0.83 ml of 72% perchloric acid in 5.8 ml of water, and then a solution of 142 mg of N-bromoacetamide in 2.5 ml of t-butyl alcohol. After the reaction mixture had been stirred for 15 minutes, a solution of 142 mg of sodium sulphite in 7 ml of water was added, after which it was evaporated to a volume of approx. 25 ml under reduced pressure and at approx. 60° C. This started the crystallization. The concentrate was cooled in an ice bath with stirring, and 35 ml of water was added. After stirring for 20 minutes, the crystalline product was isolated by filtration. The crystals were washed with water and dried in the air, whereby 406 mg of 6α-methyl-9α-bromo-11 (3,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione-21-acetate (1 -dehydro-6a-methyl-9a-bromohydrocortisone-21-acetate with melting point 173-177° C (under decomposition).

Preparation 13

6a- methyl- 9fi, llif- oxido- 17a- 21-dihydroxy- 1, 4- pregnadiene- 3, 20- dione-21- acetate

A solution of 406 mg of 6α-methyl-9α-bromo-lip,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione-21-acetate in 15 ml of acetone was added to 406 mg of potassium acetate, and the re- starved suspension was heated under reflux for 18 h. The mixture was then evaporated to a volume of 5 ml on a water bath, after which 10 ml of water was added. This caused the potassium acetate to dissolve and the steroid product to crystallize out. The product was filtered off and recrystallized from acetone, whereby 232 mg of 6a-methyl-9p,1ip-oxido-17a,21-dihydroxy-1,4-pregnadiene-3,20-dione-acetate was obtained in two portions with a melting point of 255 — 263°C.

In the following, some embodiments of the method according to the invention are described as examples.

Example 1

6a- methyl- 9a- fluoro- ll$, l 7a, 21 - trihydroxyl- 1, 4- pregnadiene- 3, 20- dione- 21-acetate ( l- dehydro- 6a- methyl- 9a- fluoro-hydrocortisone-21- acetate)

A solution of 230 mg of 6(i-methyl-9β,1β-oxido-17α,21-dihydroxy-1,4-propegna-diene-3,20-dione-21-acetate in 5 ml of methylene chloride was added 1, 2 ml of a 48% solution of hydrogen fluoride. The two-phase mixture was stirred for 20 hours, then diluted with 15 ml of methylene chloride and carefully poured into 40 ml of water containing 4 g of sodium bicarbonate. After shaking to neutralize the excess of hydrogen fluoride, the methylene chloride was separated and the aqueous phase was extracted with a further amount of methylene chloride. The mixed methylene chloride extracts (about 75 ml) were dried over anhydrous sodium sulfate, diluted with 25 ml of ether and chromatographed in 20 g of synthetic magnesium silicate (Florisil). .The column was eluted as follows:

Fractions 2 to 13 containing a total of 140 mg were combined and evaporated. The residue thus obtained was recrystallized from a mixture of acetone and "Skellysolve B" hexanes, as well as from methyl chloride, whereby 89 mg of 6a-methyl-9a-fluoro-1ip,17a,21-trihydroxy-1 was obtained, 4-pregnadiene-3,20-dione-21-acetate (1-dehydro-6a-methyl-9a-fluorohydrocortisone-21-acetate) with a melting point of 233—237° C. The absorption in the ultraviolet region of the spectrum was as follows: l 238.5 mu .; aM = 15.325. The absorption in the infrared region of the spectrum measured in 'Nujob mineral oil was as follows: hydroxyl, 3430 cm-i; 21-acetoxy-20-keto, 1735, 1717 cm-i; conjugated 3-keto group, 1658 cm-i, A14 double bonds, 1615, 1610 cm-i; acetate C-O bond, 1270, 1239 cm-i.

With the method stated in example 1, but using the corresponding 6p-isomers, 6p-methyl-9a-fluoro-lip,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione-21-acetate is obtained , 6p-methyl-9a-fluoro-17a,21-dihydroxy-1,4-pregnadien-3,11,20-trione-21-acetate, 6p,methyl-9a-fluoro-lip,17a,21-trihydroxy- 4-pregnene-3,20-dione-21-acetate and 6β-methyl-9α-fluoro-17«, 21 -dihydroxy-4-pregnene-3,1 1,20-trione-21-acetate.

When, instead of the acetates as starting material, other esters such as e.g. the propionate, butyrate, isobutyrate, valerate, benzoate, hexanoate, heptanoate, octanoate, phenylacetate, phenylpro-

the pionate, laureate or similar, of 6a-

or 6p-methylhydrocortisone or 1-dehydro-6a- or 6p-methylhydrocortisone, one obtains the corresponding esters 6a- or 6p-methyl-9a-fluoro-hydrocortisone or of 1-dehydro-6a-methyl-9a-fluoro-hydrocortisone and

-cortisone.

Example 2

6a- methyl- 9a- fluoro- llfi, 17a, 21- trihydroxyl- 1, 4- pregnadiene- 3, 20-dione ( 1-dehydro- 6a- methyl- 9a- fluorohydro-

cortisone)

100 mg 6a-methyl-9a-fluoro-lip,17a,21-trihydroxy-1,4-pr egnadiene-3,20-dione -

21-acetate was dissolved in a mixture of 2 ml of methanol and 0.1 ml of water which had previously been deoxygenated by passing nitrogen through it. The solution was

put 50 mg of potassium carbonate. It was then left to stand at room temperature for 6 hours in a nitrogen atmosphere, after which it was neutralized

special with 5 percent aqueous hydrochloric acid. The solution was then diluted with 5 ml of water and cooled. The mixture was then recrystallized from a mixture of acetone and "Skellysolve B" hexanes, whereby pure 6α-methyl-9α-fluoro-lip, 17α, 21-trihydroxy-1,4-pregnadiene-3,20-dione-( 1-dehydro-6α-methyl-9α-fluorohydrocor-

thison).

Example 3.

9a-methyl-9a-fluoro-l 7a,21-dihydroxy-l,4-pregnadien-3,ll,20-trione-(l-dehydro-6a-methyl-9a-fluorocortisone).

In the manner indicated in example 2, hydrolysis of 6a-methyl-9a-fluoro-

17a, 21-dihydroxy-1,4-pregnadiene-3,11,20-trione-21-acetate with potassium hydroxide in methanol 6a-methyl-9a-fluoro-17a,21-di-hy droxy -1,4.- pregnadiene - 3,11,2 0 -trione-U-dehydro-ea-methyl-ga-fluorocortisone).

Example 4.

6a- methyl- 9a- fluoro- llfi, 17a, 21- trihydroxy- 4- pregnene- 3, 20-dione-( 6a-methyl- 9a- fluoro- hydrocortisone).

In the manner indicated in example 2, 6α-methyl-9α-fluoro-lip,17α,21-trihydroxy-4-pregnene-3,20-dione-21-

acetate with sodium hydroxide under a nitrogen atmosphere to give 6α-methyl-9α-fluoro-lip,

17a, 21-trihydroxy-4-pregnene-3,20-dione-(6a-methyl-9a-fluoro-hydrocortisone).

Example 5.

6a- methyl- 9a- fluoro- 17a, 21- dihydroxy- 4- pregnene- 3, 11, 20- trione-( 6a- methyl- 9a- fluorocortisone).

In the manner indicated in example 2, hydrolysis of 6a-methyl-9a-fluoro-

: 17a, 21-dihydroxy-4-pregnene-3,11,20-,trione-21-acetate with sodium carbonate; dissolved in ethanol, and in a nitrogen atmosphere ,6α-methyl-9α-fluoro-17α,21-dihydroxy-4-pregnene-3,20-dione-(6α-methyl-9α-fluoro-; cortisone).

: In the treatment of 1-dehydro-6-methyl-9a-halo-hydrocortisones and -corti-; zones in which the halogen atom is chlorine, bromine is iodine, with an acylating agent consisting of halides or anhydrides of I organic carboxylic acids, in particular of coal-hydrogen-substance carboxylic acids with f.o.m. 1 to 12

'carbon atoms in the molecule, preferably at ! room temperature in pyridine solution, the corresponding 21-esters of 1-dehydro-6-methyl-9a-halohydrocortisone and 1-dehydro-6-methyl-9a-halocortisone are obtained. The starting materials 1-dehydro-6-methyl-9a-halohydrocortisones and -cortisones in which the halogen is chlorine, bromine or iodine can be prepared by known methods such as, for example by letting 6-methyl-17a,21-! the dihydroxy-1,4,9 (11)-pregnatriene-3,20-jdione-21-ester (from preparation 11) react with N-bromo-, N-chloro- or N-iodosuccini-

Imid in the presence of an acid as shown

: under preparation 12, whereby it is obtained [corresponding to 6a, methyl-9a-halo-lip, 17a,

. 21 - trihy dr oxy -1,4 -pregnadiene -3,20 - idion-21-ester. By mild hydrolysis un-

Under acidic conditions with sulfuric acid at room temperature, the corresponding free triol 1-dehydro-6a-methyl-9a-halo-hydrocortisone is obtained.

Claims (1)

Process for the production of compounds with a high glucocorticoid effect, namely 1-dehydro-6-methyl-9a-fluorohydrocortisone and 21-acylates of this compound, characterized by treating a corresponding 6-methyl-9p . with hydrogen fluoride, whereby one obtains l-dehydro-6-methyl-9a-fluoro- hydrocortisone-21-acylate, which. optionally hydrolyzed with a base, whereby 1-dehydro-6a-methyl-9a-fluoro-hydrocortisone is obtained.