BE565975A - - Google Patents

Description

       

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   The present invention relates to novel egnadienic compounds of the formula:
 EMI1.1
 

 <Desc / Clms Page number 2>

 
 EMI2.1
 in which R1p ft2 and R3 represent hydrogen or free or esterified hydroxyls, R4 hydrogen or a methyl group, Y two hydrogen atoms, an oxo group or hydrogen and a free hydroxy group or es terified in a or ss orientation, X1 is hydrogen, a chlorine or fluorine atom and X2 is a chlorine or fluorine atom.

   Indicated ester residues are, for example, those of carboxylic acids
 EMI2.2
 saturated or unsaturated aliphatic or cyclo-allphatic, aromatic or heterocyclic dicarboxylic acids, for
 EMI2.3
 example of formic, acetic, propionic acids, butyric acids, valeric acids such as n-valeric acid or trlmethylaodtlque acid, oaproic acids, such as -tr1methyl-proplonlque acid, oenanthic, caprylic, pelargonic acids, capric, undecyllic acids.,
 EMI2.4
 for example undecylenic acid, lauric, myristic, palmitic, or stearic acids, for example oleic acid, ayclopentyl-, cyclohexyl- or
 EMI2.5
 phenyl-acetic or propionic acids, benzoic acids, phenoxy-alkanoics,

   such as phenoxy-acetic acid, p-chloro-phenoxy-acetic acid, 2,4-dichloro-phenoxyacetic acid, 4-tertio-butyl-phenoxy-acetic acid, 3-phenoxy-propionic acid, 4-phenoxy-butyric acid, furan-2-aarboxyl3ic acid, 5-tertlo-butyl-turan-2carboxylic acid, 5-bromo-furan-2-carboxylic acid, nlootlnic acids , as well as dicarboxylic acids such as

 <Desc / Clms Page number 3>

 
 EMI3.1
 oxalic, succinic and glutaric acids, substituted carboxylic acids, such as 5-keto-carboxylic acids, for example acetylacétlquep propionylacétique, butyrylacét1que or opin4u, amino acids etc.



  Instead of carboxylic acid residues, the ester residues can also be sulfonic acid residues, as well as phosphoric or sulfuric acids.



   The products of the process are characterized by high biological activity. It is appropriate to quote parti-
 EMI3.2
 particularly 6a-chloro- and 6a-fluoro-derivatives of prednisolone, prodnisone, 9a-fluoro- and o-oloroprodnisolone and -prdniona, 9a-fluoro- and ga-chaoro-16ahydroxy-prednleolone and - prednisone, as well as the corresponding 21-esters such as 21-tri-methylacetates, 21-cyclopentylproplonateze, 21-phenylproponatea and 21-esters of dioarboxylic acids, for example, aucolnic acid which show high activity in the liver glycogenic test and the particle size test.

   Against many non-halogenated corticosteroids at position 6a, the compounds
 EMI3.3
 The pregnancies indicated do not show, or at least show only a very small extent, the side effect of sodium retention.
 EMI3.4
 



  These new pregnadienic compounds are obtained by dehydrogenating 6-chloro- or 6-fluoro-A -prégnene-3,20-diones in position 1,2. The introduction of the double bond

 <Desc / Clms Page number 4>

 1,2-bran in the starting materials can be obtained by treatment with selenium compounds having dehydrogenating action or by causing aerobic cultures of 1,2-dehydrogenating microorganisms to act.



   Examples of selenium compounds which exert a dehydrogenating effect are mainly selenium dioxide, for example in sublimated form, or selenious acid. The reaction according to the process takes place in an aqueous or non-aqueous solvent. The organic solvents used above all are those which, at the temperature chosen, do not react or at least react only to a small extent with the selenium compound exerting a dehydrogenating effect.



  As solvents, tertiary alcohols such as tertiary butanol or tertiary amyl alcohol have been shown to be favorable in particular, in the presence of bases such as tertiary organic amines, such as pyridine or collidine. The reaction mixture is optionally heated under pressure or it is boiled under reflux. When the reaction is complete, the selenium formed is filtered off and the reaction product is isolated from the filtrate according to known methods.



   To introduce the 1,2-double bond microbiologically, aerobic cultures of Fusarium solani, Fusarium caucasicum, Calonectria deeora, Alternaria passiveiorae, Ophlobolus heterostrophus, Ophiobolus Miyabeanus, Didymella lycopersici or

 <Desc / Clms Page number 5>

 
 EMI5.1
 CoynebatGr1um simplexe For the implementation of the micobiological process, the substances of ddpurt can be incubated with cultures of the microorganisms indicated, under aerobic conditions known in FlleB-Mllme #. Growth takes place in surface culture or, which is technically advantageous, in is! S! @ pgë @ p culture by shaking or shaking.



  Crops contain rich carbon, notably carbohydrates, as well as, where appropriate, closed substances.
 EMI5.2
 flavoring, for example corn swelling water or beer wort, and inorganic salts. We can, therefore, use. natural, synthetic or
 EMI5.3
 seml-synthdtlqueo. A practically very simple process is deduced hereinafter without the invention being however limited by these indications: The organisms are cultivated in apparatus and under conditions identical to what is known for the manufacture of antibiotics according to the process known as submerged culture.

   When the cultures have developed, the starting substances indicated under the heading are added.
 EMI5.4
 in the form of a fine dlsperalon or an aolutlon, by oxenple in methanol, acetone or éth.yléne.élycol, and pouroult the incubation. Finally, the mycelium is separated, the filtrate and / or the mass of mycelium are extracted, and the extracts are isolated.
 EMI5.5
 compounds of A -pgnad1n of a man1ea in itself known, for example by the method of distribution -between solvents or mixtures of solvents immiscible with each other

 <Desc / Clms Page number 6>

 the others, by adsorption, chromatography, crystallization, transformation into functional derivatives, for example into esters and the like.

   These reactions can also be carried out by first separating the active enzymes from the aerobic cultures of the organisms indicated and using them to the exclusion of the growing cultures. It is thus possible, for example, to separate the mycelium formed from aerobic cultures of the indicated organisms, to suspend it in water or in buffer solutions, to add the indicated starting substances to these suspensions and to incubate.



   The products of the process which contain free hydroxyls can, in a manner known per se, be converted into their esters, in particular their 21-esters. In these esters, the acid residues are those of the acids indicated at the beginning.



   In the compounds indicated comprising esterified hydroxyls, these can, by chemical or enzymatic hydrolysis, for example using acidic or basic agents or by alcoholysis, be converted into free hydroxyls.



   The usual dehydrogenation agents, for example chromium trioxide in glacial acetic acid or the complex of chromium trioxide and pyridine, are used for the conversion of the 11a- and 11ss-hydroxycompounds into the corresponding 11-oxo-compounds.



   As starting materials for the present process,

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 EMI7.1
 6-chlopo- and 6-fluor-A4 of formula
 EMI7.2
 
 EMI7.3
 in which Rl, R2 and R3 represent hydrogen or free or esterified hydroxyls, R4 hydrogen or a methyl group, X1 hydrogen or a chlorine or fluorine atom X2 a chics * or fluorine and Y two hydrogen atoms, an oxo group or hydrogen and a free or esterified hydroxyl in a or ss orientation.



   As specific starting substances, mention will be made of
 EMI7.4
 6a-chloro- and 6ot-fluoFO-dës'ivë8 of ps'og @ µt4ron @ ,, of 17a hy6 oxy progesterone, deoxycortleosterone, 17ahydoxJ-deoxYcort1costerone, cortlconce of hyd2'ocortlaone, ga-chloro- and 9a-fluo + o-aortisone and -hydrocort1 $ one, 2a-methyl-cortisone and 2a-methylhydrocortisone, 9a-chloro- and 9a-fluoro-2a-methyl-cortlsoà-ie and hydroao1soneD of 9s-ehloFO- 'and 9a-riuo o-x6a-hy4 oxycortisone and -hydrocortloone, as well as their esters, include their 21-mono-estors and their 17a, 21-esters.

   The starting substances indicated are new; they can be prepared

 <Desc / Clms Page number 8>

 according to the process described in the BELGIUM patent application filed on March 8, 1958, under N 447.028, for: "Nieuive verbindingen van de pregaanreeks en werkwijze ter bereiding daarvan",,
 EMI8.1
 for example starting from 5a., 6a-oxldo-3., 20-dîoxo-pregnanes in which at least the oxo group in position 3 is ketalized, by treatment with hydrochloric acid or hydrofluoric acid or with substances that give
 EMI8.2
 acids of this kind, the 5a-hyd oxy-6fi-chlorinated or -6ss-fluorinated compounds which can form as intermediates being treated with strong acids.

   The starting substances for this process which contain free hydroxyls can be converted into their esters, in particular their 21-esters, in a manner known per se. In such compounds which have esterified hydroxyls, these can be converted into free hydroxyls by chemical or enzymatic hydrolysis.



   The present invention is described in more detail in the non-limiting examples which follow in which the temperatures are indicated in degrees centigrade.

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   Example l.



   A suspension of 500 mg of 21-acetate from the mixture is heated under reflux for 70 hours under a nitrogen atmosphere.
 EMI9.1
 6a-chloro-A 4-prregnene-17a, 21-diol - ,, 11,20-tr1one in 25 cm 3 of tert-butanol. anhydrous 150 mg of selenium dioxide and 0.05 cm3 of pyridine. The cooled mixture is diluted with 50 cm 3 of ethyl acetate, filtered through celite washed well with ethyl acetate The ethyl acetate solution is evaporated to dryness in vacuo and the ethyl acetate solution is covered. residue with water and filter.

   The dry precipitate is chromatographed on a column of 25 g of washed alumina and eluted with a mixture of benzene and ether, and with ether, the eluates are combined, evaporated to dryness and the residue crystallized using a mixture of acetone and hexane; this gives 105 mg of 21-acetate
 EMI9.2
 α-chloro-A '-prgnadine-17a, 21-d101 - ,, 1120-tr1one with a melting point of 217-19 C. y max. 238 mg, loglm 4.18.



   A solution of 100 mg of the above acetate in 20 cm3 of methanol is cooled with ice at 0 C and, under a nitrogen atmosphere, it is mixed with 12.5 mg (1 molar equivalent) of sodium methoxide. After having left it to stand for 15 minutes at 0 ° C., the solution is nautralised with acetic acid, concentrated to close to dryness and diluted with water. We separate the precipitate it crystallizes
 EMI9.3
 in acetonc, and thus obtains 6a-chio + o-à'-p + esnad1ene-17a, 21-diol- "120tr1one.

 <Desc / Clms Page number 10>

 



   Instead of using sodium methoxide for the saponification described above, one can also use an equal weight of sodium or potassium hydroxide.



   Example 2.
 EMI10.1
 



  500 mg of 6o-ehloro-l'-gsgrae.d.nc-17a.21-diol-3,11,20-trione are dissolved in 5 in, 3 of pyridine, and mixed with 0.5 em3 of anhydride. The mixture is kept at room temperature for 4 hours, poured into water, and the precipitate is extracted with methylene dichloride, the solution washed with dilute hydrochloric acid, water, solution. of sodium bicarbonate, then water, dry it over sodium sulfate and evaporate to dryness. Crystallization of the residue from a mixture of acetone and hexane
 EMI10.2
 gives lq 6c-ch.oro-l'-prgnadànc-lqs 21-propionate, 21-dlol-3ell # 20-trione.



    , Example ,.



   A mixture of 500 mg of 6α-21-acetate is heated for 70 hours at reflux under a nitrogen atmosphere.
 EMI10.3
 ohloro-A-prregnene-11, 17a, 21-triol-320-dlone, 25 em3 of, tert-butanol. anhydrous, 150 mg of selenium dioxide and 0.05 cm3 of pyridine. The cooled mixture is diluted with 50 cm3 of ethyl acetate, filtered through celite and washed well with ethyl acetate. The ethyl acetate solution is evaporated to dryness in vacuo and the residue is triturated with water and filtered.

   The dry precipitate is chromatographed on a

 <Desc / Clms Page number 11>

 column of 25 g of washed alumina, and elution is carried out with a mixture
 EMI11.1
 of benzene and ether and with Ildther, the eluates are combined, evaporated and recrystallized using a mixture of acetone and hexane; we thus obtain the 21-acetate of 6a-chloro-
 EMI11.2
 Al, 4¯pnad1ene-11D17a, 21-tr101-, 20-d10ne mp 204-205 C.



   Cooled with ice, at 0 C, in a nitrogen atmosphere, a solution of 100 mg of the above acetate in
 EMI11.3
 20 "cm" of methanol, then this solution was mixed with 12.5 mg (approximately one molar equivalent) of sodium methoxide. After allowing it to stand for 15 minutes at 0 ° C., the solution is neutralized with acetic acid, evaporated under vacuum to dryness, then triturated with water. The precipitate is separated and crystallized from acetone;

   we obtain
 EMI11.4
 thus the 6a-chlOO-Al, 4¯prégnad1àne-1117a, 21-trlo1 - ,, 20- dione free, melting at 195 - 1960 C
In an analogous manner, 20-ethylene is dehydrogenated. ketal of the starting material above and we get the
 EMI11.5
 6a-ChlorO-Al, 4¯Pregnad1ene -11,11a, 21-tiol-3,20-d1one 21-acetate.



  Example) 1. @ 4.



  500 mg of the 6α-chloro-pregnndiene-11,17a, 21-triol - ,, 20-dion are dissolved in 5 cm 3 of pyridine and mixed with 0.5 cc of propionic anhydride. After keeping the mixture for 4 hours at room temperature, it is poured

 <Desc / Clms Page number 12>

 in ice water and extract with methylene diahloride. The extract is washed with dilute hydrochloric acid, with water, with sodium bicarbonate solution and again with water, dried over sodium sulfate and the solvent removed by distillation. The residue is crystallized from a mixture of acetone and hexane, which gives
 EMI12.1
 fa-ahloro-l'-Pregn.d3n-11,17a-, 21-triol-3,20 dione 21-propionate.



     If, in the example above, one replaces the anhydride of the acid propioniuqe by the anhydride of trimethyl-
 EMI12.2
 acetic, cyclopentylpropionic, phenylpropionic or sucolnlque, one obtains, respectively, 21tridthylactat, 21-cyclopentylpropionatee, 21-phenylpropionate or 21hemisuccinate of fsx-ahioro-l'-prgnadins-11,17ac, 21-triol-3,20- dione.



  ¯ temple 5.,
A mixture of 500 mg of 6afluoro-cortisone 21-acetate, 25 cm3 of anhydrous tertiary butanol, 150 mg of selenium dioxide and 0.05 cm3 is refluxed for 70 hours, under a nitrogen atmosphere. of pyridine.



    After cooling, the mixture is diluted with 50 cm3 of ethyl acetate, filtered through celite and washed well with ethyl acetate. The filtrate and the washings are combined and the solution washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under

 <Desc / Clms Page number 13>

 
 EMI13.1
 reduced pressure. The residue is triturated with filtered water, the precipitate, dried and chromatographed on 25 g of washed dualumine. Elution is carried out with a mixture of bens @ n @ and dqéthoe and with 1 # ethe> ;, the eluate is combined, evaporated and cr1t & 111 0 using a mixture of acetone and hezance, the iliiol le is obtained. 6α-fluo? O-pyedKis 21-acetate <Mia with a melting point of 235 - 2.8 o C.



  Analogously, the 2X-acetate of 6afluor-â4¯pregn # n-11a11a, 21-trlo1-3,20 diane, by oxidation with selenium dioxide, is converted into 21-acetate of 6a-rluo Al, 4 ¯Pregnadiene-11, 17a 21-triol'D20-dione with a melting point of 235 - 2'7 o C. Due to this compound by treating it with a methanol solution of a base, such as almond ethylate , sodium hydE'osy <3 @ or potassium hydroxide according to ozemplou 1 and µ, we obtain 6a-riuor-à "-prégnadien-lip, 17a, z1-trioi-3, zo-dione. nnon ie 6.



  A mixture of 500 mg of 6α-fluoro-prodnlsolone, 5 em of pyridine and 0.5 em3 of acetic anhydride is maintained at room temperature for 4 hours, then the verao in ice water and extracted with methy16e d1chloure.



  The extra is washed with dilute hydrochloride # 1 acid, sodium sulfate, filtered and evaporated in a bag. The c1ta1liatton. of the residue in a mixture of acetone and hexane gives 6α-fluoro-prednlcolone acetate, melting point 235 - 2'10 C.

 <Desc / Clms Page number 14>

 



   Likewise, by reaction with anhydrides or acid chlorides having 2 to 12 carbon atoms, the corresponding 21-esters of the 6α-fluorinated derivatives of prednisone and prednisolone can be prepared.



   Example 7.



   A mixture of 3 g of 6α-chloro-acetate is heated at reflux for 70 hours under a nitrogen atmosphere.
 EMI14.1
 9g-fluoro-hédoaortispne, 150 em3 of anhydrous tertiary butanol, 900 mg of selenium dioxide and 0.3 cm3 of pyridine, cooled and diluted with ethyl acetate. The mixture is filtered through celite, washed what remains on the filter with ethyl acetate and the filtrate is evaporated to dryness in vacuo, the filtrate combined with the washing waters. The residue is triturated with water, the precipitate is separated, dried and chromatographed on 150 g of washed alumina.

   The fractions eluted from the column with a mixture of benzene and ether and with ether are combined, evaporated and the residue is recrystallized using a mixture of acetone and hexane; we thus obtain
 EMI14.2
 6a-chioro-9a-fluoro-p ednisoione 21-acetate with a melting point of 150 C, after agglomeration at 110 C.



   The oxidation of the 11 @ -hydroxy group can be carried out as follows:
To a solution of 1 g of 6a-chloro-ga-fluoro-prednisolone 21-acetate in 30 cm3 of acetic acid is added dropwise a solution of 150 mg of chromium trioxide.

 <Desc / Clms Page number 15>

 in 5 char of 80% acetic acid, while shaking and taking care that the temperature of the mixture does not exceed 20 C.

   After having kept it for 2 hours at room temperature, the mixture is poured into ice-cold water, the precipitate is separated, washed with water, dried and recrystallized from a mixture of aoetone and hexane. We thus obtain the
 EMI15.1
 SI-acetate due to 6a-chloro-9a-tluoro-prodnlsone with a melting point of 227-229 C.



   Example 8.
 EMI15.2
 



  Rotroldlt at 0 0 $ and treated under a nitrogen atmosphere with 120 g of sodium methoxide, a solution of 1 g of 6a-chloro-9a-fluoro-prednlsolone 21-acetate in 200 cm3 of methanol. After allowing it to stand for 15 minutes at o C, the mixture is neutralized with acetic acid, evaporated almost completely to aec and diluted with water. The precipitate is separated and recistallized in
 EMI15.3
 1 "a, c # tone is thus obtained free 6a-chloro-9a-tluoro-prednisolone.



   Likewise, acetoxy groups can be saponified.
 EMI15.4
 others composed of 6a-cnloX'o-9a.-h $ .logenets, such as the 6a-chloro-9a-rluorinated, 6a-chloro-ga-brominated and 6e, 9a-dichlorinated derivatives of prednisone and prednisolone.



   Example 9.



   We let it stand overnight, at temperature
 EMI15.5
 ordinary, a mixture of 1 g of 6a-chioro-9a fiuo o-p etlniBy-

 <Desc / Clms Page number 16>

 lone obtained according to the method described in the example
 EMI16.1
 previous with 20 em3 of pyridine and 1 em3 of anhydride was propionic acid, then poured into water. The product is extracted with ethyl acetant, the solution washed with water, dilute hydrochloric acid, water, sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
 EMI16.2
 of the residue in pàthanol gives 6a-ohloro-9a-fluoro-prednisolone 21-proplonate.



   Likewise, by reaction with anhydrides or acid chlorides, preferably containing 2 to 12 carbon atoms, the Si-esters of all compounds can be prepared.
 EMI16.3
 6a-ohloro-ga-halogenated obtained according to the methods described in the preceding examples.



   Example 10.



   A mixture of 500 mg of 6α-21-acetate is heated under reflux for 70 hours. Or @ an atmosphere of nitrogen.
 EMI16.4
 tluoro16a-hydroxw-cort1sone, 25 em3 of anhydrous tertiary butanol, 150 mg of selenium dioxide and 0.05 cm3 of pyridine, then cooled, diluted with 50 cm3 of ethyl acetate, filtered through celite , wash what remains on the filter with hot ethyl acetate, and combine the washings and the filtrate.

   The solvent is removed under reduced pressure, the residue triturated with water, dried and purified by chromatography on 25 g of washed alumina. Elution with a

 <Desc / Clms Page number 17>

 mixture of bensene and ether and ether, followed by recrystallization of the product obtained by evaporation of the
 EMI17.1
 solvents, gives 6ct-fluox'o-16K-hyd? cxy-prednisons 21-acetate.



     The above starting material can be prepared as follows:
A solution of g of 21-acetate is cooled to 0 C
 EMI17.2
 u "cycloethylene-b1s-oetal in 50 cm3 of pyridine, add em3 of thlonyl oh2.02.uro and osogue IÇ mix at 0 C for one hour. The shad back is in ice water, extracted with ethylene chloride.wash the extract with water, dry over anhydrous sodium sulfate
 EMI17.3
 and evaporates it to dryness.

   We abog the ra1du, and we obtain the 21-acetate of 6a-tluoro - ,, 20-bis-ethylnedioX1- â5,16pregnad1ene-21-o1-11-oneo r
Shaken for one hour, under a nitrogen atmosphere, a mixture of 5 g of this compound and 50 cm3 of a 1% methanolic solution of potassium hydroxide, neutralized with
 EMI17.4
 Acetic acid salt, diluted with water, separates by filtration, washed with water, dried and purified by reoistallization in a mixture of acetone and havana to obtain 6α-fluoro - ,, 20- bi-thYlene-d10xy-5,16¯pégnad1ene 21-01-11-one.



   A mixture of 4 g of this compound, 700 cm3 of ethanol and 100 cm3 is refluxed for 40 minutes.

 <Desc / Clms Page number 18>

 of dilute sulfuric acid (8% by volume), cooled, neutralized with solid sodium bicarbonate, concentrated to a small volume (in vacuo), diluted with 1 water, filter, dry the solid product and recrystallize it at l using a mixture of acetone and hexane, to obtain 6a-fluoro-¯4,16-pregnadiene-21-ol-3,11,20-trions.



   A solution of 3 g of the aforementioned compound, 60 cm3 of dry benzene and 2.8 cm3 of pyridine is treated with 3 g of osmium tetroxide, at room temperature, keeping for 4 days in the dark. The osmic ester is hydrolyzed by adding 150 cm3 of water, 60 cm3 of benzene, 1110 cm3 of methanol and 10 g of sodium bisulfite, then 18 g of sodium bicarbonate is added and continues to shake at room temperature for 4 hours. 200 cm3 of chloroform are added, the black precipitate is removed by filtration, then washed with 800 cm3 of hot chloroform. The filtrate and the washing waters are combined, the organic layer is separated and washed with a saturated solution of sodium chloride.

   The chloroform solution is then dried over anhydrous sodium sulfate and finally evaporated under reduced pressure. The residue is triturated with acetone to afford crude 6α-fluoro-16a-hydroxy-cortisone. By concentrating the mother liquors, an additional crystal fraction is obtained. The analytical sample is prepared by repeated recrystallization using a mixture of acetone

 <Desc / Clms Page number 19>

 
 EMI19.1
 and dehozane.



  A solution of ig of crude 6afluo o-16a-hyd oxy-eozstl * one in 10 OM3 of pwrid1n8 is cooled to 10 ° C., approximatlvoment Oe3 OM3 (1.1 mol) d8 & nhydw1d is allowed to be ropoced for 3 hours at room temperature. It is then poured into 19ea> a, extracted with dodthyl acetate, washed with hydrochloride acid dilute a solution of sodium blearbonate, then water, the echo on anhydrous sodium sulphate and evaporated to dryness. .

   The reo 1s% allization in ethyl acetate provides the 21-acetate of 6a-fiuoro-16a-hyàroxy-oo tisonee

 <Desc / Clms Page number 20>

 
Example 11
A mixture of 1 g of 6a, 9a-difluoro-hydrocortisone 21-acetate, 50 cm3 of anhydrous tertiary butanol, 300 mg of selenium dioxide and sodium is refluxed for 70 hours under a nitrogen atmosphere. 0.1 cm3 of pyridine, cooled and filtered through celite after dilution with ethyl acetate. The precipitate is washed well on the filter with ethyl acetate, the filtrate and the washings are combined and evaporated to dryness under reduced pressure.

   The residue is triturated with water, the precipitate is separated, dried and purified by chromatography; this gives the 21-acetate of 6a, '9-difluoro-prednisolone
In an analogous manner, an additional double bond is introduced between the carbon atom 1 and the carbon atom 2 in the 6a-fluoro-9a-brominated and 6a-fluoro-9a-chlorinated derivatives of hydrocortisone acetate so as to produce, respectively, the 21-acetates of 6a-fluoro-9a-bromo-prednisolone and 6a-fluoro-9a-chloro-prednisolon.



  The 6a-chlorinated derivatives of 9a-chloro- and 9a-fluoro-cortisone and-hydro-cortisone acetates are dehydrogenated in the same way to 6a-chlorinated derivatives of 9a-ohloro- and 9a-fluoro-prednisone and prednisolone acetates, respectively. .



   While stirring, treated at a temperature below 20 C, a solution of 1 g of 21-acetate

 <Desc / Clms Page number 21>

 
 EMI21.1
 6a-fluoro-9a-bromo-prednisoioné in 300 cm 3 of acetic acid, by adding dropwise a solution of 150 mg of chromium trioxide in 6 cm 3 of 80% acetic acid. The mixture is left to stand for 2 hours at room temperature and then poured into ice water.



  The precipitate is separated by filtration; washing it with water, drying it and recrystallizing it from a mixture of acetone and hexane; 6α-fluoro-9a-bromo-prednisone 21-acetate is thus obtained.



   By the same oxidation method as that described above, the 21-acetates of the derivatives are converted
 EMI21.2
 & a, 9a-dihalogens of prednisolone to those of prednisone, namely 6a-fluoro-9a-bromo-prednisone 21-acetate, 6a-fluoro-ga-chloro-prednisone 21-acetate and 21-acetate of 6a, 9-diiuoro-prednisone, respectively.



   The starting materials of the above example can be prepared as follows:
Cooled to 0 C a solution of 5 g of 6a-fluoro-hydrocortisone 21-acetate in 50 cm3 of pyridine and, while stirring, added dropwise, with stirring, 5 cm3 of thionyl chloride, taking care that the temperature of the mixture does not rise above 0 ° C. The mixture is stirred at 0 ° C. for a further 24 hours, then poured into ice-cold water and extracted with ethyl acetate. The extract is washed with water, with acid

 <Desc / Clms Page number 22>

 Dilute hydrochloric acid, with 5% sodium carbonate solution and again with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.



  Crystallization of the residue from a mixture of acetone and hexane affords the 21-acetate of 6a-fluoro-¯4.9 (11) ¯ pregnadiene-17a, 21-diol-3,20-dione.



   A solution of 2.5 g of this diene-dione in 25 cm3 of pure dioxane containing 4 cm3 of normal 0.4 perchloric acid is treated at room temperature and in the dark, with 1.2 g of N-bromoacetamide. which is added over an hour while stirring. The mixture was stirred for an additional hour and treated with 10% sodium sulfite solution until a starch potassium iodide paper test no longer gave a blue color. 30 cm3 of chloroform are then added, the organic layer is separated and washed, one after the other, with water, with a solution of sodium bicarbonate, then again with water. The extract is evaporated to dryness under vacuum in a bath with a temperature below 25 ° C.

   Trituration of the residue with about 10 cm3 of acetone and cooling gives crystalline 6α-fluoro-9abromo-hydrocortisone 21-acetate. Concentration of the mother liquors gives another fraction of crystals of the same compound.



   A solution of 2.5 g of the

 <Desc / Clms Page number 23>

 
 EMI23.1
 21-acetate of 6a-f.uoro-a-bror, o - hrdrocorà.soxe, in 10 cases of dioxane, to a mixture of., 6 g of anhydrous potassium acetate and 20 cm3 of absolute ethanol which has been before
 EMI23.2
 heated to the point of clon. The mixture is heated under reflux for 45 minutes and, while stirring, cooled and diluted with 50 cm3 of ice water. The precipitate is separated by filtration, washed with water and dried, which gives
 EMI23.3
 6α-fluoro-9p.llp-oxido-A 4¯pregn% ene-17a, 23-d.ol-3, 24-dione 2l-acetate.



   2 g of this epoxide are dissolved in 20 cm3 of pure chloroform, cooled to 0 C and mixed while stirring with 4 em3 of a 0.5 normal solution of dry hydrochloric acid in chloroform, keeping the mixture at 0 C. The mixture is stirred for one hour at this temperature, then poured into water. The chloroform layer is separated, washed with water, with a 5% solution of sodium carbonate, then again with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

   Crystallization of the residue from acetone
 EMI23.4
 provides 6a-fluoro-9a-chloro-hydrocortisone 21-acetate
2.5 g of 21-acetate are dissolved in a polyethylene container fitted with a mechanical stirrer.
 EMI23.5
 6a-fluoro-9,11-oXldo4¯pregnene-17a, 2l-diOl-3,20-dione, obtained as described above, in 40 cm3 of chloroform

 <Desc / Clms Page number 24>

 pure. The solution was cooled to 0 C and mixed over 20 minutes, while stirring, with 0.4 g of anhydrous hydrofluoric acid. The mixture is stirred for 2 hours at 0 C, then neutralized by carefully adding aqueous sodium bicarbonate. The reaction mixture is transferred to a funnel with a tap, washed with water and concentrated under reduced pressure until a bulky precipitate separates out.

   The mixture is cooled, the precipitate is separated and redissolved in 100 cm3 of hot ethyl acetate. The solution is freed by filtration of a small amount of insoluble matter, then cooled; 6a, 9a-difluoro-hydrocortisone 21-acetate is thus obtained.



   Example 12
A solution of 1 g of the 21-acetate of 6a, 9a-difluoro-prednisone in 200 cm3 of methanol is cooled to 0 ° C. and mixed with 120 mg of sodium methoxide, under a nitrogen atmosphere, taking care that the temperature or maintained at 0 ° C. After 15 minutes at 0 ° C., the mixture is neutralized with acetic acid, evaporated to dryness under vacuum and the residue is triturated with water. The precipitate is separated and recrystallized from acetone; thus obtaining 6a, 9a-difluoro-prednisone.



   By a similar method, the 21-acetoxy groups of all 5α-flucor-9a- compounds are saponified.

 <Desc / Clms Page number 25>

 halogenated compounds obtained according to the preceding examples, to form the corresponding 21-hydroxy compounds.



   A mixture of 1 g of 6α-fluoro-9-chloro-prednisolone, 20 cm3 of pyridine and 1 cm3 of propionic acid anhydride is left to stand overnight at room temperature, then poured into ice water. The product is extracted with ethyl acetate and the extract is washed successively with water, with dilute hydrochloric acid, with water, with sodium bicarbonate solution and with sodium bicarbonate. water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallizes from a mixture of acetone and hexane, thereby obtaining 6a-fluoro-9a-chloro-prednisolone 21-propionate.



   Likewise, reaction with anhydrides or chlorides of acids containing from 2 to 12 carbon atoms, for example with trimethylacetic acid, cyclopentyl-propionic acid, phenylpropionic acid or succinic acid, provides the corresponding 21-esters of all the 6a-pluoro-9a-halogen compounds prepared according to the method described in the preceding examples.



   Example 13
A medium is prepared consisting of a 0.1% yeast extract in distilled water, which is divided into

 <Desc / Clms Page number 26>

      30 cc portions in 125 cc Erlenmeyer flasks, each of these portions is inoculated with a 24 hour culture of Corynebacterium simplex ATCC 6946 in the same medium, and incubated at 28 ° C for 24 hours.



   Then added to each culture 1 cm3 of an ethanolic solution of 21-acetate of 6α-chloro-cortisone containing 10 mg of steroid; this solution is prepared shortly before use, in distilled ethanol and without heating. The incubation is continued for 48 hours while stirring and maintaining the temperature at 28 ° C. In other tests the incubation period was 72 hours, but the final result obtained is the same.



   The contents of the vials are combined, the whole is divided into three portions and each extracted 5 times with portions of 500 cm 3 of methylene dichloride.



  The extracts are reunified, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure and at low temperature. The total crude product thus obtained contains 6α-chloro-prednisone.



   The crude product is dissolved in 3 cm3 of pyridine and treated with 3 cm3 of acetic anhydride. The mixture is kept for 20 hours at room temperature, poured into water and extracted with methylene dichloride. The extract is washed with acid

 <Desc / Clms Page number 27>

 dilute hydrochloric acid, with 5% sodium carbonate solution and with water, dry it over anhydrous sodium sulfate, filter and evaporate to seo. The residue is chromatographed on a column of 15 g of washed alumina.



  Elution with a mixture of benzene and ether (80:20) provides 70 mg of the 21-acetate of 6α-chloro-prednisone, mp 212-214 C.



   If the crude product of the microbiological dehydrogenation is not acetylated, and if the crude product is purified directly by chromatography on a 15 g silica column, elution from the column with a mixture of ether and chloroform gives 6a-chloroprednisone. ,
By an analogous method, 6a-fluoro-cortisone is converted to 6a-fluoro-prednisone 21-acetate, 6a-chloro-cortisone to 6a-chloro-prednisone 21-acetate, 6a-ohloro-hydrocortisone to 6a-chloro-prednosolone 21-acetate and 6a-fluor-hydrocortisone to 6a-fluoro-prednisolone 21-acetate.



   By operating in an analogous manner, but using cultures of Dydymella lycopersici, the starting substances mentioned above can be dehydrogenated to 1,2.

 <Desc / Clms Page number 28>

 



   Example 14 ------------
A mixture of 5 g of the diacetate of the mixture is heated at reflux for 70 hours under a nitrogen atmosphere.
 EMI28.1
 6a-luoro-d-prégnéne-17a, 21-diol-3,20-dione, 250 th of anhydrous tertiary butanol, 1.5 g of selenium dioxide and 0.5 cm3 of pyridine, then cooled, diluted with ethyl acetate and filter through celite; the product which remains on the filter is washed with hot ethyl acetate and the filtrate is evaporated to dryness under reduced pressure, to which the washing waters have been added. The residue is triturated with water, the precipitate is separated, dried and purified by chromatography on 250 g of washed alumina.

   Elution from the column with a mixture of benzene and ether and with ether, and evaporation to dryness of the fractions gives crystalline products which are combined and recrystallized from a mixture of acetone and hexane; we
 EMI28.2
 thus obtains the diacetate of 6n-fluoro-A '-pregnadiene-17a, 21-diol-3,20-dione.



   A suspension of 2 g of the diacetate is mixed
 EMI28.3
 6a-fluoro-Al, 4¯pregnad1ene-17a, 2l-diOl-3,20-d1one in 20 cm3 of absolute ethanol with a solution of sodium methoxide in methanol, prepared by dissolving 120 mg of sodium in 5 cm3 of absolute methanol; the addition is carried out while stirring, under a nitrogen atmosphere, at 0 ° C., stirring is continued under a nitrogen atmosphere for 2 hours

 <Desc / Clms Page number 29>

 at 0 C, then the mixture is poured into 50 cm3 of water containing 1 cm3 of acetic acid. The precipitate is then filtered off. washing it with water, drying it and recrystallizing it from a mixture of acetone and hexane, which provides 6a-fluoro-
 EMI29.1
 A1'-Pregnadiene-17a, 21-diol-3,20-dione.



  A mixture of 1 g of α-fluoro-A1'-prenadine-17a, 21-diol-3,20-dione, 10 cm3 of pyridine and 1 cm3 of acetic anhydride is maintained for 4 hours at room temperature, then pour the mixture into ice water. The precipitate is separated, washed with water, dried and recrystallized from a mixture of acetone and hexane,
 EMI29.2
 which provides the 21-acetate of 6α-fluoro-A "'-pregna-eniene-17a, 21-aiiol-J, 20 dione
When replacing acetic anhydride with propionic anhydride in the process described above,
 EMI29.3
 the 21-propionate of 6a-fluoro-A1'-pregnadiene-17a, 21-aiol-3,20-aione is obtained.



   Example 15
A mixture of 1.5 g of 16,21-diacetate is heated at reflux for 70 hours under a nitrogen atmosphere.
 EMI29.4
 6a-ehloro-9a-fluoro-d-pregnne-11,16a, 17a, 21-tetrol-3,20-dione, 75 cm3 of tertiary butanol, 450 mg of selenium dioxide and 0.3 cm3 of pyridine. The reaction mixture is cooled, diluted with ethyl acetate,

 <Desc / Clms Page number 30>

 the filter through celite, wash the product which remains on the filter with hot ethyl acetate, combine the filtrate with the washings, evaporate the solvent under reduced pressure and triturate the residue with water .

   The solid product is separated by filtration, dried and purified by chromatography on neutral alumina.
 EMI30.1
 thus obtains the 16,2l-diacstate of 6α-chloro-9a-fluoropregnadi% ene-11P.16a, 17, 21-tetrol-3,20-dîone.



   Example 16 ----------- The mixture is heated at reflux for 70 hours, under
 EMI30.2
 nitrogen atmosphere, a mixture of 1.5 g of 16,21-diacetate of 6a-ahloro-9a-iuoro- -pregn-16a, 17a, 21-triol-3,1,20-trione of 75 cm3 of anhydrous tertiary butanol, 450 cm3 of selenium dioxide and 0.2 cm3 of pyridine. The reaction mixture is cooled, diluted with ethyl acetate, filtered through celite, the solid product which remains on the filter is washed with hot ethyl acetate, the filtrate is combined with the washing water, evaporates the solvent under reduced pressure and triturates the residue with water.

   The solid product is separated by filtration, dried and purified by chromatography on neutral alumina, in this way the 16,21-diacetate of 6a-chloro is obtained.
 EMI30.3
 9a-fluoro-GZ'-prgnadiene-6a, 17a, 21-triol-3,11,20-trione.

 <Desc / Clms Page number 31>

 



   Example 17
A mixture of 5 g of the 21-acetate of the gas is heated under reflux for 70 hours under a nitrogen atmosphere.
 EMI31.1
 6α-chloro-11-epi-hydrooortisone, 21.5 g of selenium dioxide, 250 cc of tertiary butanol and 0.6 μm of pyridine, the reaction mixture is filtered through celite, the remaining product washed. on the filter with hot tertiary butanol, combines the filtrate and the washing water and concentrates up to approximately 50 cm3, under pressure results.

   The residue is cooled, diluted with ethyl acetate, the solution washed several times with water and the washings re-extracted with ethyl acetate. The combined ethyl acetate solutions are evaporated to dryness, the residue is dissolved in 600 tons of acetone, 5 g of decolorizing charcoal is added, and the mixture is refluxed for half an hour. The carbon is removed by filtration and the filtrate is concentrated, cooled to
 EMI31.2
 that the 21-acetate of 6α-chloro-li-epi-prednisolone separates out in the crystalline state.



   Example 18
Is prepared, in an aqueous yeast medium
 EMI31.3
 (0.1), 30 cultures of Corynebaaterium simplex ATCC 6946, each culture (30 cm3) being placed in flasks

 <Desc / Clms Page number 32>

   125cc Erlenmeyer flask; for inoculation, a culture obtained in 24 hours, in an identical medium is used.



  The inoculated contents of the Erlenmeyer flasks are incubated at 28 ° C., with shaking for 24 hours.



   To each of these cultures is added 1 m 3 of ethanol containing 10 mg of 6a-chloro-ll-epi-hydrocortisone, the ethanolic solution of the steroid is prepared shortly before use, in distilled ethanol and without heating. The incubation was extended for 48 hours by continuously shaking and maintaining the temperature at 28 ° C. In other tests, the incubation time was extended to 72 hours, without changing the final result.



   The contents of the vials are then combined and the whole is divided into three portions, each of which is extracted five times with methylene chloride, using 500 cm 3 of this solvent for each extraction. The combined extracts are washed with water, dried over anhydrous sodium sulfate and the methylene chloride is evaporated to dryness under reduced pressure, at low temperature. The residue contains crude 6α-chloro-11-epi-prednisolone.



   To prepare the 21-acetate of 6a-chloro-11-epi-prednisolone, this residue is treated with 1.1 molecular equivalents of acetic anhydride in solution of pyridine at 0 C, overnight, the reaction mixture is poured.

 <Desc / Clms Page number 33>

 in water, the precipitate is separated by filtration, washed with water, dried and recrystallized from ethyl acetate. This gives the 21-acetate of 6a-chloro-11-epi-prednisoloen,
The 21-acetate of 6a-chloro-11-epi-hydrocortsion is incubated, exactly as described above, to obtain, with simultaneous saponification of the acetoxy group, the crude 6a-chloro-11-epi-prednisolone identical to the product. obtained by incubation of the free compound.



   Example 19
A mixture of 2 g of 6α-chloro-progesterone, 100 cm3 of tertiary butanol, 0.8 g of selenium dioxide and 0.5 cm3 is refluxed for 72 hours under a nitrogen atmosphere. of pyridine, cool, filter through celite, then wash the product which remains on the filter with hot tertiary butanol and combine the filtrate and the washings. The solvent is evaporated off under reduced pressure, the residue dissolved in acetone, the solution decolorized with decolorizing charcoal, dried over anhydrous sodium sulfate and evaporated to dryness. By chromatography on neutral alumina, 6a-chloro-¯1,4-pregnadiene-3,20-dione is obtained.



   In an analogous manner, 6α-chloro-17a-acetoxy-pr9ogesterone is converted to 6α-17-acetate.

 <Desc / Clms Page number 34>

 
 EMI34.1
 ehloro-L's -rrégna9iâne -. 'a-o'i - 9 20-dione ..



  Similarly, 6α-fluoro-progesterone is also converted to af, uoro-a1'-prégad.zae-3,20-dione, and α -. Uoro-.7a-actov: γ-progestrone to 6a-fluoro-A i, 4¯pregnadiene-17a-ol-3,20-dione 17-acetate.



   Example 20
A mixture of 1 g of 6a-chloro-2a-methyl-hydrocortisone 21-acetate, 50 cm3 of anhydrous tertiary butanol, 300 mg of selenium dioxide is refluxed for 70 hours, under a nitrogen atmosphere. and 0.1 cm3 of pyridine, cooled, diluted with ethyl acetate and filtered through celite; the filtrate and the washing water are then combined, and evaporated to dryness under reduced pressure. The residue is triturated with water, the precipitate is separated, dried and purified by chromatography to give the 21-acetate of 6a-chloro-2a-methyl-prednisolone.



   In an analogous way, we convert the
 EMI34.2
 6a-ahloro-2a-methyl-cortisone 21-acetate to 6a-chloro-2a-methyl-prednieone 21 acetate.


    

Claims (1)

Claims. I. A process for the preparation of novel pregnadienes, characterized in that dehydrogenates in position 1,2 of 6-chloro- or 6-fluoro-¯4-pregnene-3,20diones and, if desired, that the hydroxyl compounds obtained are esterified or that esterified hydroxyls are hydrolyzed, and / or that the hydroxyl compounds in 11 are dehydrogenated to 11-oxo compounds The present process can be further characterized by the following points: 1) For the dehydrogenation, selium dioxide or selenious acid is used. 2) Dehydrogenation is carried out with selenium dioxide or with selenious acid in the presence of a tertiary alcohol such as tertiary butanol or tertiary amyl alcohol, and of a tertiary organic base such as pyridine or collidium. 3) Dehydrogenation is carried out using 1,2-dehyudrogenating microorganisms. 4) The following organisms are used for the dehydrogenation; Fusarium solani, Fusarium caucasicum, Calone ctria deoora, Alternaria passivelorae, Ophlobolus heteroatrophus, Ophiobolus MiyabeanuB, Didymella licopersici or Corynebacterium simplex. <Desc / Clms Page number 36> 5) The hydroxyl compounds are transformed into EMI36.1 21 obtained in their 21-trim6thylacetates, 21-cyclopentylpropionates, 21-phenyl-propionates or 21-hemi-aucolnates. 6) As starting substances, EMI36.2 compounds of formula: CH 1 pi 00 T in which R1, R2 and R3 represent hydrogen or free or esterified hydroxyls, R4 hydrogen or a methyl group, X1 hydrogen, a chlorine or fluorine atom, X2 a chlorine or fluorine atom and Y two hydrogen atoms, an oxo group or hydrogen and a free or esterified hydroxyl in orientation a or. 7) As starting substances 6a- EMI36.3 chloro-progesterone and 6α-fluoro-progestdrone. 8) As starting materials 6a-chloro-17a-hydroxy-progesterone and 6a-fluoro-17a-hydroxy-progesterone, as well as their esters are used. 9). As starting substances 6a- EMI36.4 chloro-deoxy-corticosterone and 6α-fluoro-dsoxy-corticosterone, as well as their esters. 10) As starting materials 6achloro-17a-hydroxy-deoxy-corticosterone and 6a-fluoro- <Desc / Clms Page number 37> EMI37.1 17a-hydroxy-coricoaronea and their esters. II) As starting substances 6a-chloro-cortisone and 6a-fluoro-cortisone, as well as their esters are used. 12) As starting substances 6a- EMI37.2 chloro-hydrooortisone and 6a-fluoro-hydrocor'L-Pîso-ne, as well as their esters. 13) As starting substances 6a- EMI37.3 chloro-derivatives and 6α-fluoro-derivatives of ga-chlorocortisone and 9a.-fluoro-cortisone, as well as their esters. 14) As starting substances 6achloro-derivatives and 6a-fluoro-derivatives of 9a-chloro are used. EMI37.4 hydrocortisone and 9α-uoro-hydrocorisone, as well as their esters. 15) As starting substances 6a- EMI37.5 chiorodeiflivates and 6a-fluoro-derivatives of 2a-methylcortlaone, 2a-niethyl-ga-chloro-cortisone and 2a-methyl-9a-fluoro-eottisone, as well as their esters. 16) As starting substances, 6a-chloro-derivatives and 6a-fluoro-derivatives of 2a-methylhydrocortisone, 2a-methyl-9a-chloro-hydrocortisone and 2a-methyl-ga-fluoro-hydrocortisone are used , as well as their esters. 17) As starting substances 6a- <Desc / Clms Page number 38> EMI38.1 ohloro-derivatives and 6a-fluoro-derivatives of 9a-chlorol6a-hydroxy-cortisone, 9a-fluoro-16a-hydroxy-cortisone, 9a-ehloro-16a-hyàroxy-hydroaorti? one and go- fluoro-16a-hydroxyhydrocortisone, as well as their esters. II. As a new industrial product and for their uses other than in human therapy; EMI38.2 18) The compounds <e formula: Ci2R2 r R4 y Co ... R 2 3 bzz j2 in which R1 R2 and R3 represent hydrogen or free or functionally modified hydroxyls, R 4 hydrogen or a methyl group , Y two hydrogen atoms, an oxo group or hydrogen and a free or esterified hydroxyl in a or ss orientation, X1 is hydrogen or a chlorine or fluorine atom and X is a chlorine or fluorine atom . EMI38.3 19) 6a-chloro- and 6a-luoro-1-dehydro-rogesterone. 20) 6a-chloro- and 6a-fluoro-i-dehyàro-17hhydroxy-progesterone and their esters. 21) 6a-chloro- and 6a-fluoro-1-dehydrodesoxy-corticosterone, and their esters. <Desc / Clms Page number 39> EMI39.1 22) 6a-chloro- and 6a-fluoro-1-dhydro-lahydroxy-dasoxyoortisosterone, and their esters. 23) 6a-chloro- and 6a-fluoro-prednlsone and EMI39.2 their esters. EMI39.3 24) 6a-chloro- and 6a-fluoro-prednisolone and EMI39.4 their esters. EMI39.5 25) The 6α-chloro-derivates and 6α-fluoro-derivatives of ga-chloro-cortleone and 9α-fluoro-cortisone, and EMI39.6 their esters. EMI39.7 26) The 6a-chloro-derîvda and 6a-fluoro-ddrîvés of 9a-ohloro-hydrocortisone and ga-fluoro-hyâro- EMI39.8 cortisone, and their esters. EMI39.9 27) The 6a-chloro-derivatives and 6a-Pluoro-derivatives of 2a-methyl-cortisone, 2a-methyl-9a-chloro-cortisone and 2a-methyl-9a-fluoro-cortisone, and their EMI39.10 esters. EMI39.11 28) 6a-chloro-dri s and 6a-fluoro-derivatives EMI39.12 2a-methyl-hydrocortisone, 2a-methyl-9a-chloro- EMI39.13 hydrocortisone and 2a-methyl-ga-fluoro-hydrocortisone, EMI39.14 e their esters. EMI39.15 29) The 6a-chloro-deriv6s and 6a-fluoro-derivatives of 9a ± chloro-16a-hydroxy-cortisone and 9a-fluoro- EMI39.16 16α-hydroxy-cortisone, and their esters. EMI39.17 30) 6a-chloro-derivatives and 6a-fluoro-derivatives EMI39.18 9a-chloro-16a-hydroxy-hydrocortisone and 9a- <Desc / Clms Page number 40> EMI40.1 fluoro-I6a-hytira, x-hydrocortiaone, and their esters. 31) 21-trimthylaetarces, 21-cyclopentylpropionates, 21-phnylpropionateB, and 21-hemi-sucainates of the compounds indicated above. 32) The compounds obtained by carrying out the process defined under T. and 1) to 17). 33) The new compounds described in the examples.