DE1270041B - Process for the preparation of delta 4-3, 20-diketo-6alpha-fluoro-16alpha, 17alpha, 21-trihydroxy compounds of the pregnane series and functional derivatives thereof - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

German class:

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C07c

A61k

12 ο-25/05

30 h-2/10
30 h-2/36

P 12 70 041.3-42 September 7, 1960 June 12, 1968

The invention relates to a process for the preparation of zl ⁴ -3,20-diketo-6a-fluoro-16a, 17a, 21-trihydroxy compounds of the pregnane series and functional derivatives of these compounds.

It is already known that leads to 6a-fluoro steroids of the androstane or pregnane series are obtained when corresponding output steroids with 5 (6) -ständiger double bond with hydrofluoric acid and an N-bromo amide or N-Bromimid reacted at temperatures of about 0 ⁰ C, the Brominated fluorinated product reductively debrominated and the 6/3 fluorine compounds obtained in a known manner, for. B. isomerized with hydrogen chloride in acetic acid.

It has now been found that when a 21-acylate of 3,20-diketo-5a- bromo-6ß -fluoro-16a, 17a-oxydo-21-hydroxypregnans is treated with hydrogen bromide or hydrogen chloride in the presence of acetic acid in one and the same In the process stage, the 4 (5) position is dehydrobrominated, the configuration at C _{6 is} reversed and the 16a, 17a oxidizing ring is split into the corresponding 16 /? - bromohydrin or 16 / i-chlorohydrin. In this way, 6α-fluoro-6β-halogen-zl ⁴ -prene-17tt, 21-diol-3,20-dione or its 21-acylate, which can then be reacted further, is obtained in a simple manner. The simultaneous reaction at two different points on the steroid ring with the simultaneous isomerization of the C ₆ is new. In view of the numerous interactions that can occur in steroid chemistry, it could not be envisaged that the reaction would proceed in the desired manner and with reasonably good yields. The inventive method represents a technically advantageous route into the group of

Process for the preparation of ^ ⁴ -3,20-diketo-6a-fluoro-16a, 17a, 21-trihydroxy compounds of the pregnane series and functional derivatives thereof

Applicant:

Syntex S. A., Mexico (Mexico) Representative:

Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. Pulse and Dipl.-Chem. Dr. rer. nat. E. Frhr. v. Pechmann, Patentanwälte, 8000 Munich 9, Schweigerstr. 2

Named as inventor:

John Stuart Mills,

Albert Bowers, Mexico (Mexico)

Claimed priority:
Mexico 7 September 1959

6a-fluoro- / f-pregnen-16a, 17a, 21 -trihydroxy-S ^ O-dione compounds because the starting material is made from abundant raw materials easily and with is accessible in good yields.

The process according to the invention for the preparation of ^ ⁴ -3,20-diketo-6a-fluoro-16a, 17a, 21-trihydroxy compounds of the pregnane series and functional derivatives thereof of the general formula

CH ₂ OR ₁

wherein X is a hydrogen, fluorine or chlorine atom and acyl radical or R ₂ and R ₃ together represent the radical of a Y is a hydrogen atom and a / 3-OH group or cyclic 16a, 17a acetal or ketal, is keto oxygen which Bond between the carbons is now characterized in that a 21-acylate substance atoms 1 and 2 is optionally unsaturated, the S ^ O-diketo-Sa-bromo-oß-fluoro-löa.na-oxido-R ₁ , R ₂ and R ₃ each represents a hydrogen atom or a 21-hydroxypregnans at temperatures around ⁰ ° C. below

a «» 9/533

Reacts anhydrous conditions with hydrogen bromide or hydrogen chloride in the presence of acetic acid, the resulting 6a-fluoro-16/9-halogen- / l ⁴ -pregnen-17a, 21-diol-3,20-dione or the 21-acylate of this compound in on acylated in a known manner in the 17- and 21-position or only in the 17-position, the 17,21-diacylate obtained is treated with potassium acetate in acetic acid under reflux, then the 16-acetate-21-acylate obtained in a manner known per se

also introduce by making the connection z. B. with a strain of Cunninghamella blakesleana ATCC 8688 a or ATCC 8688 b.

For the production of 6 <z-fluoro-16a-hydroxycortisone becomes the 16,21-diacetate of 6a-fluoro-16a-hydroxyhydrocortisone treated with chromic acid in aqueous acetic acid, and the acetoxy groups are then saponified. Following standard procedures will be furthermore other 16,21-diesters of 6a-FIuor-16a-hy-

of the oa-fluorine - ^ - pregnen-loojna ^ l-triol-S ^ O-dione ₀ droxyhydrocortisone and of the 6 <z-fluoro-16a-hydroxy saponified to the free trioldione, then produced in the 11 ^ -position cortisone. Starting from the 16,21-dihydroxylated, optionally at the same time in the 9a-position
introduces a fluorine or chlorine atom, optionally

dehydrated in 1 (2) position and / or the llß-Hy-

Pyridine. Also with the 1,4-diene steroids obtained in this way the ester groups on carbon atoms 16 and 21 are saponified and the resulting

Are hydroxyprednisolone 6a-fluoro-9a-halogen in addition to the 6a-fluoro-16a-hydroxyhdrocortison and 6a - fluoro - - 16a (fluoro or chloro -) - 16a-hy-

esters of the above-mentioned 6a-fluoro-16a-hydroxysteroids, a further double bond is optionally introduced between the carbon atoms 1 and 2, and the hydroxyl group is oxidized, the latter degree being e.g. B. by boiling under reflux with selenium dioxide can be carried out in any order tert-butanol in the presence of catalytic amounts and / or the 16a-acetate group and
21-acylate group saponified and re-esterified or the
any 16a, 17a, 21-triol compounds obtained are converted again in the usual way into their cyclic 16a, 17a-ketals or acetals 20 free hydroxyl groups and the 21 -hydroxyl-esterified thereupon, if necessary,
group esterified.

In the process according to the invention, the 3,20-diketo-5a-bromo-acylated in the 21-position

6 / J-fluor-16a, 17a-oxydo-21-hydroxy-pregnane, eg 25 droxyderivate of bark hormones with the help of the 21-acetate assumed. This connection is described by Fried and coworkers in J. Am. Chem. Soc, obtained in good yield by preparing the 21-acetate of 16a, 17a-oxido-J ⁵ -pregnen- in the process already known in 79, 1130 (1957). By reaction with mesyl chloride in di-3 / 3,2l-diol-20-one in methylene chloride at -8O ⁰ C methylformamide-pyridine, the 16,21-diesters with anhydrous hydrogen fluoride and N-bromoacet- 30 des 6a - fluorine - 16a - Hydrocortisone or amide is reacted and the obtained crude 21-acetate of 6u-fluoro-16a-hydroxyprednisolons is dehydrated of 5a - bromine - 6ß - flour - 16a, 17a - oxidopregnan- and the corresponding. r ^(U 'compounds obtained. 3 / i, 2 l-diol-20-one in acetone solution at 0 ⁰ C under these compounds by reaction with nitrogen with a solution of chromic acid for 5-bromo hypobromous acid into the corresponding bromo-6 ^ -fluoro-16a, 17a-oxido-21-acetoxypregnan-3,20-dione 35 hydrine and finally oxidized by treatment with sodium acetate in acetone of the 9 / U1 / i-oxide ring

This starting compound is then closed in acetic acid. Finally, this ring is opened by treating with hydrogen fluoride or water chloride below 0 ° C with hydrogen bromide or with hydrogen chloride under anhydrous conditions at temperatures. The 16,21 -Distoff treated in this way is obtained. In the 4 {5) position, the 6a-fluoro-9a-halogen (fluorine or chlorine) -brominated is dehydro- 40 ester, the 6 /? - fluorine isomerized and the epoxy 16a-hydroxyhydrocortisone or the corresponding ring in 16a, 17a position open. This gives 6a-fluoro-9a-halogen (fluoro- or chlorine) -16a-hydroxy on treatment with hydrogen bromide, the 21-acetate prednisolone. It is preferable to start from the 16,21-Dides oa-Flour-Lö / U-brom-J ^ -pregnen-n ^ l-diolO ^ Odi- acetate and then get the diacetates of the dions. This compound is in Πα-position with 45 halogenated hormones.
Acetic anhydride in the presence of 70% per- Then, as already described, the

chloric acid acetylated in glacial acetic acid and converted into the 16,21-diacetate of 6a-fluoro-J ⁴ -pregnen-16a, 17a, 21-triol-3 _f 20-dione by refluxing with potassium acetate and acetic acid.

If the epoxy ring is opened with hydrogen chloride under these specified conditions, it occurs as a halogen atom on the carbon atom of the 16 / J-halohydrin obtained, to a lesser extent, chlorine and

16,21-diacetate groups hydrolyzed and re-esterified or another double bond is introduced between carbon atoms 1 and 2 and the 11 / i-hydroxyl group is oxidized to the keto group, whereby one the corresponding 6a-fluoro-9a-halogen- (fluorine or chlorine) -16a-hydroxyderivate of the free Hydrocortisone and Prednisolone, which may be present on carbon atoms 16 and 21

J-pregnen-17a, 21-diol-3,20-dione is now used in 17 / f- and acetylated in the 21-position as described above and by reaction with potassium acetate in acetic acid

mainly bromine. In addition, the 21-acetate-55 are esterified.

group saponified. The obtained 6a-fluoro-16/3-halogen- The primary and secondary hydroxyl groups

are preferably by reaction with the chloride or anhydride of a carboxylic acid with up to to 12 carbon atoms in pyridine at room temperature

esterified into the desired 16a-acetoxy compound. For the esterification of the tertiary hydroxy 1-delt. group on carbon atom 17 is the implementation

The 16,21-diacetate of 6a - fluoro - J ⁴ - pregnen - preferably with acid anhydrides in benzene and in 16a, 17a, 21-triol-3,20-dione is then made in the free presence of p-toluenesulfonic acid. Trioldione compound converted, for example by The tertiary hydroxyl group can also be treated with sodium carbonate in methanol. Acetylate by 65 acetic anhydride in acetic acid in the presence of subsequent incubation with adrenal glands of perchloric acid. The Anhy steers used are obtained, the δa-fluoro-löa-hydroxyhydride are preferably derived from the carboxylic acids cortisone. One can remove the !! ^ - hydroxyl group with less than 12 carbon atoms, which

optionally unsaturated, straight-chain, branched, cyclic or mixed cyclic-aliphatic and optionally are substituted. Typical esters are the acetates, propionates, butyrates and the half esters of succinic acid, the dnants acid esters, caproic acid esters, aminoacetic acid esters, phenoxyacetic acid esters, Trimethyl acetic acid ester, benzoic acid ester, cyclopentyl propionic acid ester or / I-chloropropionic acid ester.

The 16a and 17a hydroxyl groups according to the invention Preparable compounds can also be in the form of a cyclic 16,17-ketal or 16,17-acetal be connected to each other. Typical acetal and ketal groups are the methylenedioxy, ethylidenedioxy, Isopropylidenedioxy or benzylidenedioxy groups. The 16a, 17a-dihydroxy compound is used for ketalization z. B. suspended in acetone in the presence of perchloric acid.

example 1

A solution of 6 g of 5a-bromo-6 / i-fluoro-16a, 17u-oxido-21-acetoxypregnan-3,20-dione in 20 ml of acetic acid is mixed with 20 ml of a saturated solution of hydrogen bromide in acetic acid and at a temperature between 0 and 5 ° C for 5 ¹ I ₂ hours. After pouring into water, the precipitate is collected, washed with water, dried under reduced pressure and recrystallized from acetone-hexane. This gives 3.5 g of the 21-acetate of 6a-fluoro-16 / i-bromo-J ⁴ -pregnen-17u, 2l-diol-3,20-dione, mp. 125 to 130 ⁰ C with loss of solvent. An analytical sample is obtained by recrystallization from methanol. The pure compound melts at 115 to 120 ⁰ C, solidifies upon further heating and then melted with decomposition at 180 to 183 ° C; [«]" = + 65 ° (in chloroform); λ _{,! ιαχ} - 236 ηΐμ; log f = 4.21.

A mixture of 3 g of this compound, mp. 125 to 135 ° C in 120 ml glacial acetic acid is mixed with 30 ml of acetic anhydride and 1.5 ml of 70 / _o perchloric acid and allowed to stand for 4 hours at room temperature. The mixture is then poured into water and the crystals formed are filtered off, washed with water and recrystallized from methylene chloride-methanol. 2.4 g of the diacetate of 6 «-fluoro-16 /? ^{-Bromo-I 4} -pregnen-17a, 21-diol-3,20-dione of melting point 167 to 170C decomposition are obtained; [a] o = + 4T (in chloroform); A _11111x = 235ηΐµ; logf = 4.14.

2 g of this compound of melting point 165 to 167 "C and 6 g of potassium acetate in 70 ml of glacial acetic acid are refluxed for 3 hours, and most of the acetic acid is then distilled off under reduced pressure. The residue is cooled and the product is added by adding Water is precipitated. It is extracted with methylene chloride, the extract is washed with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and the solvent is evaporated. Unicrystallization of the residue from methanol gives 1.2 g of the 16,21-diacetate of 6a-fluoro-J ⁴ - pregnen-16a, 17a, 21 -triol-3,20-dione. The crystals contain solvents and show a double melting point at 155 ° C and 204 to 205 ° C; [a] _D = 4- 3Γ (in chloroform); X _mux = 236 ιημ; löge = 4.15.

In the manner described above, or according to the modifications described in Example 2 below, 123 g of the 16,21-diacetate of 6α - fluoro - zJ ⁴ - pregnen -16α, 17α, 21 - triol - 3,20 - dione are prepared . This compound is dissolved in 2.41 methanol, a solution of 40 g of sodium carbonate in 240 ml of water is added ^{at 0} ° C. under nitrogen and the mixture is stirred for 2 ¹ I for _{2 hours.} The mixture is then neutralized with 15 ml of acetic acid; the crystals are filtered off, washed with water and dried. This gives 89 g of 6a-fluoro-J ⁴ -pregnen-16a, 17a, 21-triol-3,20-dione in free form having a melting point of 200 ⁰ C. The pure compound melts after recrystallization from acetone at 226 to 228 ° C; O] ο = + 63.5 ° (in chloroform); k _max = 236 ηΐμ; log f = 4.20.

Example 2

A suspension of 4 g of the acetate des 5a-bromo- 6ß- fluoro-16a, 1 Ta- oxidopregnan-21-oil-3.20-dione (see Example 1) in 40 ml acetic acid is at about 0 ⁰ C with dry Treated hydrogen chloride for about 30 minutes and then left to stand at 0 ⁰ C for a further 4 1/2 hours. The mixture is poured into water and the product is filtered off, washed with water, dried and recrystallized from methanol. 2.8 g of a product which melts between 180 and 187 ° C. with decomposition are obtained; k _max = 236 πΐμ; logf = 4.18. It was found that this compound is a mixture of the 6'-fluoro-16 / i-bromo

) ⁴ -pregnen-17a, 21-diol-3,20-dione and des 6a-fluoro.16 / J- ^{chloro-l 4} -pregnen-17a, 21-diol-3,20-dione.

Then 2 g of this compound according to Example 1 are acetylated. 1.4 g of the diacetate are obtained with a melting point of 160 ° to 167 ° C., decomposition; X _max = 236 ηΐμ, logf = 4.17. Boiling under reflux with potassium acetate in glacial acetic acid gives the 16,21-diacetate of 6a - fluorine -, I ⁴ - pregnen -16 «, 17a-21-triol-3,20-dione, which is obtained with the compound described in Example 1 is identical.

Example 3

The following solutions "A", "B" and "C" are created using distilled water prepared as a solvent: 425 ml of a 1.74% solution of dipotassium hydrogen phosphate are mixed with 75 ml of a 1.38% solution of sodium dihydrogen phosphate for solution A mixed. 1 1 4.5% Sodium chloride solution is mixed with 40 ml of 5.75% strength potassium chloride solution and 10 ml of 19.1% strength magnesium sulfate solution mixed and diluted to 5 l to form solution B. 20.9 g of fumaric acid and 14.4 g Sodium hydroxide is dissolved in 1 liter of water, the solution is diluted to 1.2 liters to form solution C. There are 450 ml of solution A with 4.321 the Solution B and 1.2 l of solution C mixed.

The adrenal glands of freshly slaughtered bulls are stripped of fat and the glands are placed in Grind in a meat grinder until you get a homogeneous mass.

^{6 g of 6a-fluoro-] 4} -pregnen-16a, 17a, 21-triol-3,20-dione, which are suspended in 61 of the mixture of solutions A, B and C, are added to 9 kg of this mass, for 3 hours incubated in open Erlenmeyer flasks with constant stirring. The contents of the flasks are then combined, acetone is added and the mixture is stirred at room temperature for 1 hour. The solid substances are filtered off, the filter is washed with acetone, the filtrate and the washing solutions are combined, and the solvent

is distilled off under reduced pressure until the volume is reduced to about one third. The residue is then extracted with two portions of 41 hexane and the extract is discarded. The mixture is then extracted with three portions of 5 1 each of methylene chloride, the extracts are combined, washed with water, dried over sodium sulfate, and the solvent is distilled off. The residue is stirred with about 30 ml of methylene chloride, cooled and the crystals are filtered off. 3 g of crude 6a-fluoro-16a-hydroxyhdrocortisone are obtained greenish in color and have a melting point of 220 to 225 ^° C.

Recrystallization from acetone-methanol and decolorization with activated charcoal gives the pure compound with a melting point of 233 to 236 ^° C .; [a] ₀ = + 95 ° (in dioxane); A _mox = 236 to 238 πΐμ; lo = 4.18.

Example 4

A mixture of 1.2 g of 6a-fluoro-16a-hydroxyhydrocortisone, 4 g of acetic anhydride and 8 ml of pyridine are heated to 60 ° C. for 2 hours and then left to stand at room temperature for 2 hours. Ice and water are then added to the mixture, and the crystals are filtered off, washed with water, dried and recrystallized from methylene chloride-methanol. 1.05 g of the 16,21-diacetate of oa-fluoro-loa-hydroxyhydrocortisone (solvated) with a melting point of 182 ° to 187 ° C. ° C. After recrystallization from the same solvents, the compound is obtained with a lower constant melting point of 175 to 177 ° C .; [α] n = + 70 ° (in dioxane); A _mex = 238πΐµ; lo = 4.20.

2.94 g of the 16,21-diacetate of 6 <z-fluoro-16a-hydroxyhydrocortisone are mixed with 60 ml of dimethylformamide, 3.6 ml of pyridine and 2.4 ml of methanesulfonyl chloride and heated on the steam bath for 2 hours. The 6a-fluoro-16a-hydroxyhydrocortisone diacetate was prepared in the manner described above and further purified by azeotropic distillation with benzene. The dimethylformamide was freshly distilled. After the 2-hour treatment on the steam bath, the mixture is cooled and stirred into saturated aqueous sodium bicarbonate solution. The product is extracted with methylene chloride, the extract is washed with water and dried over sodium sulfate and the solvent is distilled off. The residue is chromatographed on 90 g of silica gel and the product is eluted with methylene chloride-acetone 9: 1 and then recrystallized from methylene chloride-methanol. Obtained in this way 1.6 g of the 16,21-diacetate, of 6a-fluoro ^ ^{4-9 (11)} -Pregnadien-16a, 17a, 21-triol-3,20-dione, mp 110 to 114 °. C; the analytically pure compound melts at 115 to 117 ^° C .; [e] "= + 23.5 ° (in chloroform), X _max = 234 to 236 πΐμ; log e - 4.18.

A mixture of 1.38 g of this compound in 15 ml of dioxane is mixed with 1.9 ml of a 0.5 N aqueous Perchloric acid solution and 600 mg of N-bromoacetamide. The latter substance appears in the dark added in three portions within 30 minutes with constant stirring. The mixture is then Stirred for a further 1% hours in the dark and then unreacted reagent by adding decomposed by aqueous sodium bisulfite solution and ice water. The product is made with methylene chloride extracted, the extract washed with water, dried over sodium sulfate and the solvent distilled off under reduced pressure. A yellow oil is obtained, which is the 16,21-diacetate des Contains 6a-fluoro-9a-bromo-16a-hydroxyhydrocortisone, which is used in the next stage without further purification.

The crude bromohydrin is mixed with 2.5 g of potassium acetate and 60 ml of acetone and refluxed for 6 hours. The acetone is then distilled off, water is added to the residue and the product is extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and the solvent is evaporated. After recrystallization of the residue from methanol, 800 mg of the 16,21-diacetate of 6a-fluoro-9 / S, II /? - oxido- ^ ⁴ -pregnen-16a, 17a, 21-triol-3,20-dione from Mp. 120 to 124 ° C. Chromatography of the mother liquors on silica gel gives a further 180 mg of the same compound with a melting point of 117 to 119 ° C. The analytically pure compound is obtained by recrystallization from methanol. It melts at 125 to 127 ⁰ C; [a] ₀ = -13 ° (in chloroform); X _max = 238 ηΐµ; loa = 4.14.

To a solution of 1.6 g of anhydrous hydrofluoric acid in 2.85 g of tetrahydrofuran and 10 ml of methylene chloride, 'on - is cooled 6O ⁰ C, a solution of 650 mg of the 16,21-diacetate is of 6a-fluoro-9j3, lljS-oxido <d ⁴ -pregnen-16a, 17a 21-triol-3,20-dione, where, in 20 ml of methylene chloride and the mixture allowed to stand for 72 hours at -1O ⁰ C. The mixture is then stirred into saturated aqueous sodium bicarbonate solution, the organic layer is separated off, washed with water, dried over sodium sulfate and evaporated. The residue is re-acetylated by heating with 3 ml of acetic anhydride and 6 ml of pyridine for 1 hour on the steam bath. The solvents are distilled off under reduced pressure and the residue is chromatographed on 30 g of silica gel. After EIuierung with methylene chloride-acetone 9: 1 and recrystallization of the residue from methylene chloride-methanol to obtain 290 mg of the 16,21-diacetate, the oa ^ a-difluoro-loa-hydroxyhydrocortisons which melts with release of solvent at 140 to 15O ⁰ C . After recrystallization from acetone-hexane gave the pure compound is obtained which is dried at 130 ⁰ C. This compound then melts at 182 to 185 ⁰ C; [α] «, = + 77 ° (in dioxane); X _max = 234ηΐµ; lo = 4.20.

Example 5

290 mg of the 16,21-diacetate des j6a, 9a-difluoro-16a-hydroxyhydrocortisone in 30 ml of tert-butanol and 0.5 ml of pyridine are refluxed with 150 mg of selenium dioxide for 53 hours under nitrogen. The reaction mixture is then cooled, ethyl acetate is added and it is filtered through diatomaceous earth (known under the trade name Celite). The solvent is distilled off under reduced pressure and the residue is triturated with water. The crystals are filtered off, washed with water and dried. The product is then chromatographed on 10 g of silica gel (silica gel). The solid fractions eluted with acetone-methylene chloride 1:19 are recrystallized from methylene chloride. 68 mg of the 16,21-diacetate of 6 ", 9" - Difluor -1 6u - hydroxyprednisolons vom

Melting point 212 to 215 ° C; [α] ₀ = + 51 ° (in dioxane); A _11111x = 238 ηΐµ; logf = 4.23.

Examples

430 mg of the 16,21 -diacetate des 6 ", 9" -difluoro-16n-hydroxyprednisolone in 15 ml of methanol and 2.2 ml of 4% strength aqueous potassium hydroxide solution are stirred at 0C under nitrogen. The crystals soon go into solution and after 30 minutes reprecipitation occurs. The mixture is then stirred for a further hour at OC under nitrogen, then neutralized with acetic acid and the methanol is distilled off under reduced pressure. The residue is rubbed with water, the crystals are filtered off, washed with water, dried and recrystallized from ethyl acetate-methanol. This gives 285 mg of the free 6a, 9 "difluoro-16a-hydroxyprednisolons mp 258 to 26O ⁰ C. The analytically pure compound melts at 266 to 268'C. [a] _D = +43 ^: (in dioxane); X _max - 238 πΐµ; log ? = 4.23. This compound contains some solvent from which it could not be stripped.

B e i s ρ i e 1 7

1 g of the 16,21-diacetate of the oa-fluoro-loa-hydroxyhydrocortisone described in Example 4 is stirred with 300 mg of chromium trioxide in 50 ml of 80% acetic acid for 1 hour at room temperature. After dilution with water, the precipitate formed is filtered off, dried and recrystallized from acetone-hexane. The 16,21-diacetate des6a-fluoro-16i.! -Hydroxycortisone is obtained; mp. 175 to 177 ^: C; [a] ₀ = 70 °; λ, _ηαχ = 237 πΐμ; log f = 4.20.

Example 8

35

140 mg of the 6'-fluorine-16'-hydroxyhydrocortisone described in Example 4 are suspended in 5 ml of acetone containing 2 drops of 72% perchloric acid. After stirring for 5 minutes, the compound goes into solution. The mixture is then stirred for a further 15 minutes, diluted with water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated. An oily residue is obtained, to which 1 ml of acetic anhydride and 2 ml of pyridine are added and the mixture is left to stand overnight at room temperature. The mixture is then diluted with ice water, the crystals formed are filtered off, washed with water, dried and recrystallized from acetone-hexane. The 6u-fluoro-1δα, 17a-isopropylidenedioxy-21-acetoxy- is obtained. I ⁴ -pregnenII / i-ol-3,20-dione of m.p. 261 to 263 ° C; [a] ₀ = + 135 ° (in chloroform); λ, _ηαχ = 236 to 238 ηΐμ; logf = 4.18.

155 mg of this compound are dehydrated in the manner described in Example 7 with selenium dioxide. The 6a-fluoro-16a, 17'-isopropylidene dioxide - 21 - acetoxy - is obtained. I ¹ · ⁴ - pregnadiene -11 / (- ol-3,20-dione of melting point 266 to 268 "C; [«] "= +97" (in chloroform); A _11111x = 240 to 242 μm; log; = 4.16.

Example 9

In the manner described in the previous example, the acetonide of 6u, 9 "-Difluor-16" -hydroxyprednisolons (see. Example 7) produced. M.p. 265

Example 10

2 g 6a, 9a-difluor-16a-hydroxyhydrocortisone (cf. Example 7) in 10 ml of pyridine are mixed with 3 ml of propionic anhydride and overnight at room temperature ditched. The mixture is then poured into water for 30 minutes Heated for 1 hour on the steam bath, cooled, and the crystals are filtered off, washed with water, dried and recrystallized from acetone-hexane. The 16,21-dipropionate des 6fi, 9u - difluoro -16 "- hydroxyhydrocortisone is obtained. After treatment with chromic acid in aqueous acetic acid in the manner described in Example 8 is obtained the 16,21 -dipropionate des 6a, 9a-difluoro-16 «-hydroxycortisone.

Example 11

2 g of the 16,21-diacetate des 6a-fluoro-9 / ?, il / i-oxido-1 ⁴ -pregnen-16u, 17a, 21-triol-3,20-dione (see Example 5) in 20 ml pure chloroform are cooled to OC and treated with 4 ml of a 0.5 η solution of dry hydrogen chloride in chloroform. The mixture is stirred at 0 ° C. for 1 hour, then water is added and the chloroform layer is separated off, washed with water, then washed with 5% strength aqueous sodium carbonate solution and finally again with water, dried over sodium sulfate and evaporated under a reduced truck. After recrystallization of the residue from acetone, the 16,21-diacetate of 6a-fluoro-9a-chloro-16a-hydroxyhydrocortisone is obtained.

This compound is then dehydrated with selenium dioxide in the manner described in Example 6. The 1-dehydrosteroid is obtained. Furthermore, the hydroxyl group in the 11 /? Position of the 16,21-diacetates of the 6-fluoro-9a-chloro-U / i-hydroxy-I ⁴ - and - ^ - compounds to the keto group is oxidized in the manner described in Example 8.

Claims (1)

Claim: Process for the preparation of 1 ⁴ -3,20-diketo-6a-fluoro-16a, 17a, 21-trihydroxy compounds of the pregnane series and fractional derivatives thereof of the general formula CH ₂ OR ₁ ^l - OR ₃ to 266 C; [>] "= +95
= 238 ιημ; log = 4.21. (in chloroform); wherein X is a hydrogen, fluorine or chlorine atom and Y is a hydrogen atom and a / i-OH group or keto oxygen, the bond between carbon atoms 1 and 2 is optionally unsaturated, R _; , R ₂ and R ₃ each represent a hydrogen atom or an acyl radical or R ₂ and R ₃ together represent the radical of a cyclic 16a, 17 "-acetal or -cal, characterized in that a 21-acylate of the 3,20-diketo 5ü-biT>m-6p'-fluoro-16<j, 17 <j-oxido-21-hydroxy-pregnans at temperatures around OC 809 559/531 is reacted under anhydrous conditions with hydrogen bromide or hydrogen chloride in the presence of acetic acid and the resulting 6 "-fluoro-16 / i-halogen- / 1 ⁴ -pregnen-17a, 21-diol-3,20-dione or 21-acylate of this compound acylated in a manner known per se in the 17- and 21-position or in the 17-position, the 17,21-diacylate obtained is treated with potassium acetate in acetic acid under reflux, then the 16-acetate-21-acylate obtained is des 6 "-Fluorl ⁴ -pregnen-16u, 17a, 21-triol-3,20-dione saponified to the free trioldione, then in the 1! // position hydroxy- lated, possibly at the same time in the 9u position introduces a fluorine or chlorine atom, optionally dehydrated in the 1 (2) position and / or the 11 / ^ '- hydroxyl group is oxidized, the latter three measures can be taken in any order and / or the 16a-acetate group and 21-acylate group saponified and re-esterified or the optionally obtained 16 ", 17", 21-triol compounds into their cyclic ones 16u, 17a-ketals or acetals transferred and optionally the 21-hydroxyl group thereupon esterified. 809 559/533 5.68 θ Bundesdruckerei Berlin