BE562772A - - Google Patents

Description

       

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   The present invention relates to steroids and in particular to 1-dehydro-6-methyl-9 -fluorohydrocortisone, to 1-dehydro-6-methyl-9 -fluorocortisone, to their 21-esters and to their preparation processes.



   The compounds and processes of the present invention are represented by way of illustration below of formula:

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 EMI2.1
 

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In these formulas, X is a halogen whose atomic number is between 17 and 35 inclusive and R is chosen from the group comprising hydrogen and an acyl, the acyl radical being that of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing 1 to 12 carbon atoms inclusive.



   The process of the present invention comprises:
 EMI3.1
 hydration of a 21-ester of 1-dehydro-6-methylhydrocortisone or free alcohol (I), for example with sulfuric acid or, preferably, with hypohalogenous acid and then with anhydride sulphurous anhydrous to obtain the 21-ester of 6-methyl-
 EMI3.2
 17 C <-, 21-dîhydro> = y-1, y, 9 (lJ.) - prégnatriene-3> 20-dione corresponding or respectively alcohol (II).

   Addition of a hypohalogenous acid, such as hypochlorguy or hy pobroinui-L- ,, gives 6-methyl2-9 acid. -halo-11. (1, 1? il,, l.trshyclroan, .l, h-prégnadiene-3, .0- dione or free alcohol (II!), which, by treatment with a base, such than anhydrous potassium acetate, give the epoxy compound
 EMI3.3
 6-Methyl-9 (1111: 'rcyda-17, -1-dihydroxy-1,1.pregnadiene-3, .0-dione or respectively the unesterified product, respectively, represented by formula IV.

   Treatment of the epoxy compound (IV) with fluoro # <ohy.d.iic acid or other fluorine / hydric acid releasing agents produces: The physiologically active fluoro derivative, namely 6-methyl 21-acylate -9 -fluoro-11 III, 17, '\.,, Ltr.hydrxy> l, h..prêgnadiene-3, Ow.dione or triol, I.ibre, 1-dehydro-6-methyl-9 < 'X -fluorohydrocortisone, represented by formula V. Oxidation of the compound (V) eszér4-bound with chromic acid or acetic acid gives 6-methyl- 21-acylate.
 EMI3.4
 9: -fluoro-17D :,? 1-.dihydroxy-1,1-prégwaaièned3,11,0-tn.one (VI).



  Hydrolysis of the ester (VI) with a base gives the free alcohol, 6, methyl-ll '',, 21-dihydroxy-l, lè-pregnadiene-3,11,20-trione (1-de- hydro-6-methyl-9 [alpha] -fluorocortisone).

 <Desc / Clms Page number 4>

 An object of the present invention is to provide the
 EMI4.1
 new adrenocortical hormones; 1-dehydro-6-methyl-9Ci fluorohydrocortisone, 1-dehydro-6-methyl-9. -fluoroc6rtisone and their 21-esters, in particular in the 6-epimer form. Another object of the present invention is to provide a process for
 EMI4.2
 production of 1-dehydro-6-methyl-9 -fluorohydrocortisone, 1-dehydro-6-methyl-9 -fluorocortisone and their 21-esters.



  A further object of the present invention is to provide the intermediates for the production of the adrenocortical compounds.
 EMI4.3
 mentally active agents, such as 6-methylf17 oc 21-acylate. , 21-dihydroxy. ' 1,1,9 (11) -Pregnatriene-3, U-dione, 6-methyl-9 (11) 21-acylate oxydo-17 X, 21-dihydroxy-1,4-pregnadiene-3,20-dione , 9T 21-acylates. -chloro- and 9 CI: -bromo-6 methyl-11, 17 -3 <:, 21-trihydroxy-1,4-pregnadiene-3,20-dione and their free alcohols. Other objects of the present invention will be apparent to those skilled in the art.
 EMI4.4
 



  The new I-dehydro-6-methyl-9 (-fluorohydrocortisone, 1-dehydro-6-methyl-9 x-fluorocortisone and their esters, in particular the 6 .x-epimers, namely l-d6hydro-6> 1 -methyl-9 x -fluorohydrocortisone and 1-dehydro-6 x-méthyi-9 a -fiuorocortisone, are adrenocortically very active hormones, surpassing the glucocorticoid activity of the natural hormones, hydrocortisone and cortisone, and also possessing a Extremely high order anti-inflammatory activity. They are thus of interest in parenteral and topical compositions and can be provided in the form of tablets for oral administration, in combination with binding materials and carriers, such as polyethylene glycol 4000 or 6000, lactose, sucrose, etc.

   For this purpose, 1-dehydro-6 OC-methyl-9 -fluorohydrocortisone and its esters are especially useful. In topical application, substances may

 <Desc / Clms Page number 5>

 be used, in the form of ointments, lotions, jellies, creams, suppositories, candles, aqueous suspensions, etc. Instead of the. 1-dehydro-6 -methyl-9 -fluorohydrocortisone
 EMI5.1
 or I-dehydro-6, -methyl-9 ,,, X -fluoro cortisone, their 6 p-epimers can be used in therapeutically equi amounts. valid to give the same final results.



   The starting materials of the present invention are the ester of 1-dehydro-6 -methylhydrocortisone, as described in
 EMI5.2
 preparations there lef, Instead of I-dehydro-6 C {-methylhydrocortisone, the 6 -epimer can be used to give 1.-dehydro-6 -methyl-9 -fluorohydrocortisone and i-dehydro-6 fi - methyl-9 -fluorocortisone corresponding.



   In carrying out the method of the present invention
 EMI5.3
 In particular, the 21-acylate of 6-methyl-.1 17 C (, 21-trihydroxy-1,4-pregnadiene-3,20Edione (21-acylate of I-dehydro-6-methylhydrocortisone) is dehydrated in the 21 - Corresponding 6-methyl- di acylate
 EMI5.4
 17 2l.hydr ox.yl, 1;., (11) -pregn.ât.ene -3,20-dione by methods known in the art, for example by a dehydrating agent, such as phosphorus oxychloride, hydrochloric or sulfuric acid and acetic acid, by pyrolysis as shown in patents
 EMI5.5
 U.S.A. n. 6lNOeJ and 2,640,639.

   In the preferred embodiment of the present invention, the dehydration is carried out by
 EMI5.6
 reacting the II 6 -hydroxy compound with a Nhaloallide or N-haloimide in an organic base and treating the 11-hypohalite intermediate thus produced with dry s-ulfurous anhydride in an organic base. As the reagent for the production of an 11-hypohalogenite, both N-haloamide and N-haloimide are used, in which the halogen has an atomic number of 17 to 53 inclusive, preferably chlorine or bromine.

   Examples of these compounds are N-chloroacetamide, N-bromoacetamide, N-chlo- 'rosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 3-
 EMI5.7
 bromo-5,5-dimei, hylhydantoine and le., 3-dibromo-, 5-diméthylldântone

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 Ordinarily, an amount in excess of one molar equivalent, calculated based on the starting 11 ss -hydroxy steroid is used.



  The base used in the production of 11-hypohalogenite consists of tertiary amines in which the amino nitrogen is a member of an aromatic nucleus, for example pyridines, namely pyridine, alkyl-pyridines, piccoline, lutidine, collidine, conyrin, parvulin, etc., or lower fatty amides, such as formamide, methylformamide and dimethylformamide. The base is preferably employed in a large molar excess, calculated relative to the starting 11 ss -hydroxy steroid, eg 10 molar equivalents, and is preferably the sole reaction solvent. The reaction to produce 11-hypohalogenite is generally carried out under anhydrous conditions, preferably with less than 0.1 molar equivalent of water, per mole of steroid. Large proportions of water lowering the yield.

   The temperature of the reaction is between -40 and +70 C, the lower limit being determined by the solubility of the reaction and the solvents .. and the upper limit being determined by the extent of the side reaction which normally accompanies the reaction. including any halogenated compounds at elevated temperatures. Ordinarily, room temperature (20 to 30 C) is preferred for convenience and for the uniformly high yields of the desired product which are obtained at this temperature. A reaction period of between 5 minutes and 3 hours is usually used; higher temperatures, above 30 C, short reaction times are sufficient to achieve a complete reaction.



   11-ss-6-methyl hypohalogenite 21-acylate
 EMI6.1
 11 fD -17., ', 21-trihydroxy-1, y-pregnadiene-3,20-dione thus produced is then treated with anhydrous sulfur dioxide in the presence of an organic base, as described above. . Sulfurous anhydride may be in gaseous or liquid form or in the form of a

 <Desc / Clms Page number 7>

 material which in situ produces sulfur dioxide, for example an alkali metal hyposulphite. The reaction temperature ranges substantially between -40 and +70 C, preferably room temperature (2U to 30 C).

   The product thus obtained which is a 21-
 EMI7.1
 6-methyl-170e, 21-dihydroxy-1,1., 9 (11) -pregnadiene-3,2U-dione acylate is isolated from the reaction mixture by usual means, such as extraction, after the mixture reaction mixture was poured into excess water. Organic solvents, immiscible in water, such as ether, chloroform, methylene chloride, carbon tetrachloride, ethyl acetate, benzene, hexanes, etc. are used for the extraction. The extracts thus obtained are suitably washed, sedhesed and then evaporated to give the crude 21-ester of. 6-methyl-17 #, 21-di-
 EMI7.2
 1,1-hydroxy., 9 (11) -pregnatriene-3,20-dione, which is purified by common means, such as recrystallization or chromatography, if necessary.
 EMI7.3
 



  The 6-methyl-3, .7,, 21-dihydroxy-1,1., 9 (11) pregnatriene-3,20-dione 21-acylate thus obtained is converted into 6-methyl-9 (21-acylate - \ * - halo-11 li, 17,: 21., trihydroxy-l, l.-pregnadiene-3,20-dione by addition of a hypohalogenic acid, such as hypochlorous or hypobromous acid, hypohalogenous is usually added by reacting an N-halo acid amide or an N-halo acid imide with an acid to produce the hypohalo acid in situ.

   In the preferred embodiment of the invention
 EMI7.4
 tion, the steroid, a 21-ester of b-methyl-17, wl-dihydroxy-1,1,1) .- pregnatriene 3,20-dione is dissolved in an organic solvent, such as methylene chloride , tertiary butyl alcohol, dioxane, tertiary amyl alcohol, etc., and reacted at room temperature with the hypobromous or hypochlorous acid releasing agent in the presence of an acid. One such hypohalogenous acid releasing agent can be N-bro-

 <Desc / Clms Page number 8>

 
 EMI8.1
 moacetamide, N-chlor - 3.cetamide, N-bromosuccinimide, N-iodosuccinimide, etc., in the presence of water and an acid, such as perchloric acid, dilute sulfuric acid, etc.

   The reaction is usually carried out at room temperature, between 15 and 30 C, but lower or higher temperatures are effective for this process. The hypohalogenic acid releasing agent is generally used in an amount of one mole or slightly more, for example 25% more, per one mole of steroid.



  A large excess of the hypohalogenous acid releasing agent, while working, is undesirable, since the excess hypohalogenous acid tends to react at other positions of the molecule. The reaction period is quite short and can vary from about 4 to 5 minutes to 1 hour. At the end of the reaction time, the excess hypohalogenic acid is destroyed by the addition of sodium sulphite or other sulphites or hydrosulphites.

   The
 EMI8.2
 product thus obtained, a 21-acylate of 6-methyl-9 C -halo-11, 17c, 21-trihydroxy-1,4-pregnadiene-3,20-dione, wherein the halogen atom is atomic weight between 33 and 130 (atomic number 17 to 53), is isolated from the reaction mixture by adding an excess of water and extracting the compound with organic solvents or by recovering the precipitated compound by filtration . The crude product thus obtained can be recrystallized with organic solvents, such as acetone, Skellysolve B hexane hydrocarbons, etc., to give 6- 21-acylate.
 EMI8.3
 methyl-9 "<-halo-11 17 J (1-trihydroxy-l, lpregnadiene-3, 20-dione.



   The ester thus obtained can be hydrolyzed to give
 EMI8.4
 the free triol, namely 6-methyl-9 -.Y -halo-lilb, 17, 21-trihydroxy-1, Q-pregnadiene-3,20-dione, which can be re-esterified.



  The oxidation of 21-ester, 21-acylate of 6-methyl-9 halo-11) 1.> 17, X, 21-trihydroxy-1,1-pregnadiene-3,20-dione with chromic acid produces 6-methyl-9C -halo- 21-acylate

 <Desc / Clms Page number 9>

 
 EMI9.1
 17 A 'f', 1-dihydroxy, -l, 1.-prëgnadiënē3,11, 20. corresponding pharmaceutically active trione, which, on hydrolysis, gives the free triol, 6-methyl-9 y -halo-17: '{, 21-dihydroxy-1,4-pregnadiene-3,11,20-trione.



   To obtain the 9 -fluoro compounds, the intermediates
 EMI9.2
 areas 9 (1 ', 11 r. -epoxy of the compounds mentioned above are prepared, namely the 21-ester of 6-methyl-9 (<.11 -oxydo-17. "21-> dihydroxy-1, 1-Pregnadiene-3,20.dione In carrying out this reaction, a 21-ester of 6-methyl-9 = Y -halo-11 'a, 17 Cf, 21-trihydroxy-1,4 -Pregnadiene-3,20-dione is heated in solution with an average base, preferably in the absence of water to avoid hydrolysis of the ester groups.



   The bases of interest for cyclization are potassium acetate, sodium bicarbonate, sodium acetate, etc., anhydrous, potassium acetate being preferred. Solvents, such as methanol, ethanol, acetone, tertiary butyl alcohol, etc. can be used. The reaction time is between half an hour and 24 hours; usually a period of between 3 and 12 hours is sufficient.

   The 21-acylate thus ohte-
 EMI9.3
 Nu of 6-methyl-9 / 5,11 P -o-xydo-170 (, 1-hydroxy-.1,.-pregnadien-3,20-dione is isolated from the reaction mixture by diluting it with a excess water and filtering the product when it is crystalline, or by extraction with methylene chloride or other water-immiscible solvents, such as ether, Skellysolve 'B hexanes, pentanes, benzene , ethyl acetate, chloroform, carbon tetrachloride, etc. Evaporation of the
 EMI9.4
 solvent of the extracts produces 6-methyl-9/1 21-acylate; 11 / <') - oxydo-17,21-dihydroxy-1,4-pregnadiene-3,20-dione.
 EMI9.5
 



  The 21-acylate thus obtained of 6-methyl-9, 11 rI oxydo-17: \, 21-dihydroxy-l, 4-prégnadiene-3,20-dione is then reacted with 48% hydrofluoric acid. in solution. As

 <Desc / Clms Page number 10>

 solvent for this reaction, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, etc., are of interest, with methylene chloride being preferred. The reaction is carried out at room temperature (20 to 30 C), preferably with stirring. The reaction period lasts from 1 to 24 hours, a period of 1 to 12 hours usually being sufficient. At the end of the reaction, the mixture is poured into water and neutralized with a dilute base, such as sodium bicarbonate, potassium bicarbonate, etc.

   It is also possible to use an excess of strong bases. The reaction mixture is then extracted with a water immiscible solvent, such as methylene chloride, the organic layer is separated from the aqueous mixture, washed with water, dried and evaporated to give the crude 21-acylate of
 EMI10.1
 6-methyl-9 f. ' -fiuoro-11f, 17 µm, 2l-trihydroxy-1,4-pregnadiene-3,20-dione. The crude compound thus obtained can be purified by recrystallization or chromatography.
 EMI10.2
 



  The 21-esters of 6-methyl-9 c -fluoro-11, 17CX, 21trihydroxy-l ,, l-pregnadiene-3,20-dione, obtained by this process, can be hydrolyzed to give 6-methyl-9 o -fluoro-11,17 Ci (, 21-trihydroxy-1,4-pregnadiene-3,20-dione which can be reesterified, if desired, with acyl halides or acid anhydrides, in a solution of pyridine at room temperature to give further 21-esters.



   Oxidation of 6-methyl-9 -fluorodione 21-acylate with chromic acid produces 21-
 EMI10.3
 13. r, 17, 21-trihydrox-l, l-pregnadiene-3, 20. Corresponding b-methyl-9 cx -fluoro-17 J (, 2l-dihydroxy-1,4-pregra-diene-3,11 , 20-trione which can be hydrolyzed, for example with a base, such as sodium carbonate in ethanol in a nitrogen atmosphere to give the free diol, namely 6-methyl-
 EMI10.4
 9 (-fluoro-17ûf, 21-dihydroxy-1,4-pregnadiene-3,11,20-trione.



  The use of 6-methylhydrocortisone 21-acylate, instead of 1-dehydro-6.-methyl 21-acylate, hydrocortisone in the

 <Desc / Clms Page number 11>

 above sequence of reactions provides 6-methyl-9c -fluorohydrocortisone and 6-methyl-9 -fluorocortisone and their es-
 EMI11.1
 ters, these compounds having a strong anti-inflammatory and glucacorticoid activity. 6-methyl-9c '-fluorohydrocortisone and 6methyl-9 r. Fluorocortisole are, therefore, of interest for topical uses as ointments for inflammatory conditions, or for internal uses, in tablet form, for arthritis symptoms.

   Likewise, using
 EMI11.2
 With other 6-alkyl- or 6-phenyl-1-dehydrohydrocortisones as starting materials, 1-dehydra-b-alkyl-9 '--fluorohydrocortisones, 1-dehydro-6-alkyl-9 c. -fluorocortisones, their esters and their 6-aryl analogs, wherein the alkyl group is, for example, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc. , and the ally group is, for example, phenyl.



   The following preparations and examples are illustrated for the process and products of the present invention, but do not constitute a limitation thereof.
 EMI11.3
 



  Preparation 1 - 5 ex. 6 oC -oxydo-11, J, 'o, 21-trihydroxyallopré-
 EMI11.4
 genan-3,20-dione 3,20-bis- (ethylene ketal).



  To a solution of 0.901 gr of 11 μl, 17 μm, 21-trihydroxy-5-pregnene-3,20-dione 3,20-bis- (ethylene ketal) in 1 ml of chloroform was added a solution of 331 m1 perbenzoic acid in 5.19 ml of chloroform. The resulting solution was allowed to stand in a refrigerator (about 4 ° C) for a period of 24 hours, and then at room temperature for a further 72 hours. The reaction solution was then washed with 5% sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to.

 <Desc / Clms Page number 12>

 dryness to give 1.031 g of crude solid.

   Recrystallization from acetone gave 431 g of material having a melting point of 230 to 247 C. The mother liquor, after evaporation to dryness, was dissolved in methylene chloride and chromatographed on 25. gr of acid washed alumina. The column was developed, with three fractions, each comprising methylene chloride plus 5,10,15,20y25 and 50% acetone, acetone, and acetone + 5% methanol.

   The eluate obtained with acetone + 5% methanol gave an additional 279 g of the high-melting point product. The high melting point material, namely 5 #, 6 # -oxydo-11 ss, 17 #, 21-trihydroxyallopregnane-3,20-dione 3,20-bis- (ethylene ketal), was recrystallized three times. with acetone and methanol to give a pure product having a melting point of 263-268 C. Other lower melting eluate fractions contained the 5 ss, 6 ss-isomer.



   In the same way as in Preparation 1, other 5 #, 6 # -oxydo-11, 17 #, 21-trihydroxyallopregnane-3,20-dione 3,20-bis- (alkylene ketals) can be prepared in reacting hydrocortisone diketals, in which the ketal group has been formed by reacting the steroid 3,20-dione with ethylene, propylene, 1,2-, 1,3- or 2,3-butylene glycol or pentane:

  -, hexane. , heptane- or octanediols in which the alcohol groups are in neighboring positions, such as 1,2 - 2,3- 3,4, etc., or separated by a carbon atom, such as 1-3, 2 -4, 3-5, etc., with an organic peracid, such as performic, peracetic, perbenzoic, monoperphthalic, etc. acids. For the purposes of the invention, starting compounds having ethylene ketal groups are preferred, since these ketals are generally more readily prepared in high yield than the ketals produced by the reaction of 3,20-diketo compounds with. des. :: upper ane- diols.

 <Desc / Clms Page number 13>

 
 EMI13.1
 



  Preparation 2 - 5 (j, 11, 17 fl 21-tetrahydroxy-6 'Pdlemethyl-allopregnane-3,20-dione 3,20-bis- (ethylene ketal).



   A solution of 1.115 gr of 5 #, 6 # -oxydo-11,
 EMI13.2
 17,21-trihydroxyallopregnane-3,20-dione 3,20-bis- (ethylene ketal) in 165 ml of tetrahydrofuran (the tetrahydrofuran being dried by distillation over lithium aluminum hydride) was added dropwise. to a solution of 95 ml of methyl magnesium bromide in ether (the magnesium bromide having a four times molar concentration). To this mixture was added 575 ml of benzene and the reaction mixture was then stirred and refluxed for 26 hours.

   After cooling, the reaction mixture was poured into 700 ml of ice-cold saturated ammonium chloride solution, stirred for a period of 30 minutes, and the benzene layer was separated from the aqueous layer. The aqueous phase was extracted with three 200 ml portions of ethyl acetate, and the extracts were added to the benzene shower. The combined benzene-ethyl acetate solution was then washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 1.314 g of crude solid. Trituration of this material with ether left 1.064 g of crystalline product having a melting point of 2210 to
 EMI13.3
 2300.

   Recrystallization of this material gave 5 t, 11, 17 cy, 21-tetrahydroxy-6 -methylallopregnane-3,20-dione 3,20-bis- (ethylene ketal) having a melting point of 2280 to 233 and a rotation. [#] of -11 in chloform.



   D
 EMI13.4
 Analysis: Calculated for C6H1r0 $: C = 64.70; H = 8s77 Found: C = 64.29; H, 8.69.



  Preparation 3 - 5 0 (11, 17 Cx, 21-tetrahydroxy-6 r '-ethylal-lopregnane-3,20-dione 3,20-bis- (ethylene ketal).



   In the same way as in preparation 2, the 5 #, 6 # -
 EMI13.5
 oxido-11, 17 li ', .1.-trihydroxyallopregnane-3,0-dione 3,20-bis- (ethylene ketal) was reacted with ethyl bromide.

 <Desc / Clms Page number 14>

 
 EMI14.1
 gnesium in ether solution to give the corresponding 5,11,17 ° C 1-tetrahydroxy-6 .ethylallopregnane-3,0-dione 3, bia (ethyl ketal).
 EMI14.2
 



  In the same way as in preparations 2 and 3, other 5 oc) 11 0-3.7 o (, 21-tetrahydroxy-6 p.lky.3.alloprégnarre- 3,20-diane 3, 0-bis - (h.plene ketals,) are prepared by .reaction of 5 f4,, etol oxido-11 e, 17 0 <. i l-trihydroxyallopregne-3, a0dione 3) 20-bis- (ethylem ketal) with an alkyl metal or an aryl metal, in particular a.

   metal alkyl halide, such as a Grignard reagent, for example methyl, ethyl, propyl, iodides and bromides, butyl, isobutyl, pentyl, hexyl and phenyl magnesium or the bromides or iodides of alkyl cadminm
 EMI14.3
 and alkyl and phenyl alcium Are representative of the 6-alkylated allopregnaned thus prepared on 5 0 (', 11 A, 17 o, 21-tetrahydroxyb -propylallopregnane-3,0-dione 3,20-bis - (ethylene ketal), 5 D (, 11 fi, 17 ex 21-tetrahydroxy-6 / -butylailopregnane-3,20-dionEt 3,20-bis- (ethylene ketal), 5 oc, 11/2), 17 OC, 21-tetrahydroxy-6 J -isobutylallopregnane-3, .0-dione 3,20-bis- (ethylene ketal), 5. cc, 11, 170 <.

   , 21-tetrahydroxy-6 a '-pentylallopregane-3, 0dione 3,20-bis- (ethylene ketal), 5 ex, 11, 17 q, 1-tetrahydrd-xy-6 -hexylallopregnane-3,20-dione 3 , 20-bis- (ethylene quoted, 5û (, 11, 17 c, 1-etrahdroXY-6 f.> -PhenYlallopregnane-, Odione 3,20-bis- (ethylene ketal), etc.



  Preparation 1 "- '5 C \, 11%, 17 O {, 21-tetrahydroxy-6 -methylal1 lopregnane-3,20-dione.



   We prepared a solution containing ².68 mgr of 5 #, it
 EMI14.4
 fi, 17, 21-tetrahydroxy-6 fl -methylallopregnane-3, -dione 3,20 'bis- (ethylene ketal), 38 ml of methanol and 7.7 ml of 2N sulfuric acid. This solution was refluxed for a period of 30 minutes, then neutralized with dilute 5% sodium bicarbonate solution (about 100 ml) and concentrated under pressure.

 <Desc / Clms Page number 15>

 
 EMI15.1
 icdirii6c sion reduced at 55 C to approximately 35 ml in volume. A pro-
 EMI15.2
 The product crystallized on cooling and was recovered by filtration.

   This product was recrystallized from Skellysolve B acetone hexanes to give a pure analytical sample of
 EMI15.3
 5e, 11, 17 ° C, 1tetrah.ydroxyw6 -methylallopregnane-3,20dione having a melting point of 20 'to 244 "(decomposition) and a D rotation of' <-40 in dioxane.



  Analysis: Calculated for CHE 6: C = 66.98; H = at, 69.



  Found C, 66.04; H, 8.86. frarati <? g¯5 '"5, 11 fi, 17 o, 21-tet-rahydroxy-6 f) -ethyl-
 EMI15.4
 allopregnan-3,20-dione.
 EMI15.5
 



  In the same way as in preparation 4 the 5 0 (, II ?, 17 ci .., Z.dtetrahydroxy.6 .ethylallopregnane-, 0-dione 3,20
 EMI15.6
 -bis- (ethylene ketal) was hydrolyzed with sulfuric acid
 EMI15.7
 diluted in ethanol solution to give 5 111 A, 17 0.



  21-tetrahydroxy-6 f-ethYla.llOPégnane-J, 20-dione.



  In the same way as in Preparations IF and 5, the hydrolysis of another 5 t, 11,, 17 0: .., 21-tetrahydiNoxy-6 / $ -al- 'lcy] .ailopré; n? Ne -3,20-dione 3t20-bis- (ethylene ketal), as well as 6 -ākylallopregnane3, 0-dione 3, Jb.s4 (ketals) in which the ketal group is none other than ethylene, gives the 5 -;

   Corresponding 11, 17 c, 1-tetrahydroxy-6 -alkylallopregnane-3} 30 "diones, such as, for example ;, la 5 and II P, 17 DG, 21tetrahydroxr-6 -propyiaîlopregnane-3,0-dione, la 5 oC 711P, 17 21-tetrahydroxy-6 6 "- -butylallosox egan-3,20-dione, 5 oc. , 1lf!> 17 y,, 1-tetrahydroxy.-6 Ji-içobutyla.lopregnane-3, .. dione, the 5 c {, II j3, 17 ° C, 1. tetrahydroxy.-6, i-perWylallopregnan-3,0-dione, la 5 0 (, 11 fi, 17 oC, 2l-tetrahydroxy-6 fi -: hexiylallopregnane-3,? 0dione, la 5 pC, 11J, 17 bG , 1-tetrahydrôxy - 6 -phenylaztopxgnane-3,20, -dione
 EMI15.8
 etc. '
 EMI15.9
 Preparation 6 - 6 c (-Methylhydrocortisone. '
 EMI15.10
 A stream of nitrogen is bubbled through a
 EMI15.11
 429 mgr solution of 5 ÙC, 11, 17oC,:

  21-tetrahydroxy-6) 3 '-methyl *

 <Desc / Clms Page number 16>

 allopregnane-3,20-dione contained in 100 ml of denatured alkocl alsolute, over a period of 10 minutes "To this solution was added 4.3 ml of normal 0.1 caustic soda solution which had also been treated with The mixture was allowed to stand in a nitrogen armosphere for a period of 18 hours and then it was acidified with acetic acid and concentrated under reduced pressure at 55 ° C. to dryness.
 EMI16.1
 417 mgr etaikecrystallized with acetone-hexanes Skellysolve B to give in two crops zorg mgr of 6 o - methylhydrocortisone melting between lbl and 194 ° C. An analytical sample melting at 203-208 G and consisting of 6 -methylhydrocortisone was prepared.



  Analysis: Calculated for GH3305 C = U'13 â to, 5?
Found: C = 7C, 32; H == 8.50.



   The mother liquors further contained 6 # -methylhydrocortisone, significant amounts of 6 ss -methylhydro-cortisone, which can be isolated by countercurrent processes, paper chromatography, recrystallization, and the like. means known in practice.
 EMI16.2
 



  The esterification of 6 0Z. -: Rethylhydrocortisone with acetic anhydride in pyridine at room temperature produced 6 'X' -methylhydronortisone 21-acetate having a melting point of 2l3-2llyoG.



  Analysis: Calculated for 0 "" 1 H "I. 0 :,: C 6 &, $ '' j; H = eel9 Found: C = bzz0; Il = $, lyl.



  Preparation 7 -, 6 (d -l, Iethylhydrocortiso #.



  A solution was prepared containing 27.5 g of 5, ±, 11, 17, 21-tetrahydroxy-6 (,, - methya-loprecnane-3,20-dione in 6500 ml of ethanol denatured with methanol. The solution was liberated from the oxygen of the air by bubbling oxygen-free nitrogen over a period of 15 minutes To this solution was added a 0.1 normal caustic soda solution (235 ml) prepared.

 <Desc / Clms Page number 17>

 rea being free of oxygen from the air. The solution was allowed to stand at room temperature (about 22-24 ° C) in an atmosphere of inert nitrogen for a period of 20 hours and was then acidified with 14 ml of acetic acid.

   The acidic solution thus obtained was evaporated at about 50-60 C in vacuo, the residue thus produced was dissolved in 200 ml of ethyl acetate and 200 ml of water, the aqueous layer was separated from the organic layer and discarded. , the organic layer was washed with 350 ml of a 5% aqueous sodium bicarbonate solution, then three times with water and then dried over / over anhydrous sodium sulfate and concentrated to a volume of 180 ml. . After cooling the 160 ml of solution in the refrigerator (about 5 ° C.), the solution was filtered, giving 11.9 g of material.

   This material
 EMI17.1
 re was r5d. dissolved in U18 500 ml ethyl azetate, ethyl acetate solution was concentrated to 150 ml, refrigerated
 EMI17.2
 as above, to give 6.15 gr of crude 6-methylhydrocortisone having a usion point of 2: 0 -2H G.



  Recrystallization of crude 6-fi-niethylhydrocortisone three times from ethyl acetate gave an analytical sample of 6 µmethylhyarocortisone having a melting point of 2.23 .2: 7 C, an M rotation of +105 in acetone. ; absorption in ultraviolet D 95% ethanol of 21-3 mmi- max; aM = 14,500.
 EMI17.3
 Analysis: Calculated for C22H) 205: C = '01'J; H = 8e57 Found C = 70.54;

   H = 8.91 Preparation 8 - 6 (Y -Ethylhydrocortisone
In the same way as in Preparation 6, 5 cc, 11 ss, 17 N, 21-tetrahydroxy-6 # -ethylallopregnane-3,20-dione was treated with a solution of caustic potassium hydroxide in mete.
 EMI17.4
 thanol to give at room temperature the 6 QI ..ethylhydrocortisone having a melting point of 223 -226 C and a Î1 EtOH max
 EMI17.5
 2il-3 millimicrons;

   E = 11, .525.

 <Desc / Clms Page number 18>

 In the same way, a dehydration, with un-hydroxy-
 EMI18.1
 of metal alualinxn alcoholic solution, -other 5.X, 11, 17, 21-tetrahydroxy- -alkylallopregnane-3, .G-dioies produced the 6: t -alkyl-11] 1, 17, .x '21 -trihydroxy-6-all-, yl-Ik-pregnene-3,20diones corresponding, such as 6,1 -propylhydrocortisone, 6 -butylhydrocortisone, 6 -isobutylli7ydrocortisone, -6 .x -pentylhydrocortisone, 6 <x -hexylhydrocortisane, 1α - 6, Y phenylhydrocortisone, etc.



  Preparation 9 - 1.-lhydro-6 -methylhydrocortisone (9 'eth3a.



  11 P 17 - '(1'-trihydroxy-1, t .-. Preg, nadiene-3, G-dione).



   Six 100 ml portions of medium, in 250 ml Erlenmeyer flasks, containing 1% glucose, 2% corn maceration liquor (60% solids), and tap water were set at a pH of 4.9. This medium was sterilized for 45 minutes at 15 pounds per square inch of pressure and seeded with a day or two growth of Septomyxa affinis A.T.C.C.



  6737. The Erlenmeyer flasks were shaken at room temperature (about 24 ° C) for a period of three days. At the end of this period, this volume of 600 ml was used as an inoculum for the liter of the same glucose-corn maceration liquor medium which, in addition, contained 10 ml of an anti-foam (a mixture of oil of bacon and octadecanol). The fermentation apparatus was placed in a water bath, set at 28 C, and the contents were stirred (300 rpm) and aerated (0.5 liters of air / 10 liters of liquor).

   After 17 hours of incubation, when good growth was developing and the acidity rose to a pH of 6.7,
 EMI18.2
 two grams of 6 <1-methylhydrocortisone plus 1 gr of 3-ketobisnor-t-ch.ên-.2-al, dissolved in 115 ml of dimethylformamide, etaieni added and the incubation (conversion) was carried out at the same temperature and at the same aeration for 24 hours (final pH of 7.9).

 <Desc / Clms Page number 19>

 



  The mycelium (56 g dry weight) was removed by filtration and the steroid material was extracted with methylene chloride, the extracts were evaporated to dryness and the resulting residue was subjected to chromatography on a column of magnesium silicate. synthetic Florisil. The column was packed with 200 g of Florisil and was developed with 5 fractions of 400 ml, each of methylene chloride, of 9/1, 8/2, 7/3, 1 Skellysolve B-acetone mixtures. / le and methanol. The fraction eluted with the Skellysolve B-acetone mixture (7/3) weighed 1.545 g and, on recrystallization from acetone, it gave, in three harvests, 928 mgr of a product having a melting point. from 210-235 C.



  The sample prepared for analysis melted at 245 -247. The [x] rotation was +83 in dioxane.



   D Analysis: Calculated for C22H30H5: C = 70.56; H = 8.08
Found: C = 70.53; H = 7.94
 EMI19.1
 \ EtOH = 81 millimicrons; (11, * to 75, max
Max line infrared absorption in a suspension in Nujol mineral oil gave:
 EMI19.2
 
<tb>
<tb> OH <SEP> 3430 <SEP> 3330 <SEP> 3180 <SEP> cm-1
<tb> 20-keto <SEP> 1706
<tb> 3-keto <SEP> conjugate <SEP> 1645
<tb> double <SEP> link <SEP> 1.4 <SEP> 1592
<tb>
 
Instead of being by fermentative dehydrogenation, 1-dehydro-6 # -methylhydrocortisone or its ester can be obtained by dehydrogenation of 6 # -methylhydrocortisone or an ester thereof with selenium dioxide, such as shown in preparation 10.



   Preparation 10 - Dehydro-6 # -methylhydrocortisone acetate
A mixture of 70 mg of 6 # -methylhydrocortisone acetate in 4.5 ml of tertiary hutyl alcohol and 0.45 ml of acetic acid, and 24 ml of selenium dioxide was heated to

 <Desc / Clms Page number 20>

 75 C and stirred for 24 hours. Then another 24 mgr portion of selenium dioxide was added and heated to 75 ° C, and stirring was continued. Then the mixture was cooled, filtered to remove selenium dioxide and evaporated.

   Chromatography on paper showed that the residue contained about 50
 EMI20.1
 at 55 °; 1-dehydro-6 Q-methylhydronortisone acetate, which can be recovered from the residue by recrystallization and chromatography.



   Infrared absorption in a suspension in Nujol mineral oil gave; OH 3400 3280 cn-1 11-and 20-keto 1722 1700 3-keto conjugate 1655 double bond 1.4 1611 1597
 EMI20.2
 Preparation 11 - 1-Dehydroxy-b-methylhydrocortisone
Similar to Preparation- * 9, fermentation of 6 ss -methylhydrocortisone with Septomyxa affinis in nutrient medium with 11 ss, 21-dihydroxy-4,17 (20) -prregna-
 EMI20.3
 diene-3-one, as a promoter gave 1-dehydrm-6 rû-ethylhydro-cortisone.



  Preparation 12 -
In the same way as in Preparation 11, by fermentation with microorganisms of the genera Corynebacteriurti, Didymella, Calonectria, Alternaria, Colletotrichum, Cylindrocarpon, Ophiobolus, Septomyxa, Fusarium, Listeria or Erysipelothrix. a) 6-ethylhydrocortisone (6- or 6 ss -epimer) had the corresponding 1-dehydro-6-ethylhydrocortisone; b) 6-propylhydrocortisone gave 1-dehydro-6propylhydrocortisone;
 EMI20.4
 c) 6- # ut / ylhyàrocoitisone gave 1-dehydro-6-butylhydrocortisone; d) 6-hexylhydrocortisone gave 1-dehydro-6hexylhydrocortisone;

 <Desc / Clms Page number 21>

 e) 6-phenylhydrocortisone gave 1-dehydro-6-phenylhydrocortisone.



   In the same way as Preparations 9 and 11, other 1-dehydro-6-alkyl- and 1-dehydro-6-arylhydrocortisones are produced by subjecting the corresponding 6-alkyl or 6-aryl hydrocortisone or their esters to fermentation, especially by Corynebacterium simplex or Septomyxa affinis with or without steroid promoters, such as 3-ketobisnor-4-cholen-22-
 EMI21.1
 al, 11 fa 21-dihydroxy-l, lr, crude 1'j (0) -pregnatriene-3-.one, 3-ce.tobisnor-1, -cholenic acid and progesterone.

   Representative 1-dehydro-6 C-alkyl- and 1-dehydro-6 ty, -arylhydrocortisones thus produced are: 1-dehydro-6 <-ValéryIhydrocortisone, 1-.dehydro-6.-Hexylhydrocortisone, 1-dehydro -6 0-iso butylhydrocortisone, 1-dehydro-6 # -isopropylhydrocortisone, etc.
 EMI21.2
 Preparation 1 - 1-Dehydro-6o4 -methylhy-drocortisone acetate.



   A mixture was prepared containing 500 mgr of 1-dehydro-6 # -methylhydrocortisone in ml of pyridine and 5 ml of acetic anhydride. The mixture was kept at room temperature (22-24 ° C) for a period of 6 hours, then poured into 100 ml of ice water and the resulting aqueous mixture was extracted with 3 portions of 25 ml of methylene chloride.

   The combined methylene chloride solutions were washed, dried over sodium sulfate and evaporated, and the residue thus obtained was recrystallized three times from a mixture of acetone-hexanes Skelly-solve B to give the pure 2i-acetate of 1-dehydro-6 0 (. "-Methylhydro-
 EMI21.3
 cortisone (6-methyl-11 P 17 0 (-dihydroxy-1..acetoxy-1, lpregnadien-3,20-dione.



  Preparation 14 -
In the same way as in Example 13, by treating in a solution of pyridine:

 <Desc / Clms Page number 22>

 
 EMI22.1
 a) 1-dehydro-6C .'-methylhydrocartisone with propionic ltanhydride, 1-dehydro-6 # -methylhydrocortisone 21-propionate was obtained;
 EMI22.2
 b) 1-dehydro-6 'x-methylhydrocortisone with an-21-
 EMI22.3
 Butyric hydride, 1-dehydra-6-methylhydrocortisone / butyrate was obtained; c) 1-dehydro-6 # -methylhydrocortisone with an-
 EMI22.4
 valeric hydride, one obtained the 21-valerate of 1-dehydro-6 c (methylhydrocortisone; d) the 1-dehydro-6 -'k -methylhydrocortisone with, hexanoyl bromide, one obtained the 21-hexanoate of 1-hydro- 6 # - methylhydrocortisone;

   
 EMI22.5
 e) 1-dehydro-6 ′ X -methylhydrocortisone with octanoyl chloride, 1-dehydro-6x methylhydrocortisone 21-octanoate was obtained; f) 1-dehydro-6 # -methylhydrocortisone with benzoyl chloride, 1-dehydro-6 o 21benzoate (methylhydrocortisone was obtained;
 EMI22.6
 g) 1-dehydro-6 -methylhydrocortisone with phenyl-acetyl oloride, 1-de-hydro-6 # -methylhydrocortisone 21-phenylacetate was obtained;

   h) 6 # -ethylhydrocortisone with ac- anhydride
 EMI22.7
 tick, 1-dehydro-6 acetate was obtained. -ethylhydrocortisoner
In a similar manner to Preparations 13 and 14, other starting materials can be made by esterifying 1-dehydro-6-alkylhydrocortisone or 1-dehydro-6-arylhydrocortisone in a solution of pyridine, with halides. acyl or acid anhydrides. In a similar manner, esters of 6-alkylhydrocortisone and ..-6-arylhydrocortisone can be prepared and used in the examples of the present invention.



  Starting materials thus prepared are acetates, propio-

 <Desc / Clms Page number 23>

 nates, butyrates, isobutyrates, valerates, isovalerates, hexanoates, heptanoates, octanoates, benzoates, phenylacetates, -cyclopentylpropionates, phenylpropionates, laureates, hemisuccinates, tartrates, maleates, toluenesulphonates, etc., of 1-6-alkyl dehydro-dehydro 1-dehydro-6-arylhydrocortisone hydrocortisone /, wherein the alkyl group is methyl, ethyl, propyl, butyl, pentyl or hexyl and the aryl group may be phenyl.
 EMI23.1
 



  ExEiYIPLE 1 - 21-acetate 6 G -methyl-17 ty, 21-dihydroxy1,4, 9 (11) -pregnatriene-3, .20-dionate.



  Has a solution of 530 mgr of 21-acetate of 6 ± 4-methylil, 17, 21-trihydroxy-l, 4-pregnadien-3,20-dione (21-acetate of 1-dehydro-6 (X -methylhydrocortisone) in 5 ml of pyridine, in a nitrogen atmosphere, 225 mgr of N-bromoacetamide were added. After standing at room temperature, under nitrogen, for a period of 30 minutes, the reaction solution was cooled to 10 to 15 C and after stirring sulfur dioxide was passed over the surfaces until the solution did not color with the acidified starch-iodine paper. During the addition of the sulfur dioxide, the reaction was getting hot.



  The temperature was maintained at 30 ° C. by external cooling and by varying the rate of addition of sulfur dioxide. After standing at room temperature for a period of 15 minutes, the reaction mixture was poured into 30 ml of ice-water and the resulting gummy precipitate was extracted with 50 ml of ether. The ether extract was washed with 5% hydrochloric acid solution and with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 371 mg of material. This material was recrystallized from Skellysolve B acetone-hexanes to give 318 mgr of 6 # 21-acetate -
 EMI23.2
 methyl-17,21-dihydroxy-l, t, 9 (11) -pregnatriene-3,20-dione having a melting point of del ... 191.5 C.



  EXAMPLE 2 - 21-Acetate of 6 (u -methyl-9 -bromo-11,170; ', 21-

 <Desc / Clms Page number 24>

 
 EMI24.1
 trihydroxy-1,4'-Pégnadiene-3,20'-dione (1-tohydro-6 X-methyl-9 # -bromohydrocortisone 21-acetate).



   Has a solution of 332 mgr of 21-acetate of 6 @ -methyl-17a, 21-dihydroxy-1,1,9 (11) -pregnatriene-3,0-dione in 5 ml of methylene chloride and 9.9 ml of tertiary butyl alcohol,
 EMI24.2
 Add a solution of 0.3 ml of 72% perchloric acid in 5 ml of water, then a solution of 142 ml of: ü-bromoacetamide in 2.5 ml of tertiary butyl alcohol. After mixing the reaction mixture for 15 minutes, a solution of 142 mgr of sodium sulfite in 7 ml of water was added and the reaction mixture was concentrated to a volume of about 25 ml under reduced pressure at about 60 C. At this point, crystallization began.



  The concentrate was cooled in an ice bath with stirring and 35 ml of water added. After stirring for a period of 20 minutes, the crystalline product was isolated by filtration, the crystals were washed with water and air dried to obtain.
 EMI24.3
 give 406 mg of 6 IX -methyl-9 -bromo-11 '21-acetate, 17, 2l-trihydroxy-1,4-pregnadiene-3,20-dione (1-dehydro-6tX 21-acetate - 9-methylbromohydrocortisone) having a melting point of 173 -177 0 (with decomposition).



  EXAMPLE 3 - 21-6'-911 P -oxydo-17: ¯ 1-dihydroxy-1,1.-pregnadiene-3, 20-dione acetate.



  To a solution of 406 mg of 6 Ct 21-acetate -methyl-9 a -bromo-11, 17 0 (,, 21-trihydraxy-1,1-prFgnadiene-3,, 20-dione in 15 ml of acetone, 406 mg of potassium acetate were added and the resulting suspension was heated under reflux for a period of 18 hours. The mixture was then concentrated to 5 ml volume on a water bath and then 10 ml of water was added. 'water.



  This caused the potassium acetate to go into solution and the steroid product to crystallize. The product was filtered off and recrystallized from acetone to give in two re-
 EMI24.4
 coltes 232 mgr of 6 x -me 21-acetate; 9-hyl: -: U. - -oxydo-17 <.ī, 21-dihydroxy-l, lr..pregnadiene-3,0.-dione having a melting point

 <Desc / Clms Page number 25>

 from 255-263 C.
 EMI25.1
 



  EXAMPLE 4 - 6, - -methyl-9 (X-fluoro-11p, 17 6 (21-trihydroxy-1,4-pregnadiene-3,20-dione (1-dehydro-6 ct 21-acetate) acetate -methyl-9 x -fluorohydrocortisone).



  To a solution of 230 mg of 6 C 21-acetate (-methylJ '9, 11 -oxydo.-17 ,;, 21-ihydroxy-l, lr-pregnadiene-3,0-dione in 5 ml of chloride of methylene, 1.2 ml of a 48% hydrofluoric acid solution was added. The two-phase mixture was stirred for a period of 20 hours, then diluted with 15 ml of methylene chloride and carefully poured into 40 ml. of water containing 4 g of sodium bicarbonate After shaking to neutralize the excess hydrofluoric acid, the methylene chloride was separated and the aqueous phase was extracted with an additional quantity of methylene chloride.

   The combined methylene chloride solution (about 75 ml) was dried over anhydrous sodium sulfate, diluted with 25 ml of ether and subjected to chromatography on 20 g of Florisil synthetic magnesium silicate.



  The column was eluted as follows.



     TABLE 1
 EMI25.2
 
<tb>
<tb> Fraction, <SEP> n <SEP> Solvent.
<tb>



  1 <SEP> Methylene ether <SEP> <SEP>
<tb> (100 <SEP> ml) <SEP> (3/1)
<tb> 2-6 <SEP> Hexane <SEP> Skellysolve <SEP> B <SEP> + <SEP> acetone <SEP> (12%)
<tb> (40 <SEP> ml <SEP> each)
<tb> 7-16 <SEP> Hexane <SEP> Skellysolve <SEP> B <SEP> + <SEP> acetone <SEP> (15%)
<tb> (40 <SEP> ml <SEP> each)
<tb> 17-21 <SEP> Hexane <SEP> Skellysolve <SEP> B <SEP> + <SEP> acetane <SEP> (20%)
<tb> (40 <SEP> ml <SEP> each)
<tb> 22-26 <SEP> Hexane <SEP> Skellysolve <SEP> B <SEP> + <SEP> acetone <SEP> (25%)
<tb> (40 <SEP> ml <SEP> each)
<tb> 27-30 <SEP> Hexane <SEP> Skellysolve <SEP> B <SEP> + <SEP> acetone <SEP> (50%)
<tb> (40 <SEP> ml <SEP> each)
<tb>
 
Fractions 2 to 13 inclusive, containing a total of 140 mgr, were combined,

   evaporated and the residue thus obtained was recrystallized from acetone-hexane Skellysolve B and in

 <Desc / Clms Page number 26>

 methylene chloride to give 89 mgr of 6 @ 21-acetate
 EMI26.1
 9-methyl-c-fluoro-111; , 17. \:, 2l..trihydroxy-1, tF.-pregnadiene-.3,20dione (1-dehydro-6. \ - methyl-9, 1-iluorohydrocortisone 21-acetate) having.a dot fusion of 233-237 C. The absorption in the ultraviolet is as follows: # = 238.5 millimicrons; aM = 15.325. The infrared absorption measured in Nujol mineral oil is as follows: hydroxyl, 3430 cm-1; 21-acetoxy-,
 EMI26.2
 20-keto, 1735.1? 17 cm-1; conjugated 3-keto group, 1658 cm-1 ;, double bonds A 114 1615.1610 cm-; 1 acetate C-0 bond, 1270, 1239 cm-1.
 EMI26.3
 



  EXEM: PLE 5 21-acetate of 6 (. '(-Methyl-9 i-i-fluoro-17 ,, 21 .-- di-hydroxy-1,4-pregnadiene-3,11,20-trione (21- 1-dehydro- 6 <3 (-methyl-9 -fluorocortisone) acetate. A solution containing in 1 ml of acid was prepared.
 EMI26.4
 acetic, 50 mgr of 6 4 -methyl-9 --fluoro-11 - fil 21-acetate, 17 ex 21-tri-hydroxy-1,4-preenadiene-3,20-dione, 20 mgr of anhydri- chromic acid and a drop (about 50 mgr) of water. This mixture was shaken several times at room temperature and left to stand for 4 hours. Then it was poured into 10 ml of water and refrigerated for 20 hours at about 5 C.

   The steroid which separated from the aqueous mixture was collected on filter paper and recrystallized twice from acetone to give 21-acetate,
 EMI26.5
 of 6 C <..- methyl-9, K -fluoro-17,21-dihydroxy-1,4-pregnadienes-3,11,20-trione (1-dehydro-6 # -methyl-9 - acetate fluorocortisone).
 EMI26.6
 EXEl-IPLE 6 X -methyl-9 - \ -fluoro-11 1, 17, x, 21-trihydroxy-4-pregnene-3,20-dione 6-21-acetate.



   In the same way as in Example 1, we dealt with 21-
 EMI26.7
 6à -methyl-11 r, 17 v \, 21-trihydroxy-1-pregnen-3,20-dione acetate with N-chlorosuccinimide to give the corresponding intermediate hypochlorite, namely 11 ss -hypochlo 21-acetate -
 EMI26.8
 rite of 6. <-methyl.-11 y, 17 .'i, 21-trihydroxy-1, @ - prëgnadiene-3,2Ù-

 <Desc / Clms Page number 27>

 dione, which was then treated with sulfur dioxide
 EMI27.1
 to give 6 01 -methyl-17 cc, 21-dihydroxy-4,9 (II) -pregnadiene-3 ,,0-dione 21-acetate.



  The treatment of the 21-acetate of 6 IX -methyl-17 ce ', 21dihydroxy-1,9 (11) -pregnadiene-3,20.dione thus obtained with N-chloroacetamide in the presence of aqueous perchloric acid, as shown in Example 2 produced 6 # -methyl- 21-acetate
 EMI27.2
 9 0 <-chloro-11% :, 17 cc, 2l-trihydroxy.-.-Pregnen-3,20-dione.



  The treatment of 6t 21-acetate: {-methyl-9 q-chloro-, 11, 17. , 21-t: dhyroXY-4-pregnene-3, 20-dione thus obtained with potassium acetate in a solution of acetone under reflux conditions, as shown in detail in Example 3,
 EMI27.3
 gave the corresponding 6: γ-methyl-9 y'.J,11 / -oxydôj17,21-dihydroxy-4-pregnene-3,20-dione 21-acetate.
 EMI27.4
 



  The treatment of the 21-acetate of 60 (-methyl-9 fi ', 11! Oxydo-17, 21-dihydroxy-1H-pregnene-3,20-dione thus obtained with hydrofluoric acid in a solution of Chloroform produced 6c {-methyl-9 G -fluoro-11 (, 17 ::, 2l-trihydroxy-4-pregnene-3,20-dione 21-acetate.



  EXAMPLE 7 - 6-methyl-9 IX 21-acetate -fluoro-17, qf, 21-dihy-, droxy-ik-pregnene-3,11,20-trione.



  Oxidation, as in Example 5, of 6 methyl-9 rv -fluoro-11 A, 17 X, 21-trihydroxy-4-pregnne-3,20-dione 21-acetate with chromic anhydride produced 6 X -methyl /, 9 -fluoro-17 N, 21-dihydroxy-4-pregnene-3,11,20-.trione 21-acetate (21-acetate).
 EMI27.5
 tee / 6 c-9-methyl-fluorocortisone).



   As given in Examples 1 to 7 but. by using, as starting material, the 6 ss isomers corresponding in the sequence illustrated in particular in Examples 1 to 5, xxxxx
 EMI27.6
 obtains 6 J!) -methyl-9 -fluor-11 21-acetate, Li7 Ji, 21trihydroxy-1,1H-pregnadiene-3,? 0-dione, 6 I -methyl 21-acetate (

 <Desc / Clms Page number 28>

 
 EMI28.1
 9; ',, - fluoro-17 cg, 21-dihydroxy-1,4-pregnadiene-3,11,20-trione, 6 P -methyl-9 tX.-fluoro-11 17,2l- trihydroxy-4-pregnene-3,20-dione, 6 'J-methyl-9 -fluoro-17 L 21-acetate, 21-dihydroxy-4-pregnene-3,11,20-trione.

   Using, instead of acetates, other esters as starting materials in the series exemplified by Examples 1 to 5, such as propionate, butyrate, isobutyrate, valerate, benzoate, hexanoate, heptanoate, octanoate, phenylacetate, phenylpropionate, winner, etc, of 6
 EMI28.2
 or 6 -methylhydrocortisone or 1-dehydro-6 OE - or 6? -methylhydrocortisone, the corresponding esters of 6t5C - or 6 µ -methyl-9 -fluorohydocortisone or of 1-dehydro-6 û (-methyl-9 <? (.- fluorohydrocortisone and fluorocortisone) are produced.

   Instead of 6-methylhydrocortisone and 1-dehydro-6 01, -methylhydrocortisone, other 1-dehydro-6-alkyl- and 1-dehydro-6-aryl-hydrocortisones can be used to subsequently give phases illustrated in
 EMI28.3
 Examples 1 to 5, the corresponding esters of 6,, t -alkyl-9 0 (-fluorohydrocortisone or respectively the esters of 1-dehydro-6 -aryl-9 x -fluorohydrocortisone and the 11-keto analogues, namely the esters of 1-dehydro-6 tÉ-alkyl-9 <N -fluorocortisone and esters of 1-dehydro-6u -aryl-9 01 - ± luoroc.ortisone, in which the alkyl groups may be ethyl, propyl , isopropyl, butyl, isobutyl, pentyl, hexyl, and the aryl group can be phenyl, benzyl, etc.
 EMI28.4
 



  EXAMPLE 8 - 6 1, X NIethyl-9 -fluoro-11, 17 d (, 21-trihydroxyl, 4-pregnadiene-3,20-dione (1-dehydro-6 C 1 -methyl-9 Q -fluorohydrocortisone).



  100 mgr of 21-acetate of 6 and -methyl-9 0 (-fluoro-11%, 17, 21-trihydroxy-1,4-pregnaciene-3,20-dione were dissolved in a solution comprising 2 ml of methanol and 0 ,, 1 ml of water, previously purged of oxygen from the air by passing nitrogen through it, and 50 mgr of potassium carbonate were added thereto.

 <Desc / Clms Page number 29>

 
 EMI29.1
 left to stand at room temperature for a period of 6 hours in a nitrogen atmosphere, then neutralized with a
 EMI29.2
 hydrochloric acid solution to 5, diluted with 5 ml of water
 EMI29.3
 and refrigerated.

   The mixture was then filtered and the solids were recrystallized from Skellysolve B acetone-hexanes to give
 EMI29.4
 6 -methyl-9 (, -fluoro-11f, 17, 21-trihydroxy-1,4-pregnadiene-3,20-dione (1-dehydro-6 -methyl-9 ,, -fluorohydrocortisone EXEEPLE 9 - 6 ' -Methyl-9 1 '(-fluoro-17,: 2l-dihydroxy-1,4;

  'pre-. . gnadiene-3,11,20-trione (1-dehydro-6 c -methyl-9 c <. -fluorocortisone As given in Example 8, the hydrolysis of 6 -methyl-9 -fluoro-17 acetate '", 21-dihydroxy.l, 1-pregna-
 EMI29.5
 diene-3,11,20-trione with caustic potash in methanol
 EMI29.6
 gave z -methyl-9 C (-fluoro-17,2l-dihydroxy-1,4-pregnadiene-3,11,20-trione (1-dehydro-6 '-methyl-9 1 - ± luorocortisone).
 EMI29.7
 sorting
 EMI29.8
 EXE1.IPLE 10 - 6 eX ttethyl-9 -.fluoro-11,17 ce 2l.Lhydroxya-lpregnene-3,2G-dione (6 c -methyl-9 ¯ -fluorohydrocortisone).



  As given in example a, the hydrolysis of 21-acetate of 6 k -methyl-9 c (-fluoro-11 /, 17, 21-trihydroxy-4-pre-
 EMI29.9
 genene-3,20-dione with caustic soda in an atmosphere
 EMI29.10
 of nitrogen produces 6 ce -methyl-9 1X -fluoro-11, 17 eg 21-trihydroxy -.- pregnene-3,20-dione (6 -methyl-9 01 - ± luorohydrocortisone).
 EMI29.11
 21
 EMI29.12
 EXffi # LE 11 - 6 ethyl-9 -fluoro-17 ../- dihydroxy-1-pregnene-3,11,20-trione (6 Y-9-methyl-α, -fluorocortisone).



  As given in Example 8, hydrolysis', with
 EMI29.13
 sodium carbonate in a solution of ethanol in an atmospheric
 EMI29.14
 nitrogen pher, 6 <-methyl-9 a -fluoro-17 ra, 21-dihydroxy-1-pregnene-3,11,20-trione produced 6-methyl-9 fluoro-17 X,, 21-dihydroxy-4-pregnene-3,20-dione (6 lX -methyl-9 x -
 EMI29.15
 fluorocortisone).
 EMI29.16
 



  EXI.iPLE 12 - 21-6 'X -methyl-9 2 \: - ± luoro-III) 17 c 21-trihydroxy-1, .- pregnadiene-3,2G-dione (1-dehydro 21-propionate -6 û.-methyl-9 '4-fluorohydrocortisone)' L

 <Desc / Clms Page number 30>

 We prepared a solution containing 50 mgr of 6 # -
 EMI30.1
 9-methyl ry -fluoro-11,17; , 21.-trihydroxy-1,1 tr-pre; nadien-3, 0-dione in 1 ml of pyridine and 1 ml of propionic anhydride. The solution was left to stand at room temperature for a period of 21 hours and then poured into 10 ml of water.

   The reaction mixture was then extracted with 3 x 10 ml portions of methylene chloride, the methylene chloride extracts were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue which was recrystallized. in ethyl acetate to give 21-propionate
 EMI30.2
 6; ' Pure -methyl-9- ± luoro-11, 17x, 21-trihydroxy-lyh-pregnadiene-3,20-dione.



  EXIX3 <IPLE 13 - 21-Benzoate of 6 t -methyl-9 -fhoro-11 P 17 21-trihydroxy-1,4-pregnadiene-3,20-dione (1-dehydro- 6 # -methyl- 21-benzoate 9 -fluorohydrocortisone).



   A solution was prepared containing 6 # -methyl-
 EMI30.3
 9 '-Y-fluoro-11/1, 17, 21-trihydroxy-1,4-pregnadien-3,20-dione in 1 ml of benzoyl chloride. The mixture was left to stand overnight for a period of 18 hours and was then diluted with 10 ml of water. The aqueous solution was extracted three times with methylene chloride, the methylene chloride fractions were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue. This was recrystallized from methanol to give 21-benzoate :.
 EMI30.4
 of 6 1 -methyl-9 0 '-fluoro-11 1, 17!' , 2l-trihydroxy-1, l.-Pregnadiene-3,20-dione.



  EEEI <iPLE 11. - 21-Hemi'succinate 6 r: x -methyl-9 -fluoro-11 17 <. , 21-trihydroxy-1,1-pregnadiene-3r20-dione (1-dehydro-6,2 \ -met? Hemisuccinate: yl-9: -fluorohydrocortisone).



  A solution was prepared containing 0.5¯, g of succinic anhydride, 0.1 g of 6 'Y-nethyl-9 -fluoro-11 l, 17, 21-trihydroxy-1,1 ..- pregnadiene-3, 20-dione in 0 ml of pyridine. The solution

 <Desc / Clms Page number 31>

 The mixture was left to stand overnight for a period of 20 hours, was then diluted with water and the mixture was refrigerated and filtered. The precipitate thus collected on filter paper was recrystallized twice from methanol to give the
 EMI31.1
 6 <x-methyl-9 d, -fluoro-11,17 ev, 21-trihydroxy-1,4-pregnadiene-3,20-dione 21-hemisuccinate.



  EXAMPLE 15 ..; 6, X -methyl-9 CY-fluoro-11 a, .7, 2lTrihydroxy-1, lk-pregnadiene-3,20-dione sodium salt, sodium (1-dehydro-6 1-hemisuccinate sodium salt , ty-methyl-9 6- ± luorohydrocortisone).



   A solution of caustic soda (0.1 normal) was slowly added to a stirred solution of 100 mgr of 6 # -methyl-
 EMI31.2
 9 ex. -fluoro-11, 17 c {, '; 21-trihydroxy-l, I, .- pregnadiene -), 20-dine, dissolved in 2 ml of acetone, until the pH rises to about 7 , 4. During the addition of the caustic soda solution, 5 ml of water were also added. The solution was then concentrated at 25 ° C. under vacuum to remove acetone. The aqueous solution
 EMI31.3
 The resulting sodium salt of 6 D \, -methyl-9 C 21-hemisuccinate (fluoro-11, 17c e2l-trihydroxy-1,4-pregnadiene-3,20-dione was filtered, freeze dried and recrystallized to give 6-methyl-9 ± L-Fluoro-11 21-hemisuccinate sodium salt, 17, 1-trihydroxy-1,1H-pregnadiene-3,0-dione.



    EXAMPLE 16 -
As given in Examples 12 to 14, by reacting in a solution of pyridine at room temperature (20 to 30 C):
 EMI31.4
 a) α1-dehydro-6 t-methyl-9 ct-fluorohydrocortisone with butyric anhydride, 1-de-hydro-6 t -methyl-9, -fluorohydrocortisone 21-butyrate was obtained; b) 1-dehydro-6 c -methyl-9 o (-fluorohydrocortisone with valeric anhydride, 21-valerate of
 EMI31.5
 1-dehydrdo (X-methyl-9 -fluorohydrocortisone;

 <Desc / Clms Page number 32>

 
 EMI32.1
 c) 1-dehydro-6 methYl-9. {"" fluorohydrocortiso 'ne with lauryl chloride, 1-de- 21-laurate was obtained.
 EMI32.2
 hydro-6 <11 -methyl9, '-fluorohydrocortisone;

   d) 1-dehydro-6 y '-. methyl-5', -fluorohy.rocort.- sone with phenylacetyl chloride, 21-phenyl-
 EMI32.3
 1-dehydro-6 i? -met'iyl-9 i \ -fluorohydrocortisone acetate; e) 1-dehydro - 6; --methyl-g, c -.fluorohydrocortisone with phenylpropionyl bromide; 1-dehydro-6, y -methyl 21-phenylpropionate; L-9 (-fluorohydrocortisone; f) 1-dehydro-6 0 (-mehyl-9 -fluorohydroc {J-rti> (). with -cyclopentylpropionyl chloride, 2l - (- cyclopentylpropionate of 1-dehydro-6 o (-methyl-9 -X-fluorohydrocortisone; g) of 1-dehydro-.ô -methyl-9; -fluorocortisone with from propionic anhydride, 1-dehydro-6 C \ -methyl-9 r -fluorocortisone 21-propionate was obtained;

   h) 1-dehydro-6 ... \ -methyl-9 O (-fluorocortisone with valeric anhydride, 1-de-hydro-6 # -methyl-9 -fluorocortisone 21-valerate was obtained;
 EMI32.4
 i) 1-dehydro-6 qr -methyl-9 "? (-fluorocortisone with chloride (benzoyl, 1-dehydro-6 () () (-methyl-9 -fluorocortisone 21-benzoate) was obtained; ) dehydro-6 -methyl-9 -fluorocortisone with phenylacethyl chloride, 21-phenylacetate of
 EMI32.5
 1-di.hydro-6, -methyl-9 (, -fluorocortisone;

   k) 1-dehydro-6 -methyl -fluorocortisone with undecylenyl chloride, 1- d-hydro-6 # -methyl-9 # -fluorocortisone 21-undecylated / nate was obtained;
1) 6 # -methyl-9 # -fluorohydrocortisone with propionyl anhydride, 6 # r mehyl-9 # -flaorohydrocotisone 21-propionate was obtained;

     m) 6 # -methyl-9 -fluorocortisone with an-
 EMI32.6
 propionyl hydride, 6 <\ -methyl 21-propionare was produced. 9 # -fluorocortisone.

 <Desc / Clms Page number 33>

 In a manner similar to that of Examples 12 to 14,
 EMI33.1
 other esters of 1-dehydro-6 0,: - methyl-9 0 (-fluorohydrocortisone and of 1-dehydro-6 c (-methyl-9 r ,, .. fluorocortisone, as well as esters of 6 cc, -methyl-9 c (-fluorohydrocortisone and 6 0 <.. -methyl-9 -fluorrocortisone,. are prepared by reacting these steroids with the anhydride or acyl halides of organic carboxylic acids, especially carboxylic acids. hydrocarbons containing from 1 to 12 carbon atoms inclusive.

   As representative 21-esters thus prepared there are in particular, in addition to those of the above examples, butyrates, isobutyrates, valerates, isovalerates, hexanoates, heptanoates, cotanoates, benzoates, phenyacea-
 EMI33.2
 tates, phenylpropionates, 1.1 -cyclopentylpropionates, .butyl tertiary acetates /, toluates, 2-furoates, benzenesulfonates, toluenesulfonates,
 EMI33.3
 etc, from 1-dehydrlÀ 0 (-methyl-9, - ± 1, uoi <ohydr-ocortisone, from 1-dehydro-6 e <..- methyl-9 c¯ -fluoro cortisone, from 6 .gaz -methyl- 9 C (-fluorohydrocortisone and 6 C (-methyl-9 0 (-fluorocortisone. In the same way, the 21-esters of the 6 ss-methyl epimers and the 1-esters of the 6 ce-and 6 ss- analogs can be prepared. alkyl- and aryl of these compounds.
 EMI33.4
 



  The treatment of 1-dehydro-6-methyl-9 ± C-halohydrocor, tisones and halocortisones, in which the halogen atom is chlorine, bromine or iodine, with an acylating agent chosen from halides or anhydrides organic carboxylic acids, especially hydrocarbon carboxylic acids containing from 1 to 12 carbon atoms inclusive, preferably at room temperature in a solution of pyridine, produces the 21-esters
 EMI33.5
 corresponding 1-dehydro-6-methyl-1-9 C ± -halohydrocortisone and 1-dehydro-6-methyl-9 <3-halocortisone.



  1-dehydro-6-methyl-9, tl -halohydrocortisones and halo,
 EMI33.6
 : ty 1 word starting cortisones, in which the alphaogen is chlorine, - proven bromine or iodine, are produced by processes known in

 <Desc / Clms Page number 34>

 practical, such as a reaction of 21-ester of 6-methyl-17 ', 21-
 EMI34.1
 1,1-dihydroxy, 9 (11) -pregnatriene-3, Gw.ione (from example 1) with N-bromo-, N-chloro- or N-iodosuccinimide in the presence of an acid., such as shown in example 2, to give the corresponding 21-ester
 EMI34.2
 of 6 o -methyl-9 -halo-11 / $, 17 <1 2l-trihydroxy-1,1-prebmadiene-, 3,20-dione.

   Mild acid hydrolysis with dilute sulfuric acid at room temperature produces the corresponding free triol.
 EMI34.3
 dant, namely 1-dehydro-6 ce-methyl-9 halohydrocortisohe.



  Oxidation of the Si-ester of 6-methyl-, 9 a -halo-11 jl, 17 N, 21-trihydroxµ-1, @ - pregnadiene-3,2C-dione with chromic anhydride produces the 21-ester of 1-dehydro-6-methyl-9 -halocortisone which, by acid hydrolysis, as mentioned above, gives the free diol, namely 1-dehydro-6-methyl-9 -halocotisone.



   It should be understood that the invention is not limited to the operating details and to the exact compounds given and described, since obvious variations and modifications will appear to specialists in this field, without departing from the scope of the present document. patent.



   CLAIMS
1. A steroid selected from the group consisting of 1-
 EMI34.4
 dehydro-6-methyl-9 Ci -fluorohydrocortisone, 1-dehydro-6-methyl-9 -fluorocortisone, 1-dehydro-6-methyl-9-fluorohydrocortisone 21-acylate and 1-dehydro-6 21-acylate -methyl-9 y - fluorocortisone, wherein the acyl group is the acyl radical of a hydrocarbon carboxylic acid containing 1 to 12 carbon atoms inclusive.
 EMI34.5
 



  2. L-to 1-dehydro-6 -methyl-9;) {-fluorohydrocortisone.



   3. 1-Dehydro-6 -methyl-9 # -fluoro hydrocortisone 21-acetate.
 EMI34.6
 



  1. Lia 1-dehydro-6 - c -methyl-9 y -fluoro cortisone.



  5. 1-Dehydro-6-methyl-9-fluo-cortisone 21-acetate.

 <Desc / Clms Page number 35>

 



   6. A process for producing 1-dehydro- '6-methyl-9 # -fluorohydrocortisone 21-acylate, wherein the acyl group is the acyl group of an organic carboxylic acid containing from 1 to 12 carbon atoms inclusive. , a process which comprises treating the corresponding 21-acylate of 6-methyl-9 ss, 11 ss -oxydo-
 EMI35.1
 17 ', 1-dihydroxy-1,1,1-p-reggnadiene-3,20-dion with hydrofluoric acid to obtain 1-dehydro-6-methyl-9-fluorohydrocortisone 21-acylate.



  7. A process for the production of 1-dehydro-6 -methTl- 9 g-fluorohjrdrocorfisone, which comprises: processing the 21-acylet of 6 y -mPthyl-9 .J, 11 Pl -oxydo-1 J = j, h -dihydrox5r-1, lr.-pr Pgmadiene-3,20-dione, in which the acyl group is the acyl radical of an organic carboxylic acid containing 1 to 12 carbon atoms inclusive, with hydrofluoric acid to obtain
 EMI35.2
 1-dehydro-6a 21-acylate; -¯methyl-9 ..- fluorohydrocortisone corresponding; and hydrolysis of the ester thus obtained with a base to obtain 1-dehydro-6; -methyl-9.-fluorohydrocortisone.