DE1211197B - Process for the preparation of 15beta fluorosteroids - Google Patents

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FEDERAL REPUBLIC OF GERMANY GERMAN S / WWWl · PATENT OFFICE

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German class: 12 ο -25/05

1211197
U9315IVb / 12o
October 10, 1962
February 24, 1966

The invention relates to a process for the production of 15 / S fluorosteroids of the general formula

HO

Process for the production of
15 / J fluorosteroids

5 applicants: The Upjohn Company,
Kalamazoo, me. (V. St. A.) CH ₂ OAc Representative: C = O
) _ 1 OH ¹⁰ Dr. W. Beil, A. Hoeppener and Dr. HJ Wolff,
Lawyers,
Frankfurt / M.- Höchst, Adelonstr. 58 i

in which X is hydrogen or fluorine, Y is hydrogen, fluorine or the methyl group and Ac is the acyl radical Means hydrocarbyl carboxylic acid and in which there is a further double bond in the 1 (2) position can. These compounds are obtained by a known manner Compound of the general formula

CH ₂ OAc

HO

Named as inventor:
Donald Emory Ayer,
Kalamazoo, me. (V. St. A.)

in which X, Y and Ac have the meaning given above, in the presence of an oxidizing agent with Osmium tetroxide is oxidatively hydroxylated if X is hydrogen is, optionally via the corresponding 9 (11) -dehydro and 9j3, ll ^ -oxido compound Introduces the 9a-position fluorine atom and optionally the compound obtained in the 1 (2) position chemically or microbiologically dehydrated.

The compounds prepared in this way have glucocorticoids, mineralcorticoids and anti-inflammatory Effect. Its anti-inflammatory effect is considerably greater than that of the analogous compounds without fluorine substituents in ao claimed priority:

V. St. v. America 9 October 1961 (143 557)

as 15/3 position. At the same time, they are far less likely to inhibit sodium excretion than the compounds that are not fluorinated in the ISjö position. They are therefore preferably used for the treatment of inflammatory conditions of the skin, eyes, airways, bones and internal organs caused by bacteria or viruses, of contact dermatitis and allergic phenomena and rheumatoid arthritis.
They also have a progestational effect and influence the secretion of the gonadotropins, i.e. control ovulation and the development of the uterine mucosa and placenta, especially when used together with estrogenic substances such as ethinylestradiol and androgenic compounds such as] ga-fluorine-llje-hydroxy- na-methyl-testosterone. They reduce fertility and allow an effective therapy for dysmenorrhea, amenorrhea, endometriosis and for feared miscarriages.

Another valuable property is its calming effect on the central nervous system. They can therefore be used as sedatives and anesthetics in humans and mammals.
For therapeutic administration, the compounds which can be prepared according to the invention are used alone or in admixture with other compounds which supplement or enhance their effect

609 509/420

3 4

usual forms of administration processed. One can in a known manner, for example: by treatment with osmium, e.g. B. dissolve in a liquid carrier, emulsify tetroxyd and an oxidizing agent such as water or suspend or mix them with a solid carrier material peroxide or N-methyl-morpholine oxide peroxide and form tablets, powders, capsules or according to the US patents 2,769,823, Process Pills. The liquid preparations are pre-solutions than 5 1. described 769,824 or 2,769,825 methods, emulsions, suspensions, syrups or taken. Elixirs before. - ■ · - * - ^: - · - ' - In the 15 _i 5 _: Fluor-ll _l e, 17a, 21-trihydroxy-4-pregnen-

For the preparation of the invention in the invention, 3,2Ö-dione-21-acylate, if necessary, z. B. drive the starting materials used can be ISa-Hy- after the process of the USA.-Patent 2 838 499, droxy-11-keto-prögestefön, produced by-hydroxy-io introduced a fluorine atom in the 9 "position. this happens lation of 11-keto-progesterone with Penicillium in such a way that the 9 (11) position is dehydratiurticae ATCC10120, with a fluorinating agent, e.g. B. by reaction with an N-halogen general Formula amide, such as N-bromoacetamide, and subsequent loading

- --- treatment with sulfur dioxide, the zJ ⁸ ( ¹¹ ) -ver-

Ii 15 bond by adding a suitable underhalo-

Ri · \ ·. _..- ,. I -I genigen acid into the corresponding 9 «-halogen-

^ N-'CCX ₂ IIjS-hydroxyderivat transferred and this by conversion

Ra I j settlement with a weak base such as potassium acetate,

FX ₁ converts to the 9 / ?, llj8 epoxy.

20 From the. Epoxy is created by treatment with

implement abzusammen ₂ lower alkyl radicals or ^'J hydrogen fluoride or a hydrogen fluoride in which R ₁ and R with the nitrogen atom a five- to imaging agents the corresponding 9a, 15 / - represent Difluorsiebengliedrigen heterocyclic radical, X ₁ ll / U7α, 21-trihydroxy? -4-pregnen-3,20-dione-21-acylate. Chlorine or fluorine and 'X ₂ chlorine, fluorine or the tri-The compounds obtained in this way are optionally fluoromethyl. The reaction is then chemically or microbiologically inert in the 1 (2) position. Solvent, preferably in counter-'dehydrated. The microbiological dehydrogenation can be carried out using an acidic catalyst, with the use of a microorganism of the genus under inversion, the 15-position hydroxyl group being exchanged for Septomyxa according to the method of the USA Selenium dioxide is formed after de 15 / S-fluoro-U-keto-progesterone; 30 the Meystreet.al procedure (see British

The 15/3 fluoro-ll-keto-progesterone obtained is. Patent specification 864 414).

then with more than 2 molar equivalents of sodium The following example explains the invention

methylate as well as alkylpxalate and then with appropriate procedures: Bromine implemented. * Treatment with sodium

methylate in methanol gives a 2-bromo-3,1-di-35 - example. -

keto-15 ^ -fluoro-4,17 (20) - [cis] -pregnadiene-21-carbon- ■ ·,. ^ ₁ 5 _y 3. _Fluor . ₁₁ ^ _17aj 21-trihydrox _y -4-pregnen- . acid alkyl esters. By ■ implementation with a Re- ..- "■ ' ^y 3 on λ · 01 ■ t +

reducing agents such as zinc + acetic acid or chromium (II) - ■ -. ·· ^ - ^αιοτί - ^ - ^} ^Άτ

chloride, the bromine is then removed. One can _r A mixture of 1.93 g ^ ll, 21-dihydroxy-15j8-fluoro this also by treatment of the 2-bromo compound 40 4.17 (20) - [cis] -Pregnadien-3-one 21-acetate ,; 106 mltert.-with sodium iodide in acetone and subsequent conversion. Butyl alcohol, 0.6 ml of pyridine, 12 mg of osmium tetroxide. Reducing agents or and 6 ml. (2.75 molar equivalents) N-methyl-morphomite to achieve collidine * - Linoxydperoxide is preferably used in tert-butanol and was left to stand under nitrogen for 21 hours at room temperature in accordance with the working instructions of the USA patent. 2790 814. The ester obtained is then after 45 Then, a solution of 0.25 g of sodium was Hydro method of USA. Patents 2 707 184 or% - wallows in 50 ml of water, stirred 2,758,993 in 3- 30 minutes Position. ketalized. The preferred and narrowed to a small volume. The back-ketalizing agent is ethylene glycol. The resulting stand was extracted with ethyl acetate and the 3-ketal extract is then converted to the 3-ketal of 3-keto-15 / J-fluorine one after the other with water, aqueous sodium bicarbonate-4,17 (20) -pregnadiene-II | S, 21- diols reduced, e.g. B. washed through 50 solution and water, over magnesium sulfate treatment with lithium aluminum hydride in counter-dried and filtered. The filtrate was concentrated to the waiting of an inert solvent such as ether or dryness, the residue in methylene-tetrahydrofuran, such as i. is dissolved in 'the USA patent and described on synthetic magnesium-2,695,906. silicate chromatographed. The column was with

The acylation of the. 21-position hydroxyl group 55 eluted hexane hydrocarbons, which increasing with a suitable acid halide or acid. Contained amounts of acetone. Those fractions, anhydride in the presence of a - tertiary base such as those on the basis of a paper chromatographic pyridine with subsequent decetalization, z. B. contained the desired product by analysis, hydrolysis with a mineral acid results in the combined and evaporated to dryness. The starting material 3-keto-60 used according to the invention was recrystallized from aqueous methanol. 15 (S-fluoro-4,17 (20) -pregriadiene-llß21-diol-21-acylate: This gave 0.63 g of 15 ^ -fluoro-IIIs, 17 ", 21-trihydroxy- or its in 6- and 9-substituted derivatives, 4-pregnene-3,20-dione-21-acetate in the form of a one kristalwenn linen solid from the corresponding starting materials, mp = 206 to 208 ⁰ C (decomposition), runs out of for the preparation. By repeated recrystallization from aqueous

In the context of the present invention protection not 65 methanol, an analytical sample from the melt was desired. dot210 to 211 "C (decomposition) obtained. The

To carry out the inventive UV spectrum of the compound (in ethanol) showed a driving the oxidative hydroxylation in itself maximum at 241 rnp .. The IR spectrum (in mineral

oil) had maxima at 3580, 3360, 1730, Π15, 1662, 1630, 1620 (shoulder), 1595, 1265 and 1245 cm- ¹ .

Analysis for C ₂₃ H ₃₁ FO ₆ • 1/4 H ₂ O: Calculated ... C 64.96, H 7.44, F 4.45; · Found ... C 64.54, H 7.68, F 4.41.

The anhydrous product is obtained by drying in a high vacuum.

b) 9 ", 15β-difluoro-II, δ, 17a, 21-trihydroxy-pregnen-3,20-dione-21-acetate " ■

A solution of 0.7 g of 15 / S-Fluor-II / S, 17 «, 21-trihydroxy-4-pregnen-3,20-dione-21-acetate in 15 ml of pyridine was admixed with 0.38 of n-bromoacetamide. The overall - "mixing was stirred under nitrogen for 20 minutes at 25 ⁰ C and then cooled to 1O ⁰ C .. On the surface of the cooled solution for 15 minutes sulfur dioxide then was passed, after which it was diluted with ice water, the separated solid was äbfiltriert. washed with water and dried The obtained 15 /? -fluoro-17 «, 21-dihydroxy-4,9 (U) -pregnadiene-3,20-dione-21-acetate (0.53 g) was in a mixture of 10 ml of methylene chloride and 18 ml of tert-butanol were dissolved and 0.16 ml of 70% perchloric acid in 1.25 ml of water and 0.25 g of bromoacetamide in 2.5 ml of tert-butanol were added stirred until 3O ⁰ C and treated with 0.25 g of sodium sulfite in 2.5 ml of water. the resulting solution was concentrated under reduced pressure and the residue diluted with ice-water. the precipitated solids in this way was filtered off, washed with water and dried. The obtained 9a-bromo-15 /? - fluoro-II | 3,17a, 21-trihydroxy-4-pregnen-3,20-dione-21-acetate (0.55 g) was dissolved in 15 ml of acetone and refluxed with 0.6 g of potassium acetate for 24 hours. It was then evaporated to dryness and the residue was shaken with a mixture of water and methylene chloride. The methylene chloride phase was separated off, washed with water and dried over magnesium sulfate. The dry solution was filtered and the filtrate was evaporated to dryness. The residue (0.486 g) was dissolved in methylene chloride and chromatographed over synthetic magnesium silicate. The column was eluted with hexane hydrocarbons containing 12.5 percent by volume acetone. The fractions which, on the basis of analysis by paper chromatography, contained the desired product were combined and evaporated to dryness. 0.359 g was obtained 15 _l 9-fluoro-17 ', 21-dihydroxy-9j3, ll _j 5-oxido-4-pregnene-3,20-dione-21-acetate in the form of a crystalline solid; F. = 205 to 207 ° C.

A solution of 0.35 g of 15 /? - fluorine-17 «, 21-dihydroxy-9/3, ll / 3-oxido-4-pregnen-3,20-dione-21-acetate in 3.5 ml of methylene chloride was Cooled 70 ° C and added to a mixture of 3 g of anhydrous hydrogen fluoride and 5.3 ml of tetrahydrofuran at -2O ⁰ C. Then, first for 16 hours at -20 ⁰ C and then for 4 hours at + 5 ° C was allowed to stand. The mixture was then added, with stirring, to an ice-cold solution of 21.6 g of sodium bicarbonate in 100 ml of water. The mixture was extracted with ethyl acetate, the extract washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was recrystallized twice from a mixture of acetone and hexane hydrocarbons. 110 mg was obtained ί - difluoro -11 / 3,17 ", 21 - trihydroxy -A- pregnene-3,20-dione-21-acetate in the form of a crystalline solid; M.p. = 213 to 214 ° C (decomposition). The UV spectrum of this compound (in ethanol) showed a maximum at 238 ηψ.

Analysis for C ₂₃ H ₃₀ F ₂ O ₆ :
. Calculated ... C 62.71, H 6.87, F 8.63;
Found ... C 63.02, H 6.85, F 8.12.

c) 9a, 15/3-difluoro-ll ^, 17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione-21-acetate

A mixture of 300 mg 9a, 15 ^ -Difluor-II / 5.17 «, ^ l-trihydroxy ^ -pregnen-S ^ O-dione ^ l-acetate, 40 ml tert-butanol, 0.4 ml acetic acid and 150 mg of selenium dioxide was refluxed for 44 hours. After adding a further 150 mg of selenium dioxide, the mixture was heated again for 19 hours. The mixture was then filtered and the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate, the solution successively with cold aqueous sodium bicarbonate solution; aqueous ammonium polysulfide solution, dilute ammonia, water, dilute hydrochloric acid and water, dried over magnesium sulfate and filtered. The filtrate was concentrated to dryness and the residue was dissolved in methylene chloride, which contained 5 percent by volume acetone, and chromatographed over 100 g of synthetic magnesium silicate. The column was eluted with 1.5 liters of methylene chloride containing 7.5 percent by volume of acetone and then with 750 ml of methylene chloride containing 12.5 percent by volume of acetone. The eluate was evaporated to dryness and the residue (200 mg) recrystallized twice from a mixture of acetone and hexane hydrocarbons, whereupon 60 mg 9öi, 15) 3-difluoro-II / S, 17a, 21-trihydroxy-1,4-pregnadiene 3,20-dione-21-acetate was obtained as a crystalline solid with a melting point of 232 to 233 ^° C. (decomposition). The UV spectrum (in ethanol) showed a maximum at 238 πιμ (ε = 16,000). The IR spectrum (in mineral oil) had maxima at 3560, 3470, 3330, 1750, 1740, 1710, 1665, 1625, 1608, 1230 and 1215 cm- ¹ .

Analysis for C ₂₃ H ₂₈ F ₂ O ₆ :
Calculated ... C 63.00, H 6.44, F 8.67;
Found ... C 63.26, H 6.24, F 8.62.

Claims (2)

Patent claims: 1. Process for the preparation of 15 / S fluorosteroids the general formula CH ₂ OAc HO in which X is hydrogen or fluorine, Y is hydrogen, fluorine or the methyl group and Ac is the acyl radical denotes a hydrocarbon carboxylic acid and in the 1 (2) position there is a further double bond can be located, thus identified 7 8 draws that a compound of the general formula can be obtained in a manner known per se HO in which X, Y and Ac have the meaning given above, in the presence of an oxidizing agent oxidatively hydroxylated with osmium tetroxyl, if X is hydrogen, optionally via the appropriate 9 (11) -dehydro and 9j8, ll / 3-oxido compounds introduces a 9a fluorine atom and optionally the compound obtained in the 1 (2) position chemically or microbiologically dehydrated. 2. The method according to claim 1, characterized in that the starting material Ilj8,21-dihydroxy-15/3-fluoro-4,17 (20) - [cis] -pregnadien-3-one-21-acetate and selenium dioxide is used as a chemical dehydrating agent. 609 509/420 2.66 © Bundesdruckerei Berlin