DE1063165B - Process for the preparation of 6-methyl-9alpha, 21-difluoro-11beta, 17alpha-dioxy-4-pre20-dione - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY KL. 12 O 25/05

# INTERNAT. Class C 07 C.

PATENT OFFICE

EXPLAINING PUBLICATION 1063165

U 4782 IVb / 12 ο

REGISTRATION DAYi 9 SEPTEMBER 1957

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EXPLORATION PAPER: AUGUST 13, 19 5 9

The present invention relates to a process for the preparation of 6-methyl-9a, 21-difhiorll / ?, 17a-dioxy-4-pregnen-3,20-dione and 6-methyl-9a, 21-difluoro-17a-oxy-4-pregnen-3, ll, 20-trione.

The new compounds and the process for their Production are represented by the following formula:

CH ₂ OH

Method of manufacture

of ö-methyl-iia ^ -difluor-11 β, 17a-dioxy-

4-pregnen-3,20-dione

CH,

C = O

OH

CH,

Applicant:

The Upjohn Company, Kalamazoo, Mich. (V. St. A.)

Representative:

Dr. W. Beil and A. Hoeppener, lawyers, Frankiurt / M.-Höchst, Antoniterstr. 36

Claimed priority:

_ao V. St. v. America September 10, November 23, 1956, and March 6, 1957

Q =

CH,

CH ₂ OSO ₂ R

C = O

Frank Harris Lincoln Jr., William Paul Schneider and George Basil Spero, Kalamazoo, Mich. (V. St. A.),

have been named as inventors

HO

O = -

CH ₂ I.
C = O

c-OH

CH,

OH

CH,

909 607/430

CH

CH,

CH ₂ F

I.
C = O

“JL.-0H

CH,

CH.F

CH.

UP ₃ |, -

VI

CH _n

CH ₂ F

C = O

CH ₃ |

HO

CHJ ...

OH

VIII

CH,

O =!

CH,

CH _a

CH,

CH ₂ F

C = O - OH

VII

o = l

OH

IX

CH _a

The new product VIII can also be produced by modifying the process in the following series of stages:

CH

CH ₂ OAc

C = O

3 I.

HIGH,

CH,

CH _S

CH ₂ OAc

C = 3 I OH

O = ¹

XI

CH,

CH _x

CH ₂ OAc

HO -

XII

XIII

XV

HO

CH,

XIV

HO

CH ₁

CH.OSO..R

C = O

CH,

OH

XVI

HO

* k-- OH

XVII

HO

CH,

CH ₂ F

C = O
CH ₃ L .... _OH

in which X is a halogen with an atomic number between and 35 including, R represents an organic radical such as methyl, ethyl, phenyl, tolyl, naphthyl, etc., is, with methyl being preferred, and Ac the acyl radical ■ of an organic carboxylic acid, preferably one Hydrocarbyl carboxylic acid from 1 to inclusive Represents carbon atoms.

The new process represented by the series of formulas I to IX consists in that 6-methyl-l Iß, 17a-21-trioxy-4-pregnen-3,20-dione (6-Me-

thylhydrocortisone of the formula) with an organic sulfonyl halide, to the corresponding 21-ester, a 21-alkyl- or 21-arylsulfonate, the resulting 21-alkyl- or 21-arylsulfonate of 6-methyl-II / 9.17a, 21 -trioxy-4-pregnen-3,20-dione of the formula II with an alkali metal] odide, such as sodium iodide in acetone solution, to o-methyl-ll ^ lVa-clioxy ^ l-iodine- ^ pregiien-S.aO-dione (Formula III), this reacts with silver fluoride, preferably in acetonitrile solution, to 6-methyl-II / ?, 17ct-dioxy-21- £ luor-4-pregnen-3,20-dione (IV), with 6-methyl-11 ^ 3,17 a-dioxy-21 -fluor ^ -pregnen-S ^ O-dione can also be obtained by reacting the sulfonate (II) with potassium fluoride, the 6-methylll / ?, 17a-dioxy-21-nuor- 4-pregnen-3,20-dione, e.g. B. with Tliionylchlorid or preferably with an N-halo acid amide or imide and then with anhydrous Schwcfcldioxj'd to the corresponding 6-methyl-17a-oxy-21-fluoro-4,9 (II) -pregnadiene-3,20-dione (V) reacts, the resulting product with a hypohalic acid, z. B. with hypochlorous or hypobromous acid to the corresponding 6-methyl-9a-halo-II / 3,17a-dioxy-21-fluoro-4-pregnen-3,20-dione (formula VI) and this with a weak base, e.g. B. with sodium or potassium acetate, to the corresponding o-methyl-9 / 3,11 ß-oxido-l 7a-oxy-21-fluoro-4-pregnen-3,20-dione (formula VII), this oxido compound with hydrogen fluoride to 6-methyl-9a, 21-difluoro-II / S, 17a-dioxy-4-pregnen-3,20-dione (formula VIII) and optionally the resulting product with chromic anhydride or with a dichromate or with other oxidizing agents oxidized to 6-methyl-9a, 21-difluoro-17a-oxy-4-pregnen-3, ll, 20-trione (formula IX).

In the modification of the first optional process, the fluorination steps performed in reverse order, d. that is, the 9ct-fluoro group in the 6-methylhydrocortisone ester is added first and then the 21 hydroxyl group is replaced by fluorine. This method comprises the following stages: dehydration of an o-methylhydrocortisone ^ l-acylates with thionyl chloride or with an N-halo acid amide or imide and then with anhydrous sulfur dioxide to form 6-methyl-17a, 21-dioxy-4,9 (U) -pregnadiene-3,20-dione-21-acylate (Formula XI); Implementation of the product obtained with a hypohalic acid, e.g. B. with hypochlorous or hypobromous acid, to the corresponding 6-methyl-9a-halogen-II / 3.17a, 21 -trioxy ^ -pregnen-S ^ O-dione-21-acylate (Formula XII); Reaction of the product obtained with a base, e.g. B. with anhydrous potassium or Sodium acetate, to the corresponding epoxy compound, i.e. to ß

4-pregnen-3,20-dione-21-acylate (Formula XIII); implementation of the product obtained with hydrogen fluoride to the corresponding 6-methyl-9a-fluoro-11 ^, 17a, 21-trioxy-4-pregnen-3,20-dione-21-acylate (Formula XIV); Hydrolysis of this ester by the usual method with a base, preferably in a nitrogen atmosphere, to give the corresponding triol, d. H. to 6-methyl-9a-fhiorhydrocortisone (Formula XV); Implementation of the resulting o-methyl ^ e-fluorohydrocortisone with an organic one

ίο sulfonyl halide, to the corresponding 21-sulfonate of o-methyl ^ a-fluorohydrocortisone (formula XVI); Implementation of the obtained o-methyl ^ a-fluorohydrocortisone sulfonate (formula XVl) with sodium iodide in acetone solution to 6-methyl-9 a-fluoro-11 ß, 17 a-dioxy-21-j od-4-pregnen-3,20-dione (Formula XVII) and the reaction of the 21-iodine compound (XVII) obtained with an excess of silver fluoride, preferably in acetonitrile solution, to 6-methyl-9a, 21-difluoro-11β , l 7a-dioxy-4-pregnen-3, 20-dione (Formula VIII). If the sulfonate of the formula XVI, as shown in Example 3a, is treated with chimney fluoride, 6-methyl-9a-21-difluoro-11 / 3,17adioxy-4-pregnen-3,20-dione (formula VIII) is also obtained .

The new 6-methyl-9 a, 21-difluoro-11 ß, l 7 a-dioxy-4-pregnen-3,20-dione and the 6-methyl-9a, 21-difluoro-17a-oxy-4-pregncn -3, ll, 20-trione have a high physiological, in particular glucocorticoid, effect that is several times greater than that of hydrocortisone or cortisone. Furthermore, they do not cause salt retention, but rather have pronounced diuretic properties. The new synthetic corticosteroid hormones also have a strong anti-inflammatory effect and are therefore suitable for the treatment of joint inflammation, in particular in those cases in which chronic congestive heart defects, nephrotic syndromes and other circulatory disorders are present at the same time. The connections can e.g. B. be administered in the form of oral preparations and tablets. The new 6a-methyl-9a, 21-difluor-II / ?, 17a-dioxy-4-pregnen-3,20-dione, which is also available locally in the form of ointments, lotions, jellies, creams, suppositories, bougies, is particularly valuable , aqueous suspensions, etc. can be administered.

The superior anti-inflammatory effectiveness of the substances that can be prepared according to the invention is demonstrated by the following comparison tests. The comparative substance used was the 9,21-difluoro-1 1 / 9,17 a-dioxy-4-pregnen-3,20-dione corresponding to the compounds obtainable according to the method but unsubstituted in the 6-position, as well as the standard compound for anti-inflammatory compounds and glucocorticoids. Effect applied hydrocortisone used. The effect of hydrocortisone was assumed to be 1.

Anti-inflammatory effectiveness, determined by 9,21-difluoro-llj ?,
] .7a-dioxy-4-prcgnen-
3,20-dione Hydrocortisone 6a-methyl-9a,
21-difluor-l Iß,
17a-di oxy-4-pregncn-
3,20-dione a) the granuloma test
[Andre - Robert and coworkers, Acta Endocrino-
logica, 25, 105 (1957)]
b) the. Liver Glycogen Deposition Test
[Stafford et al., Proc. Soc. Exp. Biol. And
Med., 89, 371 (19SS)] 1.5
0.9 1.0
1.0 21.0
18.0

To carry out the process according to the invention, the steroid is used with the alkyl or aryl sulfonyl will6-methylhydrocortisone, 6-Μετ1ψ-1-11 / ?, 17α, 21-ίπ halide in solution, e.g. in pyridine, benzene, toluene oxy-4-pregnen-3,20-dione, (I) dissolved in a known manner with or the like, at a temperature between -10 and treated with an acid halide of a sulfonic acid. + 30 ° Cum, provided that at the lower Tem-Nach In the preferred embodiment of this invention, the solvent has not yet solidified. the

9 10

The reaction time is generally from 30 minutes to an excess of 6, e.g. B. in an amount of 10 molar equivalents, or 8 hours. At the end of this time, you will preferably be the only solvent for the tene o-methyl-lljS. ^ a ^ l-trioxy-'l-pregnen-S ^ O-dione reaction, which is generally carried out under anhydrous 21-alkyl or aryl sulfonate, takes place according to a customary Ver conditions, so that preferably less than drive, e.g. B. by evaporation of the solvent until 0.1 molar equivalent of water is present per mole of steroid. a dry residue precipitates out, or by extraction. Large amounts of water reduce the yield, of the substance from an aqueous solution by means of suitable The reaction temperature is between -40 and Extraction mjttcl won. After removing it to +70 "C, the lower limit being the solubility Extraction used by the distillation of the reaction substance and by the nature of the solvent tion remains the crude o-methyl-ll / J.na ^ l-trioxy- ^ preg- io solvent and the upper limit by the amount of nen-3,20-dione-21 ^ alkyl or aryl sulfonate (II) back. Side reactions are determined to be normally any

The Steroidsilfonatester can unpurified further conversion of halogen compounds at higher Temwendet will. accompany temperatures. Generally one works at

By converting the 21-alkyl or 21-aryl sulfonate to room temperature. The reaction time is usually 5 minutes to 3 hours with sodium or potassium iodide in a dialkyl ketone. At higher temperatures solution, z. B. in acetone, one obtains the corresponding (above 30 ° C) short reaction times to obtain 21-iodine compound. A complete implementation is used for this implementation.
expediently a molar excess of sodium iodide The resulting ö-methyl-lljS. ^ a-dioxy ^ l-fluorine

(3 to 20 moles of sodium iodide per mole of steroid). The reaction 4-pregnen-3,20-dione-II /? - hypohalogenite is then, as described above, mixture of the 6-methyl-1 1β , 17 a, 21-trioxy-4-preg- ao described above, with anhydrous Sulfur dioxide nen-3,20-d'ion-21-alkyl- or -21 -arylsulfonat and Na- treated in the presence of an organic base. The triumiodine in acetone is anhydrous low-carbon dioxide for 3 or 4 minutes to ^{1 and} ₂ hours and can be heated in gaseous or refluxing form and the 6-methyl-liquid formed is present or formed in situ, such as 11 / ?, 17a-dioxy-21-iodine -4-pregncn-3,20-dione then by z. B. by an Alkahmetallliyposulnt. The reaction evaporation of the solvent is isolated. It is not necessary, the temperature is between -40 and + 70 ° C, the preferred product for the subsequent conversion is carefully at room temperature. Purify the 6-methylz \ i obtained. 17a-oxy-21-nuor-4,9 (II) -pregnadien-3,20-dione is used according to

The crude o-methyl-II / S. ^ a-dioxy ^ l-iodine ^ -pregnen- a customary process, for example by extraction according to 3,20-dione, is then introduced into a suitable solvent in the reaction mixture in a container with silver fluoride with the exclusion of light and stirring with an excess of water isolated from the reaction mixture. A 50% aqueous solution is preferably used. Suitable organic silver fluoride solution with water is used for the extraction, at least 2 mol of silver fluoride immiscible solvents being used. The extracts ic mol steroid for obtaining the theoretical amount are appropriately washed, dried and then necessary. The reaction is usually carried out with evaporated, after which the crude 6-methyl-17a-oxyr 40 to 60 ¹¹ C, but also lower or 35 21 -fhior-4,9 (II) -pregnadiene-3,20-dione ( V) obtained after higher temperatures, ie between 10 and about 75 ^C C, a conventional process, for. B. effective by recrystallization. The silver fluoride is purified in parts within, or chromatography,
added at a certain time. The reaction time The 6-methyl-17a-oxy-21-fluoro-4,9 (ll) - thus obtained

Usually takes ¹ _{hour 2} to 6 hours. The product is pregnadiene-3,20-dione is conveniently isolated in an orgada by evaporating off the solvent. Pregnen-butyl alcohol, dioxane, tertiary amyl alcohol or the like, 3,20-dione (IV) dissolved with a suitable solvent and under-extracted at room temperature with a. The cleaning is carried out according to the usual bromine or hypochlorous acids. Means in driving, e.g. B. implemented by extraction, recrystallization or the presence of an acid. Such means are through chromatography. 45 N-bromoacetamide, N-chloroacetamide, N-bromosuccinimide

The 6-methyl-l 1 ^ 8,17a-dioxy-21-fluoro- or the like obtained in this way in the presence of water and an acid. the 4-prcgnen-3,20-dione is usually used at room temperature, known procedures, e.g. B. by dehydrating agents, but lower or higher temperatures can also be used by pyrolysis as used in the USA patents.

2,640,838 \ md 2,640,839, or by 5 <> The subhalogenous acid donor is converted in a similar process to o-methyl ^ l-l-fluoro- ^ a-oxy- in a molar ratio of 1: 1 or in one slightly increased, 4.9 (1 l) -pregnadiene-3,20-dione dehydrated. After a z. B. increased by 25 ⁰ I ₀ , amount used per mole of steroid. Embodiment of this invention is the dehydration A large excess is effective, but undesirable, tization by reacting the 11/8 oxy compound with since the excess hypohalic acid tends to react with an N-halo acid amide or imide, in which the 55 other positions to react in the molecule. The reactive halogen is preferably chlorine or bromine, in an organization time can vary between about 4 to 5 minutes and niche base and by subsequent treatment of 1 hour. After the reaction time has elapsed, the 11-hypohalite formed as an intermediate product is replaced by the excess hypohalic acid with dry sulfur dioxide in an organic base. Addition of sodium sulphate or other sulphites or

In particular, N-chloroacetamide is used; ⁶⁰ hydrosulfites are destroyed. The resulting 6-methyl-N-bromoacetamide, N-chlorosuccinimide, N-bromosuccinimide, 9a-halogen-II / ?, 17a-dioxy-21-fluoro-4-pregnen-3,20-dione, N-iodosuccinimide or S-bromine -S ^ -dimethylhydantojn, (VI), in which the halogen atom has an atomic weight between Usually used, based on the starting 33 and 130, is thereby isolated from the reaction mixture used 11/3 oxy-steroid, one above the molar equiva- that this is an excess of water lent amount. In the preparation ⁶ 5 are added as bases and the compound is used with organic solutions of the 11-hypohalites, tertiary amines, extracted in a medium or the precipitated compound of the amine nitrogen, a member of an aromatic compound, is obtained by filtration. The obtained raw ring is, or lower fatty acid amides. Preferably product can be made from organic solvents, e.g. B. from one uses the base, based on the starting point acetone, Hcxan hydrocarbons (known under the turned 11/3 oxy-steroid, in a large molar? O trade name Skellysolyc B) or the like. Recrystallized

11 12

are, and you get pure 6-methyl-9 α-halogen- These esters (formula X), which according to the usual esterification

II / 3,17a-dioxy-21-fluoro-4-pregnen-3,20-dione. manufacturing processes are, as in the case of

By oxidation of the 6-methyl-9a-halogen-l 1 / 9,17a-di- bond I shown to o-methyl- ^ a-oxy ^ l-acyloxy-

oxy-21-fluoro-4-pregnen-3,20-dione dehydrated with chromic acid ent-4,9 (II) -pregnadiene-3,20-dione (IX) ". This

if the corresponding, pharmaceutically active 6-methyl-5 compound XI is shown in the series V to VHI

9a-halogen-17a-oxy-21-fluoro-4-pregnen-3, ll, 20-triorj. Subjected treatment steps, after which 6-methyl-

To obtain the 9α-fluorine compounds, 9u-fluorine-II / 3,17a, 21-trioxy-4-pregnen-3,20-di-21-acylate is prepared the corresponding 9 / 3,11 / 3-epoxy Intermediate product (XIV) obtained by the known process, ie the aforementioned compounds, ie 6-methyl with a base, preferably in a nitrogen atmosphere 9/3, 11/3-oxido-17a-oxy-21-ihior -4-pregnen-3,20-dione. io to the free triol, ie to 6-methyl-9a-fluoro-II / S, 17a. For this, a 6-methyl-21-trioxy-4-pregnene-3,20-dione (XV) is heated in a known manner will.
9a-halogen-II / 5,17a-dioxy-21-nuor-4-pregnen-3,20-dioriin This o-methyl ^ a-fluoro-II / ?, 17a, 21-trioxy-4-pregnen solution with a weak base and preferably in 3,20-dione is then subjected to the same treatment as the absence of water in order to avoid any hydrolysis of the bond I in the order I to IV: ver-ester groups. 15 esterification with an aryl or alkyl sulfonate to

As a solvent, methanol, ethanol, acetone, bond XVI, implementation of this 21-aryl or 21-alkylene

tertiary butyl alcohol, etc. can be used. The sulfonates of o-methyl ^ a-fluoro-ll / J.na ^ l-trioxy ^ preg-

Reaction time is ¹ Z ₂ to 24 hours; generally nen-3,20-dione (XVI) with sodium iodide in acetone

3 to 12 hours are sufficient. The resulting 6-methyl compound XVII and subsequent implementation of this

9 _l ö, ll / 9-oxido-17a-oxy-21-nuor-4-pregnen-3,20-dione becomes ao 21-iodine compound XVII with silver fluoride to the product

isolated from the reaction mixture by following the first process, i.e. H. to 6-methyl-9a, 21-difluoro-

the latter diluted with excess water and the 11 / 3,17a-dioxy-4-pregnen-3,20-dione (VIII) .CompoundVIII

Product, as soon as it is in crystalline form, can also be nitrided off, as shown in example 3d, by reaction

or that it can be obtained with methylene chloride or another, with the sulfonate XVI with potassium fluoride.

Water-immiscible solvents extracted and 25 The following examples serve to illustrate

this evaporates. of the method according to the invention.

This 6-methyl-9 / 3,1 1/5-oxido-l 7a-oxy-21 -fluoro-4-preg-

Nene-3,20-dione is then treated with hydrofluoric acid in solution
puts. Can be used as a solvent for this reaction

e.g. methylene chloride, tetrahydrofuran, ethylene dichloride, 30 ^a ) 6a-MethyMl / ?, 17a, 21-trioxy-4-pregnen-3 ^ (Mion chloroform, carbon tetrachloride or their mixtures ^ 21-methanesulphonate
used. When using methylene chloride for (o-methylhydrocortisone ^ l-methanesulfonate)
Room temperature is generally aqueous, 48 ^c / <> strength A solution of 1 g (2.65 mmol) of 6a-Mcthylhydro-hydrofluoric acid and, when using tetrahydrofuran at cortisone in 7 cc of pyridine was cooled to 0 ° C and low temperature , use liquid hydrogen fluoride 35 0.3 ecm methanesulfonyl chloride treated. Then det. The reaction takes place with stirring at room - the solution was left to stand for 2 hours at 0 to 5 ° C, temperature when methylene chloride is then diluted as a solvent with water and used three times with 25 ecm each, and extracted at low temperature (0 to methylene chloride. The extracts were converted to -80 ° C) when tetrahydrofuran is combined in the presence of chlorinated compounds and hydrocarbons are used for so long with cold, dilute hydrochloric acid. The reaction time 40 washed until the aqueous layer in a p _H of -Wcrt is 1 to 24 hours; In general, 1 to 2 to 3 is enough, then again with cold sodium for 12 hours. After the reaction has ended, the bicarbonate solution is washed with water and added as a closing mixture to water and dried over anhydrous sodium sulfate with a dilute borrowed solution. After base, e.g. B. with sodium bicarbonate, potassium bicarbonate Evaporation of the methylene chloride extract obtained od. The like. Neutralized. It is also possible to use an excess of 45 as a white glassy product 6a-methyl-llj3, 17a, 21-trioxy-strong bases. The reaction 4-pregnen-3,20-dione-21-methanesulfonate.
mixture is then not mixed with water by means of a. ",,,. ,,,., _,. ". . , """",.
bar solvent, such as methylene chloride, extracted, ^b ) 6a-methyl-110,17a-dioxy-21-] od-4-pregnen-3,2O-dione the organic layer is from the aqueous mixture The crude 6a-methyl-II / 3,17a, 21-trioxy-4-pregnen-3, 20-separated, washed with water, dried and one 50 dione-21-methanesulfonate of Example 1 a) was evaporated in, after which the crude 6-methyl-9a , 2l-difluoro-15 ecm acetone and obtained with a solution of 1 g Na-11 / 3,17a-dioxy-4-pregnen-3,20-dione (VIII). This trium iodide is treated in 10 ecm acetone. The crude compound mixture can be purified by recrystallization or refluxed with stirring for 15 minutes, chromatography purified. after which the heat is reduced and the mixture under

By oxidation of the 6-methyl-9a, 21-difluoro-J.l ^, 17a-di-55 reduced pressure to a third of its volume

oxy-4-pregnen-3,20-dione in the usual way, e.g. B. was concentrated with. Ice and water were added

Chromic anhydride or an alkali chromate in solution, and the precipitated product is nitrated off with water

as in acetic acid, washed and dried at a temperature between 0 and, after which 1.1. g 6a-methyl-

40 ° C the o-MethyWa ^ l-difhior-nct-oxy ^ -preg- ll / 3,17a-dioxy-21-iodine-4-pregnen-3,20-dione with a

nen-3,11,20-trione. 60 obtained melting point of 135 to 140 ° C with decomposition.

The reactions in the second, optionally applicable process, which is carried out through steps X to XVII up to the analysis for C ₂₂ H ₃₁ O ₄ J:

Compound VIII was prepared correspond to the precalculated J 26.09 ° / ₀ ;

found standing in the stages from compound I to VIII. J25, O5 ° / _O.

written conversions, only the 9a-65

Fluorine atom and then the fluorine atom in the 21 position _{c) 6a} _ _methyl 4iA _17a _ _d i _oxy _21-fluoro-4-pregnen-3,20- <lion leads. The starting material used in the second process is not 6-methylhydrocortisone but one of its A solution of 1 g of oa-methyl-II / J. ^ a-dioxy ^ l-iodine ester, e.g. an acetate, propionate, butyrate, pentanoate, 4 -pregnen-3,20-dione in 150 cm of acetonitrile (commercial hexanoate, benzoate, phenyl acetate or the like, used. 7 ° quality) was heated to its boiling point

13 14

manufactured. After cooling to 40 ° C, the solution _{e) 6a} -methyl-17aK> _X y-21-fl _u or-4,9 (li) -pregnadi _e n-3,20 ^ ion was protected from light, and 0.8 ecm 50 ° / ₀ ige, aqueous silver ' ^JJK ' ^{r ö}

Fluid solution was added with stirring. 1 hour A mixture of 1 g of 6a-methyl-II / ?, 17a-dioxy-21-fluorine

stirring was continued at about 40 ° C., then 0.7 ecm of 4-pregnen-3,20-dione (see example! c), 650 mg of N-bromine-silver fluoride solution added and after again 1 hour 5 acetamide and 6 ecm pyridine was taken for 30 minutes Was stirred, were stirred again 0.7 ecm aqueous exclusion of light. The mixture was in one Silver fluoride solution added. Ice-water bath cooling was continued for 2 hours and sulfur dioxide became so heated and stirred. The brown mixture was then poured long onto the surface of the stirred mixture a layer of diatomaceous earth (known as conducts until the potassium iodine starch test was negative, the trade name Celite) filtered and the filtrate under io Then 50 ecm of water were added to the mixture, reduced pressure from a bath at one temperature and the mixture was allowed to stand at about 5 ° C for 30 minutes 50 ° C evaporated. The brown residue was held. The precipitated white solid was filtered off, Washed twice with 100 ecm warm methylene chloride each time thoroughly with water and dried in vacuo. To lent extracted, the combined extracts were recrystallized from acetone to give about 0.7 g Washed with water, over anhydrous sodium sulfate 15 6a-methyl-17a-oxy-21-fluoro-4,9 (II) -pregnadiene-3,20-dione. dried, concentrated to about 100 ecm and over 50 g

synthetic magnesium silicate (known under the _f) ^ methyl ^ a-bromo-l 1 / 3,17a-dioxy-21-fluoro-4-pregnen-trade name Flonsil). Fractions of 3 20-d'on each

200 ecm were taken as follows: '

20 To a solution of 0.5 g of 6a-Mcthyl-17a-oxy-21-fluoro-4,9 (ll) -Pregnadien-3,20-dione in 20 cc of a solution of 1 was Methylcnchlorid ECM 71 ° / _c perchloric acid in 10 ecm water and 200 mg N-bromoacetamide in 50 ecm tertiary butyl alcohol added. The solution was kept at room temperature for 15 minutes and then mixed with a solution of 0.3 g of sodium sulfite in 12 ecm of water. The mixture was distilled under reduced pressure until the remaining solution became cloudy. The product was then precipitated by adding 100 ecm 30 of an ice-water mixture. The white crystal

A hexane mixture of hexanes (known line precipitate was filtered off, washed with water, under the trade name Skellysolve B) was used. then dried and from a mixture of fractions 5 to 8 inclusive were combined and acetone and hexane hydrocarbons ("Skellysolve B") evaporated to 283 mg crystals, which after re-as oa-methyl-ga-bromo-ll ^. ^ a-dioxy ^ l-fluor ^ -pregnenauskristallisation from acetone- "Skellysolve B" 260 mg 35 3,20-dione recrystallized.
6a-methyl-II / 3,17a-dioxy-21-fluoro-4-pregnen-3,20-dione

with a melting point of 220 to 223 ° C. > _{Λ ΛΤ t,, n / <f ,, irr} ~. _a ,

^{1 6} g) oa-methyl-9 (II) -oxyd-17a-oxy-21-nuor-4-pregnen-

Analysis for C ₂₂ H ₃₁ O ₄ F: 3,20-dione

until
his Parliamentary group no. Table I. solvent 10
15th 9. Hexane-Acetone 90:
Hexane-Acetone 85: 1
10 12th Acetone, 100% 13th

oxy-21-fluoro-4-pregnen-3 g

Infrared spectra in Nnjol mineral oil suspension: lium acetate and 20 ecm acetone was left on for 5 hours

Q 2440 -1 heated to reflux temperature. The mixture was then

2Q jr'l . ₇ 2 ₄ ^cm cooled, added to water and treated with methyl chloride

j Tr, ° . ,. _ * 5 extracted. The methylene chloride extract was dried

λ 4 n "" VL "" j ι cc \ q ^{un <} l ül> ^er a column of 25 g synthetic >; Florisü «-

^ Double bond 1608 magnesium silicate poured. The column was with

Hexane hydrocarbons (»Skellysolve B«), which are increasingly

d) 6a-methyl-17a-oxy-21-nuor-4-pregnen-3, ll, 20-trione contained mendc amounts of acetone, developed. That

Contained 50 eluate from>. · Skellysolve B "plus 10 ° / ₀ acetone

A mixture of 0.5g 6a-methyl-l 1 / 5,17a-dioxy-21 -fluoro-6a-methyl-9 (l 1) -oxyd-17a-oxy-21 -fluor - ^ - pregnen ^^ dione. 4-pregnen-3,20-dione, 0.15 g chromic acid, 10 ecm glacial acetic acid and 0.5 ecm water was prepared. This Ge ΙΛ AM +1 1 Q 11 Λ · Λ ΛΛΟΛ
the mixture was stirred and then for 8 hours at ^h) oa-MethyWa ^ l-difluor-ll ^.
Left to stand at room temperature. Then it became 55 '" ^1On
mixed in 50 ecm of ice water and neutralized by adding a solution of Ig 6a-methyl-9 (II) -oxide-17 <i-oxyvon diluted sodium hydroxide. The 21-fluoro-4-pregnene-3,20-dione was precipitated in 50 ecm of methylene and dissolved on a gc chloride filter. Were added 5 cc of 48 ° / "igc Flußsammelt and three times from ethyl acetate and acid Hexankohlen- and 0.5 cc of 71 ° / ₀ perchloric acid. The mixture of hydrogen ("Skellysolve B") as oct-methyl- ^ a-oxy-60 was stirred vigorously for 6 hours and then converted into a 21-fluoro-4-pregnen-3, n, 20-trione. Excess of cold, aqueous, 5 ° / ^ εΓ sodium bicarbonate

Instead of the oa-methylhydrocortisone can be entered in the above solution. The methylene chloride layer was

Examples also use the 6/3 epimerc. separated, dried with anhydrous sodium sulfate

The conditions are kept approximately neutral, and then through a column of 100 g of synthetic

this is how the 6 /? epimers such as 6 / S-methyl-II / 3,17a-di-65 "Florisil" magnesium silicate can be cast. The column became

oxy-21-nuor-4-pregnen-3,20-dione, from the reaction with hexane hydrocarbons ("Skellysolve B") and

isolate mixture. The acetone can be developed from these 6 /? Epimers. The 10 ° / ₀ . Acetone containing frac-

6a-epimers were made from acetone and hexane hydrocarbons by treatment at room temperature

with an acid or a lye in an organic (! 'Skellysolve B «) recrystallized, after which one pure

Solvents such as ethanol can be obtained. 7 ° 6a-methyl-9a, 21-difiuor-ll ^, 17a-dioxy-4-pregnen-3,20-dione

with a melting point of 210 to 212 ° C with decomposition and a rotation [<z] d in acetone of - | -89 ^O.

Analysis for C ₂₂ H ₃₀ O ₄ F ₂ :

Calculated F9.58 ° / _O ;

found F 9.24%.

■ It can in the manner described in Example 1, d) in the corresponding 11-keto derivative can be converted.

Example 2

a) α-methyl-l 7a, 21-dioxy-4,9 (l 1) -prcgnadicn-3,20-dione, -21-acetate

A solution of 8.5 g of 6a-methyl-l 1 / 5,17a, 21-trioxy-4-pregnen-3,20-dione-21-acetate (oa-methyl-hydrocortisone-21-acetate) in 42.5 ecm pyridine was added 5.63 g of N-bromoacetamide. The reaction solution was allowed to stand at room temperature for 15 minutes and then cooled to 5 to 10 ° C. While shaking, gaseous sulfur dioxide was passed over the surface of the solution until the solution did not stain acidified starch iodine paper. During the introduction of the sulfur dioxide the mixture warmed up. The temperature was kept below 30 ° C. by external cooling and by changing the rate at which sulfur dioxide was introduced. 400 ecm of ice water were then added to the reaction mixture, and the resulting precipitate was filtered off. This substance was recrystallized from acetone-hexane hydrocarbons ("Skellysolve B"), after which 5.78 g of 6a- methyl-17a, 21-dioxy-4.9 (11)-pregnadiene-3.20-dione 21-acetate were added a melting point between 165 and 169 ° C.

The mother liquors were evaporated to a partially crystalline residue of 182 g. This substance was dissolved in methylene chloride and chromatographed over 75 g of Florisik. The column was washed with 2000 cc 8 ° / ₀ acetone (92%) -. VSkeUysolve B "and 1000 cc 15 ° / _o acetone (85%) - Skellysolve B <>'eluted. The eluate was collected in fractions of 200 ecm each. Fractions 3 to 7 are combined, evaporated and the residue is crystallized from acetone-hexane hydrocarbons (--Skellysolve B "), after which 0.88 g of 6 <x -methyl-17a, 21-dioxy-4,9 (ll) -pregnadiene is obtained -3,20-dione-21-acetate with a melting point; between 169 and 172 ⁰ C received. The yield was a total of 6.66 g, ie 82.4 ° / _0th An analytical sample obtained by crystallization from acetone-hexane hydrocarbons ("Skellysolve B") gave 6a-methyl-17a, 21-dioxy-4,9 (li) -pregnadicn-3,20-dione-21-acetate with a melting point of 175 to J 76 ° C and an optical rotation [a] i> in chloroform of + 91 °.

Analysis for C ₂₁ H ₃₂ O ₅ ;

Calculated ..... "C 71.97, H 8.05%;
found ..... C 71.75, H 7.71%.

b) 6a-methyl-9a-bromo-1 l / ?, 17a, 21-trioxy-4-pregnen-

3,20-dione-2l-acetate
(öa-methyl ^ a-bromohydrocortisoil ^ l-acetate)

A solution of 5.68 g of 6'-methyl-17a, 21-dioxy-4,9 (1 l) -pregnadiene-3,20-dione-21-acetate. In 100 ecm methyl chloride and 250 ecm tertiary butyl alcohol, a solution of 14 ecm 72% perchloric acid in 100 ecm water and then a solution of 2.34 g N-bromoacctamide in 60 ecm tertiary butyl alcohol was added. After stirring for 15 minutes, the reaction was stopped. a solution of 2.8 g of sodium sulfite in 140 ecm of water was added to the mixture. This reaction mixture was concentrated under reduced pressure ecm at about 5O ⁰ C to about .500. At this point crystallization started. The concentrate was cooled in an ice bath and 500 ecm of water were added with stirring. After stirring for one hour, the crystalline product was filtered off, the crystals were washed with water and air-dried, after which 6.88 g (98.9% yield)

ίο 6a-methyl-9a-bromo-l 10,17a, 21-trioxy-4-pregnen-3,20-dione-21 -acctate (6a-methyl-9a-brorohydrocortisone-21 -acetate) with a melting point of 159 to 161 ⁰ C (with decomposition) received. An analytical sample with a melting point of 153 to 155 ° C. and an optical rotation [<x] _D in chloroform of + 148 ° was obtained from dilute acetone.

Analysis for C ₂₁ H ₀₃ O ⁶ Br:

Calculated Br 16.07%;

found Br 16.01%.

c) 6a-methyl-9 | g, 110-oxido-17a, 21-dioxy-4-pregnene-3,20-dione-21-acetate

6.78 g of potassium acetate were added to a solution of 6.78 g of 6a-methyl-9a-bromo-II / 5.17a ^ 21 -trioxy ^ -pregnen-S ^ O-diori ^ l acetate in 175 ecm of acetone. The resulting suspension was refluxed for 17 hours. The mixture was then concentrated to about 60 ecm on a reduced pressure steam bath, then diluted with water and extracted with methyl chloride. The methylene extracts were agrees ver _r, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was redissolved in methylene chloride and chromium chromatographed over 200 g of anhydrous. »Florisik magnesium silicate. The column was filled with 1050 ecm of 5% acetone (95%) - hexane hydrocarbons. (;> Skellysolve B "), 1750 ecm 8% acetone (92%) -." SkellysolveB ", 3500 ecm 10% acetone (90%) -. ·. · Skellysolve B" and 350 ecm acetone eluted. The eluate was collected in fractions of 350 ecm each. Fractions 6 to 16 contained 4.981 g (88.1% yield) completely more crystalline. Material. This shock was used for the next step without further purification: An analytical sample (yi-Mcti \ y \ -9ß, liß-oxi do-lTa ^ l-dioxy- ^ pregnen-S.ZO-dion ^ l-acctat, the by recrystallizing part of the peak fraction from acetone-hexane hydrocarbons ("Skellysolve. B") , had a melting point of 180 to 182 ° C and an optical rotation [α] ο in chloroform of + 65 °.

Analysis for C _{21 H} ,, _O; :

Calculated C 69.20, H 7.75%; .

found C 69.41, H 7.93%.

■ d) 6a-methyl-9a-fluorine-II / ?, 17a, 21 -trioxy-4-pregnen-

3,20-dione-21-acetate
(6a - methyl - 9a - fluorohydrocortisone-21-acetate)

A mixture of about 1.3 g of hydrogen fluoride and 2.3 cc of tetrahydrofuran, the polyethylene flask was contained in a and - was cooled 6O ⁰ C, was added a solution of 500 mg (0.0012 mol) 6-methyl-9 / ^ l ^ oxido47a, 21-dioxy-5-prcgnen-3,20-dione-21 -acetate (combined chromatographic fractions) in 2 ecm of methylene chloride added. The steroid solution was flushed in with another cubic centimeter of methylene chloride. The bright red colored solution was then

17 18

1 hour to about -30 ° C and then 2 hours point from 219 to 220 ° C and a turn [a] _ö in

held at -10 ^° C. After this time had elapsed, acetone at + 113 ^° C. was obtained. ... · ..

careful with excess cold sodium analysis for C HOF

carbonate solution mixed, and the organic matter became ■ - "- ,, .. ^{M 3S} *"> λαγκ tt7A9 vaisoi.

extracted with the aid of additional methylene chloride. The S Calculates:. C 66 03, H 7.62, F 4.35%;

combined extracts were washed over with water. found: 65.69, H 7.49, F 4.29% .C.

anhydrous sodium sulfate and dried to about . , "" .. "·, _n " _{Λ Λ o} . _{n o <. Λ}

35 ecm concentrated. This solution was over 40ccm ^ T ^ ¹ "^;*"?; ¹¹ A ¹⁷ "^'21 ^ ⁰ T v ^ f ^

anhydrous »Florisil ^ Magnesiumsüicat chromatography 3,20-dione-21-acetate (optional method to be used) phiert. The column was filled with 400 ecm of 7% strength acetone - a solution of 250 mg of 6a-methyl-9/9, H /? - oxido-

(93%) - Hexane hydrocarbons (»Skellysolve B«), 17a ₍ 21-dioxy-4-pregnen-3,20-dione-21-acetate in 5 ecm Me-

500 ecm 10%: in acetone (90%) - »Skellysolve Β«, ethylene chloride was 1 ecm of a 48% fluorous water

1000 ecm of 12% acetone (88%) - »Skellysolve Β« and substance solution added. The two phase mixture was

100 ecm acetone eluted. The eluate was stirred in fractions for 20 hours, then with 15 ecm of methylene chloride

collected from each 100 ecm. Fractions 11 to 17 were diluted 15 and carefully in 40 ecm of water containing 3.5 g

combined and evaporated, after which they contained a total of sodium bicarbonate, entered. For the purpose of

439 mg (84.2%) of crystalline product was obtained. A neutralization of the excess hydrogen fluoride was carried out

Crystallization from acetone - Skellysolve B « resulted in two shaken, then the methylene chloride separated and

Crystal connections 0.23 g with a melting point of the water phase with further methylene chloride extra-218 to 220 ⁰ C and 0.16 g with a melting point of ao hiert. The combined methylene chloride solution (about 75 ecm)

201 to 208 ^° C. The overall yield was 74.7%. One was dried over anhydrous sodium sulfate with

Analytical sample was diluted from ethyl acetate-hexane carbon 25 ecm of ether and about 20 g of synthetic

Hydrogen (Skellysolve B) chromatographed as a needle-like, pure 6ct Me- »Florisik magnesium silicate. The co-

ethyl 9a-fluorohydrocortiside-21-acetate with a melting bar was eluted as follows:

Table II

Fraction. Kr.

■ 1 (100 ecm).

■ 2 to 6 (each 40 ecm) 7 to 16 (each 40 ecm) 17 to 21 (40 ecm each) 22 to 26 (40 ecm each) 27 to 30 (40 ecm each)

solvent

Methylene chloride ether (3: 1)
;; Skelrysolve-B «-hexane + acetone (12%)» Skellysolve-B «-hexane + acetone (15%)» Skellysolve-B «-hexane + acetone (20%)» Skellysolve-B «-hexane + acetone ( 25%) "Skellysolve-B" -hexane + acetone (50%)

Fractions 3 through 13 inclusive were pooled and sized. ■ The mixture was poured on a water bath from

evaporated. The residue obtained was from ethyl- 6O ⁰ C under reduced pressure to about * /, its Vo-.

acetate - ;; Skellysolve-B «-hexane and concentrated from methylene chloride lumens. Then 250 ecm of water was added

recrystallized, after which 95 mg of oa-methyl ^ a-fluoro-40 were added and the mixture was cooled. The crystalline

11 (8,170,21-trioxy ^ -pregnen-S ^ O-dione ^ l acetate was obtained. The product was filtered off, washed with water and

λ iL -Μ χι 1 r> r, <i o, j. . - _{<< nftl} , dried, after which 2.43 g (83%) of crude 6a-methyl-

f) ^ methyl ^ - ^ lTB ^ -di ^ y- ^ pregnea-a, !! ^ - ^ fl ^ ydrocortisone received. A! ^ Crystallization out

on ^ l-acetate-methyl-ga-fluorocortisone ^ l-acetate) methanol and SkellysolvcB gave pure 6a-methyl-

A solution was prepared, which in 1 ecm acetic acid 45 9a-nuorhydrocortisone (6aMethyl-9a-fluoro-II (5,17a, 21-tri-

50 mg 6a-methyl-9a-fluoro-l 1 / ?, 17a, 21-trioxy-4-pregnen-oxy-4-pregnen-3,20-dione) with a melting point of

3,20-dione-21-acetate, 20 mg chromic anhydride and 228 to 230 ⁰ C and a rotation \ a \ _D in acetone of

contained one drop (about 50 mg) of water. This ge +112 ⁰ C.

The mixture was mixed several times at room temperature. _A 1 *, ·· _r ττ η ττ

,,. ,,.,,. _ ^ j ·. , * 11 · η 1 analysis for C ₂₂ Ho ₁ ü _K r;

shakes and left to stand for 4 hours. Then 50 _β ,, _{+ r} " _os ", "» ".".,

it was added to 10 ecm of water and calculated for 20 hours C 66.98, H 7.92, F 4.82%;

cooled to about 5 ° C. The steroid that differs from that. ^{found c 67} . ²⁰ - ^{H 8} ^ ¹ . ^F 5.47%.

aqueous mixture separated, a further 0.24 g (8.2%) of o-methyl ^ a-fluorohydrocortisone was applied to filter paper

collected and three times from acetone as oa-methyl were obtained by using the filtrate

9a-fluoro-17a, 21-dioxy-4-pregnen-3, ll, 20-trione-21-acetate 55 saturated sodium chloride and with methylene chloride

(oa-MethyWa-fluorocortisone ^ l-acetate) recrystallized. extracted, the extracts dried over sodium sulfate

; ; . · "". '. · And evaporated and the residue obtained

· Example 3 Benzene-methanol recrystallized.

'"a) oa-MethyWa-nuQr-ll / S.na ^ i-trioxy ^ -pregnen- _6o b) 6a-Methyl-9a-fluoro-II / 3,17a, 21-trioxy-4-pregnen-. 3 , 20-dione (oa-methyl ^ a -fluorohydrocortisone) 3,20-dione-21-methanesulfonate

3.25 g of 6a-methyl-9a-fluoro-l 1 / 5,17a-21-trioxy-4-pΓegnen- a solution of 2.13 g of 6a-methyl-9a-nuor-II / 3.17a-

3,20-dione-21-acetate were dissolved in 325 cc of methanol, the 21-trioxy-4-pregnene-3,20-dione in 20 mg of pyridine, which was liberated on previously characterized by atmospheric oxygen, that one 0 ⁰ C was cooled , 1 ecm of methanesulfonyl chloride was bubbled through with nitrogen for 10 minutes, dissolved. Hiiizu- 65 added. The reaction mixture was added a solution of 1.63 g of potassium bicarbonate at 5 ⁰ C was added stirred for 17 hours and then added N hydrochloric acid solution, 200 cc of aqueous 1 in a mixture of ice and 30 cc of water, which also freed of oxygen. That would. The mixture was nitrated for 5 hours in a nitrogen-formed methanesulfonate, left to stand in a water atmosphere at room temperature and washed, pressed dry on a porous plate and then neutralized with 2.14 ecm acetic acid in 40 ecm water then in a vacuum at 70 ⁰ C further dried, after which

one 2.49 g of 6 ~ methyl-9a-fluoro-110,17a, 21-trioxy-4-pregnene-3,20-dione-21-methanesulfonate (97.8 ° / _o yield) received. Recrystallization of this substance from acetone gave pure α-methyl ^ a-fluorohydrocortisone ^ l-methanesulfonate with a melting point of 217 to 218 ° C. with decomposition.

Analysis for C ₂₄ Hs ₃ O ₇ FS:

Calculated C 58.45, H 7.04, S 6.78%;

found C 59.13, H 7.06, S 6.25%.

3,20-dione

150mg raw 6 (
4-pregnen-3,20-dione-21-methanesulfonate was dissolved in 15 ecm acetone and treated with a solution of 0.5 g sodium iodide in 5 ecm acetone. The mixture was refluxed with stirring for 15 minutes. Then the heat was decreased and. the mixture under reduced pressure to ^l / ₃ of its volume concentrated. Ice and water were added and the precipitated product was filtered off, washed with water and dried over anhydrous sodium sulfate, after which crude 6a-methyl-9a-fluoro-llj3,17a-dioxy-21-iodo-4-pregnen-3,20- dion received.

d) 6a-methyl-9a, 21-difluoro-1 iß, 17a-dioxy-4-pregnen-3,20-dione

A solution of 0.1 g of 6a-methyl-9a-fluoro-II / ?, 17a-dioxy-21-iodo-4-pregnen-3,20-dione in 15 ecm of acetonitrile was prepared by heating to its boiling point. After cooling to 40 ⁰ C, the solution was protected from light, and 0.1 cc of a 50% aqueous solution of silver fluoride solution was added with stirring. 1 hour, further stirred at 40 ⁰ C, then 0.1 cc of silver fluoride solution was added again. After stirring for a further hour, a further 0.1 ecm of silver fluoride solution was added. Heating and stirring were continued for 2 hours. Then, the brown mixture was filtered through a layer of vCelite "-Diatomeenerde and the filtrate evaporated under reduced pressure from a bath at a temperature of 50 ⁰ C. The brown residue was extracted thoroughly three times with 10 ecm warm methylene chloride each time, the extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to about 8 ecm. The material was then filtered again, evaporated and recrystallized three times from methanol and water, after which oa-methyl ^ a ^ l-difluoro-ll /}, 17a-dioxy-4-pregnen-3,20-dione with a melting point of 210 received up to 212 ° C with decomposition.

6ct-methyl-9a, 21-difluoro-11 / 3,17a-dioxy-4-pregnen-3,20-dione can also be obtained directly from the 6a-methyl-9a-fluoro-l 1 / 3.17a, 21-trioxy-4-pregnen-3,20-dione-21-methanesulfonate obtained in Example 3a) getting produced. One proceeds in the following way:

By heating to about 100 ° C λ \ τΐΓαε from 1.10 g were matographed. Fractions of 100 cm each were taken in the following manner:

Table III

Parliamentary group no.

Ibis 5.
ίο 6 to 15.

16

Hexane hydrocarbons

("Skellysolve B") - Acetone 90:10
Hexane hydrocarbons

(vSkellysolve B «) - acetone 88:12
acetone

y /

on-21-methanesulphonate and 10 ecm dimethylsulphoxide produced a solution. Then 550 mg of potassium fluoride was added. The resulting suspension was stirred and ^{heated to 100 to HO 0} C for 18 hours. The mixture was then cooled, 200 ecm of water was added and the aqueous phase was extracted with methylene chloride. The extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to about 40 ecm, the over 50 g of anhydrous magnesium silicate (known under the trade name "Florisil") were chro-The fractions 7 to 12 were combined and evaporated to 282 mg of residue, after recrystallization from acetone-hexane hydrocarbons ("Skellysolve B") 0.2 g of 6a-methyl-9a, 21-difluoro-II / S, 17a-dioxy-4-pregnen-3,20-dione with a melting point of 210 to 212 ⁰ C and a second crystal fraction of about 30 mg with

ao a melting point of 205 to 209 ⁰ C resulted.

Analysis for C ₈₂ H ₃₀ O ₁ F ₂ :

Calculated C 66.64, H 7.62, F 9.58%;

found C 66.35, H 8.07, F 9.24%.

Claims (1)

Claim: Process for the preparation of 6-methyl-9a, 21-difluoro-lljö, 17a-dioxy-4-pregnen-3,20-dione, characterized in that 6-methylhydrocortisone is treated in a known manner with an organic sulfonyl halide, the 21 -Sulfonate is reacted with an alkali metal iodide in acetone to form 6-methyl-11 ^, 17a-dioxy-21-iodo-4-pregnen-3,20-dione and this is then converted into 6-methyl-1 l / S, 17a with silver fluoride -dioxy-21-fluoro-4-pregnen-3,20-dione transferred, this dehydrated, the 6-methyl-17a-oxy-21-fluoro-4,9 (II) -pregnadiene-3,20-dione obtained a hypohalogenic acid, the resulting 6-methyl-9a _: halo- gen-ll / S ^ a-dioxy ^ l-fluor ^ -pregnen-S ^ O-dione with treated with a weak base and the 6-methyl-9, l 1 -oxido-17a-oxy-21-fluorine-4-pregnen-3,20-dione obtained with hydrogen fluoride, whereupon an oxidation of the 11 permanent hy- hydroxyl group is attached, or that an δ-methylhydrocortisone ^ l-acylate is first dehydrated, the 6-methyl-17ct, 21-dioxy-4,9 (II) -pregnadiene-3,20-dione-21-acylate obtained reacts with a hypohalogenic acid, the obtained 6-methyl-9a-halogen- ll / i, 17a, 21-triox5'-4-pregnen-3,20-dione-21-acylate with treated with a weak base, the 6-methyl-9 / ?, ll /? <> xido-17a, 21-dioxy-4-pregnen-3,20-dione-21-acylate obtained reacted with hydrogen fluoride, hydrolyzed the ester obtained, the 6-methyl-9a-fluorll / ?, 17a, 21-trioxy-4-pregnen-3,20-dione formed reacts with an organic sulfonyl halide, the obtained 21-sulfonate of o-methyl ^ a-fraorhydrocortisone with treated with an alkali metal] odide and the 21-iodine compound obtained with an excess of silver fluoride converts or the 21-sulfonate of 6-methyl-9a-fluorohydrocortisone with caustic fluoride converts directly into 6-methyl-9a, 21-difluorohydrocortisone, whereupon an oxidation of the 11-position hydroxyl group is connected, if necessary. Drawn up under consideration:
Act. Chem. Sand., 9, p. 987 (1955);
Journ. Amer. Chem. Soc, 78, pp. 2012, 2658, (1956). ® 909 607/430 8.59