BE534587A - - Google Patents

Description

       

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   The present invention relates to the synthesis of valuable steroids. One of the objects of the present invention is an advantageous process for preparing 11 ss-hydroxy- and 11-keto-steroids of the pregnan series (including pregnene), in particular cortisonei and hydrocortisone.
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  A subject of the invention is also certain compounds which can be used in the preparation of physiologically active steroids and (in certain cases) which can also be used for their own physiological action.



   Compounds according to the present invention include: (a)
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 110 (-sulfonyloxy-steroids of the Pregnane series; (b) the 9 3 11 3-ogy-do-steroids of the Pregnane series, and the steroids of the Pregnago series having a 90 (-halogen and A \ lbsti: 1; uant 11-keto or 11 P-hydroxy 'The process according to the present invention consists essentially in converting an 11 al -hydroxy-steroid of the pregnane series into an ester of 11 C4 i-sulfonic acid. Such a steroid, converting this ester to the corresponding 9d-1 compound and converting the ± ± compound to the corresponding 9d-halo-11β-hydroxy compound.

   The latter new compound can be dehalogenated, in order to obtain the corresponding hydroxylated compound 11 ss (for example, 17 # acetate - hydroxy-corticosterone), or can be oxidized, in order to obtain the compounds 11- corresponding keto (eg, 9-halocortisone gene).



   Among the compounds according to the invention, mention may be made of those which have the following general formula
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 (the 4 and 5 positions being linked by a double bond or being saturated) in which R is -H, R 'is -OH or R and R' together form -0 or a
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 group transformable into = 0 by hydrolysis, R "is H, R" "is ((3) -H or R" and R "'together form = 0, X is a (ci) -halogen group, Y denotes -H, -CE or-O- (acyl), and Z denotes -H or (#) -OH (Among: groups convertible into a keto group, mention may be made of acetal groups and especially cyclic acetal groups).
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  The 11 0 (-sulfonyloxy-steroids can be obtained from the corresponding 11 o (, - hydror-steroid) by reaction with the appropriate sulfonyl halide. In the case of compounds containing a 21-hydroxy- group, this is true. made after protection of this group by formation of an ester (in particular a lower fatty acid ester), for example by acetylation with acetic anhydride, in the presence of pyridine.

   Among these reagents, there may be mentioned, inter alia, alkylsulfonyl halides (such as methanesulfonyl chloride) and aryl-sulfonyl halides - (such as p-bromo-benzene sulfonyl chloride and p-chloride -toluene-sulfo-

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 EMI2.1
 Preferred reactants are methanesulfonyl and p-toluenesulfonyl halides, the resulting elan 'esters: referred to as "mesylates" and "tosylates".



    The conversion of the 11 # -sulfonic acid esters of steroids to the corresponding compound # 'is best accomplished by heating the ester.
 EMI2.2
 aVeC1UD. alkali metal salt of a lower fatty acid in a substantially anhydrous liquid lower fatty acid 1 for example, sodium acetate (anhydrous) in acetic acid (glacial) or potassium formate in formic acid. This conversion can also be carried out by treatment with sodium iodide, potassium iodide or lithium bromide in acetone or glacial acetic acid, the latter acid being preferably used.
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  The conversion of compound 9111 to the corresponding 9 0 (. -Bromo-11 -hy- droxylated compound can, for example, be effected by reacting an N-bromo-amide (including an imide) of a carboxylic acid. (including derivatives of this acid), inter alia, by reaction with N-bromoacetamide (or N-bromo-amide of another lower fatty acid with N-bromusuccinimide or with dibromo -dimethylhydantoin This conversion takes place preferably in the presence of perchloric acid or of another relatively strong acid (for example p-toluenesulfo acid).
 EMI2.4
 nic acid or triehloraê8-ggu) not forming an ester with the 3-hydroxy compound 11.

   This conversion is an advantageous process for preparing, in general, bromo-11 (3-hydxoxy-steroids (eg, from steroids too,) because it gives higher yields of bromine. 11 p-hydroxy # sterols, since no ester is formed as a by-product.



  The oxidation of 9 O -halo-11N-hydroaysteroid to the corresponding ketone compound (when desired) can be accomplished by the techniques.
 EMI2.5
 oxidation processes, for example with the aid of diacid atliromî4ù-à-de-de, acetic''glacial acid, and The corresponding steroid (unsubstituted in 9) can be carried out using zinc powder in a dilute lower alcohol (such as ethanol or methanol) or in a lower fatty acid (such as 7! acid).
 EMI2.6
 acetic. - the 110 (, -hydro: z;

  γ-steroids of the pregnan series which can be used in the process according to the invention, there may be mentioned Ó. -pregnènf ---, 11 d, 17 cf,, 21-triol-3,20-dione (also called 11-epi-17 C4 -hydroxy corticosterone or epi F), 11 th -hydroxyprogesterone, 11 c (. , 1701 -dihydroxyprogesterone, and epicorticosterone The preparation of these compounds is described, for example, in J. Am. Chem. Soc., 74, 3962 (1952).



   Pregnane A 4-steroids with a substituent
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 C1-halogen and an 11-keto or 11p-hydroxy substituent (and esters of those which have a 21-hydroxy group) possess, unlike as one would expect, corticosteroid activity in the liver glycogen assay. (The compounds according to the present invention which have a 21-hydroxy group can be obtained directly as their fatty acid esters or can be easily converted into these esters, especially lower fatty acid esters.



   Another advantage of the synthesis process according to the present invention resides in the fact that it allows the introduction of a halogen or radioactive tritium into the stable position 9, during a final operating stage. In order to allow a clearer understanding of the preceding general description and of the following detailed description of the invention, reference will be made to the following schematic analysis (in which representative reagents are used, "Ts" denoting a p-toluene radical

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 sulfonyl, and "Ms' a" methanesulfonyl "radical):

   
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The following examples will serve to illustrate the invention (All temperatures are given in degrees centigrade and all dilutions are made with water, unless otherwise indicated):
EXAMPLE 1.- Preparation of 9 # -bromocortisone acetate (XVI) .- (a) epi-F-21-acetate (IV) from epi-F (# 4-pregnene-11 #, 17 # 21 -triol-3,20-dione) (I) .-

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 Has a solution of 50 gr of pure epi-F rp.F. : 217, [c (.] I33. +117 (CHCL 3) ¯7 in 200 cc of pyridine, a solution of 14.3 cc of acetic anhydride in 40 cc of pyridine.

   After completion of the addition, which took about 2 hours, the mixture is kept at 0 for a further four hours, after which it is allowed to warm to room temperature (23) overnight. The acetylation mixture is then concentrated in vacuo until most of the pyridine and acetic anhydride
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 evaporated, the residue obtained being dissolved in embrofaxam and Isba chloroform solution washed successively with water, dilute hydrochloric acid, dilute sodium bicarbonate and again water. The chloroform solution is dried with sodium sulfate and the solvent is removed in vacuo.

   The dried amorphous residue (about 69 g) which represents substantially pure epi-F 21-acetate, is used in the next reaction without further purification.
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 b 11 OC -tosylate-21-acetate of 4- rene e-11 17 Cl 21-triol- 3 20-dione (VIS) from 21-acetate of - reene-11o ± 1 0 (21-triol- 3.20 dione (IV) .-
The amorphous residue obtained in a (approximately 69 g) is dissolved in 250 cc of anhydrous pyridine. To the resulting solution, immersed in an ice bath, is added dropwise, with stirring, a solution of 70 g of pure p-toluene sulfonyl chloride in 100 cc of alcohol-free chloroform.

   The addition requires about 2 hours, after which time the reaction mixture is allowed to stand at 0 for a further four hours, and then to return to room temperature overnight. 10 g of ice are added and after half an hour the solution is concentrated under vacuum to small volume. The resulting residue is taken up in chloroform and water and the chloroform solution is washed with cold dilute hydrochloric acid, dilute sodium bicarbonate and finally with water. The chloroform solution is dried over sodium sulfate and evaporated in vacuo to dryness. The crystalline residue (about 88.4 g is triturated with 200 cc of absolute ethanol and the mixture is filtered after cooling briefly in an icebox.

   The first harvest of crystals amounts to around 58.6 gr and melts at around 165-166 (dec.). By concentration of the mother liquors, a second crop of 5.6 g of material is obtained. A small sample, recrystallized, for analysis, in ethyl acetate and dried at 56,
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 has the following properties: m.p .: about 165.5-166; / "e <I D: + 106 (C: 1.0 in CHC1); analysis: calculated for CH 0 S: C = 64.51%; H = 6.81; s = 5.73%; found (approx : i.matively): c * 64Î'5 #; É = µ, 84µE, s = 5.77jE.



  (b: variant) - deacetylation of the 11 oC -tosylate 21-acetate of A 4 pregnene-11 ot, 1 out, 21-triol-3, 20-d one (VII).



  To a solution of 115 mgr of 11 aC -tosylate 21-acetate of 4 pregnene-11, 17 Ol 21-triol-3,20-dione in 1 cc of chloroform, 5.5 cc of methanol is added. The resulting mixture is heated to 40 and is added 86 mgr of potassium bicarbonate dissolved in 1.6 cc of water.



  The yellow solution is left to stand at room temperature for 18 hours and, after addition of 2 cc of water, is concentrated in vacuo to a small volume. The residual mixture is extracted with chloroform and the chloroform solution is washed with water and dried over sodium sulfate. After removal of the solvent by evaporation, a residue of approximately 119, mgr) is obtained, which readily crystallizes from acetone.

   The 11 # -tosy-
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 pure -pregnene- 11 0 (, e 1% -21-triol-3. 20-dione (VIII) late thus obtained has the following properties: mp: approximately 130.5-131 (dec); [#]: + 70 (c = 1.0 in CECI); analysis: calculated for C 8H360 S:
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 C, 65.12%; H = 6.97%; found (approximately); c = 65.29f; Ho.

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 A sample of this I1 oC -tosylate of / ,, 4-pregnene-11 170 (,, 21-triol-3,20-dione gives, by reacetylation with pyridine and acetic anhydride, 21-acetate (VII );

   P.F. 164-166 (dec.)
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 (c) 21-acetate of /,.4'9(l')-pregnadiene-17,,21-dio1,3,20-dione (XI) from 11C ± -tosylate 21-acetate of -prenene (llcr ., 17c (21-triol-3, 2Q.dione (TII) .- A solution of 58.6 gr of 11-tosylate 21-acetate of h.4¯pregnene 11 ° C! 170 (, 21-triol-3, 20-dione and 117.2 g of anhydrous sodium acetate in 1 liter of glacial acetic acid is heated under reflux for one hour. After evaporation of the major part of the acetic acid in vacuo, the residue is taken up in chloroform and extracted with water,
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 then with dilute sodium bicarbonate and again with water.



  The chloroform solution containing the 21-acetate of, 4'91-pregnadien-170 (. 21-diol-3i20-dione; (I) is dried over sodium sulfate and the chloroform is removed in vacuo. The crystalline residue. (approximately 40.6 g is triturated with 140 cc of acetate and the resulting suspension is filtered with suction. By recrystallization of the dried crystals (approximately 33 g) from ethyl acetate, 21-acetate of # 4 is obtained. , -Pregnadiene
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 17o (, 21-diol-320-dione! Having the following properties; mp approx. 234-235.5; [o (-7 fi6 + 117 c = 10 in CECI-); analysis: calculated for 0 Ir 0 - C = 71.50%; H = 7.77; Found (-approximately): C = 7156; E = 7.85 # H = 7) 0570.



  (c -variante) .- 114,9 (11) -pregnadiene-17,21-diol-3,20-dione 21-acetate is also prepared by refluxing a solution of 150 g of 11 -tosylate 21-acetate of, - pregnene-11 17 C 21-triol- 3,20-dione and 250 mgr of potassium formate in 215 cc of 98% formic acid for one hour, and by treatment of the resulting mixture, as described in d.
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  (C-variant) .- Ilyalyzes 4'9 (11) -pregnadien-17-21-acetate 4, 21-diol-3,20-dione (Xl) .- To a solution of 600 mgr of 21-acetate of 4.9 (11 tprregnadiene-17 #, 21-diol-3,20-dione in 8 cc of hot chloroform, 68 cc of methanol and a solution of 920 mg of potassium bicarbonate in 16 cc of water are added. The mixture is heated at reflux for one hour, then left to stand at room temperature for 18 hours.

   After having removed the methanol and the chloroform under vacuum, the aqueous mixture is extracted with chloroform and the chloroform extract is washed with water and dried over sodium sulphate. By evaporation of the chloroform under vacuum, one obtains
 EMI6.6
 z, -Pregnadiene-17CÀ, 21-diol-3,20-dione (XII) as a crystalline residue sparingly soluble in most common organic solvents.

   By recrystallization from peroxide-free tetrahydrofuran, the pure substance is obtained, having the following properties
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 M.p .: about 244-247; òtJ 23: +100 (c = 0.4 in (IC1); analysis: calculated for C, H2804: C = 73.27% ;. H = 8.14%; found (approximately): 0 = 73.3.4% ; H8,, s (d) - 21-acetate of 9c-bromo - 4¯preII) III13, 17 tC, 21-triol-3,20-dione (XV) from 21 acetate of A-prregnadiene- 17 < Finely pulverized, 21-dioi 3,20-dione (XI) .- 6.00 gr of 21-acetate of 4s9 (11) -pregnadiene-17 ° C, 21-diol-3,20-dione are dissolved in 600 cc of hot pure dioxane. After addition of 60 cc of water, the solution is rapidly cooled.
 EMI6.8
 until temperature, while stirring. Under these conditions, the 21-acetate of  '-Pregnadiene-17 C 21-aiol-3,20-aione precipitated in the form of microcrystals.

   To the resulting suspension are added

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   300 gr of N-bromoacetamide and 30 cc of IN aqueous perchloric acid and the mixture is stirred gently from time to time, until it becomes
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 completely clear, which takes between 9 and 11 mi # raat. After a total reaction period of one hour, dilute sodium sulfate solution is added until the yellow solution has almost completely discolored. 750 cc of chloroform are then added and the small aqueous phase which floats on the surface of the mixture is separated. The chloroform-dioxane phase containing the bromhydrin (XV) is washed with dilute sodium bicarbonate and with water and dried over sodium sulfate.

   After removing the solvents in vacuo, an amorphous residue remains (about 8.0 g. Which is dissolved in 30 cc of acetone. Crystallization begins quickly and gives about 5.85 g of light cream colored crystals having the same characteristics.
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 following properties:: aéF. ! about 132-133 (dec) ;, C 23: + 133 (c = 0.75 in CHCl3); Xa c: 243 mp. (t = 14,500). An additional harvest of about 0.61max of material is obtained from the acetone mother liquors. The total yield is therefore about 6.46 gr,
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 or about 86% of the theory.

   An analytical sample dried under vacuum at room temperature gives the following results calculated for C23g3106r'C = 57'17; H = 6e4e-e Br = 16.54%; found (approximately): 0.57.40%; g = 6.56%; Br = 16.11jE, If one uses la, 4'9 (11) -pregnadien- i7Cl, 21-diol-3,20-dione (XII) instead of its acetate (XI) in the procedure given below above, 9αC-bromo-6, prregnene-11p, 17 #, 21-triol-3,20-dione is obtained.



   When the reaction is carried out with sulfuric acid, instead of perchloric acid, the yield reaches about 45% of the yield
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 theoretical, likely and f) as a result of the formation of the 11-l = ester of XV and the # 4 '7' derivative, as described in the next paragraph. ,
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 d-variant .- 4'7'i9 (11) - atriene-1 oC 21-diol-3 20-dione to. ar- tir de 21-acetate de '- re adiene-17 oC, 21-diol-3 20-dionē (XI L 3.0 gr of 21-acetate from 4a 459 (11) ¯pregnadiene-17c, 21-diol -3,20-dione are reacted with 1.34 g of N-bromoacetamide in a medium consisting of 300 cc of dioxane, 30 cc of water and 30 cc of 1N H2SO4, as described above under d.

   From the chloroform-dioxane phase, approximately
 EMI7.6
 1.80 g of 21-acetate of A -9 O -bromopregnene-ll (3.17 oC, 21-triol-3,20-dione (XV). When the aqueous phase is left to stand in a cooler for 40 days crystals form, which can be extracted into chloroform. The chloroform extract is washed with sodium bicarbonate solution and water, then dried over water. sodium sulfate.



  By evaporation of the solvent, a crystalline residue is obtained (approximately 232
 EMI7.7
 mgr) consisting of, 4i9 (ll) -pregnatriene-17 ° C, 21-diol-3,20-dione, which, after recrystallization from ketone, has the following properties: mp; about 219-221; CoC "% 3: +233 (c = 0, 99 in CHCl); '\ alc: 243 pu (- 18,000)' jumps at 237 mu (= 161600) and m 250 np (= 14,700); nmu ol 3.05., 5977119 5; 87 p., 6.00 p: analysis; calculated for C H 0 (34243); C-73.66%; H = 7.66%; found proimatively) C = 73.7f; = ', 61. A solution of 10.3 mg of f47911) -pregnatriene-17Cl, 21-aliol-3,20-dione in 1 cc of pyridine and 1 cc of acetic anhydride is left to stand at room temperature for 15 hours. The resulting mixture is evaporated to dryness under high vacuum and the residue is crystallized from acetone.

   Acetate has the properties
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 following: s mp, about 200-202; 1a c; 243 ny1 (t = 21,900), jumps at 237 mu (t = 20,300) and 250 m '- 18,000); mijol: 3, 02 p., 5, 77a., 5 81.t, 5.88} !, 6, 06z. ma, x.

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  By substituting other reagents carrying anionic component
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 with aqueous perchloric acid, the corresponding compound 90 (-bromo-llp- (anionic component)) is obtained. Thus, using methanol (or another anhydrous alcohol, such as benzyl alcohol), the compound is obtained
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 posed 9 d 1 -bromo-11 3 -alkoxy; using a lower fatty acid, the corresponding compound 90 (-bromo-II (3-alkoxy (eg, acetoxy)) is obtained and using a halogenated acid, the compound 9 0 (-bromo-11 @ - is obtained. halogenated (eg., chlorinated) corresponding.



  9-Bromo-4-pregnene-III-17,21-triol-3,20-acetate exhibits corresponding activity. to about 1/3 that of cortisone acetate in the liver glycogen deposition test according to Pabst, Sheppard and Huizenga (Endocrinology, 41,55 (1947)) '
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 Like other II (3-hydroxylated derivatives, 90 (- bromo-j, 4-pregnne-11 (3-17 OC .21-triol-3,20-dione) 21-acetate is recovered as unchanged, after treatment with pyridine and acetic anhydride at room temperature for 18 hours.
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 e - Acet of 9 o-bromocortisone XVI from 21-acetate of 9 bromo pregnene-11 (3-, 17 e <, 21-triol-3 20-dione XV .- To a solution of 149 mgr of 21- 9 -bromo acetate.

   # Pregnene 11 (3- 17 CX, 21-triol-3,20-dione in 6 cc of glacial acetic acid, a solution of 40 mg of chromoque acid in 4 cc of glacial acetic acid is added at room temperature The addition is made in 4 portions of 1 cc, waiting each time the tint of soil solution has turned from brown to green. After 70 minutes the reaction is terminated by adding 1 cc of alcohol and after another 10 minutes the solution was evaporated almost to dryness The residue was partitioned between 5 cc of water and 20 cc of chloroform and the resulting chloroform solution was extracted with bicarbonate. of diluted sodium and again with water.

   After drying over sodium sulfate, the chloroform is removed under vacuum and
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 the residue (approximately 158 mgr) containing the acetate of 9 a (-bromocortisonP (XVI) is crystallized from methanol. A total of approximately 83 mgr of talline material is obtained which, after a new crystallization, is obtained.
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 tion, the following properties: m.p .: about 220 (dec.) -.%? B3: +235 (c = 0.62 in this); - #: 237 mp. (E =: t6 .100). An analytical sample dried at 100 under vacuum gives, on analysis: calculated for c H o Br: 0 = 57.41%; H = 6.03%; Br = 16.61%; found (approximately): 0 = 7. H = 6.16; Br, 16.15%.



  9 O -bromocortisone acetate shows approximately half that of cortisone acetate activity in the liver glycogen deposition assay.



   EXAMPLE 2.-
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 Preparation of 9 c {-bromo-113-hydr.oxy-progesterone (XX) .- (a) #llo (. -Tosyloxxyprogesterone (IX) from 1I0-h. Dro ro esterone II .- 376 mgr of 11 0 (-hydroxyprogesterone are tosylated in 3 cc of anhydrous pyridine with 292 mgr of p-toluene sulphonyl chloride as described previously for epi-F (example 1, part b). 442 mgr of crude tosylate are obtained. After crystallization. in absolute ethanol, approximately 840 mg of crystals are obtained.

   Pure 11 # -tosyloxyprogesterone is obtained by additional crystallization from ethanol and has the properties
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 following priities: m.p .: 154-157 (ace); US'Llµ4: +121 (c = 0.97 in c.KJ13); analysis: calculated for 0 28 H 36 0 5 S C = 69 '; E = 7%; S, 6.61%;

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 found (approximately): C = 69.23%; H = 7.25%; S, 6.61%.
 EMI9.1
 b T q., 9 (11) - re adiene-3 20-dione (XIII) from lla-tosyloxyprogesterone - IX). - 84 mgr of lla-tosyloxyprogeptone are reacted with anhydrous sodium acetate ( 167 mgr) in glacial acetic acid (3 cc) and the reaction mixture is treated as described above for Stage VII-XI (Example 1, part c.).

   The resulting product (about 51 mgr) cannot be purified by crystallization alone. It is therefore dissolved in 1 cc of benzene and 4 cc of hexane and chromatographed on 1 g of alumina washed with sulfuric acid. A mixture of 1 part of
 EMI9.2
 benzene and 4 parts of hexane eluted about 39 mgr of ± 4.9 (11) -pregnadiene-3,20-dione, which after recrystallization from a mixture of ether and hexane has the following properties: P . '. : about 121-123; [aJ 23Q +151 (c = 0.85 in acetone); +171 (c = 0.58 in CHCl3). Analysis: calculated for C 1H2802: C = 8Oe77%; H, 8.98%; found (approximately): C-81eoeo H = 8.84%.
 EMI9.3
 Éhppee'and Reichstein (Helv. 24,351 (1941) reported a M.P. of 122 and an index [a] D: +1450 for this substance.

   (a - variant z
11a-hydroxyprogesterone can be converted to 11a-mesyloxy-progesterone by reaction with methane sulfonyl chloride, as
 EMI9.4
 described in Example 11 given below and this 17 (; msyloxyprogesterone can be converted into 4911¯pregnadiene-3,20-dione in the same way as lla-tosyloxyprogesterone.



  (c) -2a-bromo-110-ihydroic3rprogesterone (XX) from 4.9 (11) - .é nadiene-3 20-dione XIII .- 508 mgr of A4-Ll-pregnadiene-3,20- dione are reacted with 309 mgr of N-bromoacetamide and the reaction mixture is treated as described in part d of Example 1. The resulting product (approximately 780 mgr) is recrystallized from a mixture of acetone and d 'hexane
 EMI9.5
 so that 9a-bromo-ll (3-hydroxyprogesterone2 is obtained with the following properties: PF: about 148-150 (dée.) - Ca] D: +187 (c = 1.0 in C $ C13) 3alc 243 mu (t = 16,100); nu jo3.01 p, 5.90 stinks 6.00 - they 6.07 lis 6.17 inches Analysis: calculated for C21H290 (409.4): 0 = 61.61%; $ = 7.14 ° Found (approximately): C = 61.91; H = 6.92 0.



  EXAMPLE 3.- Preparation of 9 ¯flf -bromooorticosterone acetate (XVIII) .- (A) - 21-epicorticosterone acetate (VI) from epicorticosterone (III) 347 mgr of epiaorticosterone are acetylated in 4 this of anhydrous pyridine with
0.1035 cc of acetic anhydride at 0 for 18 hours.

   The amorphous and substantially pure epicorticosterone acetate (about 400 mg is isolated substantially as described above for stage I-IV (Example 1, part a).
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 b -21-acetate 11 0 (-tos late d 'iC7Dticosterone X from 21-acetate epicorticosterone (VI) .-
400 mgr of amorphous epicorticosterone 21-acetate obtained under a are treated with 400 mgr of p-toluene sulfonyl chloride in 5 ′ ce de-pyridine and the reaction mixture is treated as described above for stage IV-VII (example I, part b).



   The resulting tosylate (about 492 mge) cannot be obtained in crystalline form. It is therefore subjected to the following operating stage without further purification;

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 (c) -21-acetate 49 (11 -prenadiene-21-ol-3.20-dione (XIV) from 21-acetate 11 and -tosylate epicorticosterone (X) .-
492 mgr of 21-acetate llo (epicorticosterone -tosylate (bbtained above under b are treated with 986 mgr of anhydrous sodium acetate in 9 cc of glacial -acetic acid and the reaction mixture is treated) as described above for stage VII-XI (example 1, part c).

   The residue (about 390 mgr) quickly crystallizes in ac-
 EMI10.2
 tonecset, after freshening up in this solvent, gives about 100 mg of 9-prepregnadiene-21-ol-3,20-dione acetate having the following properties: m.p .: about 158.5-159.5; oCJ 3 +128 (c = 0.98 in acetone) and +150 (c = 1.13 in CECI.); analysis calculated for G H p0: C = 74.56%; H = 8.16 ;; found (approximately): 0-74979%; H = 0.11%.



   Shoppee and Reichstein (Helv. 26, 1316 (1943) indicate a P.F. of
 EMI10.3
 159 and an index [d.] N8 of +129 7aeton) for this compound.



   An additional quantity of pure product is obtained by chromatizing the mother liquors from / from benzene (5 cc) on alumina.
 EMI10.4
 (5 g) and eluting the acetate of, 4s (-Pregnadiene-21-ol-3,20-diane with benzene. D - acetate of 9 # -bromocorticosterone (XVII) from acetate of
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 - A -Lprenadiene-21-01-3.20-dione (XIV) .- 72 mgr of 4'9 (11-pregnadiene-21-ol-3,20-dione) acetate are treated with 38 mgr of N-bromoacetamide and the reaction mixture is worked up as described above for Stage XI-XV (Example 1, part d).



  The resulting crude product (approximately 96 mg) is recrystallized from a medium.
 EMI10.6
 mixture of hexane and acetone. This gives pure 9 O bromo-corticosterone acetate (XVII "-) having the following properties: PF: approximately 152-3 (dec.); Zi> (¯7 3: +178 (c = 0.94 in Chic13); Analysis; Calculated for G23H3105Br: 0 = 59.10%; H = 6.68; Brus Found approximately): 0 = 59ex5%; H = 6; 7 -; Br = 17.03%.



  EXAMPLE 4.- Preparation of ik 4-re ene-9 11 o do-1 Cl 21-diol-3 20-dione 4K4) or of its 21-acetate (XXI) .- (a) 4 prenene-9 (3 , Il (3-ogyd -1 0 21-diol-3,2OE-dione Cx: x) from 9a -bromo-- -prenreg-11-21-acetate (3-17 vL;; 21-triol- 3,20-dione (XV) .- To a solution of 115 mgr of 21-acetate of 9 -bromo-4-prenene -11 (3, 17 Cl, 21-triol-3,20-dione in 10 cc of methanol, a solution of 103 mg of potassium bicarbonate in 1 cc of water is added. The resulting solution is left to stand at room temperature for 18 hours, after which 4 cc of water are added and the solution is freed from methanol in vacuo Chloroform is added to the residue and, after mixing and separation of the layers, the chloroform solution is washed with water and dried over sodium sulfate.

   By evaporation of the solvent, a
 EMI10.7
 residue which readily crystallizes in acetone. Pure 6-Pregnene-9p-11poxydo-17,21-diol-3,20-dione has the following properties: m.p. about 206-208; oC t2: +23 (c = 0.75 in CHCl3), λ 243 mu (e * 13,700); analysis; calcd for C 1H2805: C = 70102g, 77; found (approximately): G = 70.39%; H = 7.95

 <Desc / Clms Page number 11>

 
 EMI11.1
 a'- variant) 21-acetate of 4- renene -11 -o do-1 cx 21-diol-3 20.- dione from -from 21-acetate of a bromo- - renene-11 l7ct 21- triol -3 20-dione (XV) .-, A solution of 2.5 gr of 9a-bromp-, 0, .4-pregnene llp, 17a-, 21, -triol-3,20-dione ( cfr part d of eo ± Bpio 1) and 6.25 gr of potassium acetate in 190 cc of absolute alcohol is heated under reflux for 50 minutes.



   After the addition of 20 cc of water, the solution is concentrated in vacuo until crystallization begins. Water (50 cc) is again added and the crystallization in a cooler is completed. The first harvest
 EMI11.2
 (approx 1.31 gr) melts at approx 2095-2105. A second revolt (about 291 mgr), melting at about 206-208, is obtained by concentration of the mother liquors * -, the analytically pure matter obtained by oristalli-
 EMI11.3
 The acetone solution has the following properties: m.p .: about 210-2120; ra -7? 3: s a ++ 41 (c = O, 70 in CHOC1 À a c. 243 mu = I5.500). Analysis: Calculated for C23H30d6: s C =, 3 'H, 5-t%; found (approximately) C = 69.02; H = 7.42.



  9fi, 11 (3-Oxido-steroids of the Pregnane series - for example XXI) are very reactive (unlike the corresponding a-oxidized compounds) and readily react with agents known for their ability to open oxidized rings in moderate conditions. Thus, the core can be opened, among other things, using hydrobromic acid so as to obtain
 EMI11.4
 the corresponding 9a-bromo-ll (3-hydroxylated compound (XV) using hydriodic acid so as to obtain the corresponding 9a-iodo-llp-hydroxylated compound (XXII), using 'hydrochloric acid so as to obtain the
 EMI11.5
 corresponding 9a-chloro-llfi-hydroxyl compound (XXIII), and with the aid of hydrofluoric acid so as to obtain the corresponding 9a-fluo-llo-hydroxyl compound (XXXVI), the reaction preferably being

   performed in an alcohol-free solvent. Some of these conversions have been shown schematically below.
 EMI11.6
 

 <Desc / Clms Page number 12>

 
 EMI12.1
 



  EXAMPLE 5.-
 EMI12.2
 Preparation of 21-acetate of 9a.-bromo 1 4 pregnene-11Q, 17a, 21iriol-3,20 dione (XV) .- To a solution of 21 mgr of 4-pregnene-91 ° -oxydo acetate 17a, 21 -diol-3,20-dione (XXI) in 0.5 this glacial acetic diacid and 0.5 cc of carbon tetrachloride, 0.04 cc of 30% hydrobromic acid is added at room temperature in glacial acetic acid. After 10 minutes, 10 cc of chloroform are added and the mixture is extracted with
 EMI12.3
 of diluted sodium bicarbonate and using water. The chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue (weighing approximately 33.5 mgr) is crystallized from acetone.

   We
 EMI12.4
 obtains about 29 mgr of 9 ° -bromo- + -pregnene-11 ° 17a, 21-triol-3,20-dione 16-acetate having the following properties: mp: about 126-128 c; toJ O: +140 ( c, 0.98 in THIS).



  EXAMPLE 6.7.



  Preparation of 9Ct-iodo-4-pregn.ene-II 21-aceto (3-1? Cx, 21-triol-3,20-dione (XXII).



  A solution of 204 mgr of acetate, -Pregnene-9 ° llp-oxydo-17a, 21-diol-3,20-dione (XXI) in 20 cc of chloroform is cooled to -20 in an ice bath and salt and 0.4 cc of freshly distilled 55% aqueous hydriodic acid are added. The mixture is stirred vigorously for 20 minutes, after which water is added and the layers are separated. The chloroform solution is washed with dilute sodium bicarbonate, with dilute sodium sulfite and with water and finally dried over sodium sulfate. Evaporation of the solvent in vacuo leaves about 279 mgr of a crystalline residue, which is recrystallized from

 <Desc / Clms Page number 13>

 ethyl acetate, making sure to keep the temperature below
 EMI13.1
 40.

   The resulting 9α-iodo-21-acetate, -pr6gnene-llp, 17ae 21-triol-3,20-dione begins to brown at about 80, clumps at about 100 and decomposes at about 110. has the following properties
 EMI13.2
 α-73: + 140 (c, 0.53 in CHCl); fi 1 a c. : 243 np (6 = 11,000-).



  Analysis: calculated for EC 0.1: C = 532.08, 5.89; 1 = 23.93%; found: C = 52,543 H = 6.44%; 1 = 22.06% "9a-iodo-4-prenene-11-, 17cc, 21-triol-3s20-dione 21-acetate has an activity which corresponds to about 1 / 10th of the activity of cortisone acetate in the liver glycogen test.



   1
 EMI13.3
 Following the procedure of part e of Example 1, but using 21-acetate of 9a-iodo-L1 -pregnene-11 (3, 11cc, 21-triol-3a20-dione, the acetate of 9a is obtained. -iodocortisone.



   EXAMPLE 7.-
 EMI13.4
 Preparation of 21-a-chloro-.4-re ene-11 17a ,, 21-triol- 3 20-dione XXIII o- A solution of 102 mg of 21-acetate, 4-pregnene-9 (3 , lez-oxydo, 17a, 21-diol-3,20-dione in 10 cc of chloroform free from alcohol, to 0, 1.5 cc of 0.5N hydrochloric acid in chloroform (3 e- molar equivalents). After 60 minutes, ice and dilute bicarbonate are added to remove the excess acid. After separation of the layers, the chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness.

   The crystalline residue, which weighs about 110 mgr, is recrystallized twice from acetone, the properties of 9a-ohloro- @ -pregnene-11p, 17a, 21-triol-3,20-dione 21-acetate pure are the
 EMI13.5
 : m.p .: about 201-202; / 'a7 d3 + 139 (c, 0.86 in CHCl A: 241 soft (t = 15,800); analysis: calculated for C23H3106Cl: cm62.93% 1H = 7.12%; Cl = 8.07%; found : C = 6323%; H = 7.41%; CI = 7.70%.



  The 21-acetate of 9a-chloro-4-pregnene-III, 17a, 21-triol-3,20-dione exhibits an activity which corresponds to about 4 / 5th of that of cortisone acetate in the test. glycogen in rat liver and which is about 10 to 15 times that of deoxycorticosterone acetate, causing sodium retention in rats.



   By following the procedure of the part in example 1, but
 EMI13.6
 using 9-chloro-17a-hydroycorticosterone 21-acetate, 9a ahlorac acetate, rvzsone (XXIV) is obtained having the following properties m.p .: 257-258 (dec.); Cal 2: +252 (c, 1.1 in Chloroform); Áa c. max 236 mu (t. = 160600); analyzed: calculated for c E 0c1: 0 = 63.22%; H = 6.54%; 01 = 8.11%; found 0 = 62.97%; H = 6.61%; 01 = 8.13% ''
9α-Chlorocortisone acetate shows an activity which is approximately four times that of cortisone acetate in rat liver glycogen assay.



   EXAMPLE 8 Preparation of Cortisone Acetate.
To a solution of 25 mgr of 9a-bromo-cortisone acetate (XVI) in 2 cc of glacial acetic acid, is added, at the temperature of the steam bath and with stirring, a total of 48 mgr of zinc powder . The additions are made in portions and the reaction is stopped after 15 minutes of treatment
 EMI13.7
 In a vaperx bath, the residual zinc is separated by centrifugation and the acetic solution is evaporated to dryness in vacuo. The residue is taken up

 <Desc / Clms Page number 14>

 in 4 cc of water and 20 cc of chloroform. After separation of the layers, the chloroform solution is washed with water, dilute sodium bicarbonate and again with water. After drying over sodium sulfate, the solution is evaporated to dryness.

   The residue (about 32 mgr) gives, after two crystallizations from acetone, crystals melting at about 238- 241 (opaque to about 85), which do not lower the melting point of a sample of cortisone acetate. authentic. The infrared spectrum of this product is identical to that of cortisone acetate.



   EXAMPLE 9. Preparation of 17α-hydroxycorticosterone acetate (XXVII) .-
A solution of 100 mgr of 21-acetate of 9a-bromo- # 4-pregnene-11ss, 17a, 21-triol-3,20-dione (XV) in 30 cc of alcohol and 5 cc of water is stirred with 1.0 gr of zinc powder at room temperature (23) for 19 hours. At the end of this period, the zinc powder is separated by centrifugation and washed with alcohol. The alcoholic solution is concentrated in vacuo until most of the alcohol has evaporated and the remaining aqueous suspension is extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo.

   The residue (which weighs approximately 84 mgr) is dissolved in 1 cc of chloroform and 4 cc of benzene, then chromatographed on 2 g of silica gel (Davison No. 923). Elution from the column with a 1: 1 mixture of chloroform and benzene gives # 4-prregnadiene-17a, 21-diol-3,20-dione 21-acetate, mp about 233-235. This compound was identified by comparing its infrared spectrum with that of an authentic sample as well as by measuring its melting point mixed with an authentic sample.

   Elution with 250 cc of chloroform gives about 25 mg of 17α-hydroxycorticosterone acetate, which, after recrystallization from acetone, exhibits the following properties: mp: 216-218.5 [a] 23: +156 (c, 0.36 in CHCl3); max. : 241 mu $ (# = 16.700). Analysis D: calculated for C23H32O6: max.



  C, 68.29%; H = 7.97%; found: C = 68.47%; H = 8.14%. 23 32
An authentic sample of 17α-hydroxycorticosterone melted at 218-220 and had an [a] 23 index of +157 (c = 0.37 in CHC1) while its infrared spectrum was identical in all respects to that in the above sample. .



   The reduction of 21-acetate 9a-iodo- # -pregnene-11ss, 17a, -21-triol-3,20-dione (XXII) with zinc powder in diluted alcohol under the conditions described above gives 17α-hydroxy-corticosterone acetate in substantially equivalent yield.



   EXAMPLE 10.- # 4-Pregnene-11a, 17a, 21-triol-3,20-dione (XXX) 11a-mesylate 21-acetate from # 4-pregnene-11a 17a, 21-triol -3 20- dione- (IV) .-
264 g of the amorphous residue of 21-acetate of # 4-pregnene-11a, 17a- 21-triol (3,20-dione (IV), obtained in the part of the example, are dissolved in 1050 cc of chloroform. and 255 cc of pyridine The resulting solution is immersed in an ice bath and over 20 minutes is added a solution of 80 cc of methanesulfonyl chloride in 250 cc of chloroform. resulting mixture is left to stand in a cooler for 16 hours, after which approximately 10 g of ice are added.



  After a further half hour of standing 0, the mixture is washed with water and then with 1N hydrochloric acid, until the last traces of pyridine are removed, and then with water, these washes

 <Desc / Clms Page number 15>

 being followed by washing with dilute sodium bicarbonate and a third washing with water. The chloroform solution is dried over sodium sulfate and concentrated to a volume of about 200cc. After addition of one liter of absolute ethanol, crystallization begins quickly and is allowed to continue in the cooler. By filtration, a first crop of crystals is obtained (about 244 g) while the concentration of mother liquors under vacuum gives a second crop (about 41 g).

   The material obtained in this way melts at 157-158. Further recrystallization provides analytically pure material possessing the properties.
 EMI15.1
 following summers; P6'Fe: about 159-160 (with browning); Lcx, j? 3 + 119 (C, l, '09 in cEcL 3); Analysis: calcd for C24H3408S (482.45): 0 = 59.73%; H = 7el -; S, 6.64-; found (approximately) 0 = 59.47%; ! = (Í; 3 = 6.36%. This material can be converted to pregnadiene-17a, 2ldiôfi32G-dione 21-acetate as described in part ad of Example 1 and the latter compound itself can be processed. as described in Example 1, parts c-variant and d + et seq.



   EXAMPLE 11.-
 EMI15.2
 49 (ll) - radiene-17a 21-diol-3,20-dione XII from Al-tosylate 21-acetate of An '- pr6gnene-lla, 17Ct, 21-triol-3s 20-dione (VII) .-
A solution containing 303 mgr of lla-tosylate 21-acetate of # 4-pregnene-11a, 17a, 21-triol-3,20-dione and 40 mgr of toluenesulfonic acid monohydrate in 25 cc of absolute methanol is heated to reflux for 6 hours. After the addition of 10 cc of water, the mixture is concentrated in vacuo
 EMI15.3
 and the residual aqueous suspension is extracted sujshioroform. The chloroform extract is washed successively with a dilute solution of sodium bicarbonate and with water, then dried over sodium sulfate.



  By crystallization of the resulting residue (about 22 mgr) in acetone
 EMI15.4
 and finally in 95% ethanol there is obtained 9-prregnadiene-17a, 21-diol-3,20-dione, melting at about 244-247 (cf. c-variant, Example 1. )
EXAMPLE 12.-
 EMI15.5
 11a, 4-renene-11a 21-dimesylate 17a 21-triol-3 20-dione XXXI from epi-F (I).



   To a solution of 10 g of epi-F (I) in 110 cc of anhydrous pyridine is added to 0 a solution of 6.6 cc of methane sulfonyl chloride in 10 cc of chloroform. The reaction mixture is left to stand at 0 for 16 hours, after which 1 g of ice is added. After an additional half hour of standing at 0, the mixture is concentrated in vacuo to a small volume. The residue obtained is taken up in chloroform and in water and the chloroform solution is washed successively with cold dilute hydrochloric acid, with a dilute solution of sodium bicarbonate and with water. 'water help. The chloroform solution is then dried over sodium sulfate and evaporated to dryness in vacuo.

   The crystalline residue (approximately 12.4 g) is recrystallized from 95% ethanol so that the analytically pure dimesylate possessing the
 EMI15.6
 following properties t mp: about 162 (die); / 'aJ7 3: +97 (050598 in dioxane analysis: calculated for C23g3409S (502.62): 0 = 53.26%; H = 660 3 = 12.36%; found (approximately): C = 53.42% ; B = 629% ts = 11, oofi. The dimesylate can be converted into 21-acetate of '-pregnadiene-17a, 21-diol-3,20-dion (XI) by the method described in part ± of example 1.

 <Desc / Clms Page number 16>

 



     EXAMPLE 13. Preparation of 9α-fluorocortisone acetate (XXXVIII) .-
 EMI16.1
 a 9¯a-fluorohyàroaortisone acetate (XXXVI) from 21-acetate of b - prenene-93, llGi - ogydo-17t., 21-diol-3,20-dione (XXI) .- Fluoride d anhydrous hydrogen is added to a solution of 15 g of 21-acetate of -pregnene-9p, llp-oxydo-17a, 21-diol-3,20-dione in 300 cc of chloroform (contained in a polyethylene container equipped with 'a copper inlet tube). During the addition, the solution is kept in an ice bath and subjected to magnetic stirring, until it takes on a predominant red tint. The inlet tube is then replaced by a polyethylene stopper and the reaction is allowed to continue, with stirring, for 4 1/2 hours at 0.

   A concentrated aqueous solution of sodium bicarbonate is then added, until
 EMI16.2
 what the mixture is slightly alkaline. The two layers are separated.



  The chloroform solution, now light yellow in color, is washed with water and, after drying over sodium sulphate, it is evaporated to dryness under video. The residue (approximately 17.0 g) is then taken up in 125 cc of hot ethyl acetate, the resulting suspension is filtered and the precipitate (collected on the filter) as well as the filtrate are treated as described below.



   In the ethyl acetate filtrate, on cooling, a precipitate of crystals occurs in the form of long needles mixed with small prisms. This material (about 6.2 g) melts at about 228-230 and is substantially pure 9α-fluorohydroxortisone acetate. For analysis this compound is recrystallized from ethyl acetate and then melts to about 233-234.



    /: Occasional samples are obtained, which soften at about 205-208, which re-solidify and finally melt at about 226-228, probably as a result of their polymorphic character.
 EMI16.3
 the compound in question has the following properties - '1 -7 D 123 (as 0.64 in CH 3); 1 ": 238 mu (± = 16,800); 2.86 p., 3.01 u, 59 62 ue 5.78 z,, 83., 6.05 ie analysis; calculated for C 23 H 3106P (422): 0 = 65.39%; H = T, 39; F = 4.52%; found (approximately); C = 65e3e-; H = 7.26;; F = 4.5o%.



  By fractionation of the mother liquor of ethyl acetate, an additional quantity of 9a fluorohydrocortis acetate is obtained, which brings the total yield to 50%. 9a: lorohydrocortisone acetate is about 11 times as ac- tif as cortisone acetate in the rat liver glycogen assay and is about 1 to 2 times as active as deoxycorticosterone acetate in causing sodium retension in rats.



   The insoluble matter (approximately 1.35 g) collected on the filter during the filtration of the ethyl acetate solution is recrystallized from acetone. The pure compound has the following properties M.P .: approximately
 EMI16.4
 259-262 l with browning; ra 7 23 1262 (0.53 in 95% ethanol) 5 239 mp. (t. = l8,000) 3 max. 2.94 mp., 3.03 ig 5.75] 1; 5.82 p, 6.07 mag. 611} 1; analysis: calculated for 0H30 06 (402): 0 = 68.63%; H = 7e51% found (approximately); C, 68.45%; H, 7.17%.



  (b) 9a-fluorohydrocortisone (XXXVII) from 9a-fluorohydro- acetate
 EMI16.5
 cortrsone (xxxvr) .-
To a solution of 103.8 g of 9α-fluorohydrocortisone acetate in 10 cc of absolute methanol is added, under a nitrogen atmosphere, a solution of 11.44 mg of sodium in 1.9 cc of anhydrous methanol. . The mixture

 <Desc / Clms Page number 17>

 is left to stand at room temperature for 30 minutes and acidified by adding a few drops of glacial acetic acid. We then add
 EMI17.1
 water and after removal of ethanol in vacuo the 9 (x-fluorohydrocortisone is extracted with ethyl acetate.

   The extract is washed with sodium bicarbonate solution and with aW pud sebhe over sodium sulphate. The evaporation of the solvent leaves a crystalline residue (about 92 mg. ), which after recrystallization from 95% alcohol exhibits the following properties: mp: about 260-262 (dec; [a] 33
 EMI17.2
 +139 (c, 0.55 in 95 alcohol) 3X :: 239 mja .; (= 17,600) u ol 3.01 u, 5.84 p, 6.07 p, 6.60; analysis: calculated for C21 H2905F (3 $ 0,: C = 6 ,, 30; i = ', 68; found (approximately); 0 = 66.49%; H = $, 22.



    @,
9α-Fluorohydrocortisone exhibits approximately the same biological activity as its acetage.
 EMI17.3
 c 9α-fluorocortisone acetate (XXXVIII) from α-fluorohydrocortisone acetate XXXVI e- To a solution of 31.2 mgr of 9αTfluorohydrocortisone acetate in 3 cc of glacial acetic acid is added a solution of 10 mg of chcomic acid in 2 cc of acetic acid. Half an hour later, 1 cc of methanol is added and the resulting mixture is concentrated in vacuo. The residue is partitioned between chloroform and water and the resulting chloroform extract is washed with water, using sodium bicarbonate solution.
 EMI17.4
 and again with water.After drying over sodium silicate and e, 4.i: Pon of the solvent in vacuo, the residue (about 25 mgr) is crystallized from
 EMI17.5
 95% alcohol.

   9α-fluorocortisone acetate has the following properties PF: about 25-215, /"a.7 -: +155 (c, 0.45 in OHC13); A :.: 234 imi (= 17,000); A! 2, 86 us 5.72 u., 5, 78, 583 il 6.05 .; analysis: calculated for C H26F: C = 65.70; H = 6.9; found (approximately) C = 65.62 / 3 H = 7,
9α-Fluorocortisone acetate is about 10 times as active as cortisone acetate in the rat liver glycogen assay.
 EMI17.6
 



  ¯ (¯d) ¯ -9a fluorocort sone (XXV) from ga-eltorocortisone acetate (XXXVIII) .-
25 mgr of 9a-fluorocortisone acetate are deacetylated in the manner described in part b of example 13. Approximately 18.4 mgr of product is obtained, which after crystallization in 95% alcohol gives 14 mgr.
 EMI17.7
 9α-'fluorooortisone having the following properties: m.p .: 261-261; Nlâ.11 D: +144 (ci cl in CHC 1); ac '"234 mp. = 16,000); A Nujoi 288 Z, 5.87 z, 6.08,; ana7; se; calculated for C21H2705P: C = 66.65 mag at 5.87 6.08 calff! ê for 21 2705P 0 = 66.65% H = 7.19%; found: C = 66.50%; H = 6.98%.



     EXAMPLE 14.-
 EMI17.8
 oc-chloroh drocortisone (XUIX) from - renene- 11 -ox do- 17a 21-diol-3î2O-dione XLX o- A solution of 30.8 mg /: J. 4¯Pregnene -9j3.11 (3-oxydo-17a, 21-diol-3y20-dione in 5 cc of chloroform, 40.55 cc of 0.45 N HCl in chloroform is added. standing at 0 for one hour, during this period crystals begin to deposit.



  The mixture is then treated with a sodium bicarbonate solution until it is slightly alkaline, after which ethyl acetate is added.
 EMI17.9
 to dissolve the deposited 9a chlorohydrooortisone. The layers are separated and the organic phase is washed with water and dried over sodium sulfate.



  By evaporation of the solvents, a crystalline residue is obtained, which after

 <Desc / Clms Page number 18>

 
 EMI18.1
 recrystallization from 99% alcohol gives 9α-chlorohydrocDrtisone having the properties suiMah45eÊ, m.p. 203 (dec.); t al D 155 (c, 0.58 in 95% alcohol); A b: 241 nyx (t = 17,000): max. : 2 94. 3.03 / 1.5? 87, 6.15; Analysis: Calculated for G2'H2905G1: C = 61.56%; H = 7.3%; found (approximately): 0 = 63.42%; H, 7.22%.



  9a chlorohydrocortisone has approximately the same biological activity as its acetate. Using hydrobromic acid or hydroiodic acid instead of hydrochloric acid in the procedure
 EMI18.2
 described above, 9a bromohydrocortisone or 9a-iodohydrocortisone are respectively obtained.



  EXAMPLE 15 Preparation of 9a-romo-11-dehydrocorticosterone acetate (XLVI) .- (a) -lla-mesylate 21-acetate depi-corticosterone (XXXV) from 21 acetate (VI) epi-corticosterone .-
To a solution of 3.27 g of epi-corticosterone 21-acetate, obtained as ± written in part a of Example 3, in 40 cc of pyridine, a solution of 0.953 cc is added to 0. of methane sulfonyl chloride in 7 cc of chloroform. When the reaction mixture has been kept for 17 hours in a cooler, a few pieces of the loosening are added.
 EMI18.3
 and the mixture is there. 1 "Se" "to" 0e "for about a quarter of the volume. The mixture is then concentrated to a small volume in vacuo and then taken up in chloroform.

   The chloroform solution is extracted with dilute acid, with sodium bicarbonate solution and finally with water. The chloroform solution is then dried over sodium sulfate and evaporated to dryness in vacuo. A residue of 3.73 g is obtained, which crystallizes from absolute ethanol.

   Pure epicorticosterone lla-mesylate 21'acetate has the following properties: m.p .: about 156-157.
 EMI18.4
 (deo [al fi3: +144 (9.0.92 in ¯ $, C13) ,,. analysis: calculated for C24H to 406S (46657): G = 6117 $; H = 7.34%; found (approximately: ): C = 62.52%; H = 7.07%. B -21-acetate 4'9 (11) - re adiene-21-ol-3 20-dione XIV from 11cc mesylate 21-acetate d 'é i-corticosterone (XXXV) ¯.-
A solution of 1.92 g of epi-corticosterone 1-mesylate 21-acetate and 3.84 g of anhydrous sodium acetate in this glacial acetic acid is heated at the boil for one hour. The reaction mixture is worked up as described in part c of Example 3.

   By crystallization of residue # 4.9 (II) (approximately 1.66 g) in acetone, one
 EMI18.5
 obtains 21-acetate of ± -Pregnaalien-21-ol-3,20-dione with a yield of 84%.



  4.9 (II) of 9a-bromocorticosterone (XVII) from 21-acetate
 EMI18.6
 '(1-Regnadiene-21-ol-3,20-dione (XIV). As part d of Example 3.



  (d) - 9 bromo-11-dehydrocorticosterone acetate (XLVI) from 9a-bromocorticosterone acetate (XVII) .-. u
 EMI18.7
 A solution of 105 mgr of 9cc-bromocorticosterone acetate in 6cc of glacial acetic acid is oxidized using a solution of 26 mgr of chromium trrioxide in 5cc of glacial acetic acid. After 40 minutes, 1 cc of alcohol is added and the reaction mixture is worked up as described in part ± of Example 13. A chloroform residue is obtained, which weighs about 101 mg.

   By crystallization of this residue from a mixture of acetone and hexane, approximately 82 mgr of 9a- acetate is obtained.
 EMI18.8
 bromo-11-Ôehydroaortiaosterone, which after further recrystallization

 <Desc / Clms Page number 19>

 in the same solvent is obtained in analytically pure form and has
 EMI19.1
 the following properties: m.p .: about 183-184 (de); [a} i 2b0 (c, 0.99 in CHCl3) 3 ma = 237 mt (, <= 16,400); max,: 5th 76 jae 5, 85 F, 6, 00 u., 6.18 ..

   Analysis: calculated for C 23 H 29 05 Br (465.37): C = 59.36; H = 6.28%; found (approximately) C = 59.26%; H = 6.03% L
EXAMPLE 16.-
 EMI19.2
 Preparation of 9α-ahloroaortiaosterone acetate (XLVIII) .- α 21-acetate of 4-reene-Il -o do-21-0l-3 20-dione XLVII from 9α-bromocorticosterone acetate (XVII). -
A solution of 253.8 mgr of α-bromocorticosterone acetate (see part of Example 3) and 625 mgr of anhydrous potassium acetate in 18 cc of absolute alcohol is heated at reflux for 50 minutes.



  After the addition of 10 cc of water, the alcohol is evaporated off in vacuo and the residual aqueous suspension is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about 205 mgr) does not crystallize and is used in the following procedure without further purification.

   
 EMI19.3
 b 9a'-chlorooorticosterone acetate XLVIII from 21-acetate of A '--pregnene-9, -o do-21-ol-3 20-dione XLVII .- To an ice-cooled solution of 100.9 mg of 21-aoetate, 4-Pregnene-9 (3, III-oxydo-21-diol-3,20-dione in 10% of chloroform, 1.6 cc of 0.49N HCl in chloroform is added. hour at 0, additional chloroform is added and the solution is extracted with sodium bicarbonate solution and with water, then dried over sodium sulfate. obtains a residue (about 124 mgr), which crystallizes easily in a mixture of ac-
 EMI19.4
 tone and hexane.

   9α-Chlorooorticosterone acetate has the following properties: m.p .: about 192 dér.s / a7: +191 (c, 0.67 CHCL3); at m 240 (= 18,800); JO: 2.87 fA '3.01 5.70 p., 5.77 p.



  5.83 Z, 5,., 6.08; analysis: calouîi "for EC 0 Cl (422.9): C = 65.31%; E = 7.38%; found (approximately): C-6595eo; H = 7.24%.



  9a, -chlorocorticosterone acetate has an older activity than cortisone acetate in the rat liver glycogen assay.



   By following the previous procedure (part b) but using hydrofluoric acid or hydroiodic acid instead of hydrochloric acid, 9a-fluorocorticosterone acetate and 9a-fluorocorticosterone acetate are obtained respectively. 9a-iodocorticosterone acetate, the former having the
 EMI19.5
 prieties: P: about 212-214 C; /'a..7 ': t + 184 (c, 0.11 in CHCl3); activated: four times that of cortisone acetate in the rat liver glycogen assay, more than ten times that of deoxycorticosterone acetate in the sodium retention assay.

   By following the procedure of part d of Example 15, but replacing the a-
 EMI19.6
 Sa-bromocorticosterono ketate by 9a-fluorocorticosterone acetate, 9a-chlorocorticosterone acetate and 9a-fluoro-II-dehydrocorticosterone acetate, 9a-chloro-11-dehydro- acetate corticostrone and 9a-iodo-11-dehydrocorticosterone acetate.



  EXAMPLE 17.a OE-bromo-11-keto no esterone 9XLIX from a-bnomo-11 o - progesterone (XX) .-

 <Desc / Clms Page number 20>

 
 EMI20.1
 100 mgr of 9cc-bromo-11 (3-hydrogynrogesterone (see example 2) are oxidized using 29 mgr of chromic acid, as described under e in example 1. The resulting crude product (approximately 48.1 mgr. mgra) is recrystallized from acetone and yields pure poetoprogesterone 9-bromo-11-ketoprogesterone.
 EMI20.2
 having the following properties: m.p .: about 165-16oNdei.); La] D +309 (c, 10, in CECI); A: 237 In} 1 (t .. = 16,600) 5A 5.87 u, 6, 00.



  6.17.; Analysis: calculated Polir C H 0 Br (407.43); a26itµÉfi; E $ 6.68: found - (approximately): 0 = 61.80%; H = 6 .6 ô.



  (b) 11-ketoprogesterone from 9a-bromo-11-ketoproges, drone (XLIX) .- To a solution of 12 mgr of 9a bromo-11-ketoprogesterone in 1.5 cc of acetone is added, under a carbon dioxide atmosphere, 0.3 cc of chromous chloride solution (separated as described in "Journal Of the American Chemical Society, 72, 4080 (1950). The reaction mixture is allowed to stand at room temperature. for 20 minutes, after which 5 cc of water is added and the acetone is removed in vacuo. The residual aqueous suspension is extracted with chloroform, after which the chloroform solution is washed with water, with water. using a solution of sodium bicarbonate and again with water, then dried over sodium sulfate.



  By evaporation of the solvent in vacuo, a residue is obtained (about 12.8 mgr), which, by crystallization from a mixture of acetone and hexane, gives pure 11-ketoprogesterone, melting at 171-172 C and having an infra spectrum. - red identical to that of genuine 11-ketoprogesterone - A melting point in admixture with an authentic sample has not been reduced.



   EXAMPLE 18.-
 EMI20.3
 Preparation of 90E-chlono-llo-hydroxyprogesterone (LIII) .- a 95-11B.-j-cimdoprogestéioqwe LII from bromo-11 h dro-sterone XX o- 103 mgr of 9a-bromo-llj3-hydroxyprogesterone are processed per 250 mgr of potassium acetate, as described in part a; variant of example 4.

   The resulting amorphous product, representing i-113-oydoprogesterone (about 90.6 mg), cannot be crystallized even after chromatography and is therefore used for the next step without purification.
 EMI20.4
 b 9a chloro-11 h dro ro esterone (LUI) from 11 o-progesterone (LII) .- 63, # mgr of 9ss, llp-oxydoprogesterone in 6.3 cc of chloroform were reacted with 1, 2 cc of 0.488 N HCl in 0 chloroform for 1 hour. The reaction mixture is worked up as described in Example 7 and the resulting residue (about 72 mg) is crystallized from a mixture of acetone and hexane.

   After recrystallization
 EMI20.5
 in absolute ethanol, we obtain 9a-chloro-llp-hydroxyprogested; pure gene, exhibiting the following properties: PF: 204 (<fficodi [al D: +199 (ce 0.47 in CECI; em: 240 mj . (t = 18.600); 12196 D fli 5.90 Fe 6.00 F '6.07 µl; analysis: calculated for 21H 2903 Cl.' 9) C = 69.13%; H = 8.01 %; found (approximately): c = $ 69.00; 'Ez $ 7.73 o
9α-Chloro-llp-hydroxyprogesterone has an activity which is 1/4 that of cortisone acetate in the rat liver glyxogen assay.



   Following the procedure described above, but using hydrofluoric acid or hydriodic acid instead of hydrochloric acid.

 <Desc / Clms Page number 21>

 
 EMI21.1
 drric, 9α-fluoro-llp-hydroxyprogesterone and 9a-iodo # llp-hydroxyprogesterone respectively are obtained, the former having the following properties: m.p .: about 216-217 C; [a] 23: +191 (c = 0.75 in CECI-); its activity equal to that of cortisone acetate in the liver glycogen assay and twice that of deoxycorticosterone acetate in the sodium retention assay.

   Likewise, the oxidation of
 EMI21.2
 9or, -fluoro-11 (3-hydroxyprogesterone - (or corresponding chlorinated or iodinated compounds) using chromic acid, in the same way as for 90E-bromo-11p-hydroxyprogesterone (cf., part to of Example 17), gives 9α-fluoro-11-ketoprogesterone (and the corresponding chlorine and iodine compounds, respectively).



   EXAMPLE 19.-
 EMI21.3
 Preparation of 90L-'bromo-ll) 3-17a-dihydroxyprogesterone (L) e- alla-tosyloxy-17a-hydroxyprogesterone LVI artir de IIa, 17a-dihy-droxyprogesterone XXVI .- 1.2 gr of Ila, 17a-dihydroxyprogesterone are treated with 1.4 g of p-toluene sulfonyl chloride and the reaction mixture is treated as described in part b of Example 1.

   The resulting tosylate (weighing 1.7 g, obtained after recrystallization from acetone, has the pro-
 EMI21.4
 priities sui ± µfi (ggiPof.: about 143-146 (dec.); /"a.7 ': 48 (c, 0, 29 in THIS)' "" '' 2 mu = 26.500) 274 mu = 006), 285 mu (= 305 max. At u 0: 3.93 p (OH); 5.88 p, 5.99. 6s 05 d.'s analysis: calculated for 8E6Qfl (500, 631 ': 0 = 67.17 %; H = 7.25%; S = 6.44 $; found approximately): 0 = 67.08%; E> 7.52% J s = 6.35% oa: variant lla-més 10 -17a- h dro (LX) from llcx- 17a-dihydroxyprogesterone XXVI 117 mgr of 11a, l7a-dihydroxyprogesterone are dissolved in 5 cc of pyridine After cooling to 0, 0.04 cc of methane sulfonyl chloride (1.5 equivalents are added. The mixture is left to stand in a cooler for 8 hours.

   The excess methanesulfonyl chloride is then destroyed by means of ice, the mixture is diluted with chloroform, washed with 1N HCl, with sodium bicarbonate solution and with using water, then dried over sodium sulfate and evaporated. By crystallization from ethanol, approximately 65 mg of the product are obtained.
 EMI21.5
 duit having the following properties to. F: about 150-152 (dec.) J [al D +640 (c, 0.49 in CHCl3); At µ / 238 mu (t = 18,200), 285 nyx (= 277); J: 5.9C "6.04p, 6.11), 6.24p; analysis; calculated for max.



  G22H32068 (424.54): α 7Z3 x = 7.60fi; 3 = 7.55%; found: 0 = 62.11%; H = 7y71ix The mother liquors give about 50 mgr of additional product. b 4'9 (11) - re adiene-1 a ol-3 20-dione (LV) from lla-tos lo - -17a-hydroxyprosesterone (h) o = 1.19 gr of lla-tosyioxy-170E- hydroxyprogesterone are treated with 2.4 g of anhydrous sodium acetate in 25 cc of glacial acetic acid and the reaction mixture is treated as described in part c of Example 1.

   The residue (approximately 693 mgr) crystallizes rapidly from acetone, giving approximately 520 mgr of '-pregnadiene 17a-ol-4,20-dione2ure having the following properties: m.p.:
 EMI21.6
 about 214-216, [aJD: g +670 (o, 0, 82 in CHCl3); Â ce: 239 min (- tur wax. l8.450); Â '' ': 2.88 p, (OH), 5.87 P (20-ketone), .99 µ, 6.04p, 6.16 (11 4-3-keton); Analysis: calcd for C21H2803 (328.44): 0 = 76.79%; H =

 <Desc / Clms Page number 22>

 
 EMI22.1
 8.59%; found (approximately): C = 76.52; H, 8.46%.



  4'911'la-mesyloy-.17Ct-hydroxyprogesterone can also be converted to α-Pregnadiene-17Ct-ol-3'20-dione by the above method.



  (c) 9a-bromo il $, 17a-dihydroxyprogesterone (LVI) from 4.9 (11) - re adiene-170E-ol-3 20-dione (LV). - 330 gr of LQ., 9 (II -Pregnadiene-i7ct ol-3, 20-dione are treated
 EMI22.2
 with 200 mgr of N-bromoacetamide and the reaction mixture is treated as described in part d of Example 1. The resulting crude product (approximately 450 mgr) is recrystallized from a mixture of acetone and
 EMI22.3
 chloroform and gives approximately 362 mgr (85%) of 90E-bromo-llfi-, 170E-dihydroxy- 3?, ", - ogesterone having the following properties: PF: approximately 189-19i (dêc} [a] D2: +12 % tc, 0.33 in CH01); alk.; 243 ny1 (= 16 .700) j \ m :; ':: 2.88 p- (EC), S, 86 z - (? 0-ketone) 6 0.04 p (4 3-ketone}; analysis: calculated for C21H2904Br (425e36): C = 5952eo; H = 6.87%; Br = h8.79; found approximately): C = 59.59%; H = 6 , 81%; Br = 18.6i.
 EMI22.4
 



  EXAMPLE 20, -
 EMI22.5
 Preparation of 90e-chloro-11-keto-170E-hydroxyprogesterone LIX) .- (a) 4 re ene-110-oxyclo-17a-01- 20-dione (LVIII) from ü-bromo-110, 17a-dihydrozyprogesterone (LVI) .- A solution of 247 mgr of 9a-bromo (11.1 $ OE-dihydroxyprogesterone
 EMI22.6
 and 630 mgr of anhydrous potassium acetate is heated at reflux for 90 minutes. The reaction mixture is worked up as described in the section of Example 4.

   The resulting crude residue is recrystallized from a mixture of acetone and hexane, so that -pregnene is obtained.
 EMI22.7
 -93,11 (3-ogydo-17ct-ol-3,20-dione ure having the following properties: mp: about 197-199; "a..7 D23: +6 (c, 0.32 in CHCl); (max, 243 mu (É = 15,200), 283 Dyp (, = 630} 3 Nuol: 2.86 p, 3.05, (on), 5s z (20-0), 6, OQ. z (1l4¯ 3-ketone); analysis: calcd for C21H2804 (344.44): 0 = 73.22%; H = 8.18f; found (approximately): C = 72.99; H =
 EMI22.8
 8.11%.
 EMI22.9
 



  (b) 90e-chloro-11fl, 17o (-dihydroxyprogesterone (LVIII) from 4¯pr- - nene-9 (3-ox.ydo-17a ol-3,20-ens (LVII).



  42 mgr of 4 pregnene-9i, llp-oxydo-17a-ol-3,20-dione are dissolved
 EMI22.10
 in 4 cc of chloroform and reacted with 0.7 cc of 0.456 N HCl in
 EMI22.11
 chlorfp3 at 0 for 1 hour - The reaction mixture is treated as described in Example 7, The resulting residue approximately 42 mgr)
 EMI22.12
 gives, after crystallization from a mixture of acetone, chloroform and
 EMI22.13
 hexane, 90E-chloro-llfl, 17a-dihydroxyprogesterone having the following properties: PF: about 245-246 (dec.): -aJ '3: +1380 (c, 0.35 in sale, 238 mu (# = 17.300) .Nujol, 2 91 (OH) 5.90 lU OY35 in max o. 238 1 = 17-300) max.

   (OH) 5190p (20-ketone), 6.05 µl (4-3-ketone); analysis: calcd for C21H2904Cl 390.90): C = 66.21; H-Z67, b; Cl = 9.31%; found (approximately): C = 66.18f H = 7.38%; 01 = 9.64%. c a-chloro-ll-keto-17a-h drox ro esterone LXI from a chlora- 11 17oc-dih drog ro esterone LVIII a-
 EMI22.14
 41 mgr of 9a-chloro-llp, 17a-dihydroxyproesterone are oxidized in

 <Desc / Clms Page number 23>

 10 cc of glacial acetic acid with 15 mgr of chromic acid. The reaction mixture is worked up as described in part ¯ of Example 1.

   By crystallization from a mixture of acetone, chloroform and hexane, 9a-chloro-11-keto-17a-hydroxy-progesterone is obtained having the following properties: m.p. about 260-261 (dec.); [a] 23: +177 (c, 0.17 in CHCl3); Analysis: calcd for C21H27O4Cl (378.89); C = 66.57% H = 7.18%; found (approximately): C = 66.12%; H, 7.45%.



   By following the process of pardie d, but using hydrogen fluoride or hydroiodic acid instead of hydrochloric acid, 9a-fluoro-11ss, 17a-dihydroxyprogesterone and 9a-iodo- respectively are obtained. 11ss, 17α-dihydroxyprogesterone, the first of these compounds having the following properties: PE: about 274-276 C; [a] 23:136 (C, 0.3 in dioxane); activity: 1/3 that of cortisone acetate in the liver gycoyene test. The compounds in question can be oxidized by the process described in part e, so that, for example, 9a-fluoro-11-keto-17a-hydroxyprogesterone is obtained.



   CLAIMS.-
1.- Process for preparing a steroid of the pregnane series,. having a 9a-fluorinated substituent and an 11-keto or llp-hydroxy group, having a 9a-fluorine substituent and an 11-keto or 11ss-hyaroxy group, pregnan with an agent providing hydrogen fluoride.


    

Claims (1)

2. A process according to claim 1, wherein the hydrogen fluoride is reacted with the 9ss, 11p-oxydo steroid in an alcohol-free solvent. 3. - The method of claim 1, wherein the steroid of the pregnane series comprising a 9a-fluorine substituent and an 11-keto or 11ss-hydroxy group has the following general formula: EMI23.1 in which position 4,5 has a double bond or is saturated R denotes hydrogen, R 'denotes an Oh group or R and R' denote = 0 'or' a 'group which can be transformed into = 0 by hydrolysis, R " denotes hydrogen, R "'is a (p) -OH group or alternatively R" and R "' denote together -0, Y denotes -H-OH or -0- (acyl) and Z denotes-0 or (a) -OH, the 9ss, 11ss-oxidosteroid has the general formula: <Desc / Clms Page number 24> EMI24.1 wherein position 4,5 has a double bond or is saturated and R, R ', Y and Z have the meanings given above. 4.- A method according to either of claims 1 and 2, EMI24.2 wherein the 3s I1 (3-oxydosteroid is A-prégnane-9 (3, 11-oxydo-170e-21J-dioi-3,20-àione or an ester thereof, while the steroid of the series of Pregnane having a 90th-fluorine substituent and an 11-keto- or 11p-hydroxy substituent is 9cc-fluoro-cortisone of 90-fluorooortioosterone or an ester of the latter compounds. 5: - Process according to either of claims 1 and 2, in which the 9fi, 11 (3-ogydo-steroid is 4-prégngMe, 9P 113-oxydo-21-ol-3,20- dione or an ester thereof, while the pregnane series steroid having a 9a-fluorine substituent and an 11-keto or 11ss-hydroxy substituent is 9a-fluoro-ll-dihydrocorticosterone EMI24.3 fluoro-corticosterone or an ester thereof. 6. A process according to either of claims 1 and 2, wherein the 9,113-oxido-steroid is 9 (3-llp-oxidoprogesterone and wherein the layman series steroid comprising a 9a-fluorinated substituent and an 11-keto or 11-hydroxy substituent is 9a-fluoro-11p-hydroxyprogesterone or 9a-fluoro-11-ketoprogesterone. EMI24.4 7.- Process according to one or the other of the 4revendi cati ons 1 :: 'and 2, in water the 90, 11fi-oxyào-steroid is 4-prégnège ..: - 9 (3 lla-oxydo 17a -ol-3,20-dione and wherein the pregnane series steroid having a fluorinated 9a substituent and an 11-keto or llp-hydroxy substituent EMI24.5 is α-fluoro-11 (3 17α-dihydroxyprogesterone. 8. Pregnane steroid comprisinga 9oc-fluoro substituent and an 11-keto or 11ss-hydroxy substituent. 9.- Steroid of general formula: EMI24.6 <Desc / Clms Page number 25> and in which position 4,5 represents a double bond or is saturated, R denotes hydrogen, R 'denotes an OH group or R and R' denote = 0 or a group convertible into = 0 by hydrolysis , R "denotes hydrogen, R" 'is a (p) -OH group or else R "and R"' denote together = 0, Y denotes -H-OH or e0- (acyl) and Z denotes -0 or (a) -OH, 10.- 9α-fluorocortisone or an ester thereof. II.- 9α-fluorohydrocortisone or an ester thereof. 12. - 9α-fluorocorticosterone or an ester thereof. EMI25.1 13.- 9α-fluoro-11-dehydrocortioosterone or an ester thereof. 14.-9α-fluoro-llp-hydroprogesterone. 15.- 9α-fluoro-11-ketoprogesterone. 16.- 9a-fluoro-11p-17a-dihydroxyprogesterone. EMI25.2 17.- 90E-fluoro-11-aeto-170E-hydroxyprogesterone.