NO151043B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 9-FLUORPREDNISOLON DERIVATIVES - Google Patents

Description

The present invention relates to an analogue process

way in the preparation of therapeutically active new 9-fluoroprednisolone derivatives.

9-fluoroprednisolone ( = 9ct-fluoro-113,17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione) is well known. (J. Amer. Chem. Soc.,

77, 1955, 4181). This corticoid is unsuitable as an active ingredient

part for pharmaceutical preparations for the topical treatment of inflammatory diseases as they exhibit a strong systemic effect.

It has now been found that hitherto unknown derivatives of 9-fluoroprednisolone are only weakly systemically active, but when administered topically surprisingly exhibit a strong anti-inflammatory activity that surpasses most of the active available corticoids.

The invention thus relates to an analog method

in the production of therapeutically active 9-fluoroprednisolone-

derivatives of general formula I

where denotes a group -COR where R denotes alkyl with 1-5 C atoms or phenyl and X denotes chlorine or the group -OCOR' where R<1> denotes alkyl with 2-5 C atoms or phenyl.

The analogy method according to the invention is characterized in that

a) the epoxy ring in a compound of general formula II

is opened with hydrogen fluoride, or

b) a 9-fluoro derivative of the general formula III

in which it has the previously indicated meaning, is halogenated

or remastered in the 21 position or

c) for the preparation of 9-fluoroprednisolone derivatives of general formula I in which X denotes a chlorine atom, that

an orthoester of general formula IV

in which R3 denotes a hydrogen atom, an alkyl group or a cycloalkyl group with up to 7 carbon atoms or a phenyl group and R2 denotes an alkyl group with 1-4 carbon atoms, is cleaved with trimethylsilyl chloride or triphenylmethyl chloride.

The method according to method alternative a

can be carried out under the conditions described in US patent documents 3 678 034, 3 710 671 and 3 828 083. The starting compounds for this method can be prepared under the conditions described in US patent documents 3 152 154 and in German publication 23 40 591 and 20 55 221 .

The method according to alternative b is likewise carried out under in and of itself known conditions, preferably by reacting the compound of formula III in an inert solvent containing hydrogen fluoride. Suitable solvents are, for example, ether (diethylether, diisopropylether, tetrahydrofuranpyridine) or chlorinated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane).

The procedures according to alternative b are likewise carried out under conditions known per se.

Thus, the hydroxysteroid can be esterified with acyl chlorides or acyl anhydrides in the presence of acids, such as e.g. hydrogen chloride-p-toluenesulfonic acid, trifluoroacetic acid or in the presence of bases, such as potassium carbonate, pyridine, collidine or p-dimethylaminopyridine.

A preferred method for chlorinating the compounds of general formula III consists in the 21-hydroxy group being esterified with a sulphonic acid, preferably methanesulphonic acid or p-toluenesulphonic acid, after which the sulphonic acid group is exchanged for chlorine. The esterification of the 21-hydroxy group takes place, for example, by the action of a sulphonic acid chloride in the presence of an organic base such as pyridine or in the presence of aqueous alkali on compounds of formula III. The exchange of the sulphonic acid group for a chlorine atom preferably takes place by reacting the 21-sulphonic acid ester with an alkali chloride such as lithium chloride in the presence of a polar solvent such as e.g. dimethylformamide.

The method according to alternative, c is likewise carried out under conditions known per se.

The cleavage of the ortho ester of general formula IV with trimethylsilyl fluoride, trimethylsilyl chloride or triphenylmethyl chloride preferably takes place in an inert solvent such as a dipolar aprotic solvent (dimethylformamide, N-methyl-pyrrolidone, dimethylsulfoxide, hexamethylphosphoric triamide), an ether (diethylether, diisopropylether, tetrahydrofuran, dioxane, glycoldimethylether), a chlorinated hydrocarbon (methylene chloride, chloroform, tetrachloroethane), a hydrocarbon (benzene, toluene, cyclohexane) or a mixture of these solvents.

The starting compounds for the method can be prepared in a simple way and in high yield from prednisolone, which in turn can be synthesized relatively easily from diosgenin. This means that the new compounds can be produced with relatively low costs in a total yield of approx. 15% from diosgenin.

In contrast, the synthesis of the known active corticoid from diosgenin is significantly more expensive and the total yield achieved is significantly lower (approx. 0.5 to 5%). This is due to increasing difficulties in obtaining suitable starting compounds for the corticoid synthesis in sufficient quantity, and on the basis of the high costs of the corticoid-containing legernid partial preparations not without significance.

The new compounds exhibit, as previously indicated,

with topical administration strong anti-inflammatory activity but is only weakly active with systemic administration.

The anti-inflammatory activity was determined as follows: On human skin, a hyperemia was induced in the following manner.

On the backs of male and female subjects, the stratum corneum was applied by 20 overlapping tearings with a 2 cm wide tesa film and a pronounced hyperemia was thus induced.

On the marked 4 cm 2 field within the torn area, approx. 50 mg of the ointment preparation.

In order to achieve comparable starting values, relative indications were used, as the color of the untreated skin as well as the red color of the hyperemic area differs from individual to individual.

The color value of untreated skin was determined as 100 and the marked skin as 0.

The skin color value for skin in vasoconstriction (100) was indicated through a ratio.

Weak, medium and high vasoconstriction were correspondingly indicated between 0 and 100.

In the following table, mean values derived from examinations of different samples and different areas of the back are given.

The systemic effect of the compounds was determined using the Adjuvant-Odem test.

SPF rats weighing from 130 to 150 g were injected with 0.1 ml of a 0.5% Mycobacterium butyricum suspension (available from Difko) in the right hind paw to induce inflammation. Before the injection, the rats' paw volume was measured. 24 hours after the injection, the paw volume was again measured to determine the extent of edema. Then the rats were orally administered different amounts of the test compound. After a further 24 hours, the paw volume was determined again.

From the paw volumes obtained, the amount of test compound necessary to provide a 50% reduction of the paw edema was determined in the usual way.

The results obtained are shown in the following table:

The same results are obtained when the systemic activity of the new 9-fluoroprednisolone derivatives is determined by means of the known thymolysis test or the known sodium-potassium retention test.

The new compounds are suitable in combination with the usual carriers in galenic pharmacy for the local treatment of contact dermatitis, eczema of various types, neurodermatoses, erythroderma, burns, Pruritis vulvae et ani, Rosacea, Erythematodes cutaneus, Psoriasis, Lichen ruber planus et verrucosus and similar skin diseases.

Preparation of the medicinal preparations takes place in the usual way by transferring the active ingredient with suitable additives to the desired administration form, such as e.g. solutions, lotions, ointments, creams or plasters. In the drug formulated in this way, the concentrations of active ingredient depend on the form of administration. In the case of lotions and ointments, a concentration of active ingredient of 0.001 to 1% is preferably used.

Furthermore, the new compounds, possibly in combination with common carriers and excipients, are also well suited for the production of inhalation agents, which can be used for the treatment of allergic diseases in the respiratory tract, such as e.g. bronchial asthma or rhinitis.

The following examples illustrate the invention.

Example 1

a) 500 mg of pyridine tosylate which had been evaporated to dryness twice with benzene in vacuo was placed in 500 ml of benzene and 40 ml

N,N-dimethylformamide added 5 g of 9a-fluoro-prednisolone. At a bath temperature of 130° C., 50 ml of solvent was distilled from and 6 ml of orthoacetic acid triethyl ester was added. In the course of 2.5 hours, the rest of the benzene was distilled off and after the addition of 2.4 ml of pyridine, the mixture was evaporated in vacuo. 17α,21-(1-ethoxyethylidenedioxy)-9α-fluoro-113-hydroxy-1,4-pregnadiene-3,20-dione was isolated as a yellow oily epimer mixture.

b) A solution of the thus obtained oil in 150 ml of methanol was refluxed with a mixture of 54 ml

0.1N acetic acid and 6 ml of 0.1N aqueous sodium acetate solution for 1 hour at 90° C. The mixture was evaporated to dryness, added water and extracted with ethyl acetate. The organic extract was washed with water, dried and evaporated in vacuo. Yield: 9 g of 17α-acetoxy-9α-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione as a foam.

c) 3.0 g of 17α-acetoxy-9α-fluoro-113,21-dihydroxy-1,4-preg-nadiene-3,20-dione was stirred in 17 ml of pyridine and 8 ml of propionic anhydride for 1.5 hours at room temperature . After ice water precipitation, the mixture was filtered, the residue was taken up in methylene chloride and, after washing and drying over sodium sulphate, this was evaporated. 4.9 g were isolated and chromatographed on 450 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 2.96 g of 17α-acetoxy-9ct-fluoro-lip-hydroxy-21-propionyl-oxy-1,4-pregnadiene-3,20-dione. Melting point 219° C. [a]<25 >+81° (pyridine). UV: e23g = 15100 (methanol). D

Example 2

4.5 g of 17α-acetoxy-9α-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione was stirred in 50 ml of pyridine and 25 ml of butyric anhydride overnight at room temperature. The reaction product was precipitated with ice water, filtered off and dissolved in methylene chloride. The solution was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on 700 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 3.6 g of 17α-acetoxy-21-butyryloxy-9α-fluoro-11|3-hydroxy-1,4-pregnadiene-3,20-dione. Melting point 218° C.

Example 3

1.0 g of 17α-acetoxy-9α-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione was reacted as described in example 2 with 6 ml of valeric anhydride instead of butyric anhydride in 10 ml of pyridine. Yield: 68.0 mg 17α-acetoxy-9α-fluoro-113-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Sm.p. 213°C.

Example 4

3.0 g 17α-acetoxy-9α-fluoro-113,21-dihydroxy-1,4-

pregnadiene-3,20-dione in 30 ml of pyridine was stirred with 15 ml of caproic anhydride for 1.5 hours at room temperature. The processing took place analogously to what is described in example 2. The crude product was chromatographed on 450 g of silica gel with a methylene chloride-acetone gradient (0 - 12% acetone). 2.36 g of 17a-acetoxy-9a-fluoro-21-hexanoyloxy-11fi-hydroxy-1,4-pregna-diene-3,20-dione were isolated. Sm.p. 222° C. U]25 = +82° (pyridine). UV:

e239 = 1550n (methanol).

Example 5

3.0 g of 17α-acetoxy-9α-fluoro-11[3,21-dihydroxy-1,4-pregnadiene-3,20-dione was stirred with 15 ml of trimethylacetic anhydride in 30 ml of pyridine for 48 hours at room temperature. As described in example 2, the impure product was isolated and chromatographed on 700 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 2.06 g of 17α-acetoxy-9α-fluoro-IIo-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione. Sm.p. 227° C. [<*]q<5> = +79° (pyridine). UV e239 = 15500 (methanol).

Example 6

5.0 g of 9a-fluoro-113,21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione prepared analogously to what is described in examples la and lb from orthopropionic acid triethyl ester instead of orthoacetic acid triethyl ester and 9a- fluoro-prednisolone was stirred in 50 ml of pyridine with 25 ml of propionic anhydride for 2 hours at room temperature. The preparation took place analogously to what is described in example 2. 4.8 g of impure product was chromatographed on 4 50 g of silica gel with a methylene chloride-acetone gradient (0 - 15%). Yield: 4.62 g of 9α-fluoro-113-hydroxy-17α,21-di-propionyloxy-1, 4-pregnadiene-3, 20-dione. Sm.p. 191° C. f0^^<5> = +51° (chloroform). UV: e23g = 15700 (methanol).

Example 7

5.0 g of 9a-fluoro-110,21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione was reacted analogously to what is described in example 2 with butyric anhydride. The crude product was chromatographed on 450 g silica gel with a methylene chloride-acetone gradient (0-12% acetone). 4.93 g of 21-butyryl-

oxy-9α-fluoro-113-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione. Sm.p. 179° C. fa]<25> = +51° (chloroform). UV: e23g = 15700 (methanol).

Example 8

5 g of 9α-fluoro-113,21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione was reacted with valerian anhydride instead of butyric anhydride as described in example 2. The preparation took place as described in example 2. The impure product was chromatographed on 750 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 5.03 g of 9α-fluoro-113-hydroxy-17α-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Sm.p. 190° C. [<g>Jq<5> = +54° (chloroform). UV: e23g = 15800 (chloroform).

Example 9

5.0 g of 9α-fluoro-113,21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione was reacted with caproic anhydride instead of butyric anhydride as described in example 2. The crude product of 5.8 g was chromatographed on 700 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). 4.32 g of 9α-fluoro-21-hexanoyloxy-113-hydroxy-17α-propionyl-oxy-1,4-pregnadiene-3,20-dione were isolated. Sm.p. 208° C. [c]q<5> = +52°

(chloroform). UV: e23g = 15900 (methanol).

Example 10

5.0 g of 9a-fluoro-113,21-dihydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione was, as described in example 2, reacted with trimethylacetic anhydride instead of butyric anhydride and worked up. 5.9 g of impure product was chromatographed on 450 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 2.23 g of 9α-fluoro-113-hydroxy-17α-propionyloxy-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione. Sm.p. 214°C.

[α]25 = +53° (chloroform). UV: e23g = 15700 (methanol).

Example 11

a) 25 g of 9a-fluoro-prednisolone was stirred in 250 ml of pyridine and 125 ml of butyric anhydride overnight at room temperature.

After ice water precipitation, the mixture was filtered and the residue was dissolved in methylene chloride. The solution was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed over 2.5 kg of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 23.1 g of 21-buryryloxy-9α-fluoro-113,17α-dihydroxy-1,4-pregnadiene-3,20-dione.

b) To a suspension of 24 g of copper (I) iodide in 580 ml of dry tetrahydrofuran at 0° C under an argon atmosphere was added dropwise

added 100 ml of a 5% solution of methyllithium in ether. The yellow mixture was cooled to -30°C and a solution of 22.3 g of 21-butyryloxy-9α-fluoro-113,17α-dihydroxy-1,4-pregnadiene-3,20-dione in 400 ml of dry tetrahydrofuran was added . The mixture was stirred for 3-4 hours at this temperature. Excess reagent was destroyed with an aqueous ammonium chloride solution. After extraction with methylene chloride, the organic phase was washed, dried over sodium sulfate and evaporated in vacuo. Yield: 20.3 g of 17α-butyryloxy-9α-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione.

c) 2.0 g of 17α-butyryloxy-9α-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione was reacted as described in example 1c

with propionic anhydride, worked up and purified. 1.4 g of 17α-butyryloxy-9α-fluoro-113-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione was isolated. Sm.p. 146°C.

Example 12

1.5 g of 17a-butyryloxy-9a-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione was reacted as described in example 2 with valerian anhydride instead of butyric anhydride to 17a-butyryloxy-9a-fluoro -113_hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. Sm.p. 220°C.

Example 13

a) 3 g of 9a-fluoroprednisolone were stirred in 30 ml of pyridine and 15 ml of valeric anhydride overnight at room temperature.

The mixture was then stirred into ice water and extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate and evaporated in vacuo. Excess valeric acid was removed from the residue by steam distillation. The impure product was chromatographed on 300 g of silica gel with a

methylene chloride-acetone gradient (0 - 15% acetone). Dividend:

2.87 g of 9α-fluoro-113,17α-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. b) 2 g of 9a-fluoro-113,17a-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione was rearranged as described in example 11b

with lithium dimethyl cuprate to 1.86 g of 9α-fluoro-113,21-dihydroxy-17α-valeryloxy-1,4-pregnadiene-3,20-dione.

c) 1.8 g of 9a-fluoro-113,21-dihydroxy-17a-valeryloxy-1,4-pregnadiene-3,20-dione was, as described in example 2, reacted with

propionic anhydride instead of butyric anhydride to 920 mg of 9α-fluoro-113-hydroxy-21-propionyloxy-17α-valeryloxy-1,4-pregna-diene-3,20-dione. Sm.p. 206°C.

Example 14

3.4 g of 9a-fluoro-113,21-dihydroxy-17a-valeryloxy-1,4-pregnadiene-3,20-dione was treated analogously to what is described in example 2 with butyric anhydride and worked up. 1.96 g of 21-buryryloxy-9α-fluoro-113-hydroxy-17α-vale-ryloxy-1,4-pregnadiene-3,20-dione were isolated. Sm.p. 234°C.

Example 15

3.1 g of 17a-benzoyloxy-9a-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione prepared analogously to what is described in examples la and lb from orthobenzoic acid triethyl ester instead of orthoacetic acid triethyl ester and 9a- fluoroprednisolone was stirred in 30 ml of pyridine and 15 ml of propionic anhydride for 1 hour at room temperature. The preparation took place analogously to what is described in example lc. The impure product was purified on 450 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 1.34 g of 17α-benzoyloxy-9α-fluoro-113-hydroxy-21-propionyloxy-1,4-pregnadiene-3,20-dione. Sm.p. 235° C (decomposition).

[a]<25> = +22° (pyridine). UV: e234<=><2>8800 (methanol).

Example 16

3.0 g of 17a-benzoyloxy-9a-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione was reacted in 30 ml of pyridine and 15 ml of butyric anhydride as described in example 2 and worked up. After purification of the impure product on 4 50 g silica gel with a methyl

lene chloride-acetone gradient (0-12%), 1.9 g of 17α-benzoyloxy-21-butyryloxy-9α-fluoro-113-hydroxy-1,4-pregnadiene-3,20-dione was isolated. Sm.p. 218° C (decomposition). [a]<25> = +21° (pyridine). UV: e234 = 28900 (methanol).

Example 17

2.8 g of 17α-benzoyloxy-9α-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione was, as described in example 2, reacted with valerian anhydride instead of butyric anhydride and worked up. The crude product was purified on 450 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). 1.81 g of 17α-benzoyloxy-9α-fluoro-113-hydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione were obtained. Sm.p. 208° C. [<*]<25> = +22° (pyridine). UV: e234 = 29000 (methanol).

Example 18

10 ml of hexamethylphosphoric acid triamide was stirred at 0° C. with 1.3 ml of thionyl chloride for 30 minutes. Then 800 mg of 17α-acetoxy-9α-fluoro-113,21-dihydroxy-1,4-pregna-diene-3,20-dione was added and the mixture was stirred for 5.5 hours at 0° C. The mixture was completely into ice water, extracted with acetic acid and the extract was washed neutrally with sodium bicarbonate and water. The product was dried over sodium sulphate and after evaporation in vacuo 1 g of impure product was isolated which was chromatographed on 65 g of silica gel with a methylene chloride-acetone gradient (0-15% avetone). Yield 535 mg of 17α-acetoxy-21-chloro-9α-fluoro-113-hydroxy-1,4-pregnadiene-3,20-dione. Sm.p. 265° C (decomposition). [a]^<5> = +101° (pyridine). UV: e23g = 15800 (methanol).

Example 19

1.2 g of 9a-fluoro-113,21-dinydroxy-17a-propionyloxy-1,4-pregnadiene-3,20-dione was reacted with thionyl chloride in hexamethylphosphoric acid triamide as described in example 18. The impure product was chromatographed on 150 g of silica gel with a methylene chloride-acetone gradient (0 - 15% acetone). Yield: 860 mg of 21-chloro-9α-fluoro-113-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione. Sm.p. 229° C (decomposition). U]<25> = +98° (pyridine). UV: e23g = 15900 (methanol) .

Example 2p

9 50 mg of 9a-fluoro-113,21-dihydroxy-17a-isobutyryloxy-1,4-pregnadiene-3,20-dione was treated as described in example 18 with thionyl chloride in hexamethylphosphoric acid triamide. Purification of the impure product took place with 120 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 520 mg of 21-chloro-9a-fluoro-113-hydroxy-17a-isobutyryloxy-1,4-pregnadiene-3,20-dione. Sm.p. 216°C.

Example 21

2.5 g of 17α-benzoyloxy-9α-fluoro-113,21-dihydroxy-1,4-pregnadiene-3,20-dione was reacted as described in Example 18 and the impure product was purified on 250 g of silica gel with a methylene chloride acetone gradient (0 - 12% acetone). Yield: 1.1 g of 17α-benzoyloxy-21-chloro-9α-fluoro-113-hydroxy-1,4-pregnadiene-3,20-dione. Sm.p. 256° C (decomposition). [<*]q<5> = +15° (pyridine). UV: e234 = 28600 (methanol).

Example 22

a) A suspension of 8.7 g of 21-fluoro-17α-hydroxy-1,4,9(11)-pregnatriene-3,20-dione in 100 ml of diethylene glycol dimethyl ether was

stirred with 12 g of N,N-dimethylaminopyridine and 8.8 ml of acetic anhydride for 6.5 hours at 80° C. The reaction mixture was diluted with methylene chloride and washed with 2N hydrochloric acid. After steam distillation, the product was extracted with methylene chloride, dried over sodium sulfate and isolated after evaporation, whereby 7.9 g of 17a-acetoxy-21-fluoro-1,4,9(11)-pregnatriene-3,20-dione were obtained.

b) 7.6 g of 17α-acetoxy-21-fluoro-1,4,9(11)-pregnatriene-3,29-dione was dissolved in 76 ml of dioxane and 7.2 g of N-bromosuccinimide was added. After the dropwise addition of 38 ml of 10% aqueous perchloric acid, the reaction mixture was stirred for 30 minutes at room temperature, after which the reaction solution was added to a solution of 3.5 g of sodium hydrogen sulphite in 350 ml of water. The precipitate was separated and after drying, 10 g of 17α-acetoxy-9α-bromo-21-fluoro-113-hydroxy-1,4-pregnadiene-3,20-dione were obtained. c) 10 g of the impure product specified above was boiled in 600 ml of ethanol under reflux with 14.0 g of potassium acetate for 2 hours at 110° C. The reaction solution was evaporated in vacuo and poured into ice water. The precipitate was filtered off and the impure product was purified on 700 g of silica gel with a methylene chloride-acetone gradient (0-6% acetone). Yield: 3.4 g of 17a-acetoxy-9,11g-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione. d) 31 ml of a 70% (HF)^/pyridine solution was cooled to -60° C and a solution of 3 g of 17α-acetoxy-9,113-epoxy-21-fluoro-1,4-pregnadiene- 3,20-dione in 3 ml of pyridine. The reaction solution was stirred for 10 hours at -5° C. and was then stored for 3 days in a refrigerator. The mixture was poured into ammoniacal ice water and the precipitate was filtered off. The crude product was purified on 350 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 2.15 g of 17α-acetoxy-9α,21-difluoro-113-hydroxy-1,4-pregnadiene-3,20-dione. Sm.p.

276° C (decomposition). [a]<25> = +16° (chloroform). UV: e23<g><= >15800 (methanol).

Example 23

a) Analogous to what is described in example 22a, from 7.9 g of 21-fluoro-21-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and propionic anhydride, 5 g of 21-fluoro -17a-propio-nyloxy-1,4,9(11)-pregnatriene-3,20-dione, which under the conditions described in example 22b was reacted with N-bromosuccinimide. Yield equal to 8.5 g of 9α-bromo-21-fluoro-113-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione. b) 8.5 g of the impure product indicated above was reacted with potassium acetate under the conditions described in example 22c.

The crude product was purified on 700 g of silica gel with a methylene chloride-acetone gradient (0-6% acetone). Yield: 5.3 g of 9,113-epoxy-21-fluoro-17a-prop onyloxy-1,4-pregnadiene-3,20-dione. c) In a similar way as described in example 22d, 5.0 g of 9,113-epoxy-21-fluoro-17a-propionyloxy-1,4-pregnadiene-3,20-dione was treated with a 70% (HF)n/pyridine solution . The reaction product was purified on 700 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 3.98 g of 9α,21-difluoro-113-hydroxy-17α-propionyloxy-1,4-pregnadiene-3,20-dione. Sm.p. 214° C. fa]<25> = +15° (chloroform). UV: e23g = 15800 (methanol).

Example 24

a) 20.0 g of 17a-butyryloxy-21-fluoro-1,4,9(11)-pregnatriene-3,20-dione (prepared analogously to example 22a from 21-fluoro-17a-hydroxy-1,4,9 (11)-pregnatriene-3,20-dione and butyric anhydride were treated with N-bromosuccinimide analogously to what is described in example 22b yield equal to 24.9 g of 9a-bromo-17a-butyryloxy-21-fluoro-113-hydroxy -1,4-pregnadiene-3,20-dione b) Under the conditions described in example 22c, the impure product indicated above was treated with potassium acetate. 16.1 g of 17a-butyryloxy-9,11|3-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione were isolated. c) Analogous to what is described in example 22d, 15.1 g of 17a-butyryloxy-9,113-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione was treated with 70% (HF)n/ pyridine solution. The crude product was purified on 1.5 kg of silica gel with a methylene chloride-acetone gradient (0-15% acetone). 13.4 g of 17α-butyryloxy-9α,21-difluoro-113-hydroxy-1,4-pregnadiene-3,20-dione were obtained. Smoop. 126° C. [a]23 = +11° (chloroform). UV: c 23 Q = 15300 (methanol).

Example 25

a) Analogous to what is described in example 22a, from 9.0 g of 21-fluoro-17a-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and valeric anhydride, 7.1 g of 21 -fluoro-17a-valeryloxy-1,4,9(11)-pregnatriene-3,20-dione which is analogous to what is described in example 22b was treated with N-bromosuccinimide. Yield equal to 8.7 g of 9α-bromo-21-fluoro-113-hydroxy-17α-valeryloxy-1,4-pregnadiene-3,20-dione. b) 6.0 g of the impure product specified above was reacted with potassium acetate as described in example 22c. After purification of the reaction product on 700 g of silica gel with a methylene chloride-acetone gradient (0-5% acetone), 4.2 g of 9,113-epoxy-21-fluoro-17a-valeryloxy-1,4-pregnadiene-3,20 was obtained -dion. c) As described in example 22d, by reacting 3.8 g of 9,113-epoxy-21-fluoro-17a-valeryloxy-1,4-pregnadiene-3,20-dione and a 70% (HF)n/ pyridine solution prepared 3.1 g of 9α,21-difluoro-113-hydroxy-17α-valeryloxy-1,4-pregnadiene-3,20-dione which after purification on 4 50 g of silica gel with a methylene chloride-acetone gradient (0 - 15% acetone) melted at 139°C. l0-]^ = +10° (chloroform) . UV: £- 239 = 15800 (methanol) .

Claims (1)

Analogous method for the preparation of therapeutically active 9-fluoroprednisolone derivatives of general formula I where denotes a group -COR where R denotes alkyl with 1-5 C atoms or phenyl and X denotes chlorine or the group -0C0R' where R' denotes alkyl with 2-5 C atoms or phenyl, characterized in that on i and for known manner a) the epoxy ring in a compound of general formula II is opened with hydrogen fluoride, or b) a 9-fluoro derivative of the general formula III in which it has the previously stated meaning, is halogenated or transesterified in the 21-position or c) for the production of 9 -fluoroprednisolone derivatives of general formula I in which X denotes a chlorine atom, at an orthoester of general formula IV in which R-j denotes a hydrogen atom, an alkyl group or a cycloalkyl group with up to 7 carbon atoms or a phenyl group and R 2 denotes an alkyl group with 1-4 carbon atoms, is cleaved with trimethylsilyl chloride or triphenylmethyl chloride.