IE44347B1 - Steroid (16,17- ) dioxanes - Google Patents

Description

This invention relates to new chemical substances Τ'lihich are steroidal dihalo-dioxanes, and provides new compounds vzhich are steroidal 9,lip - dihaloEl6o,17 - b] 1,4 - dioxanes, and are useful as anti-inflammatory agents.

The new compounds of the invention have the formula: In formula I, and throughout the specification, the symbols are as defined below: Z is hydrogen, hydroxyl, alkyl-C-05? cycloalkyl-C-O-, or II aryl-C-0-, or halogen; X is chlorine or fluorine; A^ is—CH^— CH^— or is a —C=CH—, R2O-CH-CHj-, —c-ch2-, or r3c-o-ch-ch2radical in which the = CH— or —CH^— group is attached to the f bond of the dioxane ring.

P and Q are independent of each other and each is hydrogen, methyl, or halogen; R^ is hydrogen, alkyl or aryl; R2 is hydrogen or alkyl; and R3 is alkyl, cycloaikyl, or aryl.

The dotted lines in the 1, 2 and 6, 7-positions of formula I represent the optional presence of double bonds. ¢3 47 The term alkyl, as used throughout the specification, refers to both branched and straight chain alkyl groups having 1 to 8 carbon atoms. Alkyl groups of 1 to 4 carbon atoms are preferred.

The term cycloalkyl, as used throughout the specification, refers to cycloalkyl groups having 3 to 6 carbon atoms.

The term aryl, as used throughout the specification, refers to phenyl or phenyl substituted with halogen, alkyl, or alky1-0=. Phenyl is the preferred aryl group.

The term halogen as used throughout the specification, refers to fluorine, chlorine, bromine and iodine.

The steroids of formula I are physiologically active substances which possess glucocorticoid and anti-inflammatory activity and hence can be used in lieu of know glucocorticoids in the treatment of rheumatoid arthritis, for which purpose they can be administered in the same manner as hydrocortisone, for example, the dosage being adjusted for the relative potency of the particular steroid. In addition, :.3· . the steroids of this invention can be used topically in lieu of known glucocorticoids in the treatment of skin conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema, and anogenital pruritus.

When given orally, the compounds of this invention may be used in a dosage range of 0.1 to 200 milligrams, preferably 0.3 to 100 milligrams. If administered topically, the compounds of this invention may be used in the range of 0.01 to 5.0% by weight, preferably 0.05 to 2.0% by weight, in a conventional cream or lotion.

Those steroids of formula I wherein A,is -CH--CH--, 0 12 2 R2O-CH-CH2-, -&-CH2-, or R3<5-O-CH-CH2(this subgrouping is referred to hereinafter as A2) can be prepared from the corres The to yield dehydration of 110-hydroxy steroids of formula II -steroids having the structure -5can be carried out using'any one of several processes known in the art. Exemplary of such processes are; 1) dehydration with phosphorous oxychloride and pyridine; and 2) dehydration with methanesulfonyl chloride and pyridine. (11) Reaction of a A -steroid of formula III with N-chlorosuccinimide and an acid of the formula IV H-X yields the corresponding steroidal 9,llf5-dihalo-El6a,17-bZI-l,4~ dioxane having the structure The reaction can be run in a solvent, e.g., glacial acetic acid at a temperature of from 0°C to 30aC, for 1 hour to s hours. «1 Those steroids of formula I wherein A^ Is -C=CH“ are prepared from the corresponding llg-hydroxy steroids of the structure In formula VI, and throughout the specifica11 tion, R4 is alkyl or aryl; and Z' is hydrogen, alkyl-C-O-, 5 cycloaXkyl-§-0-,aryl-$-O~, or halogen.

Conversion of an llg-hydroxy steroid of formula VI to the corresponding 9,llg-dihalo steroid can be accomplished using the procedures described above (i.e., dehydration of the llg-hydroxy steroid followed by halo10 genation). The resultant 9,116-dihalo steroid can be reacted with a slurry or solution of an organic acid such as ^-toluenesulfonic acid, in an organic solvent such as benzene, to yield the corresponding steroid of structure VIII wherein is alkyl ‘ or aryl. Conversion of an llg-hydroxy steroid of for-76067 « mula VII to the corresponding 9,118-dihalo steroid can be accomplished using the procedures described above (i.e., dehydration of the 118-hydroxy steroid followed by halogenation). The resultant 9,118-di5 halo steroid can be reacted successively with a peracid, an oxidizing agent, and a slurry an acid in a solvent such as benzene, to yield a steroid having the structure ch2z' Q wherein is hydrogen. 4 3 4 7 Cycloborate esters of 16a,17-dihydroxy steroids having ΓΠ 7 the formula . 2 can be used for the preparation of the steroids of formulas XI, VI and VII. The cycloborate esters of formula IX are known; see, for example, United States patent 2,831,003, issued April 15, 1958.

Diazoalkenes havinq the formula I1 X CH2=C — chn2 are also used for the preparation of the steroids of formula OH 0 0 II wherein A2 is -CH-CH2“, R3-C-O-CH-CH2-, -C-CH2-, or -CH2”CH2“ and the steroids of formula VI and VII. In formula X, those diazoalkenes wherein is hydrogen or alkyl are known; see, for example, the Journal of the American Chemical 15 Society, 91, 711 (1969). The preparation of the diazoalkene of formula X wherein R^ is aryl is described in the examples of this specification.

Reaction of a cycloborate ester of formula IX with a diazoalkene of formula X yields a steroid having the formula -9CH2Z I Q The reaction can be conducted in an organic solvent, preferably a lower alkanol such as methanol, at a temperature of about -10°C to +40°C for about 30 minutes to 4 hours, preferably at 0°C to 20°C for 30 minutes to 1 hour. The steroid and the diazoalkene are reacted in at least a 1:4 molar ratio.

The steroid of formula XI. (if z is hydroxy, it should first be protected by acylation) can be reacted with m-chloroperbenzoic acid to yield a steroid having the formula CHgZ1 The reaction can be conducted in an organic solvent, preferably a halogenated hydrocarbon such as dichloromethane, at a temperature of from about 0°C to 40°C for about 1 hour to 96 hours, preferably at room temperature for about 2 hours 3.5 to 72 hours. The steroid-Of formula XI and the m-chloroperbenzoic acid are reacted in approximately a 1:1 molar ratio. 1044347 Reaction of a steroid of formula XII when is alkyl or aryl, with a strong oxidizing agent such as periodic acid, yields a steroid having the formula cii.z' Q Reaction of a steroid of formula XII when is hydrogen yields a cyclic lactol (formula XIV) which is in equilibrium with the corresponding aldehyde (formula XlVa), i.e., XIV XlVa 1q These oxidation reactions can be conducted in an organic solvent, such as tetrahydrofuran, mixed with water at a temperature of about 0°C to 40°C, for about 1 hour to 8 hours, preferably at room temperature for 2 hours to 4 hours.

Reaction of a steroid of formula XIV with an anhvdride II having the formula (R3C)2O yields a steroidal [16a,17-b]1,4dioxane having the formula I Q The reaction can be conducted in an organic solvent such as pyridine at a temperature of about 0“C to 4Q°C for about 30 minutes to 4 hours, preferably at room temperature for 1 hour to 2 hours.

Oxidation of a steroid of formula XIV with Fetizon’s reagent (Angew. Chem. Internat. Edit., 8., 444 (1969)) yields a steroid having the formula CH-Z ' Q The reaction can be conducted in an organic solvent such as benzene ’or toluene, at a temperature of about 80°C to 110°C for about 2 hours to 48 hours, preferably at reflux temperature for about 24 hours.

Reaction of a steroid of formula XIV with sodium boro15 hydride yields a steroid having the formula •1244347 Q The reaction can be carried out in an organic solvent, preferably a lower alkanol such as methanol at a temperature of from about -10°C to 20°C for about 10 to 60 minutes, preferably at about O’C for 10 minutes to 30 minutes.

A 16a-hydroxyethoxy steroid of formula XVII can be reacted with a methanesulfonyl halide (methanesulfonyl chloride is preferred) to yield a steroid having the formula Q The reaction can be carried out in an organic solvent such as pyridine, in an inert atmosphere, at a temperature of about -10’C to 40°C for 30 minutes to 4 hours, preferably at about O’C for 1 hour to 2 hours.

Reaction of a steroid of formula XVIII with sodium bicarbonate in a dipolar aprotic solvent such as dimethylsulfoxide yields a steroidal[16a,17-b)1,4-dioxane having the formula -13XIX CIl-Z' J Q The reaction can be conducted at a temperature of from about 60°C to 130°C for about 1 hour to 24 hours, preferably at about 100°C for 2 hours to 4 hours.

Steroidal[16a,17-b]1,4-dioxanes of formula II can be prepared from the cycloborate esters of 16a,17-dihydroxy steroids of formula IX and diazoethers having the formula XX (alkyl-o) 2CIICHN2 The diazoethers of formula XX are known; see, for example, Chem. Ber. 100, 1491 (1967).

Reaction of a cycloborate ester of formula IX with a diazoether of formula XX yields a steroid having the formula XXI The reaction can be conducted in an organic solvent, preferably a lower alkanol such as methanol, at a temperature of from about -10°C to 40°C until nitrogen evolution ceases. The. preferred reaction temperature is from 0°C to 20°C. -1444347 The steroid of formula XXI can be reacted with an organic acid such as ^-toluenesulfonic acid ih an organic solvent such as benzene to yield a steroidal[16a,17-b]1,4dioxane having the formula CII Z I The reaction can be carried out at a temperature of about 60°C to 140°C for about 1 hour to 24 hours, preferably 80°C to 110°C for 2 hours to 4 hours.

Reaction of a steroid of formula XXI with a mineral acid, e.g., hydrochloric acid, yields a steroidal!16a,17-b]1,4-dioxane of formula XIV. The reaction can be carried out in an organic solvent such as tetrahydrofuran at a temperature of from about 0°C to 100°C for about 1 hour to 24 hours, preferably 40°C to 60°C for 2 hours to 8 hours.

A steroid of formula XIV can be used to obtain a steroid of formula XV, a steroid of formula XVI and a steroid of formula XIX following the procedures set forth above.

Steroidal[16a,17-b]1,4-dioxanes of formula II wherein A?, is -Cl^-CIlj- can be prepared from the cycloborate esters of 16a,17-dihydroxy steroids of formula IX and 2-(tetrahydropyran-2-yloxy)-1-diazoethane, the preparation of which is set forth in the Examples below. -15Reaction of a cycloborate ester of formula χχ with 2-(tetrahydropyran-2-yloxy)-l-diazoethane yields a steroid having the formula XXIII ?H2Z -oO The reaction can be carried out in an organic solvent, prefer5 ably a lower alkanol such as methanol, at a temperature of from about -10°C to 40°c, preferably 0°c to 20°C. The reaction is continued until nitrogen evolution ceases. Λ steroid of formula XXIII (if Z is hydroxy, it should first be protected by acylation) may be cleaved with an acid to yield a steroid of formula XVII. The cleavage reaction can be conducted in water at a temperature of from about 0°C to 40°C, preferably at room temperature, for about 1 hour to 24 hours, preferably 2 hours to 8 hours. Both organic and inorganic acids can be used in this reaction.

The preparation of a steroid of formula II wherein A2 is -CHj-CHj- from a steroid of formula XVII is set forth above.

This invention specifically contemplates the tf-, Δ1'4-, Δ4'®-, and A^'^'^-pregnenes of formula I. The /f14 and Δ ' - pregnenes are preferred. Those steroids of formula II, VI ahd VII containing ethylenic unsaturation in the· 6,7-position can be prepared as described above with the additional step of selectively introducing a carbon-carbon -15* 4347 double bond in the 6,7-position of either a cycloborate ester of a 16a,17-dihydroxy steroid of formula IX or a steroid product of formula XIII, XV, XVI, XIX, or XXII, without effecting other functional groups of the steroid. Ex5 emplary of the oxidizing agents which meet the above requirements is 2,3-dichloro-5,6-dicyano-l,4-benzoquinone when used in the presence of an acid. About one molar equivalent of the oxidizing agent is used per molar equivalent of steroid. The oxidation reaction can be conducted in an organic solvent such as benzene or toluene or dioxane; dioxane is preferred. The reaction can be carried out for about 1 hour to 96 hours at a temperature of about 50°C to 150°C, preferably for about to 24 hours at about 70°C to 130°C. Alternatively, a Δ4,β14 6 or Δ ' ' -pregnene corresponding to formula IX may be used as a starting material. These may be prepared by reacting the 4 6 14 6 known Δ ' - or Δ ' * -pregnene-16a,17-diols with boric anhydride as described in United States patent 2,831,003.

Additional methods for the preparation of the compounds of this invention will be readily apparent to a person of ordinary skill in the steroid art. For example, those steroids of this invention having a halogen in the 21-position can be prepared from the corresponding 21-hydroxy steroid by reacting the latter with an alkyl or aryl sulfonyl halide (e.g., methanesulfonyl chloride or £-toluenesulfonyl chloride), in the presence of an organic base such as pyridine, to yield a 21-alkyl (or aryl) sulfonyloxy steroid. The 21-alkyl (or aryl)sulfonyloxy steroid intermediate can be reacted with alkali metal halide (e.g., potassium fluoride, lithium chloride, lithium bromide or sodium iodide) to yield the corresponding 21-halo steroid. -1744347 Using procedures well known to those of ordinary skill in the steroid art it is also possible to prepare 21-acyloxy steroids of this invention·from the corresponding 21-hydroxy steroids. Other variations will be apparent to the practitioner of this invention.

The following Examples are specific embodiments of this invention. -1844347 Example 1 9,llS-Dichloro-21-hydroxypregna-l,4-dieno[16α,17-b][l,4]dioxane-3,20-dione, 21-acetate A. 16g-[2- (Tetrahydropyran-2-yloxy)ethoxy]-11R,17,21tr ihydroxypregna-1,4-diene-3,20-dione a) Tetrahydropyran-2-yloxy acetonitrile This material is prepared by the method of J. Davoll and D. H. Laney, J. Chem. Soc., 2129 (1956) and has a boiling point of 78-79°C at 2 mm. b) 2- (Tetrahydropyran-2-'yloxy) ethylamine A solution of 35 g of tetrahydropyran-2-yloxy acetonitrile in 100 ml of ether is added dropwise to a slurry of 10 g of lithium aluminum hydride in 300 ml of ether and 100 ml of tetrahydrofuran. The slurry is refluxed for 210 minutes, cooled, and 25 ml of saturated potassium carbonate solution is added at a rate that maintains gentle reflux. After 90 minutes the slurry is filtered and the solid is washed with ether. The filtrate is evaporated in vacuo and distilled to give 33.6 g of 2-(tetrahydropyran-2-yloxy)ethylamine, boiling point 41.5 - 46°C at 0.5-0.8 mm. c) N-[2-(Tetrahydropyran-2-yloxy)ethyl]urea A mixture of 33.2 g of 2-(tetrahydropyran-2-yloxy)ethylamine, 50 g of ice, and a solution of 35 g of potassium isocyanate in 80 ml of water is stirred well as 45.6 ml of 5N hydrochloric acid (cooled to -40°C) is added in one portion. The resulting solution is refluxed for 90 minutes, cooled, and extracted with four 150 ml portions of chloro-19- form. The chloroform extract is dried and evaporated in vacuo to give 39.6 g of oil.· d) N-Nitroso-N-(2-(tetrahydropyran-2-yloxy)ethyl]urea A solution of 39.6 g of N-[2-(tetrahydropyran-2yloxy)ethyl]urea in 400 ml of ether and 10Q ml of methylene chloride is slurried with 50 g of sodium acetate and cooled to -10°C with mechanical stirring. A solution of 30 g of nitrogen dioxide in 100 ml of ether is added over a 30 minute period, the slurry is stirred at -10°C for 20 minutes and then filtered. The filtrate is washed with saturated sodium bicarbonate solution, dried, and evaporated to give 41.8 g of yellow oil. e) 2-(Tetrahydropyran-2-yloxy)-1-diazoethane A solution of 41.8 g of N-nitroso-N-[2-(tetrahydropyran-2-yloxy)ethyl]urea in 200 ml of ether and 100 ml of pentane is added to 450 ml of IN sodium hydroxide solution at 1°-4°C over a 25 minute period. The solution is stirred for an additional 30 minutes and the layers are separated.

The organic layer is dried over sodium hydroxide pellets at O’C for 5 minutes, and then filtered. -2044347 f) 16α-[2-(Tetrahydropyran-2-yloxy)ethoxy)118,17,21-trihydrpxypregna-l,4-diene-3,20-dione A solution of 2- (tetrahydropyran-2-yloxy)-1-diazoethane (prepared from 69.1 g of N-[2-(tetrahydropyran-2-yloxy)ethyl)urea by the procedure described in (c) - (e) above) in 600 ml of 3:1 ether-pentane is stirred with 200 ml each of ether and methanol at 0°C. Fourteen g of 118,16a, 17,21tetrahydroxypregna-l ,4-diene-3,20-dione, 16,17-cycloborate is added in portions. After nitrogen evolution ceases the solvents are removed in vacuo and the residue is dissolved in chloroform and chromatographed on a 150 g-silica gel column. Elution with chloroform and then 1:1 chloroformethyl acetate gives 4.0 g of TLC pure 16«-(2-(tetrahydropyran-2-yloxy) ethoxy]-118,17,21-trihydroxypregna-l,4-diene3,20-dione.

B. 16a-[2- (Tetrahydropyran-2-yloxy)ethoxy]-118,17,21trihydroxypregna-l, 4-diene-3,20-dione, 21-acetate A solution of 3.75 g of 16a-[2-tetrahydropyran-2yloxy)ethoxy]-118,17,21-trihydroxypregna-l,4-diene-3,20dione in 15 ml of pyridine and 5 ml of acetic anhydride is kept at room temperature for 4 hours and the solvents are then evaporated in vacuo. The residue is dissolved in chloroform and washed with dilute hydrochloric acid, water, dilute sodium bicarbonate solution, and dried. Solvent removal gives 4.9 g of crude 16a-[2-(tetrahydropyran-2-yloxy)ethoxy]-118,17,21-trihydroxypregna-l,4-diene-3,20-dione, 21-acetate. 21· C« 16u-(2-Hydroxyethoxy)-118,17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acotato A solution of 4.9 g of crude 16a-[2-(tefcrahydropyran-2-yloxy)ethoxy]-118,17,21-trihydroxypregna-l,4-diene5 3,20-dione, 21-acetate in 60 ml each of acetic acid and water is stirred for 6 hours at room temperature. The solvents are removed in vacuo and the residue is dissolved in chloroform and washed with 5% sodium bicarbonate solution and dried. Solvent removal gives 3,9 g of product which is combined with 750 mg of product from a different batch and chromatographed on a 90 g-silica gel column. Elution with chloroform and then 1:1 chloroform-ethyl acetate gives 3.7 g of material which crystallizes from acetone-hexane to give 3.17 g of 16a-(2-hydroxyethoxy)-IIS,17,21-trihydroxy15 pregna-l,4-diene-3,20-dione, 21-acetate, meltinq point 138140°C.

D. 16a-(2-Mesyloxyethoxy)-118,17,21-trihydroxypregna1,4-diene-3,20-dione, 21-acetate A solution of 3.0 g of 16a-(2-hydroxyethoxy)-118,20 17,21-trihydroxypregna-l,4-diene-3,20-dione, 21-acetate in ml of pyridine is stirred with 0.75 ml of methanesulfonyl chloride at 0°C for 15° minutes. The,mixture is poured into 1.5 liter of cold IN hydrochloric acid, stirred for a short time, and filtered. The resulting solid is dis solved in chloroform, washed with water, dried, and evaporated in vacuo to give 4.0 g of crude 16a-(2-mesyloxyethoxy) 118,17,21-trihydroxypregna-l,4-diene-3,20-dione, 21-acetate -2244347 Ε. 11β,21-Dihydroxypregna-1,4-dieno[16α,17-b][1,4]dioxane-3,20-dione, 21-acetata A solution of 4.0 g of crude 16a-(2-mesyloxyethoxy)11β,17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate 5 in 200 ml of dimethylsulfoxide is stirred at 110°C under nitrogen, with 4.0 g of sodium bicarbonate for 2 hours. The slurry is cooled, poured into 2 liters of cold 2.5% hydrochloric acid, and extracted with chloroform (three 250 ml portions). The chloroform solution is washed with two 1 liter portions of 2.5% hydrochloric acid, dried, and evaporated in vacuo. The residue is dissolved in chloroform and chromatographed on a 66 g-silica gel column. Elution with chloroform gives 2.4 g of material which crystallizes from acetone-hexane to give 1.55 g of 116,21-dihydroxypregna15 l,4-dieno[16a,17-b][1,4]dioxane-3,20-dione, 21-acetate, melting point 280-282°C.

F. 21-Hydroxypregna-1,4,9(11)-trieno[16n,17-b][1,4]dioxane-3,20-dione, 21-acetate A mixture of 1.5 g of 113,21-dihydroxypregna-l,420 dieno[16a,17-b][l,4]dioxane-3,20-dione, 21-acetate, 75 ml of dimethylformamide, 37.5 ml of pyridine, and 15 ml of methanesulfonyl chloride is stirred at 0°C for 75 minutes, poured into cold dilute hydrochloric acid, and the resulting mixture extracted with chloroform. The chloroform solu25 tion is dried and evaporated x„ vacuo. The residue is dissolved in chloroform and chromatographed on a 60 g-silica gel column. Elution with 1:1 hexane-chloroform gives 1.2 g of 21-hydroxypregna-l,4,9[ll)-trieno[16a,17-b][1,4]dioxane3,20-dione, 21-acetate. -23· Go 9,1IB-l)ichloro-21-hydroxypregna-1,4-dieno[16α,17-b](1,41dioxane-3,20-dione, 21-acetate A solution of 1.2 g of 21-hydroxypregna-l,4,9(11)trieno[16a,17-b)[1,41dioxane-3,20-dione, 21-acetate and 5 5.0 g of lithium chloride in 50 ml of glacial acetic acid is stirred at 0-5eC and 413 mg of N-chlorosuccinimide is added. A solution of 126 mg of dry hydrogen chloride in 2 ml of tetrahydrofUran is added and the resulting mixture is stirred at room temperature for 2 hours,poured into 600 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to give 1.31 g of crude product. This material is plate chromatographed on three 20 x 20 cm - 2 mm silica gel plates. After two developments with 1:1 chloroform-ethyl 15 acetate the UV-active band of intermediate is excised and eluted with ethyl acetate to give 735 mg of material. Recrystallization from methanol yields 540 mg of material, melting point 256-258eC, dec. This is combihed with 137 mg of material obtained by rechromatographing the mother liquors, and recrystallized from methanol to give 575 mg of 9,118-dichloro-21-hydroxypregna-l,4-dieno[16 α,17-b)[1,4) dioxane-3,20dione, 21-acetate, .

Anal. Galc'd. for c25H3ocl2°6: C, 60.36; H, 6.08; Cl, 14.26 Found: C, 60.09; Η,’5.83; Cl, 14.23. -2444347 Example 2 9,116-Dichloro-5'L-ethoxy-21-hydroxypregn-4-ono[16a,17-bl[l,41dioxane-3,20-dione, 21-propionate A. lfia - (2,2-Dlethoxyethoxy)-118,17,21-trihydroxy5 pregn-4-ene-3,20-dione A solution of 2,2-diethoxy-l-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and B. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3s2 ether pentane is diluted with 100 ml of methanol and cooled to 0°C. 118,16α,17,21-Tetrahydroxypregn4-ene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is reerystallized from methanol to yield the title compound. ®· 51ζ-Ethoxy-llfi,21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxane-3,20-dione A slurry of 100 mg of ^-toluenesulfonic acid in 250 ml of benzene is refluxed with a Dean-Stark trap. The first 50 ml of benzene-water azeotrope is discarded and Linde (Trade Mark) type 4A molecular sieves are added to the trap. After 30 minutes at reflux, the solution is cooled and 2 mmoles of 16a-(2,2diethoxyethoxy)-118117,21-trihydroxypregn-4-ene-3,20-dione is added. The resulting slurry is refluxed for 2 hours under nitrogen, cooled, diluted with chloroform, washed with 5% sodium bicarbonate solution, water, dried and evaporated to yield the title compound. -254434? C. 5'C-Ethoxy-11B,21-dihydroxypregn-4-eno[16α,17-b][1,4]dioxane-3,20-dione, 21-propionate A solution of 1.0 g of 5'C-ethoxy-118,21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxane-3,20-dione in 20 ml of pyridine is stirred for 4 hours at room temperature with 2 ml of propionic anhydride. The solvent and excess anhydride are removed in vacuo, and the residue is dissolved in chloroform and washed with 53 hydrochloric acid, water, 5% sodium bicarbonate solution, dried and evaporated to give the title compound.

D, 5'g-Ethoxy-21-hydroxypregna-4,9(11)-dieno[16«,17-b][1,4]dioxane-3,20-dione, 21-prOpionate A mixture of 5*C-ethoxy-116,21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxane-3,20-dione, 21-propionate (4 mmoles), 75 ml of dimethylformamide, 37.5 ml of pyridine, and 15 ml of methanesulfonyl chloride is stirred at O’C for 75 minutes, poured into cold dilute hydrochloric acid, and the resulting mixture extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound. -2644347 Ε. 9,llg-Dichloro-5'C-ethoxy-21-hydroxypregn-4-eno[16a,17-b][1,4]dioxan,e-3,20-dione, 21-propionate Λ solution of 5'£-ethoxy-21-hydroxypregna-4,9 (11)dieno[16a,17-b](1,4)dioxane-3,20-dione, 21-propionate (1.4 mmoles) and 2.5 g of lithium chloride in 25 ml of glacial acetic acid is stirred at 0-5°C and 207 mg of N-chlorosuccinimide is added. Λ solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 300 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to yield the title compound.

Example 3 9,llp,21-Trichloro-5'£-ethoxy-pregn-415 eno[16a,17-b)[1,4]dioxane-3,20-dione A. 5'£-Ethoxy-21-hydroxypregna-4,9(ll)-dieno[16g,17-b][1,4]dioxane-3,20-dione, 21-mesylate A mixture of 51ζ-ethoxy-llg,21-diliydroxypregn-4-eno[16a,17-b][l,4]dioxane-3,20-dione, (4 mmoles, prepared as described in Example 2B), 75 ml of dimethylformamide, 37.5 ml of pyridine, and 15 ml of methanesulfonyl chloride is stirred at 0°C for 75 minutes, poured into cold dilute hydrochloric acid, and the resulting mixture extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound. Β. 9,118-Dichloro-5 'f,-othoxypregn-4-eno[16» , 17-bj [1,4]dioxane-3,20-dione, 21-mesylate A solution of 5'C-ethoxy-21-hydroxypregna-4,9(11)dieno[16a,17-b][1,4]dioxane-3,20-dione, 21-mesylate (1.4 5 mmoles) and 2.5 g of lithium chloride in 25 ml of glacial acetic acid is stirred at 0-5°C and 207 mg of N-chlorosuccinimide is added. A solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran is added and the re.' suiting mixture is stirred at room temperature for 2 hours, 10 poured into 300 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to yield the title compound.

C. 9,11S,21-Trichloro-5'g-ethoxy-pregn-4-eno[16a,17-b][1,4]dioxane-3,20-dione A solution of 0.8 mmoles of 9,118-djchloro-5'gethoxy-21-hydroxypregn-4-eno[16a,17-b][1,4]dioxane-3,20dione, 21-mesylate in 20 ml of dimethylformamide is stirred at 100°C with 2 g of lithium chloride for 30 minutes, cooled, and poured into ice-water. The resulting material is filtered, washed with water, and dried in vacuo to yield the title compound. -2844347 Example 4 9,ll8-Dichloro-5,21-dihydroxypregn-4~eno[16α,17-b)[1,4]dioxane-3,20-dione, 5',21-djacetate A. 5l£,llB,21-Trihydroxypregn-4-eno[16a,17-b]5 [1,4) dioxane-3,20-dione A solution of 16a-(2,2-diethoxyethoxy)-11β,17,21-trihydroxypregn-4-ene-3,20-dione (5 mmoles, prepared as described in Example 2Λ) in 100 ml of tetrahydrofuran is refluxed with 20 ml of IN hydrochloric acid for 3 hours. The solution is cooled, evaporated in vacuo to one third its original volume, and diluted with water. The resulting material is filtered and dried in vacuo to yield the title compound.

B. 51ζ,118,21-Trihydroxypregn-4-eno(16u,17-b][l,4]dioxanc-3,20-dione, 5',21-diacetato A solution of 5'£,118,21-trihydroxypregn-4-eno(16a,17-b](1,4]dioxane-3,20-dione (3 mmoles) in 25 ml of pyridine and 5 ml of acetic anhydride is stirred for 4 hours and the solvent and excess anhydride removed in vacuo. The residue is dissolved in chloroform and the solution washed with vzater, 5% hydrochloric acid, water, 5% sodium bicarbonate solution and dried. Solvent removal gives the title compound. -2944347 C. 5'ζ,21-Dihydroxyprcgna-4,9 (11)-dieno [16α, 17-b] [l,4]-dioxane-3,20-dione, 5',21-diacetate A mixture of 5'ζ,116,21-trihydroxypregn-4-eno[16α,17-b] [l,4]dioxane-3,20-dione, 5',21-diacetate (4 mmoles), 75 ml of 5 dimethylformamide, 37.5 ml of pyridine, and 15 ml of methanesulfonyl chloride is stirred at 0®C for 75 minutes, poured into cold dilute hydrochloric acid, and the resulting mixture extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound.

D· 9,llS-bichloro-5'ζ,21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxane-3,20-dione, 5 ',21-diacetate A solution of 5'ξ,21-dihydroxypregna-4,9 (11)-dieno[16a,17-b][1,4]dioxane-3,20-dione, 5',21-diacetate (2.1 mmoles) and 3.75 g of lithium chloride in 37.5 ml of glacial acetic acid is stirred at 0-5eC and 310 mg of N-chlorosuccinimide is added. A solution of 95 mg of dry hydrogen chloride in 1.5 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 450 ml of cold water, and extracted with chloro20 form. The chloroform solution is washed with water, dried and evaporated in vacuo to yield ithe title compound. -30443 17 Example 5 9, llE-Dicliloro-Gg-f luoro-51 Γ,, 21-dihydi't)xy|»rcgnat 1,4-dieno[l6α,17-b)[1,4)dioxane-3,20-dlone, 'S,21-diacetate A. 6ct-Fluoro-118,16a,17,21-tetrahydroxypregna-1,4diene-3,20-dione, 16,17-cycloborate A mixture of 6a-fluoro-118,16a,17,21-tetrahydroxypregna-l,4-diene-3,20-dione (30 mmoles) and 46 g of boric anhydride in 400 ml of methanol is refluxed for 1 hour, cooled, diluted to 2,5 liter with water, and filtered to give the title compound.

B. 6a-riuoro-16a~f(2,2-diethoxy)ethoxy)-1lp,J 7,21tr ihydroxypr egna-1, 4-diene-3,20-dione A solution of 2,2-diethoxy-l-diazoethane (prepared from 0.18 mole of precursor as described in Example 2Λ) in methanolether at 0°C is treated with 6a-fluoro-ll8, 16a, 17,21-tetrahydroxypregna-l, 4—diene-3,20-dione, 16,17-cycloborate until nitrogen evolution ceases. The solution is evaporated to give the title compound.

C. 6g-Fluoro-5'ζ,11β, 2ί-fcetrahydroxypregna-1,4-___ dieno[16a,17-b][1,4]dioxane-3,20-dionc A solution of 6a-fluoro-16a-[(2,2-diethoxy)ethoxy]118,17,21-trihydroxypregna-1,4-diene-3,20-dione (10 mmoles) in 150 ml of tetrahydrofuran is refluxed for 3 hours with 15 ml of 2N hydrochloric acid. The solution is cooled, diluted with water, and extracted with chloroform. The chloroform solution is dried and evaporated to give the title compound. -31D. 9, llP-Dichloro-6ct~f luoro-5' ξ ,21-dihydroxypregna1,4-dieno[16α,17-b][1,4]dioxane-3,20-dione, 51ξ,21-diacetate Substituting 6 Example 6 9,118,21-Trichloro-51ξ-hydroxypregna-1,4-dieno[16g,17-b][1,4[dioxane-3,20-dione, 51ζ-benzoate A. 21-Chloro-16a-(2,2-diethoxyethoxy)-ilR,17-dihydroxypregna-1,4-diene-3,20-dione A solution of 2,2-diethoxy-l-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and M. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to O’C. 21-Chloro-118,16a,17-trihydroxy pregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo to yield the title compound. -3244347 B. 21-Chloro-51ζ,116-dihydroxypregna-l,4-dienoί16α> 3.7—bi [1,4] dioxane-3,20-dione A solution of 5 mmoles of 21-chloro-16«-(2,2-diethoxyethoxy)-118,17-dihydroxypregna-l,4-diene-3,20-dione in 200 ml of tetrahydrofuran is refluxed with 40 ml of IN hydrochloric acid for 5 1/2 hours. The solvent is removed in vacuo and the residue is diluted with water, extracted with chloroform, and the chloroform solution is washed with 5% sodium bicarbonate solution, water and dried. Solvent removal yields the title compound.

C. 21-Chloro-51ζ,116-dihydroxypregna-l,4-dieno[16a,17-b][l,4]dioxane-3,20-dione, 5’f-henzoate A solution of 21-chloro“5'C,118~dihydroxypregna-l,4dieno[16a,17-b][1,4]dioxane-3,20-dione (4 mmoles) in 25 ml of pyridine is stirred with 4.4 mmoles of benzoyl chloride for 4 hours at room temperature. The resulting solution is diluted with ohloroform, washed with 5% sodium bicarbonate solution, water, 5% hydrochloric acid and dried. Solvent removal yields the title compound.

D. 21-Chloro-5lg-hydroxypregna-l,4,9(ll)-trieno[16g,17-b][l,4]dioxane-3,20-dione, 5'ξ-benzoate A mixture of 21-chloro-5'ξ,ΙΙβ-dihydroxypregna-l,4dieno[16a,17-b][1,4]dioxane-3,20-dione, 5'ξ-benzoate (2.8 mmoles), 52 ml of dimethylformamide, 26 ml of pyridine and 11 ml of methanesulfonyl chloride is stirred at 0°C for 75 minutes, poured into cold dilute hydrochloric acid, and the resulting mixture extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound. -33· Ξ, 9,11β,21-Trichloro-5'ζ-hydroxypregna-l,4-dieno[16α,17-b][1,4]dioxane-3,20-dione, 5'ζ-benzoate A solution of 21-chloro-5'ζ-hydroxypregna-l,4,9(11)trieno[16a,17-b][1,4]dioxane-3,20-dione, 5'5~benzoate (2 mmoles) and 3.6 g of lithium chloride in 36 ml of glacial acetic acid is stirred at 0-5°C and 296 mg of N-chlorosuccinimide is added. A solution of 90 mg of dry hydrogen chloride in 1.45 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 220 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to yield the title compound.

Example 7 9,ll[3-Dichloro-2 *,31-dihydro-21-hydroxy-5'-phenylpregna-1,4-dieno (16ct, 17-b][1,4]dioxin-3,20-dione, 21-acetate A. 2-Phenyl-3-diazo-l-propene a) M-(2-Phenyl-2-propenyl)pthalimide A mixture of 60 g of potassium pthalimide and'66.4 g of α-bromomethyl styrene (prepared by the method of S.F. Reed, Jr., J. Org. Chem.,30, 3258 (1965)) in 150 ml of dimethylformamide is refluxed for 2 hours, cooled, and diluted with 400 ml of water. The resulting solid is filtered and dried in vacuo to give 83.4 g of N-(2-phenyl-2-propenyl)pthalimide. A small· sample that is recrystallized from acetone-hexane has a melting point of 118-121°C. -3444347 b) Ethyl N- (2-Phenyf-2-propenytt'· carbamate A solution of 83 g of· N-(2-phenyl-2-propenyl)pthalimide and 30 g of 99% hydrazine-hydrate is refluxed for 270 minutes and cooled. The slurry is treated with 125 ml of concentrated hydrochloric acid and filtered. The solid is washed with four 100 ml portions of water and the filtrate is evaporated in vacuo to a volume of 300 ml. This solution is cooled and mixed with a solution of 60 g of sodium hydroxide in 250 ml of cold water. The resulting solution is extracted with four 200 ml portions of ether and the ether, solution is dried and evaporated in vacuo to give 30.7 g of oil. The oil is dissolved in 250 ml of ether, cooled to 0°C, and 33 g of ethyl chloroformate is added. A solution of 12 g of sodium hydroxide in 30 ml of water is added simultaneously with the second half of the ethyl chloroformate solution. After 1 hour at 10°C, the ether layer is washed with 5% hydrochloric acid, dried, and evaporated in vacuo to give 41.7 g of oil. Trituration with hexane and filtration gave 33 g of ethyl N-(2-phenyl-2-propenyl) carbamate, melting point 41-42.5°C. a) Ethyl N-Nitroso-N-(2-phenyl-2-propenyl) carbamate A solution of 21 ml (29.4 g) of nitrosyl chloride in 60 ml of pyridine (prepared at -25°C) i.s added over a period of 15 minutes to a solution of 57 g of ethyl N-(2-pheny1-2pro-penyl) carbamate in 400 ml of pyridine at -5°C. The solution is stirred for 15 minutes and poured into 4 liters of cold water. The oil which separates is extracted into -35ether (three 600 ml portions) and the ether extract is washed successively with 1 liter of 10% hydrochloric acid, water, 1. liter of 5% sodium bicarbonate solution, and dried. Solvent removal gives 63 g of red oil that shows only minor impurities by TLC. d) 2-Phenyl-3-diazo-l-propene Λ solution of 63 g of ethyl N-nitroso-N-(2-phenyl-2pro-penyl) carbamate in 300 ml of ether is added to 300 ml of 3M sodium methoxide in metha'nol at -1 to -2°C over a Ιθ period of 30 minutes. The solution is stirred for a further hour and then poured into 2 liters of ice water and 100 ml each of ether and pentane. The organic layer is separated and kept at 0°C while the aqueous layer is extracted with 300 ml of ether. The combined organic layer is washed with two 1 liter portions of ice water, dried for 10 minutes at 0°C over NaOH pellets, and filtered to give 700 ml of red solution.

B. 118,17,21-Trihydroxy-16a-(2-phenyl-2-propeiiyloxy)pregna-l,4-diene-3,20-dione A solution of l-diazo-2-phenyl-2-propene (prepared from 0.3 mole of N-nitrosourethane precursor) in methanolether at 0° is treated with 118,16a,17,21-tetra^yd»Oxypregna-1,4-diene-3,20-dione, 16,17-cycloborate (84 mmoles) until nitrogen evolution ceases, solvent removal gives the 2§ title compound. -3644347 C. ll8t17,21-Trihydroxy-16g-(2-phenyl-2-propcnyloxy)pregna-l,4-diene-3,20-dione, 21-acetate Acetylation of 118,17,21-trihydroxy-16a-(2-phenyl2-propenyloxy)pregna-1,4-diene-3,20-dione (30 mmoles) is accomplished with 100 ml of pyridine and 5 ml of acetic an hydride. After 4 hours at room temperature the solvent is removed in vacuo and a chloroform solution of the residue washed with dilute hydrochloric acid, water, dilute sodium bicarbonate solution and dried. Solvent removal gives the title compound.

D. 11B, 17,21-Trihydroxy-16ct- [ (2-phenyloxiranyl)ir,ethoxy] pregna-1,4-diene-3,20-dione, 21-acetate A solution of 116,17,21-trihydroxy-16a-(2-phenyl-2propenyloxy)pregna-l,4-diene-3,20-dione, 21-acetate (8 mmoles) in 100 ml of dichloromethane is stirred with 1.5 g of mchloroperbenzoic acid. After 3 hours the solution is washed with a mixture of dilute sodium bicarbonate solution and dilute sodium sulfite solution, dried, and evaporated to give the title compound.

E. llg,17,21-Trihydroxy-16g-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-acetate A solution of llg,17,21-trihydroxy-16a-E(2-phenyloxirany1) methoxy]-pregna-1,4-diene-3,20-dione, 21-acetate (6 mmoles) in 60 ml of tetrahydrofuran is stirred with a solution of 2 g of periodic acid in 10 ml of water for 3 hours. The solution is diluted with water and extracted with chloroform. The chloroform solution is washed with dilute sodium bicarbonate solution, dried, and evaporated to give the title compound.

F. 17,21-Dihydroxy-l6a-(2-oxo-2-phenylethoxy)pregna-1,4,9(ll)-triene-3,20-dionG, 21-acetate A solution of 118,17,21-trihydroxy-16u-(2-oxo-2phenylethoxy)-pregna-1,4-diene-3,20-dione, 21-acetate (4 mmoles) in 40 ml of dimethylformamide and 20 ml of pyridine is stirred with 10 ml of methanesulfonyl chloride for 60 minutes at 0°C, poured into dilute hydrochloric acid and ex10 tracted with chloroform. The chloroform solution is washed with water, dried, and evaporated to give the title compound.

G. 9,118-Dichloro-17,21-dihydroxy-16tt-(2-oxo-2-phenylethoxy)-pregna-1,4-diene-3,20-dione, 21-acetate A solution of 17,21-dihydroxy-16a-(2-oxo-2-phenyl15 ethoxy)pregna-l,4,9(11)-triene-3,20-dione, 21-acetate (1.4 mmoles) and 2.52 g of lithium chloride in 25 ml of glacial acetic acid is stirred at 0-5°C and 209 mg of K-chlorosuccinimide is added. A solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran i s added and the re20 suiting mixture stirred at room temperature for 2 hours, poured into 130 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried, and evaporated to give the title compound. -3844347 H. 9,llfl-bichloro-21,31-dihydro-21-hydroxy-5'-pheny1pregna-l,4-dieno(16g,17-b](l,4]dioxin-3,20-dionu, 21-acetate A slurry of 100 mg of ^-toluenesulfonic acid in 100 ml of benzene is refluxed for 1 hour with a Dean-Stark trap filled with molecular sieve. The solution is cooled and 9,11 l-lg-d±chloro-17-21-hydroxy-16a- (2-oxo-2-phenylethoxy)pregna1.4- diene-3,20-dione, 21-acetate (1 mmole) is added. After refluxing for 30 minutes under nitrogen the solution is cooled, washed with 5% sodium-bicarbonate solution, dried, and evaporated in vacuo to give the title compound.

Example 8 9,11β,21-Trichloro-21,3'-dihydro-51-methylpregnal,4-dieno[16g,17-b][l,4]dioxin -3,20-dione A. 21-Chloro-11B,16«,17-trihydroxypregna-l,4diene-3,20-dione, 16,17-cycloborate A solution of 21-chloro-llfj,16«,17-trihydroxypregna1.4- diene-3,20-dione (20 mmoles) and boric anhydride (20 g) in 300 ml of methanol is refluxed for 1 hour, cooled, diluted with water, and filtered to give the title compound.

B. 21-Chloro-llg,17-dihydroxy-16«-(2-methyl-2propenyloxy)pregna-1,4-diene-3,20-dione A solution of 2-methyl-l-diazo-2-propene (prepared from 0.3 mole of precursor) in methanol-ether at 0°C is treated with 21-chloro-ll8,16«,17-trihydroxypregna-l,4- . diene-3,20-dione, 16,17-cycloborate until nitrogen evolution ceases. Solvent removal gives the title compound. · -39C. 21-Chloro-11B, 17-dihydroxy-16g- [ (2-niethyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione A solution of 21-chloro-llg,17-dihydroxy-16a-(2methyl-2-propenyloxy)pregna-1,4-diene-3,20-dione (16 mmoles) in 30Q ml of dichloromethane is stirred vzith 3.2 g of mchloroperbenzoic acid for 3 hours. The solution is vzashed with a mixture of. 5% sodium bicarbonate solution and 5% sodium sulfite solution, dried, and evaporated to give the title compound. ., D. 21-Chloro-llg,17-dihydr0xy-16g-(2-oxopropoxy)pregna-1,4-diene-3,20-dione A solution of 21-chloro-llg,17-dihydroxy-16g-[(2methyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione (12 mmoles) in 200 ml of tetrahydrofuran is stirred with a solution of 10 g of periodic acid in 20 ml of water for 3 hours. The slurry is diluted with water and extracted with chloroform.

The chloroform solution is dried and evaporated in vacuo to give the title compound.

E'. 21-Chloro-17-hydroxy-16g- (2-oxopropoxy)pregna-1,4,9 (11)-triene-3,20-dione A solution of 21-chloro-llg,17-dihydroxy-16a- (2oxopropoxy)pregna-1,4-diene-3,20-dione (10 mmoles) in 40 ml of dimethylformamide and 20 ml of pyridine is stirred at 0°C for·75 minutes with 10 ml of methanesulfonyl chloride. The mixture is poured into cold, dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and' evaporated to give the title compound.

F. ' 9,118,21-'rrichloro-17-hydroxy-16u-(2-oxopropoxy )pregna-l, 4-diene-3, 20-dione A solution of 21-chloro-17-hydroxy-16«-(2~oxopropoxy)pregna-1,4,9(11)-triene-3,20-dione (4 mmoles) and 7.2 g of lithium chloride in 72 ml of glacial acetic acid is stirred at 0-5°C and 592 mg of N-chlorosuccinimide is added. A solution of 180 mg of dry hydrogen chloride in 2.9 ml of tetrahydrofuran is added and the resulting mixture stirred at room temperature for 2 hours, poured into 400 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried, and evaporated to give the title compound.

G. 5,118,21-Trichloro-21,31-dihydro-5'-methylpregna1,4-dieno[16a,17-b][1,4]dioxin-3,20-dione A slurry of 200 mg of £-toluenesulfonic acid in 200 ml of benzene is refluxed for 1 hour with a Dean-Stark trap filled with molecular sieve. The resulting solution is cooled and 9,118,21-trichloro-17-hydroxy-16a-(2-oxopropoxy)pregna-l,4-diene-3,20-dione (3 mmoles) is added. After re20 fluxing for 2 hours the solution is cooled, washed with dilute sodium bicarbonate solution and dried. Solvent removal yields the title compound. -41443 Example 9 9-Chloro-ll6-fluoro-5'ζ,21-dihydroxypregn-4-eno[16α(17-Η][l,4]dioxane-3,20-dione, 21-acetate A. 16g-Allyloxy-llB,17,21-trihydroxypregn-4-cne5 3,20-dione 118,16a,17,21-Tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added to a solution of vinyl diazomethane in 1:1 methanol-ether at 0°C until nitrogen evolution ceases. The solvent is evaporated to yield the title compound.

B. 16g-Allyloxy-l18,17,21-trihydroxyprcgn-4-ene3,20-dione, 21-acetate A solution of 16a-allyloxy-116,17,21-trihydroxypregn4-ene-3,20-dione (22 mmoles) in 100 ml of pyridine is stirred for 2 hours with 10 ml of acetic anhydride and the solvent is then removed in vacuo. A solution of the residue in chloroform is washed with 5% hydrochloric acid, water, 10% sodium bicarbonate solution, water, and dried. Solvent removal in vacuo yields the title compound. 2q C. lGg-(Allyloxy)-17,21-dihydroxypregna-4,9(11)diene-3,20-dione, 21-acetate A solution of 16a-(allyloxy)-118,17,21-trihydroxypregn-4-ene-3,20-dione,(10 mmoles) in 100 ml of dimethylformamide and 50 ml of pyridine is stirred for 90 minutes at 0°C with 20 ml of methanesulfonyl chloride. The solution is poured into excess 5% hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated to give the title compound. -42' D. 16α-(Allyloxy)-9-chloro-118-fluoro-17,2I-dihydroxypregn-4-ene-3,20-dione, 21-acetate A solution of 16a-(allyloxy)-17,21-dihydroxypregna-4,9(ll)-diene-3,20-dione, 21-acetate (0.5 mmoles) and N-chlorosuccinimide (67 mg, 0.5 mmoles) in dichloromethane is added to a mixture of anhydrous hydrogen fluoride (3.42 g) and anhydrous tetrahydrofuran (6 g) in a polyethylene bottle at -80°C. After 1 hour, the mixture is stirred for 30 minutes at -20°C and then added slowly to cold sodium carbonate solution. Extraction with chloroform, drying of the extract, and solvent removal gives the title compound.

E. 9-Chloro-118-fluoro-17,21-dihydroxy-16a-(oxiranylmethoxy)pregn-4-ene-3,20-dione, 21-acetate A solution of 16a-(allyloxy)-9-chloro-llS-fluoro17, 21-dihydroxypregn-4-ene-3,20-dione, 21-acetate (1.4 mmoles) in 20 ml of dichloromethane is stirred with 300 mg of m-chloroperbenzoic acid for 72 hours. The solution is washed with a cold mixture of dilute sodium bicarbonate 2o and dilute sodium sulfite solution and dried. Solvent removal gives the title compound·. -4344347 F. g-Cliloro-US-fluoro-5 'ζ , 21-dihydroxy;)rotjn-4eno[16ct,17-b][l,4]dioxane-3,20-dione, 21-acetate A solution of 9-chloro-118-fluoro-17,21-dihydroxy16a-(oxiranylmethoxy)pregn-4-ene-3,20-dione, 21-acetate (1 mmole) in 20 ml of tetrahydrofuran is stirred with 1 g of periodic acid in 4 ml of water for 7 hours. The solution is diluted with water and extracted with chloroform. Drying of this solution and solvent removal gives the title compound.

Example 10 9,21-Dichloro-118-f luoro-5 *g-hydroxypregi'i-4-eno[16a,17-b][1,4]dioxane-3,20-dione, 5'-butyrate A. 16a-Allyloxy-118,17,21-trihydroxypregn-4-ene3,20-dione, 21-methanesulfonate a solution of 16a-allyloxy-118,17,21-trihydroxypregn4-ene-3,20-dione (5 mmoles, prepared as described in Example 9A) in 50 ml of pyridine is stirred at 0°C under nitrogen for 150 minutes with 1 ml of methanesulfonyl chloride. The resulting solution is poured into cooled 51 hydrochloric acid and extracted with chloroform. The chloroform solution is washed with water, dried, and evaporated in vacuo to -yield the title compound. -4444347 B. 16g-Allyloxy-21-chloro-118,17-dihydro:-iypregn-4-ene-3,20-dione A solution of 16a-allyloxy-llB,17,21-trihydroxypregn-4-ene-3,20-dione, 21-methanesulfonate (4.6 mmoles) in 60 ml of dimethylformamide is refluxed for 1 hour under nitrogen with 5 g of lithium chloride. The solution is cooled, diluted with water and filtered. The solid is dis· solved in chloroform, washed with 5% hydrochloric acid, water, dried, and evaporated in vacuo to yield the title compound.

C. 21-Chloro-11B,17-dihydroxy-16ct-(oxirnnylmethoxy)pregn-4-ene-3,20-dione A solution of 16a-allyloxy~21-chloro-ll8,17-dihydroxypregn-4-ene-3,20-dione (3.8 mmoles) in 50 ml of di15 chloromethane is stirred with 0.76 g o£ m-chloroperbenzoic acid for 19 hours at room temperature. The resulting solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulfite solution, dried, and evapor ated in vacuo to yield the title compound.

D· 21-Chloro-51ξ,llB-dihydroxypregn-4-eno[16g,17-b][1,4]dioxane-3,20-dione A solution of 21-chloro-ll0,17-dihydroxy-16a(oxiranylmethoxy)pregn-4-ene-3,20-dione (3 mmoles) in 20 ml of tetrahydrofuran is stirred with a solution of 2 g of periodic acid in 7 ml of water for 6 3/4 hours. The • solution is diluted with water and extracted with chloroform. The chloroform extract is washed with 5% sodium -45*4347 bicarbonate solution, dried and evaporated in vacuo to : yield the title compound.

E. 21-Chloro-51 ζ, llp-dihydroxypregn-4-eno[16«,17-bl[1,4}dioxane-3,20-dione, 5'-butyrate A solution of 21-chloro-5'5,llg-dihydroxypregn-4eno[16a,17-b][1,4)dioxane-3,20-dione (5.5 mmoles) in 30 ml of pyridine is stirred at room temperature with 6 mmoles of n-butyryl chloride for 4 hours. The mixture is diluted with chloroform, washed with 5.% hydrochloric acid, water, % sodium bicarbonate solution, and dried. Solvent removal gives the title compound.

P. 21-Chloro-5'g-hydroxypregna-4,9(ll)-dieno[16a,17-bl[1,4}dioxane-3,20-dione, 5'-butyrate A mixture of 21-chloro-5'5,llg-dihydroxypregn-4-eno15 [16a,17-b}[1,4]dioxane-3,20-dione, δ'-butyrate (4 mmoles), ml of dimethylformamide, 37.5 ml of pyridine and 12 ml of methanesulfonyl chloride is stirred at 0°C for 75 minutes, poured into cold dilute hydrochloric acid, and the resulting mixture extracted with chloroform. The chloroform solution is dried and evaporated in vacub to yield the title compound.

G. 9,21-Dichloro-llB-fluoro-5'g-hydroxypregn-4-eno[16g,17-b][l,4]dioxane-3,20-dione, 5'-butyrate A mixture of 21-chloro-5'5~hydroxypregna-4,9(11)dieno[16a,17-b)[1,4]dioxane-3,20-dione, S'-butyrate (2 ' mmoles) and N-chlorosuccinimide (260 mg, 2 mmoles) in dry dichloromethane is added to a mixture of 10.13 g of anhydrous -4644347 hydrogen fluoride and 18 g of anhydrous tetrahydrofuran in a polyethylene bottle at -80°C. After 1 hour the mixture is stirred an additional 2 hours at 0°C and poured cautiously into cold sodium carbonate soiution. Extraction with chloroform gives the title compound.

Example 11 9,21-Pichloro-llB-fluoropregna-1,4-dieno[16g,17-h][1,4]dioxane-3,20-dione A. 21-Chloro-11B,17-dihydroxy-16a-[2-(tetrahydropyran2-yloxy) ethoxy]-pregna-1,4-diene-3,20-dione A solution of 2-(tetrahydropyran-2-yloxy)“1-diazoethane (prepared from 0.21 mole of N-[2-(tetrahydropyran2-yloxy)ethyl]urea as described in Example 1) in 400 ml of 3:1 ether-pentane is diluted with 100 ml each of ether and methanol at 0°C and stirred vigorously while 21-chloro118,16α,17-trihydroxypregna-l,4-diene-3,2 0-dione, 16,17cycloborate (12 mmoles) is added. After nitrogen evolution ceases the solvents are removed in vacuo to yield the title compound.

B. 21-Chloro-11B,17-dihydraxy-16a-(2-hydroxyethoxy)pregna-1,4-diene-3,20-dione A solution of 21-chloro-110,17-dihydroxy-16a-[2(tetrahydropyran-2-yloxy)ethoxy]pregna-1,4-diene-3,20-dione (8.4 mmoles) in 50 ml of acetic acid and 50 ml of water is stirred at room temperature for 6 hours, dilutea with cold water, and the resulting solid filtered and dried in vacuo to yield the title compound. -474434? C. 21-Chloro-118,17-dihydroxy-16g-(2-mesyloxyethoxy)pregna-l,4-diene-3, 20-dione A solution of 21-chloro-116,17-dihydroxy-16a-(2hydroxyethoxy)pregna-l,4-diene-3,20-dione (7.6 mmoles) in 30 ml of pyridine is cooled to 0°C and 1 ml of methanesulfonyl chloride is added. After 2 hours the mixture is poured into cold dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound.

D. 21-Chloro-ll3-hydroxypregna-l,4-dieno[16g,17-b][1,4]dioxane-3,20-dione Λ solution of 21-chloro-ll0,17-dihydroxy-16g-(2mesyloxyethoxy)pregna-l,4-diene-3,20-dione (6 mmoles) in 100 ml of dimethylsulfoxide is stirred at 110°C under nitrogen with 3 g of sodium bicarbonate (dried at 110°C in vacuo). After 1 hour the slurry is cooled, poured into 2 liters of 2.5% hydrochloric acid, and extracted with chloro form. The chloroform solution is washed with dilute hydrochloric acid, dried, and evaporated in vacuo to yield the title compound.

E· 21-Cliloropregna-l,4,9(11)trieno(16n,17-b][1,4]dioxane-3,20-dione A mixture of 21-chloro-ll0-hydroxypregna-l,4-dieno[16a,17-b][1,4]dioxane-3,20-dione (4 mmoles), 40 ml of dimethylformamide, 20 ml of pyridine, and 10 ml of methanesulfonyl chloride is stirred at 0°C for 75 minute=. poured into cold dilute hydrochloric acid, and the resulting -4844347 mixture extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound.

F. 9,21-Dichloro-llB-fluoropregna-1,4-dieno5 [16a,17-b1[1,4]dioxane-3,20-dione A mixture of 21-chloropregna-l,4,9 (ll).-trieno[16a,17-b][1,4]dioxane-3,20-dione (1.9 mmoles) and Nchlorosuccinimide (247 mg, 1.9 mmoles) in dry methylene chloride is added slowly to a mixture of 10.2 g of anhydrous hydrogen fluoride and 18 g of tetrahydrofuran at -80°C.

After 1 hour the mixture is stirred a further hour at 0°c and poured into cold sodium bicarbonate solution. The title compound is obtained by extraction with chloroform, drying, and solvent removal in vacuo.

Example 12 -19-Chloro-llB-fluoro-21,31-dihydro-21-hydroxypregn4-eno[16«,17-b][l,4]dioxin-3,20-dione, 21-acetate A solution of 9-chloro-llB-fluoro-5'C,21-dihydroxypregn-4-eno[16«,17-b][1,4]dioxane-3,20-dione, 21-acetate (0.6 mmole prepared as described in Example 9) is added to an anhydrous solution of 70 mg of ^-toluenesulfonic acid in 60 mg of benzene. After refluxing for 6 hours, the solution is cooled, washed with dilute sodium bicarbonate solution, dried, and evaporated to give the title compound. -49<43 47 Example 13 9-Chloro-ll g-fluoro-21-hydroxypregn-4-eno[16g,17-b] [l,4]dioxahe-3,5,20-trione, 21-acetate A solution of 9-chloro-llB-fluoro-5' ζ, 21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxane-3,20-dione, 21-acetate (1 mmole, prepared as described in Example 9) in 100 ml toluene is refluxed in a Dean-Stark apparatus with 7 g of Fetizon1s reagent under nitrogen for 14 hours, cooled and filtered. The filtrate is evaporated to give the title i® compound.

Example 14 9,llB-Dichloro-21-hydroxypregna-l,4-dieno[16g,17-b][1,4]dioxane-3,20-dione A solution of 9,llg-dichloro-21-hydroxypregna-l,415 dieno[16g,17-b][l,4]dioxane-3,20-dione, 21-acetate (2 mmoles, prepared as described in Example 1) in 40 ml of methanol is stirred at 0°C with 4 ml of 10% potassium carbonate solution. The resulting solution is acidified with 1 ml of glacial acetic acid and diluted with water to give the title compound Example 15 9,llB-Dichloro-21-hydroxypregna-l,4-dieno[16g,17-b][1,4]dioxane-3,20-dione, 21-cyclohexanecarboxylato A solution of 9,lls-dichloro-21-hydroxypregna-l,4dieno[16g,17-b][l,4]dioxane-3,20-dione (1.6 mmoles, prepared as described in Example 14) in 20 ml of pyridine is stirred with 400 mg of cyclohexanecarbonyl chloride for 2 hours.

The solution is diluted with chloroform, washed with 5% hydrochloric acid, dried, and evaporated to give the title compound. -5044347 Example 16 , llB-Dichloro-5’S-etho.xypregn-4-eno[16rc , 17-b)(1,4)dioxane-3,20-dione A. 51-Ethoxypregna-4,9(11)dieno[16a,17-b1[1,4]5 dioxane-3,20-dione A solution of 5'C-ethoxy-21-hydroxypregna-4,9(11)dienoI16a,17-b)(1,4)dioxane-3,20-dione, 21-mesylate (4 mmoles, prepared as described in Example 3A) in 30 ml of dimethylformamide ’is refluxed for 2 hours with 2 g of lithium iodide. The solution is diluted with chloroform, washed with dilute hydrochloric acid, water, sodium bisulfite solution, dried, and evaporated to give the title compound.

B. 9,118-Dichloro-5'f-efci)oxypregn-4-eno[16a,17-bΙΙ 1,4)dioxane-3,20-dione A solution of 5'5-ethoxypregna-4,9(ll)dienoI16a,17-bJ[l,4]dioxane-3,20-dione (1.4 mmoles) and 2.5 g of lithium chloride in 25 ml of glacial acetic acid is stirred at 0-5°C and 207 mg of H-chlorosuccinimide is added, A solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran is 2o added and the resulting mixture is stirred at room temperature for 2 hours, poured into 300 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to yield the title coinpound. 5144347 Example 17 9.110- Pichloro-5'£,21-dihydroxypregn-4-eno[16a,17-b](1,4]dioxane-3,20-dione A solution of 9,110-dichloro-5'£,21-dihydroxypregn-45 eno[l6a,17-b][1,4]dioxane-3,20-dione, 5',21-diacetate (1 mmole prepared as described in Example 4) in 40 ml of methanol at 0eC is treated with 4 ml of 10% potassium carbonate solution. After 2 hours the solution is acidifed with 2 ml of acetic acid, diluted with water, and extracted with chloroform to give the title compound.

Example 18 9.110- Dichloro-5'£,2l-dihydroxy-6a-methylpregnal,4-dieno(16g, 17-b] [1,4)'dioxane-3, 20-dione, 5' {.,21diacetate A· llg,16g,17,21-Tetrahydroxy-6a-methylpregna-1,4diene-3,20-dione, 16,17-cycloborate A solution of 8 g of 110,16a,17,21-tetrahydroxy-6amethylpregna-1,4-diene-3,20-dione in 200 ml of methanol is refluxed with 48 g of boric anhydride for 1 hour, cooled, 2o diluted with water and filtered to give the title compound.

B. 16g-((2,2-Diethoxy)ethoxy1-110,17,21-trihydrbxy6 crmethylpregna-1,4-diene-3,20-dione A solution of 2,2-diethoxy-l-diazoethane (prepared from 0.18 mole of precursor as described in Example 2A) in methanol ether at 0°C is treated with 110,16«,17,21-tetrahydroxy-6amethylpregna-1,4-diene-3,20-dione, 16,17-cycloborate until nitrogen evolution ceases. The solution is evaporated to give the title compound. 5244347 C. 5'f,, IIB , 21 -Tr ihyd roxy-bo,-me thyl pregna-1, 4diono[lf)U , 17-b] 11,4 I dioxano-3,20-dione' A solution of 16u-[(2,2-diethoxy)ethoxy I-lift ,17,21-trihydroxy-6a-methylpreyna-l,4-diene-3,20-dione (10 mmoles) in 150 ml of tetrahydrofuran is refluxed for 3 hours with 15 ml of 2N hydrochloric acid. The solution is cooled, diluted with water, and extracted with chloroform. The chloroform solution is dried and evaporated to give the title compound.

D. 9,116-Dichloro-51ζ,21-dihydroxy-6q-methylpregna1.4- dieno[16a,17-b)[1,4]dioxane-3,20-dione, 51ζ,21-diacetate Substituting 5'ζ,11β,21-trihydroxy-6a-methylpreqnal,4-dieno[16a,17-b)[1,4]dioxane-3,20-dione for the steroid reactant of Example 4B and proceeding as described in Example 4B, 4C and 4D the title compound is obtained.

Example 19 9,11β,21-Trichloro-21,3'-dihydro-5'-phenylpregna1.4- dieno[16g,17-b)[1,4]dioxin-3,20-dione A. 9,llB-Dichloro-17,21-dihydroxy-16a-(2-oxo-2phenylethoxy)pregna-1,4-diene-3,20-dione A solution of 9,llB-dichloro-17,21-dihydroxy-16a-(2oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-acetate (2 mmole, prepared as described in Example 7G) in 40 ml of methanol is stirred with 4 ml of 10% potassium carbonate solution at 0°C for 30 minutes, acidified with 2 ml of acetic acid, diluted with water, and extracted with chloroform to give the title compound. -5344347 ΒΙ 9, IIP-Dichloro-17,21-dihydroxy-16K- (2-oxo-2-phcnylethoxy).pregna-l,4-dieno-3,20-dione, 21-methanesulfonate A solution of 9,118-dichloro-17,21-dihydroxy-16a-(2oxo-2-phenylethoxy)pregna-l,4-diene-3,20-dione (1.4 mmoles) in 20 ml of pyridine is stirred at 0°C with methanesulfonyl chloride (2 mmoles) for 2 hours. The solution is diluted with chloroform, washed with 5% hydrochloric acid, dried, and evaporated to give the title compound.

C. 9,118,21-Trΐο)ι1θΓθ-17-ηνάΓοχγ-16α-(2-oxo-2-phcny1ethoxy)pregna-1,4-diene-3,20-diona A solution of 9,118-dichloro-17,21-dihydroxy-16a-(2oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-methanesulfonate (1 mmole) in 20 ml of dimethylformamide is heated at 80°C for 3 hours with 1 g of lithium chloride, cooled, diluted with water and filtered to give the title compound.

D. 9,118,21-Trichloro-21,31-dihydro-5'-phenyIprcgna1,4-dieno (16ct,17-b)[1,4]dioxin-3,20-dione A slurry of 100 mg of jj-toluenesulCc-nic acid in 100 ml of benzene is refluxed for 1 hour with a Dean-Stark trap filled with molecular sieve. The solution is cooled and 9,118,21-trichloro-17-hydroxy-16a-(2-oxo-2-phenylethoxy)pregnal,4-diene-3,20-dione (1 mmole) is added. After refluxing for 30 minutes under nitrogen the solution is cooled, washed with 5% sodium bicarbonate solution, dried, and evaporated in vacuo to give the title compound.

Compounds of Formulae II, XIV, XV, XVI, XIX and XXII referred to above as intermediates for the preparation of compounds of the present invention, are described and claimed in our Patent Specification No. 42427.

Claims (15)

1. A steroid having the structure and the 1,2 - dehydro, bisdehydro derivatives hydroxy,

2. A steroid as claimed in claim 1, wherein A^ is -^2-^2-

3. A steroid as claimed in claim 1, wherein A^is R 1 I -C=CH-.

4. A steroid as claimed in claim 1, wherein A^ is r 2 o-ch-ch 2 -.

5. A steroid as claimed in claim 1, wherein A^ is O II -C-CH 2 -. 15

6. A steroid as claimed in claim 1, wherein A^ is II R-C-O-CH-CH, 3 I 6,7 - dehydro and 1,2; 6,7 thereof, wherein Z is hydrogen alkyl-C-O-, aryl-C-O-, II cycloalkyl-C-O-, or halogen; X is chlorine or fluorine; A^ is —CH^-CH^· or is a V 1 -C=CH—, R 2 0-CH-CH 2 -, -C-CH 2 -, or R-C-O-CH-CH, 3 I 2 - 55 5 4434? radical in which the =CH- or -CH 2 ~ group is attached to the _f bond of the dioxane ring; R^ is hydrogen, alkyl or aryl; is hydrogen or alkyl; is alkyl, cyclo-alkyl or aryl; and P and Q are independent of each other and each is hydrogen, methyl or halogen; the terms alkyl, cycloalkyi, aryl and halogen being as hereinbefore defined.

7. A steroid as claimed in any of the preceding claims, wherein X is chlorine. - 56 44347

8. A steroid as claimed in any of claims 1 to 6, wherein X is fluorine.

9. A steroid as claimed in any of claims 1 to 8, wherein P and Q are each hydrogen. 5

10. 9, 118 - Dichloro - 21 -. hydroxypregna - 1,4 dieno Cl6a,17 - bj Cl,43 dioxane - 3,20 - dione, 21 - acetate

11. A compound as claimed in claim 1, substantially as herein described.

12. A compound as claimed in claim 1, substantially as 10 described in any of the foregoing Examples.

13. A method of preparing compounds as claimed in any of the preceding claims, substantially as herein described.

14. A method as claimed in claim 13, substantially as described in any of the foregoing Examples. 15

15. A compound as claimed in any of claims 1 to 12, whenever prepared by a method claimed in claim 13 or claim 14.