IE42427B1 - Steroidal 1,4-dioxanes - Google Patents

Abstract

1498132 Steroid [16α,17-b]dioxanes E R SQUIBB & SONS Inc 15 Jan 1975 [16 Jan 1974] 1776/75 Headings C2U and C2C The invention comprises 3,20-dioxo pregnenes having an 11#-hydroxy or 11-oxo group and having at position 16,17 a fused-on 1,4-dioxane or dihydro - 1,4 - dioxin ring. Preferred are the #<SP>4</SP>, #<SP>1,4</SP>, #<SP>4,6</SP> and #<SP>1,4,6</SP> compounds of formula wherein A 1 is selected from (the valence on the left being attached to the 17-oxygen atom); R 1 is H, C 1-8 alkyl, or aryl; R 2 is H, C 1-8 alkyl or aryl-(C 1-8 alkyl); R 3 is C 1-8 alkyl, C 3-6 cycloalkyl, or aryl; R 4 and R 5 are each C 1-8 alkyl, or aryl; P is H, Me or Cl; Q is H, Me or F; X is H or halo; Y is H, Y<SP>1</SP> is OH or Y + Y<SP>1</SP> = oxo; Z is H, halo, OH or acyloxy; the term "aryl" signifying phenyl optionally sub stituted with one or more halo, C 1-8 alky or C 1-8 alkoxy groups. The inventive compounds are prepared from analogous 16α,17α-diol cyclic borates by synthesizing the 16,17-dioxane ring as shown in the reaction scheme infra, and subsequently optionally introducing #<SP>6</SP> unsaturation (e.g. with DDQ) acylating at position 21 (this may also be effected on the intermediates marked * and **), hydrolysing a 21-ester group, or converting 21- OH to 21-halo via a 21-sulphonate (this may also be effected on the intermediate marked **) (R 1 , R 3 , R 4 , R 5 and Z are as above; R 6 is alkyl or aryl; R 7 is alkyl or aralkyl; each X is alkyl or the two X's together are ethylene). Reagents: (a) CH 2 :C(R 1 )N 2 ; (b) (XO) 2 C(R 4 )C(R 5 )N 2 ; (d) THP.O.CH 2 CHN 2 ; (e) m-chloroperhenzoic acid; (f) e.g. periodic acid; (g) e.g. f-toluenesulphonic acid; (h) NaBH 4 ; (i) MeSO 2 Y (Y= halo); (j) NaHCO 3 /DMSO; (k) e.g. HCl; (1) (R 3 CO) 2 O; (m) Fetizon's reagent; (n) e.g. acetic acid; (p) tautomerism. A 16,17-cycloborate is prepared from 21-chloro- 9 - fluoro - 11#,16α,17 - trihydroxypregna - 1,4- diene - 3,20 - dione by reaction with boric oxide in methanol. Potassium phthalimide + α - (bromomethyl) styrene # N - (2 - phenyl - 2 - propenyl)phthalimide # ethyl N - (2 - phenyl - 2 - propenyl) carbamate # ethyl N - nitroso - N - (2 - phenyl - 2- propenyl)carbamate # 2 - phenyl - 3 - diazo - 1- propene (Example 4). 2 - (Tetrahydropyran - 2 - yloxy)acetonitrile # 2 - (tetrahydropyran - 2 - yloxy)ethylamine # N - [2 - (tetrahydropyran - 2 - yloxy)ethyl]urea # N - nitroso - N - [2 - (tetrahydropyran - 2 - yloxy) ethyl]urea # 2 - (tetrahydropyran - 2 - yloxy) - 1- diazoethane (Example 18). Potassium phthalimide + α-bromopropiophenone # N - (1 - methyl - 2 - oxo - 2 - phenylethyl) phthalimide # 2 - (1 - phthalimidoethyl) - 2- phenyl - 1,3 - dioxolane # 2 - (1 - aminoethyl) - 2- phenyl - 1,3 - dioxolane # 2 - phenyl - 2 - [1- (ethoxycarbonylamino)ethyl] - 1,3 - dioxolane # 2 - phenyl - 2 - (1 - diazoethyl) - 1,3 - dioxolane (Example 40). Antiinflammatory compositions for oral and topical administration comprise a compound of Formula I and a carrier. [GB1498132A]

Description

42427 This invention provides 3,20-diketo pregnenes having an 11^8-hydroxy group or an 11-keto group and having fused on the 16- and 17-positions a 1,4-dioxane ring or a 1,4-dioxin ring (i.e. a 1,4-dioxane ring having a 2,3-double 5 bond). These compounds may be prepared by cyclizing the corresponding steroid having a hydroxy group in the 17-position and a 16-alkoxy group having an oxo, acetal or methanesulfonyloxy group on the beta carbon atom.

Exemplary of the steroids of the above description are steroids having the structural formula CH*Z y' c-0 q" In formula I, and throughout the.specification, the symbols 15 are as defined below.

Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y' is hydroxyl or together Y and Y' are = 0 X is hydrogen or halogen; P is hydrogen, methyl or chloro; 2o Q is hydrogen, methyl or fluoro; A^ is R. R. R. R- I1 I1 I4 I5.

—CH — CH—, — C = CH—, —C = C—, ^ 0 0 ii ii R,0—CH—CH-—, —C—CH-— or R,C—0—CH—CH2—' -2 | 2 -2.-.3, the first free bond of A^ being attached to the oxygen at the - 2 - 4242? 17-position; R^ is hydrogen, alkyl or aryl; R2 is hydrogen, alkyl or arylalkyl; Rj is alkyl, cycloalkyl or aryl; and 5 and Rg are the same or different and each is alkyl or aryl.

CH 7 Steroids having the formula | 1 y' X?-™ π J— P -γ are useful as intermediates in the preparation of the steroidal 10 Γΐ6α,17-bDl,4-dioxanes and steroidal El6o,17-b] 1,4-dioxins of formula I. In formula II, and throughout the specification, the symbol A2 is Ri o ? -C*CHa., - c———CHa. j -C-Rbj -CH-OH >' ° Π -CH-O-3-CHj ) -CH Co-Rib, or - CH*- 0~boJ 0 ^ The symbol Rg, as used throughout the specification, represents alkyl or aryl. The symbol R^, as used throughout the specification, represents alkyl or arylalkyl. - 3 - 43437 • Steroids having the formula ?H2Z IIa C=0 y* I -OH - J__1 "o-CH-A- p-'t^ i 3 I X I Q are also useful as intermediates in the preparation of the novel steroids of formula I. In formula IIa, and throughout r4 ·* the specification, the symbol represents ^ (o-alkyl) or i? ^ -c-r4.

The dotted lines in the l,2r and the 6,7-positions of the steroid formulae in this specification represents the optional presence of double bonds. . lo The term "pregnene", as used throughout the specifi cation, refers to pregnanes having ethylenic unsaturation in one or more positions. Exemplary of pregnanes specifically 4 14 4 6 contemplated are A -pregnenes, A ' -pregnadienes, A ' -pregna- 14 6 4 dienes, and A ' ' -pregnatrieneS. The A -pregnenes and the 1 4 15 Δ ' -pregnadienes are preferred.

The expression "1,4-dioxane ring", as used throughout the specification, refers to unsubstituted and substituted 1,4-dioxane rings. Exemplary substituents are alkyl, aryl- o o alkyl, aryl, alkoxy, arylalkoxy, alkyl-C-0-, cycloalkyl-C-O-, 0 0 2o arylalkyl-C-Ο-, aryl-C-O- and oxo groups.

' ' - /. - L_L V ' - - 42437 . The expression "1,4-dioxin ring", as used throughout the specification, refers to unsubstituted and substituted 1,4-dioxin rings. Exemplary substituents are alkyl, aryl-alkyl, and aryl groups. r, The term "alkyl", as used throughout the specifica tion, 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, and methyl is the most preferred.

The term "cycloalkyl", as used throughout the speci-10 fication, 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 one or more halogen, alkyl, and alkoxy groups. Phenyl and monosubstituted 15 phenyl are the preferred aryl groups.

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

The term "alkoxy", as used throughout the specification, refers to groups having the structure alkyl-O- wherein 20 alkyl is as defined above. Alkoxy groups having 1 to 4 carbon atoms are preferred, and methoxy is the most preferred.

The term "acyloxy", as used throughout the specification, refers to groups wherein the acyl portion is a physiologically acceptable acid residue derived from an 25 organic or inorganic acid. Exemplary monocarboxylic acids are those having the formula R-COOH wherein R is alkyl, cycloalkyl, arylalkyl or aryl; e.g., acetic propionic, valeric, cyclohexanecarboxylic, phenylacetic, benzoic, and toluic acids. Exemplary polycarboxylic acids are malonic, - 5 - i 42427 . succinic, qlutaric, adipic, pimelic, and phthalic acids.

Exemplary inorganic acid are sulfuric, nitric, and phosphoric acids: The steroids of formula I are physiologically active 5 substances which possess glucocorticoid and anti-inflamma tory activity and hence can be used in lieu of known 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 10 for the relative potency of the particular steroid. In addition, 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 daily dosage range of 0.1 to 200 milligrams per 70 kilograms, preferably 0.3 to 100 milligrams per 70 kilograms. If administered topically, the compounds of this invention may be used in the range of 0.01 to 5.0% 20 by weight, preferably 0.05 to 2.0% by weight, in a conven tional cream or lotion. The topical mode of administration is preferred.

Cycloborate esters of 16a,17-dihydroxy steroids having the formula - 6 - 42427 CH„Z I 2 c=o III γ> j Y---^B-OH J_po^ Q are one of the starting materials for the preparation Of the steroids of formula I. The cycloborate esters of formula III are known; see, for example, United States patent 5 2,831,003, issued April 15, 1958, They can be prepared by reacting the corresponding 16a,17-dihydroxy steroid with boric acid anhydride in an organic solvent at reflux temperature.

Exemplary cycloborate ester starting materials of 10 formula III are 118,16a,17,21-tetrahydroxypregn-4-ene~3,20-dione, 16,17-cycloborate, 9-fluoro-llg,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate, 15 6a,9-difluoro-118,16a,17,21-tetrahydroxypregn-4-ene- 3.20- dione, 16,17-cycloborate, 118,16a,17,21-tetrahydroxy-6a-methylpregn-4-ene-3,2 0-dione, 16,17-cycloborate, 21-chloro-118,16a,17-trihydroXypregn-4-ene-3,20-dione, 2o 16,17-cycloborate, 21-chloro-9-fluoro-118,16a,17-trihydroxypregn-4-ene- 3.20- dione, 16,17-cycloborate, - 7 - • 48427 . 21-chloro-6a,9-difluoro-116,16α,17-trihydroxypregn- 4-ene-3,20-diόner 16,17-cycloborate, 21-chloro-6a-fluoro-116,16a,17-trihydroxypregn-4-ene- 3.20- dione, 16,17-cycloborate, 5 21-chloro-llg,16a,17-trihydroxy-6a-methylpregn-4-ene- 3.20- dione, 16,17-cycloborate, 116,16a,17,21-tetrahydroxypregna-l,4-diene-3,20-dione, 16,17-cycloborate, 9-fluoro-116,16a,17,21-tetrahydroxypregna-l,4-diene-10 3,20-dione, 16,17-cyclOborate, 6a,9-difluoro-116,16a,17,21-tetrahydroxypregna-l,4-diene-3,20-dione, 16,17-cycloborate, 6a-fluoro-116,16a,17,21-tetrahydroxypregna-l,4-diene-3, 20-dione, 16,17-cycloborate, 15 116,16a,17,21-tetrahydroxy-6a-methylpregna-l,4-diene- 3.20- dione, 16,17-cycioborate, 21-chloro-116,16a,l7-trihydroxypregna-l,4-diene-3,20-dione, 16,17-cycloborate, 21-chloro-9-fluoro-116»16a,17-trihydroxypregna-l,4-20 diene-3,20-dione, 16,17-cycloborate, 21-chloro-6a,9-difluoro-116,16a,17-trihydroxypregna- l,4-diene-3,20-dione, 16,17-cycloborate, 21-chloro-6a-fluoro-116,16a,17-trihydroxypregna-l,4-diene-3,20-dione, 16,17-cycloborate, 25 21-chloro-116,16a,17-trihydroxy-6a-methylpregna-l,4- diene-3,20-dione, 16,17-cycloborate, 2-chloro-116,16a,17,21-tetrahydroxypregna-l,4-diehe- 3.20- dione, 16,17-cycloborate, - 8 - 42427 • 2-chloro~9-fluoro-116,16α,17,21-tetrahydroxypregna- 1,4-diene-3,20-dione, 16,17-cycloborate, 9-fluoro-ΙΙβ,16a,17,21-tetrahydroxypregna-l,4,6-triene-3,20-dione, 16,17-cycloborate.

Diazoalkenes having the formula f1 XV CH2=C —chn2 are also used as starting materials for the preparation of R1 Oil the steroids of fgrmula I wherein A^ is _c=cfj_ » -CH-CH u M ?1 2 R2-C-0-CH-CH2-, -C-CHj-, or _ · In formula IV, 10 those diazoalkenes wherein is hydrogen or alkyl are known; see, for example, the Journal of the American Chemical Society, 91, 711 (1969). The preparation of the diazoalkene of formula IV wherein R^ is aryl (e.g., 2-phenyl-3-diazo-l- propene) is described in the Examples of this specification.

Reaction of a cycloborate ester of formula III with a diazoalkene of formula IV yields a steroid having the formula CH_Z V | 2 C=0 Y' I OH T VCH0-C=CH, /sjaJ—1 i Ri l Q The reaction can be conducted in an organic solvent, preferably a lower alkanol such as methanol, at a temperature of 20 . -10°C to +40°C for 30 minutes to 4 hours, - 9 - 42427 . 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 V can be reacted with m-chloro-5 perbenzoic acid to yield a steroid having the formula CH„Z I ^ VI ' „ c=o Y JL--OH R- Y—I 0-CH-— C-CH.

P - 2 χοχ 2 0.

The reaction can be conducted in an organic solvent, preferably a halogenated hydrocarbon such as dichloromethane, at a temperature of from Q°c to 40°C for . 1 hour to 10 96 hours, preferably at room temperature for 2hours to 72 hours. The steroid of formula V and the m-chloroper-benzoic acid are reacted in approximately a 1:1 molar ratio.

Reaction of a steroid of formula VI when R^ is alkyl or aryl with a strong oxidizing agent such as periodic acid, 15 yields a steroid having the formula CH,Z I 2 c=o VII Y' I I -OH | 0-CH_—C-R, /r\ /k. S-1 2 II 6 p---p y 0 Q ‘ - 10 - 48427 . Reaction of a steroid of formula VI when R1 is hydrogen with a strong oxidizing agent yields a cyclic lactol (formula VIII) which is in equilibrium with the corresponding aldehyde (formula Villa), i.e., CH.Z CH2Z , 2 1 c=o ¥1 y-0 v0H Y I . _ OH Λ L---O-CH v I 1 r Po CH ^ X J-----J 0-CH--CH -1 u—CH2 2 „ . n : i Q q - VIII Villa These oxidation reactions can be conducted in an organic solvent such as tetrahydrofuran mixed with water at a temperature of ; 0eC to 40eC, for 1 hour to 8 hours, preferably at room temperature for 2 hours to 4 hours.

The steroids of formula VII or VIII can be reacted in a slurry or solution of an organic acid catalyst such as £-toluenesulfonic acid in an organic solvent such as benzene to yield steroidal 2',3'-dihydro[16a,17-b]l,4-dioxins having the formula CH-2 I 2 oo IX y' I _ O-C-R.

II _I O-CH i i Q “ U - 42427 . The reaction can be conducted under reflux conditions in an inert atmosphere for 2 hours to 48 hours, prefer ably 4 hours to 24 hours.

Reaction of a steroid of formula VIII with an an-V 0 5 hydride having the formula (R3C)20 yields a steroidal [16a,17-b]l,4-dioxane having the formula CH-Z v I 2 0 x i II 9=° ,0-C-R, r' 3 Y--· I ~ 0 — GH2 I · Q The reaction can be conducted in an grganic solvent such as pyridine at a temperature of 0°C to 40°C for 30 10 minutes to 4 hours, preferably at room temperature for 1 hour to 2 hours.

Oxidation of a steroid of formula VIII with Fetizon's reagent (Rngew. Chem. Internat. Edit., 8, 444 (1969)) yields a steroid having the formula CH,Z I 2 C=0 „ XI y' I , JO-c* 0— ch2 \ Q - 12 - i 48437 . The reaction can be conducted in an organic solvent such as benzene or toluene, at a temperature of 80°C to 110eC for 2 hours to 48 hours, preferably at re flux temperature for about 24 hours.

Reaction of a steroid of formula VII or VIII with sodium borohydride yields a steroid having the formula CH_Z XII | l y I C=0 JL - - OH Y--- J______J 0~CH,-CH“OH j, o 1 Q The reaction can be carried out in an organic solvent, preferably a lower alkanol such as methanol at a temperature of 10 from -10°C to 20°C for 10 to 60 minutes, preferably at 0°C for 10 minutes to 30 minutes.

A 16a-hydroxyethoxy steroid of formula XII can be reacted with a methartesulfonyl halide (methanesulfonyl chloride is preferred) to yield a steroid having the formula CH2Z Xm y, C-0 L - - OH y 0 * P' II I 0-CH,-CH-0-S-CH, p - | o 3 i * Q - 13 - 42427 The reaction can be carried out in an organic solvent such as pyridine, in an inert atmosphere, at a temperature of 1 -10°C to 40°C for 30 minutes to 4 hours, preferably at 0°C for 1 hour to 2 hours.

Reaction of a steroid of formula ΧΪΙΙ with sodium bicarbonate in a dipolar aprotic solvent such as dimethyl sulfoxide yields a steroidal[16a,17-b]l,4-dioxane having the formula CH.Z 1 R. c=o 71 xiv y* I S L _ - - 0— CH J °~CH2 Q The reaction can be conducted at a temperature of from about 60°C to 130°C for . 1 hour to 24 hours, preferably at 110°C for 2 hours to 4 hours.

Steroidal[16a,17-b]l,4-dioxanes of formula I wherein ft A1 is R20-CH-CH2- , K3-CtO-CH-CH2-, -CH=CH-, -CH2-CH2- or 15 -£-CH2- can be prepared from the cycloborate esters of 16a,17-dihydroxy steroids of formula III and diazoethers having the formula xv {r?-o)2chchn2 .

The diazoethers of formula XV are known; see, for example, Chem. Ber. 100, 1491 (1967). 7.0 r Reaction of a cycloborate ester of formula III.with a diazoether of formula XV yields a jsteroid having the formula - 14 - 42427 CH,Z XVI I 2 r <Γ° L - - - OH γ---o R7 Λ _ J_I O-CH.-CH 2 I ' O-R, o 1 I · Q The reaction can be conducted in an organic solvent, preferably a lower alkanol such as methanol, at a temperature of from -10°C to 40°C until nitrogen evolution ceases.

The preferred reaction temperature is from 0°c to 20°C.

The steroid of formula XVI can be reacted with an organic acid such as £-toluenesulfonic acid in an organic solvent such as benzene to yield a steroidalfl6a,17-b]l,4~ dioxane having the formula CH2Z XVII yf (L ^y°-R7 L___0—CH Y_ _ 1 10 ( ] \ .1" °-CH2 I · l 0.

The reaction can be carried out at a temperature of 60°C to 140°C for 1 hour to 24 hours, preferably 80°C to 110°C for 2 hours to 4 hours.

Reaction of a steroid of formula XVI with a mineral 15 acid, e.g., hydrochloric acid, yields a steroidal[16a,17-b]- 1,4-dioxane of formula VIII. The reaction can be carried - 15 - 48427 • out in an organic solvent such as tetrahydrofuran at a temperature of from 0°C to 100 °C for 1 hour to 24 hours, preferably 40°C to 60eC for 2 hours to 8 hours. Λ steroid of formula VIII can be used to obtain a 5 steroid of formula.IX (wherein is hydrogen), a steroid of formula X, a steroid of formula XI and a steroid of formula XIV (wherein R^ is hydrogen) following the procedures set forth above.

Steroidal[16a,17-b]l,4-dioxanes of formula I wherein 10 A^ is can also be prepared from the cycloborate esters of 16a,17-dihydroxy steroids of formula III and 2-(tetrahydropyran-2-yloxy)-l-diazoethane, the preparation of which is set forth in the Examples below.

Reaction of a cycloborate ester of formula III with 15 2-(tetrahydropyran-2-yloxy)-l-diazoethane yields a steroid having the formula CH,Z XVIII | 2 . C=0 Y' I JL - -OH Γ'; Λ „ J_l 0-CH0-CH.-0 -k.fy-'1 2 2 cr I · Q • The reaction can be carried out in organic solvent, preferably a lower alkanol such as methanol, at a temperature of 20 from -10AC to 40eC, preferably 0°C to 20°C. The re action is continued until nitrogen evolution ceases. - 16 - • 43427 • A steroid of formula XVIII may be cleaved with an acid to yield a steroid of formula XII (wherein is hydrogen). The cleavage reaction can be conducted in water at a temperature of from 0°C to 40°C, preferably at 5 room temperature, for 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 I wherein A^ is -CHj-CHj- from a steroid of formula XII is set forth above. R. Κ Ι4 I5 10 A steroid of formula I wherein is C- can be prepared from the cycloborate esters of 16a,17-dihydroxy steroids of formula III and diazoethers having the formula R.

I4 XIX (alkyl-O)2CCN2 K Reaction of a cycloborate ester of formula III with ^ a diazoether of formula XIX yields a steroid having the formula CI*2Z c=o V L -0H XX γ./'skx % O-alkyl 1___J O-CH - C — R4 p:---I O-alkyl J^lxJ R5 I 4 Q The reaction can be conducted in an organic solvent, preferably a lower alkanol such as methanol, at a temperature of 20 from -10°C to 40°C until nitrogen evolution ceases.

The preferred reaction temperature is from 0°C to 20°C. - 17 - 42427 . Reaction of a steroid of formula XX with a mineral acid, e.g. hydrochloric acid, yields a steroid having the structure - CH_Z I 2 XXX YI c=o /^φΑ;0Η "o-CH—C-R.

- I ii 4 Ρ"-Γ . I R 0 J^^JxJ K5 r i Q The reaction can be carried out in an organic solvent such as tetrahydrofuran at a temperature of from 0°C to 100°C for 1 hour to 24 hours, preferably 40°C to 60°C for 2 hours to 8 hours.

A steroid of formula XXI can be reacted with a slurry lo or solution of an organic acid such as £-toluenesulfonic acid in an organic solvent such as benzene to yield a steroid having the formula °Η2Ζ XXII Y' C\=0 • L_ - 0-C-R.

*· · -- II 4 0-C“R5 i • I Q The reaction can be conducted under reflux conditions in 15 an inert atmosphere for 2 hours to 48 hours, prefer ably 4 hours to 24 hours. - 18 - 48487 . Those steroids of formula I containing ethylenic unsaturation in the 6,7-position can be prepared as described above with the additional step of selectively introducing a carbon-carbon double bond in the 6,7-position of either a steroid starting material of formula III or a steroid product of formula VIII, IX, X, XI, XIV, XVII, or XXII without effecting other functional groups of the steroid. Exemplary of the oxidizing agents which meet the above requirements is 2,3-dichloro-5,6-dicyano-l,4-benzoquinone when used in the 10 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, toluene or dioxane, dioxane is preferred. The reaction can be carried out for 1 hour 15 to 96 hours at a temperature of 50°C to 150°C, preferably for 4 to 24 hours at ; 70°C to 130°C.Alternatively a borate containing unsaturation in the 6,7-position can be prepared from the corresponding, known 6,7-unsaturated 16,17-diols and boric anhydride.

Additional methods for the preparation of the com pounds 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 25 steroid by reacting the later with an alkyl or aryl sul- fonyl halide (e.g., methanesulfonyl chloride or £-toluene-sulfonyl chloride), in the presence of an organic base such as pyridine, to yield a 21-alkyl (or aryl) sulfonyl-oxy steroid. The 21-alkyl (or aryl) sulfonyloxy - 19 - 42427 • steroid intermediate can be reacted with alkali metal halide (e.g., potassium fluoride, lithium chloride, lithium bromide, sodium iodide) to yield the corresponding 21-halo steroid.

It will also be readily apparent to the practitioner of this invention that because of the stability of the dioxane and dioxin ring structures, functional groups represented by the various symbols used in formula I can be added to the steroid nucleus after the addition of the dioxane or 1° dioxin ring. .

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 15 of this invention.

Steroids of formula X wherein P and Q are hydrogen are preferred.

Steroids of formula I wherein X is halogen are preferred, and those wherein X is fluorine are most preferred.

Steroids of formula I wherein Y is hydrogen and Y' is hydroxyl are preferred* R·^ Steroids of formula X wherein A. is -CH0-CH0-, -C=CH-, 0 0 12 2 R20-CH-CH2-, -c-CHj-, or r3O0-CH-CH2- are preferred.

.Steroids of formula I wherein z is hydrogen, hydroxyl, 0 0 25 alkyl-C-O-, aryl-C-0- or halogen are preferred.

The following Examples are specific embodiments of this invention. - 20 - 42427 ' Example 1 9-Fluoro-5'g Anal. Calc'd for C^H^FOg: C, 66.04; H, 7.62; F, 4.35.

Found: C, 65.82; H, 7.83; F, 4.24.

B. 16ra-Allyloxy-9-fluoro-113,17,21-trihydroxypregn-4-one-3,20-dione, 21-acetate 20 A solution of 2.5 g of 16(K-allyloxy-9-fluoro-ll0,17, 2.l-trihydroxypregn-4-ene-3,20-dione in 25 ml of pyridine is stirred for 2 hours wi^th 2.5 ml of acetic anhydride and the solvent is then removed in vacuo. A solution of the residue in chloroform is washed with 5¾ hydrochloric acid, 25 water, 10% sodium bicarbonate solution, water, and dried.

Solvent removal in vacuo gives an oil which crystallizes from acetone-hexane to yield 2.5 g of 16«-ally.loxy~9-fluoro ·11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetato, melting point 189-191°C. - 21 - 42437 • C. 9-Fluoro-118,17,21-trihydroxy-16a-(oxiranyl-methoxy)- pregn-4-ene-3,20-dione, 21-acetate A solution of 6.44 g of 9-fluoro-16a-allyloxy-118,17, 21-trihydroxypregn-4-ene-3,20-dione, 21-acetate in 150 ml 5 of dichloromethane is stirred with 2.88 g of m-chloroper- benzoic 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 evaporated in vacuo. The residue is dissolved in di-10 chloromethane and chromatographed on a 125 g - silica gel column. Elution with chloroform and a Chloroform-ethyl acetate mixture gives 3.5 g of unreacted starting material in fractious (100 ml).-25-37 and 1,7 g (25.6%) of TIC pure product in fractions 49-61.

The 1.7 g is recrystallized from acetone-hexane to give 991 mg of material having a melting point of 191-192.5eC. A 500 mg portion of this material is recrystallized from the same solvent to give 430 mg of 9-fluoro-lle,17,21-trihydroxy-16a-(oxiranyl-methoxy)pregn-4-ene-3,20-dione, 21-acetate, 2q melting point 191-192.5eC.

Anal. Calc'd for CjgHggFOg: C, 63.15; H, 7.13; F, 3.84.

Found: C, 63.17; H, 6.84; F, 3.64.

D. 9-Fluoro-5'g,llg,21-trihydroxypregn-4-eno[16g,17-b}- J1,41dioxanc-3,20-dione, 21-acetate 25 A solution Of 20.1 g of crude 9-fluoro-llp,17,21- fci:ihydroxy-16a-(oxiranyl-methoxy)pregn-4-ene-3,20-dione, 21-acetatn in 300 ml of tetrahydrofuran is stirred with a solution of 30 g of periodic acid in 75 ml of water for - 22 - 42437 . (>i hours. The solution is diluted with water and ex tracted with chloroform. The chloroform extract was washed with 5% sodium bicarbonate solution, dried, and evaporated in vacuo to give 18.2 g of crude product. This material is 5 dissolved in 60 ml of dichloromethane and chromatographed on a 450 g -silica gel column. Fractions of 250 ml are collected as the column is eluted with 3 liters of dichloromethane, 3 liters of chloroform, and then 3 liters of 19si chloroform-ethyl acetate. Fractions 17-21 are combined and 10 evaporated in vacuo to give 4.4 g of 9-fluoro-16a-allyloxy- 118,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.

Fractions 23-31 are combined and evaporated in vacuo to give 8.1 g of slightly impure (53.2% based on recovered material) 9-fluoro-5* 5,llg,21-trihydroxypregn-4-eno[16α» 15 17-b][l,4]dioxane-3,20-dione, 21-acetate. A portion of this material is recrystallized from acetone-hexane and then from acetonitrile to give the analytical sample, malting point 205-208°C.

Anal Calc'd for C25H33FOg: C, 62.10; H, 7.50; F, 3.93.

Found: C, 62.22; H, 7.28; F, 3.69.

Example 2 9-Fluoro-2',3'-dihydro-118,21-dihydroxy-5'-methyl- pregn-4-eno[16q,17-b][l,4]dioxin-3,20-dione, 21-acetate A. 9-Fluoro-113,17,21-trihydroxy-16g-[(2-methvl-2-pro~ 25 penyl)oxy]pregn-4-ene-3,20-diono A solution of 2-methyl-3-d.iazo-l-propena in 250 ml of ethyl ether (prepared from .0.2 mole of/N-(2-methyl-2-propenyl)- carbamate by the method of J. L. Brcwbnkcr and H. Hart, - 23 - 42437 * Am.'Cheia. Soc., 91, 711 (1969)) is diluted with 300 ml of methanol and cooled to 0°C. A total of 6.5 g of 9-fluoro-ll£j ,16a,17,21-tetrahydroxypregn-4-ene- 3,20-dione, 16,17-cycloborate is added in portions until 5 the initial red color fades and nitrogen evolution ceases.

The solvent is evaporated in vacuo and the residue dissolved in chloroform and chromatographed on a 100 g - silica gel column. Elution with chloroform and chloroform-ethyl acetate. gives TLC homogeneous material which crystallizes 10 from acetone-hexane to give 3.73 g of 9-fluoro-llg,17,21- trihydroxy-16a-[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20-dione, melting point 213-215°C, softening at 198-200°C.

Anal^ Calc'd for C2gH35F06: C, 66.64; H,; 7.83; F, 4.22.

Founds C, 66.41; H, 8.03; F, 4.16.

L5 h. 9-Fluoro-llBf17,21-trihydroxy-16u-[(2-methyt-2-pro- penyl)oxy]pregn-4-ene-3,20-dipne, 21-acetate A solution of 3 g of 9-fluoro-llS,17,21-trihydroxy-16a~[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20^dione in 25 ml of pyridine is stirred for. 2 hours with 4 ml of.acetic 20 anhydride. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with 5¾ hydrochloric acid solutioh, water, 5% sodium bicarbonate solution, and dried. Solvent removal in vacuo gives a solid which is recrystalli2ed from acetone-hexane.to give 2.82 g of material 25 having a melting point of 230-231eC. Recrystallizatign of 0.6 g of this material, from acetone-hexanc gives 481 mg of 9-fluoro-llC!,.17,21-trihydroxy-16a-[ (2-methyl-2-propenyl)“ oxy]pregn-4-ene-3,20-dione, 21-acetate, melting point 230-232°C. - 24 - 42427 Anal. Calc'd for C27H37F07: C, 65.84; H, 7.57; F, 3.86.

Founds C, 65.89; H, 7.56; F, 4.06.

C. 9-Fluoro-llS,17,21-trihydroxy-16a-f(2-methyl- oxiranyl)methoxy]pregn-4-ene-3,20-dione, 21-acetate 5 A slurry of 1.0 g of 9-fluoro-118,17,21-trihydroxy- 16a-[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20-dione, 21-acetate in 50 ml of dichloromethane is stirred with 500 mg of m-chloroperbenzoic acid at room temperature for 210 minutes. The resulting solution is washed with a mixture 10 of 10% sodium carbonate solution and 10% sodium sulfite solution, dried, and evaporated to give 1.04 g of oil which solidifies. Recrystallization from acetone-hexane gives 793 mg of material, melting point 221-224°C and 160 mg of material, melting point 219-224°C. Recrystallization of 15 a mixture of 390 mg of crop 1 and 160 mg of crop 2 from acetone-hexane gives 298 mg of 9-fluoro-116,17,21-tri-hydroxy-16a-[(2-methyl-oxiranyl)methoxy]pregn—i-ene- 3,20-dione, 21-acetate, melting point 223-227eC. _Anal. Calc'd for C^H^FOgt C, 63.76; H, 7.33; F, 3.74.

Found: C, 63.96; H, 7.10; F, 3.93.

The nmr spectrum of^ this material indicates it is a mixture of epimers (ca. 2:1 ratio) at the quaternary epoxide carbon atom. - 25 - 4 48427 . D. 9-Fluoro-llS,17,21-trihydroxy~16g-(2-oxopropoxy)- pregn-4-ene-3, 20-dione, 21-acetate A solution of 1,54 g of 9-fluoro-llf5,17,21-tri-hydroxy-16a-[(2-methyl-oxirunyl)methoxy]pregn-4-ene-3,20-5 dione, 21-acetate in 50 ml of tetrahydrofuran is stirred for 270 minutes with -a solution of 2.6 g of periodic acid in 20 ml of water. The solution is poured into water and extracted with chloroform. The chloroform solution is washed with 10% sodium bicarbonate solution, dried, and 10 evaporated in vacuo to give an oily residue. This is dissolved in chloroform and chromatographed on a 40-Silica gel column. Elution with chloroform gives 400 mg of slightly impute product followed by 990 mg of TLC homogeneous solid. The 990 mg is recrystallized twice from ^ acetone-hexane to give 328 mg of 9-fluoro-118,17,21-tri- hydroxy-16a-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate, melting point 203-208°C.

Anal. Calc'd for C^H^FOg- C, 63-15; H, 7.13; F, 3.84.

Found: C, 63.01; Η,-7.04; F, 4.08.

E· 9-F Luoro-21,31-dihydro-113,21-dihydroxy-5’-methyl- pregn-4-enq[16g,17-b][1,4]dioxin-3,20-dione, 21-ace fate .

A slurry of 100 mg of £-toluenesulfonic acid in 250 ml of benzene is refluxed with a Dean-Staric trap. The first 25 50 ml of benzene-water azeotrope is discarded and Linde type 4A molecular sieves are added to the trap. After 30 minutes at reflux, the solution is cooled and 1.0 g of D-fluoro-llp, 17,21—trihydroxy-16c/.— (2-oxopropoxy) pregn-4— ene-3,20-dione, 21-acetate is added. The resulting slurry \ , - 26 - 43437 is refluxed for 5 hours under nitrogen, cooled, diluted with chloroform, washed with 5% sodium bicarbonate solution, water, dried and evaporated. The crude residue is dissolved in a small amount of chloroform and chroma-5 tographed on a 20 g - silica gel column. Elution with chloroform gives 805 mg of material which is recrystallized from acetone-hexane to give 501 mg of 9-fluoro-2',3'-di-hydro-110,21-dihydroxy-51-methylpregn-4-eno[16a,17-b][1,4]-dioxin-3,20-dione, 21-acetate, melting point 233-235°C, 10 dec.

Anal. Calc'd for C2gH33P07s C, 65.53; H, 6.98; P, 3.99.

Found: C, 65.78; H, 6.84; F, 4.14.

Example 3 9-Fluoro-21,3’-dihydro-llB,21-dihydroxy-5'-methyl-15 preqn-4-eno[I6g,17-b][1,4]dioxin-3,20-dione A solution of 886 mg of 9-fluoro-2',3'-dihydro-110, 21-dihvdroxy-5'-methylpregn-4-eno[16a,17-b] Γ1,4]dioxin-3, 20-dione, 21-acetate (prepared as described in Example 2) in 270 ml of methanol is cooled to 0°C and 27 ml of 20 10% potassium carbonate solution is added. After 15 minutes, 27 ml of acetic acid is added and the mixture is diluted with water and extracted with chloroform to give 775 mg of TLC pure 9-fluoro-2',3'-dihydro-110,21-dihydroxy-5'-methylpregn-4-eno[16ct,17-b][l,4]dioxin- 2.5 3,20-dione. - 27 - 43437 _ . Example 4 9-Fluoro-21,31-dihydro-11s,21-dihydroxy-51-phenyl-pregrt-4-eno[16n,17-b][l,4]dioxin-3,20-dione, 21-acetate 5 A. 9-FlU0ro-llB»17,21-tl:ihydroxy-16a-[ (2-phenyl-2- propenyl)oxy]pregn-4-ene-3,20-dione, 21-acetate a) N-(2-phenyl-2-propenyl)pKthalimide A mixture of 60 g of potassium phthalimide and 66.4 g of α-bromomethyl styrene (prepared by 10 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)phthalimide. a small Sample that 15 is recrystallized from acetone-hexane has a melting point of 118-121°C.

Ethyl b) /N-(2-phenyl-2-propenyl) Carbamate A solution of 83 g of N-(2-phenyl-2-propenyl) phthaliridde and 30 g of 99% hydrazine-hydrate is refluxed 20 for 270 minutes and cooled. The slurry is treated with 125 ml of cone, 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 25 of sodium hydroxide in 250 ml of cold water. The re sulting 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 - 28 - 42427 250 ml of ether, cooled to 0°C, and 33 g of ethyl chloroforms te 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 5 at 10eC, 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.

., } , TO c) Ethyl M-initroso-H- (2-phenyl-2-propenyl) - ' •I carbamate A“solution"0f 21 ml (29,4~gj of nitrosyl chloride v in 60 ml of pyridine (prepared at -25°C) is added over a period of 15 mirfuites to a solution of 57 g of ethyl N-(2-phenyl-15 2-propenyl; S^ibamate in 400 ml of pyridine at -5eC.

The solution is stirred for 15 minutes and poured into 4 liters of cold water. The oil which separates is extracted into ether (three 600 ml portions) and the ether extract is washed successively with 1 liter of 10% hydrochloric acid, 20 water, 1 liter of 5% sodium bicarbonate solution, and dried. Solvent removal gives 63 g of red oil that shows only minor impurities on TLC. d) 2-Phenyl-3-diazo-l-propene A solution of 63 g of ethyl N-nitroso-N-(2-phenyl-2-propenyl carbamate in 300 ml of ether is added to 300 ml of 3M sodium methoxide in methanol at -1 to -2°C over a period of 30 minutes. The solution is stirred for a further hour and then poured into 2 liters of ice water - 29 - 42427 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, 5 dried for 10 minutes at 0°C over NaOH pellets, and filtered to give 700 ml of red solution. e) 9-Fluoro-llB,17,2i-trihydroxy-16e-[(2-phenyl-2-propenyl)oxy]pregn-4-ene-3,20-dione The solution of 2-phenyl-3-dia2o-l-propene prepared as 10 described above is diluted with 150 ml of cold methanol and stirred well at 0eC as 13 g of 9-fluoro-llg,16«,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions, the slurry is stirred for 1 hour at i 0°C and filtered to give 9.6 g of the title compound. The 15 filtrate is stirred at room temperature for 1 hour with 4 g of the cycloborate and the resulting solution is cooled to 0°C and filtered to give 4.2 g of the title compound. The filtrate is evaporated in vacuo and the residue is dissolved in 400 ml of 3:1 ether-methanol and cooled to -10°C 20 to give a further 3.0 g of material. A small sample re- crystallized from acetone-hexane has a melting point of 161-163.5°C. - 30 - 42427 • 15 9-Fluoro-llB,17,21-trihydroxy-16a-[(2-phenyt-2- propenyl)oxy]pregn-4-ene-3,20-dione, 21-acetate A solution of 3.0 g of 9-fluoro-llB,17,21-tri-hydr6xy-16ct-[(2-phenyl-2-propenyl)oxy)pregn-4-ene-3,20-5 dione in 30 ml of pyridine is allowed to stand with 3 ml of acetic anhydride for 2 hours at room temperature. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with 5* hydrochloric acid, water, 5% sodium bicarbonate solution, and dried. Solvent re- 10 moval gives an oil that crystallizes from acetone-hexane to give 2.3 g of material. Recrystallization of 600 mg from acetone-hexane gives 510 mg of 9-fluoro-llB,17,21-trihydroxy-16a-t(2-phenyl-2-propenyl)oxy]pregn-4-ene- 3,20-dione, 21-acetate, melting point 169-171eC.

Anal. Calc'd for C32H39F07! C, 69.29; H, 7.09; F, 3.42.

Founds C, 69.13; H, 7.11; F, 3.26.

C. 9-Pluoro-llg,17,21-trihydroxy-16a-((2-phenyl-ox iranyl)methoxy] pregn-4-ene-3,20-dione, 21-acetate 20 A solution of 555 mg of 9-fluoro-ll3,17,21-trihydroxy- 16a-[(2-phenyl-2~propenyl)oxy1pregn-4-ene-3,20-dione, 21-acetate in 25 ml of dichlqromethane is stirred for 330 minutes with 200 mg of m-chloroperbenzoic acid. The solution is washed with 50 ml each of 5¾ sodium sulfite solu- 25 tion and 5¾ potassium carbonate solution. The dichloro- methane solution is dried and evaporated to give 582 mg of product. Recrystallization from acetone-hexane gives 300 mg of 9-fluoro-llB,17,21-trihyrtroxy-16a-[(2-phenyl-oxiranyl)-methoxyj pregn-4-ene-3,20-dione, 2J-acetate. - 31 - 42427 ' . t . D. 9-Fluoro-Il8f17 > 21-trihydroxy-16g-(2-phenyl-2- oxoethoxy)pregn-4-ene-3,20-dione, 21-acetate r A solution of 2.4 g of 9-fluoro-ll8,17,21-tri-hydroxy-16a-[(2-phenyl-oxiranyl)methox/]pregn-4-ene-3,20-5 fSione, 21-acetate in 75 ml of tetrahydrofuran is stirred with a solution of 5 g of periodic acid in 20^1 of water for 270 minutes. The resulting slurry is diluted with 150 ml of water and the solid is filtered and dried in vacuo to give 1.79 g of crude product. This material is 10 chromatographed on a 40 g-silica gel column. Elution with chloroform gives 1.6 g of TLC pure solid that is re-crystallised from acetone-hexane to give 1.42 g of 9-fluoro- 118.17.21- trihydroxy-16a-(2-phenyl-2-oxoethoxy)pregn-4-ene- 3,20-dioiio., 21-acetate, melting point 228-230°C.

Anal. Caic'd for CjjH^FOg: C, 66.89; H, 6.70; F, 3.41.

- Found: C, 67.07; H, 6.69; F, 3.15.

E. ,9-Fluoro-21,3l-dlhydro-llSt21-dihydroxy-5*-phenvl-procin-4-eno[16g,17-b] [-1,4]dioxin-3,20-dione, 20 21 · acetate i A.slurry of 150 mg of £-toluenesulfonic acid in 300 ml of benzene is refluxed with a Dean-Stark trap.

The first·. 50 ml of distillate is discarded, Linde 4a molecular sieves added, and the solution is refluxed for 25 30 minutes. The solution is cooled, 1.25 g of 9-fluoro- 110.17.21- trihydroxy-16a-(2-phenyl-2-oxoethoxy)pregn-4-ene-3,20-dione, 21-acetate added, and the solution refluxed for 5 hours under nitrogen. The resulting solution is cooled, washed with 5% sodium bicarbonate solution, - 32 - 48427 . dried, and evaporated in vacuo. The residue is chromato graphed on a 20 g-silica gel column. Elution with 1:1 hexane-chloroform gives 825 mg of crude product. This material is plate chromatographed on three 20 x 20 cm-2mm 5 silica gel plates. After 2 developments with 1:1 chloro form-ethyl acetate the major DV-active band is excised and eluded with chloroform to give TLC pure material. Recrystallization from benzene gives 380 mg, of 9-fluoro-2',3'-dihydro-116,21-dihydroxy-5'-phenylpregn-4-eno-10 [16a,17-b] [1,4]dioxin-3,20-diane, 21-acetate, melting point 145-147eC.

Anal. Calc’d for C31H35FO?: C, 69.13; H, 6.55; F, 3.53.

Found: : C, 68.90; H, 6.73; F, 3.58.

Example 5 15 9-Fluoro-2',3'-dihydro-llB,21-dihydroxypregn-4- eno [16ot,17-b][l,4]dioxin-3,20-dione, 21-acetate A slurry of 100 mg of £-toluenesulfonic acid in 250 ml of benzene is distilled to a volume of 200 ml and 1.0 g of 9-fluoro-5’ξ,11$,21-trihydroxypregn-4-eno[16a,17-b]-20 [l,4]dioxane-3,20-dione, 21-acetate (prepared as described in Example 1) is added. The resulting solution is refluxed with a Dean-Stark trap filled with 4A molecular sieves for 24 hours under nitrogen. The solution is cooled, diluted with chloroform, washed with 5% sodium bicarbonate 25 solution, and dried. Thg residue obtained on solvent re moval in vacuo is chromatographed on a 20 g - silica gel column. Elution with 1:1 dichloromethane-chlorofocm gives - 33 - 4 2427 510 mg of pure compound. Recrystallization from acetone-hexane gives 325 mq of TLC pure solid, in two crops. The mother liquor is purified by preparative thin layer chromatography on a 20 x 20 cm - 2 mm silica gel plate. After 5 three developments with 9:1 chloroform-ethyl acetate, the , major UV-active band is excised and eluted with chloroform-methanol. The residue obtained on solvent removal is crystallized from acetone-hexane to give 96 mg of pure material. This is combined with the 325 mg obtained above 10 and reerystallized from acetone-hexahe to give 312 mg of 9-fluoro-2',3'-dihydro-110,21-dihydroxypregn-4-eno[16«,17-b]- [l,4]dioxin-3,20-dione, 21-acetate, melting point 231-240eC, dec.

Anal. Calc'd for C, 64.92; H, 6.76; F, 4.11.

Found: C, 64.64; H, 6.54; F, 3.90.

Example 6 9-Fluoro-2'>31-dihydro-llB,21-dihydroxypregn-4-eno- [16a,17-b]£1,4]dioxin-3,20-dione A solution of 700 mg Of 9-fluoro-2',3'-dihydro-llg, 2o 21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxin-3,20-dione, 21-acetate (prepared as described in Example 5) in 75 ml of methanol is cooled to 0aC and 7 ml of 10% potassium carbonate solution is added. After 15 minutes, 20 ml of 20% aqueous acetic acid is added and the resulting solid ‘ 25 is filtered and dried in vacuo to give 310 mg of 9-fluoro- 2',31-dihydro-ΙΙβ,.21-dihydroxypregn-4-eno[16a,17-b][1,4]-dioxin-3,20-dione, melting point 255-258°C, dec. - 34 - 48437 • Example 7 21-Chloro-9-fluoro-2',3'-dihydro-lls-hydroxy~5'-methylpregna-1,4-dieno[16g,17-b] [1 ,.4] dioxin-3,20-dione 5 A. 21-Chloro-9-fluoro-llB,16a,17-trihydroxypreqna-1,4- diene-3,20-dione, 16,17-cycloborate A solution of 15.0 g of 21-chloro-9-fluoro-ll3,16a,17-trihydroxypregna-l,4-diene-3,20-dione and 60 g of boric oxide in 750 ml of methanol is refluxed for 1 hour, cooled 10 to 30°C and diluted with 1.5 liters of water. The re sulting solid is filtered and dried in vacuo to give 13.85 g of 21-chloro-9-fluoro-llg,16ct»17-trihydroxypregna-l,4-diene-3,20-dione, 16,17-cycloborate.

B. 21-Chloro-9-fluoro-118,17-dihydroxy-16g-[(2-methyl- 15 2-propenyl)oxy]pregna-1,4-diene-3,20-dione A solution of 2-methyl-3-diazo-l-propene in 150 ml ethyl of ether (prepared from 0.1 mole of/N-(2-methyl-2-propenyl)-carbamate by the method of J. L. Brewbaker and H. Hart, J. Am. Chem., Soc., 91, 711 (1969)) is diluted with 50 ml 2o of methanol and cooled to 0°C, A total of 7 g of 21-chloro- 9-fluoro-llB,16«,17-trihydroxypregna-l,4-diene-3,20-dione, 16,17-cycloborate is adde$ in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on 25 an 80 g -silica gel column. Elution with chloroform gives TLC pure material which crystallizes from acetone-hexane to give 5.4 g of 21-chloro-9-fluoro-ll0,17-dihydroxy-16a-[(2-methyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione, - 35 - 42427 . melting point 238-240°C.

Anal» Calc*d for CjgH^ClFOg: C, 64»30; H, 6.91; Cl, 7.59; F, 4.06.

Found: C, 64.53; H, 7.04; Cl, 7.74; F, 4.27.

C. 21-Chloro-9-fluoro-118 ,17-dihydroxy-16ot- [ (2-methyl- oxiranyl)methoxy]pregna-1,4-diene-3,20-dione A solution of 3.0 g of 21-chloro-9-fluoro-llS,17-dihydroxy-16a-[(2-methyl-2-propenyl)oxy]pregna-1,4-diene- 3,20-dione In 100 ml of dichloromethane is stirred with . 1.4 g of m-chloroperbenzoic acid for 2lO minutes. The solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulfite solution, dried, and evaporated in vacuo to give an oil which solidifies on standing. Reerystallj.zation from acetone-hexane gives .1.94 g as a 15 first crop, and 820 mg as a second crop. Recrystalli- zation of 600 mg of crop 1 from acetone-hexane gives 460 mg of 2l-chloro-9-fluoro-ll8,17-dihydroxy“16a-t(2-methyl-oxiranyl)methoxy]pregna-1,4-diene-3,20-dione, melting point 193-236°C.

Calc'd for C25H32C1F06: C„ 62.16; H, 6.68; Cl, 7.34; F, 3.93.

Found: C, 62.19; H, 6.67? Cl, 7.52? F, 4.07.

(The nmr spectrum of this material indicates that it is ca. a 1:1 mixture of epimers at the quaternary 25 oxirane carbon atom.) - 36 - 43427 Ν» °· 21-Chloro-9-fluoro-llB,17-dihvdroxy-16«-(2-oxo- propoxy)preqna-1,4-diene-3,20-dione A solution of 2.16 g of 21-chloro-9-fluoro-llg,17-dihydroxy-16a-[(2-methyloxiranyl)methoxylpregna-1,4-diene-5 3,20-dione in 50 ml of tetrahydrofuran is stirred with a solution of 5 g of periodic acid in 10 ml of water for 180 minutes. The solution is diluted with water and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo and the residue is dissolved in 10 chloroform and chromatographed on a 50 g-silica gel column.

Klution with chloroform and collection of 50 ml fractions gives 1.81 g of TLC pure solid in fractions 9-17. Recrystallization from acetone-hexane gives 1.15 g of first crop material and 0.50 g in crops 2 and 3. Recrystallization from 15 acetone-hexane of 600 mg of the first crop gives 490 mg of 21-chloro-9-fluoro-llg,17-dihydroxy-16a-(2-oxopropoxy)pregna- l,4-di.ene-3,20-dione, melting point 226-227°C.

Anal. Calc'd for C24H3()C1F06: C, 61.51; H, 6.45; Cl, 7.56; F, 4.05.

Found: C, 61.69; H, 6.35; Cl, 7.53; F, 3.94.

E. 21-Chloro-9-fluoro-2',3'-dihydro-llg-hydroxy-5 methylpregna-l,4-dieno[16a,17-b][l,4]dioxin-3,20-dione A slurry of 100 mg of £-toluenesulfonic acid in 250 25 ml of benzene is refluxed with a Dean-Stark trap. The first 50 ml of benzene-water azeotrope is discarded and Linde type 4A molecular sieves are added to the trap.

After 30 minutes at reflux, the solution is cooled and - 37 - 42427 . 980 mg of 21-chloro-9-fluoro-118,17-dihydroxy-16a-(2- oxopropoxy)pregna-l,4-diene-3,20-dione .is added. The resulting slurry is refluxed for 25 hours under nitrogen, cooled, and filtered to give 720 mg of solid. The filtrate 5 is diluted with chloroform, washed with 5% sodium bicar bonate solution, water, dried, and evaporated to give 210 mg of material identical by TLC to the 720 mg of solid. These materials' are combined, slurried with 50 ml of mineral oil, diluted with chloroform, and chromatographed 10 on a 100 g - .silica gel column. Elution with chloroform gives 850 mg of material which is recrystallized from . acetone to give 487 mg of 21-chloro-9-fluoro-2',3'-di-hydro-llfS-hydroxy-5'-methylpregna-l,4-dieno[16a,17-bill, 4]dioxin-3,20-dione, melting point 259-260°C. \ 15 Anal. Calcrd for C24H28°5FC1: C, 63.92; H, 6.26; Cl, 7.86; F, 4.19.

Found: C, 63.80; H, 6.49; Cl, 8.07; F, 4.13.

Example 8 51£-Ethoxy-:9-fluoro-11B,21-dihydroxypregrt-4-eno-20 [16g,17-b][l,4]dioxane-3,20-dione A. 16g-(2,2-Diethoxyethoxy)-9-fluoro-llB,l7,21-tri-hydroxypregn-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 25 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 0eC. A total of 5.5 g of 9-fluoro-118,16a,17,2l-tetrahydroxypregn-4-ene-3,20-dione, - 38 - 42427 , 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is recrystallized from methanol to give 3.4 g of slightly impure material. This is dissolved in chloro-5 form and chromatographed on an 80 g - silica gel column.

Elution with chloroform gives 2.95 g of material which is recrystallized from acetone-hexane to give 2.6 g of 16a-(2,2-diethoxyethaxy)-9-fluoro-llfS,17,21-trihydroxy-pregn-4-ene-3,20-dione, melting point 208-210eC.

Anal. Calc'd for C27H41F08: C, 63.26; M, 8.07; F, 3.71.

Found; C, 63.03; H, 7.86; F, 3.79.

B. 51 £-Ethoxy-9-f luoro-HB, 2l-dihydroxypregn-4-eno-[16a,17-b] [l,4]dioxane-3,20-dione A slurry of 100 mg of £~toluenesulfonic acid in 250 15 ml of benzene is refluxed with a Dean-Stark trap. The first 50 ml of benzene-water azeotrope is discarded and Linde type 4A molecular sieves are added to the trap.

After 30 minutes at reflux, the solution is cooled and 2 g of 16a-(2,2-diethoxyethoxy)-9-fluoro-llg,17,2l-tri-20 hydroxypregn-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. The crude residue (2.25 g) is dissolved in chloroform and chromatographed on 25 a 100 g - silica gel column. Elution with chloroform and 4:1 chloroform-ethyl acetate gives a total of 1.33 a of TLG pure material. Two recrystallizations from acetone-hexane (the last with charcoal) give 570 mg of 5'f,-ethoxy- 9-fluoro-118,21-dihydroxypregn-4-eno(16a,17—b][1,4]- - 39 - 42427 . dioxane-3,20-dione, melting point 248-250°C, dec.

Anal. Calc'd for C25H33F07: C, 64.64; H, 7.16; F, 4.10.

Found·. C, 64.75; H, 7.02; F, 3.95.

Example 9 5 5'g-Methoxy-9-fluoro-llS,21-dihydroxypreqn-4-eno- [16g,17--b1 [1,4]dioxane-3,20-dione A. 16g-(2,2-Dimethoxyethoxy)-9-fluoro-llg,17,21-tri-hydroxypreqn-4-ene-3,20-dione A solution of 2,2-diraethoxy:-l-diazoethane in 100 ml of 6:4 pentane-ether (prepared by the method of W. Kirmse and M. Buschhof f ,·. Chem. Ber., 100, 1491 (1967) utilized for the diefhoxy analog) is diluted with 50 ml.of methanol and cooled to 0°C. A total of 2 g of 9-fluoro-llo,16g,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added; After nitrogen evolution ceases the solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an alumina column (neutral, activity XXI). Elution with chloroform gives 485 mg of slightly impure material and then 1.27 g of VLC pure com- 20 pound. Recrys.tallization of the 485 mg from acetone-hexane, gives 175 mg of TLC homogeneous solid which is combined with the 1.27 g and recrystallized from acetone-hexane to give 1.09 g of 16a-{2,2—dimethoxyethoxy)-9-fluoro-113,17,21-trihydroxypregn-4-ene-3,20-dione, melting 25 point 192-194°C.

Anal. Calc'd for C25H37FOg! C, 61.96; H, 7.70; F, 3.94.

Found: C, 62.21; H, 7.79; F, 3.85. - 40 - 42427 B. 5'g-Methoxy-9-fluoro-110,21-dihydroxypreqn-4-eno-[16a,17-b][l,4]dioxane-3,20-dione Following the procedure of Example 8B, but substituting 16a-(2,2-dimethoxyethoxy)-9-fluoro-llfS ,17,21-5 trihydroxypregn-4-ene-3,20-dione for the 2,2-diethoxy- ethoxy steroid, the title compound is obtained.

Example 10 21-Chloro-5'£-ethoxy-9-fluoro-llB-hydroxypregn-4-eno[16g,17-b][l,4]dioxane-3,20-dione 10 A. 51f-Ethoxy-9-fluoro-llB,21-dihydroxypregn-4-eno- [16g,17-b][l,4]dioxane-3,20-dione, 21-mesylate A solution of 950 mg of 5'5-ethoxy-9-fluoro-ll3,21-dihydroxypregn-4-eno[16a,17-b][l,4]dioxane-3,20-diane (prepared as described in Example 8) in 10 ml of pyridine 15 is stirred at 0°C with 3 ml of methanesulfonyl chloride for 150 minutes. Ice is added and the mixture poured into cold, dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give 1.0 g. of crude mesylate.

B. 21-Chloro-51g-ethoxy-9-fluoro-llg-hydroxypregn-4- eno[16g,17-b][l,4]dioxane-3,20-dione A solution of 1 g of 5'5-ethoxy“9-fluoro-llg,21-di-hydroxypregn-4-eno(16a,17-b][l,4)dioxane-3,20-dione, 21-mesylato in 100 ml of dimethylformamide is refluxed with 25 4 g of lithium chloride for 30 minutes, cooled, and poured into ice-water. The resulting solid is filtered, washed well with water, and dried in vacuo to give 782 mg of - 41 - 42427 product. This material is dissolved in chloroform and chromatographed on a 20 g - silica gel column. Elution with chloroform gives 715 mg of TLC pure solid. Re-crystallization from acetone-hexane gives 600 mg of 21-5 chloro-5'?-ethoxy-9-fluoro-llS-hydroxypregn-4-eno[16a,_ 17-b]tl,4jdioxane-3,20-dione, melting point 235-237eC, dec.

Anal. Calc’d for C25H34C1EO6: C, 61.91; H, 7.07; Cl, 7.31: F, 3.92.

Found: C, 61.75; H, 7.27; Cl, 7.24; F, 3.85. - 42 - • Example 11 42427 9-Fluoro-5lE,llB,21-trihydroxypregn-4-eno[16ct,17-b]- [1.4] dioxane-3,20-dione A solution of 1.6 g of 16a-(2,2-diethoxyethoxy)-9-5 fluoro-llg,17,21-trihydroxypregn-4-ene-3,20-dione (pre pared as described in Example 8A) in 200 ml of tetra-hydrofuran is refluxed with 20 ml of IN hydrochloric acid for 3 hours. The solution is cooled, evaporated in vacuo to one third the original volume, and diluted with water.

The resulting solid is filtered and dried in vacuo to give 800 mg of product. Recrystallization from methanol gives 350 mg of 9-fluoro-5'ζ,ΙΙβ,21-trihydroxypregn-4-eno-tl6a,17-b](1,4]dioxane-3,20-dione, melting point 260-262°C, dec.

Anal. Calc'd for C23H31F07: C, 63.00; H, 7.13; F, 4.33.

Found; C, 62.96; H, 7.07; F, 4.48.

Example 12 9-Fluoro-5'g,llB,21-trihydroxypregn-4-eno[16g,17-b]- [1.4] dioxane-3,20-dione, 5',21-diacetate 20 To a solution of 1.3 g of 9-fluoro-5'ξ,11β,21-tri- hydroxypregn-4-eno[16a,17-b][l,4]dioxane-3,20-dione (prepared as described in Example 11) in 10 ml of pyridine is added 5 ml of acetic anhydride. The solution is kept at room temperature for 4 hours. The solvent is removed in 25 vacuo and the residue dissolved in chloroform, washed with dilute hydrochloric acid, and dried. The solvent is removed in vacuo and the residue dissolved in chloroform and chromatographed on a silica gel column. Elution with . chloroform gives 730 mg of impure compound and 506 mg of - 43 - i ., 42437 . TLC pure material. The 730 mg of impure material is dis solved in chloroform and plate-chromatographed on two 20 x 20 cm - 2 mm silica gel plates. After three developments with 1:1 chloroform-ethyl acetate, the UV-active 5 band of lowest is excised and eluted with chloroform.

The chloroform is removed in vacuo and the residue combined with the 506 mg of pure material and recrystallized from acetone-hexane to give 530 mg of 9-fluoro-51ξ,116,21-tri-hydroxypregn-4-eno[16«,l7-b][l,4]dioxane-3,20-dione, 10 5',21-diacetate, melting point 195-197°C.

Anal. Calc'd for C25H35FOg: C, 62.42; H, 6,21; F, 3.66.

Found: C, 62.37; H, 6.44; F, 3.61. : Example 13 9-Fluoro-51ξ,11B,21-trihydroxypreqn-4-enQ[16a,17-b j-15 [l,4]dioxane-3,20-dione, S'-valerate, 21-acetate A solution of 9-fl.uoro-5'5,110,21-trihydroxypregn-4-eno[16a,17-bj[l,4]dioxane-3,20-dione, 21-acetate (prepared as described in Example 1) in pyridine is stirred with excess valeric anhydride for 2 hours. The solvent is re-20 moved in. vacuo and the residue dissolved in chloroform.

The chloroform solution is washed with 5% hydrochloric acid, water, 5% sodium bicarbonate, and dried. Solvent it removal yields 9-fluoro-5'ξ,110,21-trihydroxypregn-4-eno[16a,17-b][l,4]dioxane-3,20-dione, S'-valerate, 21-acetate. -44 - 6 Example 14 42427 21-Chloro-9-fluoro-5'£,11B-dihydroxypregna-1,4- dieno[16g,17-b][l,4]dioxane-3,20-dione A. 21-Chloro-16 g-(2,2-diethoxyethoxy)-9-fluoro-llr,17- 5 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 10 methanol and cooled to 0eC. A total of 2.5 g of 21-chloro- 9-fluoro-llB,16g,17-trihydroxypregna-1,4-diene-3,2 0-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on 15 an 80 g - silica gel column. Elution wi,th chloroform gives 2.16 g Of TLC pure material that is recrystallized from acetone-hexane to give 1.75 g of 21-chloro-16g-(2,2-diethoxyethoxy)-9-fluoro-llp,17-dihydroxypregna-l,4-diene-3,20-dione, melting point 200-202°C.

Anal. Calc'd for C27H3gClF07: C, 61.30; H, 7.24; Cl, 6.70: F, 3.59.

Found: C, 61.55; H, 7.24; Cl, 6.68; F, 3.47.

B. 21-Chloro-9-f luoro-51 f. ,1 lfl-dihydroxypregna-1,4- 25 diono 116.1,17-bj [ 1 , 1 dioxane-3,20-dione A solution of 1.6 g of 21-ch.loro-16<«-(2,2-diethoxyethoxy) -9-fluoro-llfj, 17-dihydroxypregna-l ,4-dieno-3,20-dione in 200 ml of tetrahydrofuran is refluxed with 20 ml - 45 - 4 2 4 2? . of IN hydrochloric acid for 5½ 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, dried, 5 and evaporated. The residue is dissolved in chloroform - and chromatographed on a 60 g - silica gel column. Elution with a mixture of 3:2 chloroformsethyl acetate gives 1.29 g of pure material which is reerystallized from acetonitrile to give 940 mg of 21-chloro-9-fluoro-5'ξ,ΙΙβ-dihydroxy-lO pregna-l,4-dieno[16a,17-b][l,4]dioxane-3,20-dione, melting point 242-245°C, dec.

Anal. Calc'd for CjgHjgOgCiF: C, 60.72; H, 6.20; Cl, 7.79; F, 4.18.

Found: C, 60.52; H, 5.97; Cl, 7,86; F, 4.03. 4 15 Example 15 21-Chloro-9-fluoro-5'S;,llg-dihydroxypreqna-l,4-άϊβηο[ΐ6α,17-^ [l,4]dioxan6-3,20-dione, 5’-acetate To a solution of 887 mg of 21-chloro-9-fluoro-5'ς, 11β-dihydroxypregna-1,4-dieno[16a,17-b][1,4]dioxane-3,2 ΟΣΟ dione (prepared as described in Example 14) in 5 ml of pyridine is added 2 ml of acetic anhydride. The solution is kept at ambient temperature for 4 hours. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with dilute hydrochloric acid, and 25 dried. The solvent is removed iti vacuo and the residue is dissolved in chloroform and chromatographed on a silica gel column. Elution with chloroform gives 748 mg of material. Recrystallization from acetone-hexane gives - 46 - 42427 . 505 mg of slightly impure material. A second recrystalli zation from methanol gives 420 mg of TLC pure 21-chloro-9-fluoro-5'ς,11B-dihydroxypregna-1,4-dieno[16a»17-b][1,4]-dioxane-3,20-dione, 5'-acetate, melting point 242-244eC, 5 dec.

Anal. Calc'd for C25H3()07FC1: C, 58.41; H, 6.39; Cl, 7.50; F, 4.02.

Found: C, 58.23; H, 6.23; Cl, 7.40; F, 4.08.

Example 16 10 21-Chloro-9-fluoro-2',3'-dihydro-llB-hydroxypregna- l,4-dieno[16g,17-b][1,4]dioxin-3,20-dione A slurry of 300 mg of £-toluenesulfonic acid in 1.1 liters of benzene is refluxed with a Dean-Stark trap. The first 100 ml of distillate is discarded, Linde 4A molecular sieves are added to the trap and the solution is refluxed for 30 minutes. The solution is cooled, 2.0 g of 21-chloro-9-fluoro-5'ς,llB-dihydroxypregna~l,4-dieno[16w,17-b][1,4]-dioxane-3,20-dione (prepared as described in Example 14) is added, and the resulting slurry is refluxed for 36 hours 2() under nitrogen. The slurry is cooled and the benzene is removed in vacuo. The residue is dissolved in chloroform and the chloroform solution washed with 5S sodium bicar-bonate solution, water, dried, and evaporated in vacuo.

The residue is dissolved in chloroform and chromatographed 25 on a 50 g - silica gel column. Elution with chloroform gives 985 mg of solid which is recrystallized from acetone-hexane to give 528 mg of 21-chloro-9-fluoro-2',3'-dihydro-llS-hydroxypregna-1,4-dieno[16a,17-b][1,4]dioxin-3,20-diono, melting point 248-250°C, dec. - 47 - 42437 final. Calc'd for C23H26C1F05: C, 63^23; H, 6.00; Cl, 8.12; F, 4.35.

Found: C, 62.95; H, 5.88; Cl, 8.24; F, 4.22.

Example 17 5 9-Fluoro-116 ,21-dihydroxypreqn-4-eno[16ct ,17-b] [1,4]- dioxane-3,51 ,20-trione, 21-acetate A solution of 1.2 g of 9-fluoro-5'ξ,116,21-tri-hydroxyptegn-4-eno[16a,17-b][1,4]dioxane-3,20-dione, 21-acetate (prepared as described in Example 1) in 250 ml of toluene is slurried with 22 g of Fetizon's reagent (V. Balogh, M. Fetizon and M. Golfier, Angew. Chem. Internat. Edit., 8, 444 (1969)) and distilled to a volume of 200 ml. The resulting slurry is refluxed under nitrogen for 12½ hours, cooled, filtered, and the resulting solid is washed I® well with chloroform. The filtrate and washings are com bined, evaporated i.n vacuo, and the residue chromatographed on a 40 g - sili.oa gel column. Elution with chloroform gives 270 mg of oil which crystallizes from acetone-hexane to give 181 mg of-TLC pure solid. This is combined with 20 151 mg of identical material, obtained from repeating this reaction on a 1 g scale, and recrystallized from acetone-hexane to give 275 mg of 9-fluoro-116,21-dihydraxypregn- 4-eno[16g,17-b][l,4]dioxane-3,5', 20-trione, 21-acetate, melting point 217.5-220°C, dec.

Ana t. Calc'd for C25H3iF08: C, 62.75; II, G.53; F, 3.97.

Found: C, 62.6.1; H, 6.53; F, 3.73. - 48 - i . Kxample 18 42427 9-Fluoro-llB,21-dihydroxypreqn-4-eno[16¾,17-b]- [1,4]dioxane-3,2Q-dione, 21-acetate A. 9-Fluoro-llB,17, 21-trihydroxy-16g-[2-(tetrahvdro-5 pyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione a) Tetrahydropyran-2-yloxy acetonitrile This material is prepared by the method of J. Davoll and D. H. Laney,JL» Chem. Soc. 2129 (1956) and has a boiling point of 78-79°C at 2 mm. b) 2-(Tetrahydropyran-2-yloxy)sthylamine 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 aluminium hydride in 300 ml of ether and 100 ml of tetrahydrofuran. The slurry is refluxed for 210 minutes, cooled, and 25 ml of sat. 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-(tetra- 20 hydropyran-2-yloxy)athylamine, boiling point 41.5-46°C at 0.5-0.8 mm. c) Jl- [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 25 potassium isocyanate in 80 ml of water is stirred well, as 45.6 nl of 5N hydrochloric acid (cooled to -40°C) is added in £>ne portion. The resulting solution is refluxe»d for - 49 - 42427 90 minutes, cooled, and extracted with four ISO ml portions of chloroform. The chloroform extract is dried and evaporated in vacuo to give 39.6 g of oil. d) Jh-NitroSO-iL- [2-(tetrahydropyran-2-yloxy) 5 ethyl]urea A solution of 39.6 g of Ν-[2-(tetrahydropyran-2~yloxy) ethyiriurea in 400 ml of ether and 100 ml of methylene chloride is slurried with 50 g of sodium acetate and cooled to -10°C with mechanical stirring. A solution of 10 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-(tetrahydro-pyran-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 20 stirred for an additional 30 minutes and the layers are separated. The organic layer is dried over sodium hydroxide pellets at 0°C for 5 minutes, and then filtered. - 50 - 42427 f) 9-Fluoro-llβ,17, 21-trihydroxy-16g-[2-(tetra- hydropyran-2-yloxy) ethoxy]pregn-4-ene-3,20-dione A solution of 2-(tetrahydropyran-2-yloxy)-1-diazo-' ethane (prepared from 0.21 mole of precursor) in 400 ml 5 of 3:1 ether-pentane is diluted with 100 ml of cold methanol and stirred well as 5.0 g of 9-fluoro-110,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions. When nitrogen evolution ceases, the slurry is filtered to give 0.4 g of recovered borate. The 10 filtrate is evaporated in vacuo to give an oil that is dissolved in chloroform and chromatographed on a 150 g -silica gel column. Elution with 1:1 chloroform-ethyl acetate gives 4.0 g of TLC pure product. A small sample of similar material is recrystallized from acetone-hexane to 15 give 9-fluoro-llg,l?.,21-trihydroxy-16a-[2-(tetrahydro- pyran-2-yloxy)ethoxy)pregn-4-ene-3,20-dione, melting point 196-200°C.

B. 9-Fluoro-llg,17,21-trihydroxy-16«-[2-(betrahydro-20 pyran-2-yloxy) ethoxy)pregn-4-ene-3,20-dione, 21- acetate A solution of 4.0 g of 9-fluoro-llg,17,21-trihydroxy-16a-[2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione in 50 ml of pyridine is allowed to stand with 5 ml 25 of acetic anhydride for 3 hours. The solvents are re moved iii vacuo and the residue is dissolved in chloroform and washed with 5% hydrochloric acid, water, and 5% sodium bicarbonate solution. Drying and solvent removal gives 4.4 g of crude product. Crystallization of a - 51 - 42427 similar sample from acetone-hexane gives 9-fluoro-ll(J,17, 21-=trihydroxy-16a- [2-(tetrahydropyran-2-yloxy)ethoxy]-pregn-4-ene-3,20-dione, 21-acetate, melting point 150-152°C. c. 9-Fluoro-llg,17,21-trihydrOxy-16a-(2-hydroxyethoxy)-5 preqn-4-ene-3,20-dione, 21—acetate Method A A solution Of 4.4 g of 9-fluoro-ll8,17,21-trihydroxy-16a-(2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione, 21-acetate in 60 ml each of acetic acid and water la is stirred for 4 hours and the bulk of the solvent removed in vacuo. The residue is dissolved in chloroform and washed with 5¾ sodium bicarbonate solution. Drying and solvent removal gives an oil which crystallizes from acetone-hexane to give 2.4 g of 9-fluoro-llp,17,21-trihydroxy-16a~ 15 (2-hydroxyethoxy)pregn-4-ene-3,20-dione, 21-acetate, melt ing point 162-165^(2.

Method B A solution Of 1.98 g of 9-fluoro-5'ξ,11β,21-tri-hydroxypregn-4-eno-[16a,17-b][l,4]dioxane-3,20-dione, 21-20 acetate (prepared as described in Example 1) in 100 ml of methanol is cooled to 0°C and 148 mg of sodium boro-hydride is added. After 9 minutes the solution is poured into a mixture of ice and 5% hydrochloric acid and eXr tracted with chloroform to give 1.78 g of oil. This 25 material is chromatographed on a 50 g - silica gel column.

Elution with 19:1 chloroform-ethyl acetate gives 0.45 g of pure 9-fluoro-ll8,17,21-trihydroxy-l6a-(2-hydroxyethoxy)- ; pregn-4-ene-3,20-dione, 21-acetate and a total of 0.35 g of impure material. - 52 - 48427 D. 9-Fluoro-16u-(2-mesyloxyethoxy)-11β,17,21-tri-hydroxypreqn-4-ene-3,20-dione, 21-acetate A solution of 0.80 g of 9-fluoro-16a-(2-hydroxy-ethoxy) -11β,17,21~trihydroxypregn-4-ene-3,20-dione, 21-5 acetate in 10 ml of pyridine is stirred with 0.5 ml of methanesulfonyl chloride for 90 minutes at 0°C under nitrogen. The solution is poured into cold 5% hydrochloric acid and extracted with chloroform. The chloroform extract is dried and evaporated to give an oil which is chromato-10 graphed on a 20 g - silica gel column. Elution with chloroform gives 521 mg of TLC pure 9-fluoro-16a-(2-mesyloxyethoxy)-110,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.

E. 9-Fluoro-l1β,21-dihydroxypregn-4-eno[16g,17-b][1,4]- 15 dioxane-3,20-dione, 21-acetate A solution of 521 mg of 9-fl.uoro-l6a-(2-mesyloxyethoxy )-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate in 40 ml of dimethyl sulfoxide is stirred at 110°C under nitrogen for 2 hours with 600 mg of sodium bicarbonate 20 (dried at 110°C iri vacuo). The solution is cooled, poured into 5% hydrochloric acid and extracted with chloroform.

The chloroform extract is washed twice with 2% hydrochloric acid, dried, and evaporated in vacuo to give 421 mg of oil. This material is chromatographed on a 20 g - silica gel 25 column. Elution with chloroform gives 331 mg of TEC pure material which solidifies. Recrystallization from acetone-hexane gives 215 mg of 9-fluoro-llB,21-dihydroxypregn-4-eno[16ct/17-b][1,4]dioxane-3,20-dione, 21-acetate, melting poing 275-280°C, dec. i " 53 ' Anal. Calc'd for C^H^FCy. C, 64.64; Hr 7.16; F, 4.09. 42427 Found: C, 64.59; H, 7.21; F, 3.98.

Example 19 21-(3?ι1οΓθ-9-£1αοΓο-5 ' C,llg-dihvdroxypreqn-4-eno-5 tl6a,l7-b](l,4ldioxane-3,20-dione A. 16g-Allyloxy-9-fluoro-ΙΙβ,17,21-trihydroxvpreqn- 4-ene-3,20-dione, 21-methanesulfonate A solution of 1.0 g of 16a-allyloxy-9-fluaro-llB, 17.21- trihydroxypregn-4-ene-3,20-dione (prepared as de- 10 scribed in Example 1A) in 15 ml of pyridine is stirred at 0°C under nitrogen for 150 minutes toith 0.35 ml of methane-sulfonyl chloride. The resulting solution is poured into cooled 5% hydrochloric acid and extracted with chloroform. The chloroform solution is washed with water, dried, and 15 evaporated in vacuo to give 1.05 g of residue.

B. 16ot-Allyloxy-21-chloro-9-fluoro-11β,17-d ihvdroxv-pregn-4-ene-3,20-dione A solution of 1.05 of 16oc-allyloxy-9-fluoro-ll li, 17.21- trihydroxypregn-4-ene-3,20-dione, 21-methanesulfonate 20 in 65 ml of dimethylformamide is refluxed for 1 hour under nitrogen with 1.05, g of lithium chloride. The solution is booled, diluted with 400 ml of water and filtered. The solid is dissolved in chloroform, washed with 5% hydrochloric acid, water, dried, and evaporated in vacuo to 25 give 800 mg of residue. This material is dissolved in chloroform and chromatographed on an 18 g - silica gel column. Elution with chloroform gives 600 mg of TLC pure - 54 - 42427 material. Two recrystallizations from acetone-hexane give 500 mg of 16ot-allyloxy-21-chloro-9-fluoro-llH,17-di-hydroxypregn-4-ene-3,20-dione, melting point 224-225°C.

Anal. Calc'd for C24H32C1F05: C, 63.36; H, 7.09; 5 Cl, 7.79; F, 4.18.

Found: C, 63.53; H, 6.97; Cl, 7.50; F, 4.14.

C. 21-Chloro-9-fluoro-118,17-dihydroxy-16g-(oxiranyl-methoxy)pregn-4-ene-3,20-dione Following the procedure of Example 1C, but Sub-10 stituting 16a-allyloxy-2l-chloro-9-fluoro-ll(l,17-dihydroxy- pregn-4-ene-3,20-dione for 9-fluoro-16a-allyloxy-113,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate, the title compound is obtained.

D. 21-Chloro-9-fluoro-5'ζ,llS-dihydroxypregn-4-eno- 15 [16ot, 17-b] [1,4]dioxane-3,20-dione 'Following the procedure of Example ID, but substituting 21-chloro-9-fluoro-116,17-dihydroxy-16a-(oxiranyl-methoxy)pregn-4-ene-3,20-dione for 9-fluoro-116,17,21-tri-hydroxy-16ot-(oxiranyl-methoxy)pregn-4-ene-3,20-dione, 20 21-acetate, the title compound is obtained. - 55 - 42427 Example 20 21-Chloro-9-fluoro-2',3’-dihydro-11S-hydroxy-51-phenylpregna-1,4-dieno[16g,17-b][Ϊ,4]dioxin-- 3,20-dione 5 A. 21-Chloro-9-fluoro-llB,17-dihydroxy-16g-[(2-phenyl- 2-propenyl)oxyjpregna-l,4-diene-3,20-dione A solution of 2-phenyl-3-diazo-l-propene (prepared ethyl from 28.5 g of/N-(2-phenyl-2-propenyl) carbamate, prepared as described in Example 4) in 700 ml of ether 10 and 50 ml of pentane is diluted with 150 ml of methanol at 0°C and 10 g of 21-chloro-9~fluoro-llB,16a,17-tri-hydroxypregna-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 re-15 crystallized from methanol to give 6.1 g of 21-chloro-9- flubro-11β,17-dihydroxy-16a-[(2-phenyl-2-propenyl)oxy]-pregna-l,4-diene-3,20-dione, melting point 212-214°C. Anal. Calc'd. for C3QH34ClF05: C, 68.11; H, 6.48; Cl, 6.70; F, 3.59.

Found: C, 68.37; H, 6.75; Cl, 6.92; F, 3.49.

B. 21-Chloro-9-fluoro-llB,17-diliydroxy-16a-[(2-phenyl-oxiranyl)methoxy]pregna-l,4-diene-3,20-dione A solution of 4.0 g of 21-chloro-9-fluoro-llB,17-dihydroxy-16a-[(2-phenyl-2-propenyl)oxy]pregna-l,4-diene-25 3,20-dione in 100 ml of dichloromethane is stirred with 1.6 g of m-chloroperbenzoic acid for 1 hour at room temperature. The resulting solution is washed with a mixture of 100 ml each of 5% sodium sulfite solution and - 56 - 42427 5* sodium bicarbonate solution, dried, and evaporated in vacuo to give 4.8 g of crude 21-chloro-9-fluoro-ll(1,17-dihydroxy-16ct-[ (2-pihenyloxiranyl)methoxyJ pregna-1,4-diene-3,20-dione.1' 5 C. 21-Chloro-9.-fluoro-llB ,17-dihydroxy-16ot- (2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione A solution of 4.8 g of 21-chloro-9~fluoro-llB,17-dihydroxy-16a-l(2-phenyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione in 150 ml of tetrahydrofuran is stirred 10 with a solution of 10 g of periodic acid in 40 ml of water for 4 hours. The resulting slurry is diluted with 1 liter of water and filtered. The solid is dried in vacuo and recrystallized from methanol-chloroform to give 2.4 g of 21-chloro-9-fluoro-l.lB,17-dihydroxy-16oi-(2-oxo-· 15 2-phenylethoxy)pregna-1,4-diene-3,20-dione, melting point'266-268<>C, dec.

Anal. Calc'd. for C29H32C1F06: C, 65.59; H, 6.08; Cl, 6.68; F, 3.58.

Found: C, 65.28; H, 6.38; Cl, 6.62; F, 3.47. - 57 - D. 21-Chloro-9-fIuoro-2',3'-dihydro-ΙΙβ-hydroxy-5'- 4 2 4 2 7 phenylpreqna-1, 4-dieno[16g,17-b][1,4j-dioxin-3, 20-dione A slurry of 150 mg of g-toluenesulfonic acid in 750 5 ml of benzene is refluxed with a Dean-Stark trap. The first 150 ml of benzene-water azeotrope is discarded and Linde type 4A molecular sieves are added to the trap.

After 30 minutes at reflux, the solution is cooled and 1.0 g of 21-chloro-9-fluoro-118, 17-dihydroxy-16n-(2-oxo-10 2-phenylethoxy)pregna-l,4-diene-3,20-dione is added. The resulting slurry is refluxed for 6 hours under nitrogen, cooled, washed with 5% sodium bicarbonate solutioh, water, dried and evaporated in vacuo to give 955 mg of crude product. This material is dissolved in chloroform and 15 chromatographed on a 40-g silica gel column. Elution with chloroform gives TLC pure material which fails to crystallize .and is rechromatographed on a 20-g silica gel column.

Elution with 3:1 chloroform-hexane gives 525 mg of solid. Recrystallization from ethyl acetate-hexane gives 443 mg 20 of 21-chloro-9-fluoro-2,,3,-dihydro-llB-hydroxy-5l- phenylpregna-1,4-dieno[1Ga,17-b] [1,4]dioxin-3,20-dione, melting point 195-197°C.

Anal. Calcd. for C2gH30ClFO,-: C, 67.89; H, 5.90; Cl, 6,91; F, 3.71. 25 Found: C, 68.02; H, 5.84; Cl, 6.70; F, 3.59. - 58 - 43437 Example 21 21-Chloro-9-fluoro-llB-hydroxypregna-1,4-dieno-[16ujl7-b][1,4]dioxane-3,20-dione ' A. 21-ChJ.oro-9-fluoro-llB,17"dihydroxy-16g-[2-(tetra-5 hydropyran-2-yloxy) ethoxy]pregna-1,4-diene-3,20- dlone A solution of 2-(tetrahydropyran-2-yloxy)-1-diazoethane (prepared from 0.21 mole of N-[2-(tetrahydropyran-2-yloxy)ethyl]urea as described in Example 18) in 400 ml 10 of 3:1 ether-pentane is diluted with 100 ml each of ether and methanol at 0°C and stirred vigorously while 5.0 g of 21-chloro-9“fluoro-ll0,16ct,17-trihydroxypregna-l,4-diene-3,20-dione, 16,17-cycloborate is added. After nitrogen evolution ceases the solvents are removed iri 15 vacuo and the residue dissolved in chloroform and chroma tographed on a 100 g-silica gel column. Elution with .chloroform give 3.6 g of solid. Recrystallization from acetone-hexane gives 3.26 g of 21-chloro-9-fluoro-ll3,17-dihydroxy-16a-[2-(tetrahydropyran-2-yloxy)ethoxy]pregna-20 l,4-diene-3,20-dione, melting point 168-170°C.

B, 21-Chloro-9-fluoro-llB,17-dihydroxy-16g-(2-hydroxy-ethoxy) pregna-1 ,4-diene-3,20-dione A solution of 4.2 g of 21-chloro-9-fluoro-llg,17-dihydroxy-16ra-[2-tetrahydropyran-2-yloxy)ethoxy]pregna- l,4-diene-3,20-dione in 150 ml of acetic acid and 75 ml of water is stirred at room temperature for 6 hours, diluted with 1.5 liter of cold water, and the resulting solid filtered and dried in vacuo to give 2.63 g. - 59 - 42427 Recrystallization from acetone-nexane gives 2.03 g of '21'-chloro-9-fluoro-118,17-dihydroxy-16a~(2-hydroxy-ethoxy)pregna-l,4-diene-3,20-dione, melting point 226- 228°C, dec.

Anal. Calcd. for C23 H30C1FO6: C, 60.46; H, 6.62; Cl, 7.76; F, 4,16. Found; C, 60.26; H, 6.49; Cl, 7.88; F, 4.26.

C. 21-Chloro-9-fluoro-llg,17-dihydroxy-16u-(2-mesyloxyethoxy)pregna-1,4-diene-3,20-dione 1° A solution of 1.5 g of 21-chloro-9-fluoro-118,17- dihydroxy ~16ct- (2-hydroxyethoxy)pregna-1,4-diene-3,20-dione in 25 ml of pyridine is cooled to 0eC and 0.6 ml of methanesulfonyl chloride is added. After 2 hours the mixture is poured into cold dilute hydrochloric acid and 15 extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to 2.0 g of crude mesylate.

D. 21-Chloro-9-fluoro-llB-hydroxypregna-l,4-dieno-[16ot,17.-b] [1,4)dioxane-3 ,20-dione A solution of 2.0 g of 21-chloro-9-fluoro-llS,17- 20 dihydroxy-16ot-(2-mesyloxyethoxy)pregna-1,4-diene-3,20-dione in 100 ml of dimethyl sulfoxide is stirred at 110°C under nitrogen with 2.0 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 ex-25 tracted with chloroform. The chloroform solution is washed twice with dilute hydrochloric acid, dried, and evaporated iri vacuo to give 1.4 g of crude product. - 60 - 48427 This material is dissolved in chloroform and chromatographed on a 100 g-silica gel column. Elution with chloroform gives 880 mg of material which crystallizes from methanol-chloroform to give 405 mg of 21-chloro-9-5 fluoro-ll(5-hydroxypregna-l,4-dieno[16a,17-b][l,4]dioxane- 3,20-dione, melting point 320-321°C, dec.

Anal. Caled for ^3^28^^5: C, 62.94; H, 6.43; Cl, 8.08; F, 4.33. Found: C, 62.73; H, 6.20; Cl, 8.27; F, 4.27.

Example 22 ll[3,21-Dihydroxypregna-l,4-dieno[16a,17-b][1,4]-dioxane-3,20-dione, 21-acetate A. 16ct- [2-(Tetrahydropyran-2-yloxy)ethoxy]-11G,17,21- trihydroxypregna-l,4-diene-3,20-dione 15 A solution of 2-(tetrahydropyran-2-yl)oxy-l-diazo- ethane (prepared from 69.1 g of N-[2-(tetrahydropyran-2-yl-oxy)ethyl]urea by the procedure described in Example 18) in 600 ml of 3:1 ether-pentane is stirred with 200 ml each of ether and methanol at 0°C. 14 g of 11(5,16«,17, 20 21-tetrahydroxypregna-l,4-diene-3,20-dione, 16,17-cyclo borate 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 25 then 1:1 chloroform-ethyl acetate gives 4.0 g of TLC pure 16a-(2-(tetrahydropyran-2-yloxy)ethoxy]-11$ ,17,21-trihydroxypregna-1,4-diene-3,20-dione. - 61 - 42427 B. 16α-[2-(Tetrahydropyran-2-yloxy)ethoxy]-116,17, 21-trihydroxypregna-l ,4-dlene-3,20-dione, 21-acetate A solution of 3.75 g of 16cH2-{tetrahydropyran-2- ’ yloxy)ethoxy]-11β,17,21-trihydroxypregna-l,4-diene-3,20-5 dione 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-(tetrahydro- pyran-2-yloxy)ethoxy]-11β,17,21-trihydroxypregna-l,4-diene-3,20-dione, 21-acetate.

C. 16g-(2-Hydroxyethoxy)-11β,17,21-trihydroxypregna- 1,4-diene-3,20-dione, 21-acetate 15 A solution of 4.9 g of crude 16a-[2-(tetrahydro- pyran-2-yloxy)ethoxy]-11β,17,21-trihydroxypregna-l,4-diene-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 20 dissolved in chloroform and washed with 5% sodium bi carbonate 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 lsl chloro-0 s ; form-ethyl acetate gives 3.7 g of material which crystallizes from acetone-hexane to give 3.17 of 16a-(2-hydroxyethoxy)-11β,17,21-trihydroxypregna-l,4-diene-3,20-dione, 21-acetate, melting point 138-140°C. - 62 - ^ 48427 D. 16^-(2-Mesyloxyethoxy)-118,17,21-trihydroxypregna- 1,4-diene-3,20-dione, 21-acetate A solution of 3.0 g of 16a-(2-hydroxyethoxy)-llp, 17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate 5 in 15 ml of pyridine is stirred with 0.75 ml of methane sulfonyl chloride at 0®C for 150 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 dissolved in chloroform, washed with water, 10 dried, and evaporated in vacuo to give 4.0 g of crude 16 (2-mesyloxyethoxy)-11β,17,21-trihydroxypregna-1,4- diene-3,20-dione, 21-acetate 14. 11 β , 21.-1)ihydroxypregna-l, 4-dieno [ 1 f>tt, 17-b] [1 ,.4 ]- . dioxane-3,20-diono,- 21-acetate I5 A solution of 4.0 g of crude 16a-(2-mesyl.oxy-ethoxy)-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate in 200 ml of dimethyl sulfoxide 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 2o 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 25 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 11β,21-dihydroxypregna-l,4-dieno[16a, 17-b][l,4]dioxane-3,20-dione, 21-acetate, melting point 280-282°C. - 63 - 4 a « a ί ____ . Examples 23-25 Following the procedure of Example 1, but substituting the steroid listed in column I for 9-fluoro-ΐΐβ,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate, the 5 steroid listed in column II is obtained. - 64 - 43427 ° -» » | (Μ I ·—. ’ tj· ^ •H'f ^ I rl V4 *· C r-l -4) Η O H lj , N Λ 4J Λ 4J o, 1 -Id) I HI >, a) ai r- o i r- u xc *—11—i irt ·ηη nj h On) H - l c -i H U X - S rd 4J Cl rd H3 Ο Id- ID CM I ISM G >rrt - <-i H .-1 b i)O 10“' « -· - g ·η-ιΟ) loo -oo r-\ rd G C cocc Ο I - 0 >ι4)0 Ί·0 υ H r<4) .(1 I -Η >-ti I --d nu| 41 τι* Ό . --3--0 — (—i u 0) I I I I Iiin Λ eco -Co ~ | I I bKM in Oil'd in 1-- rd ?! o - 10- i hN io m n rd 4| (Ί 0 - i n. i £*- Cu i Md- o >i« *C >i o omo e x g 4i x b HH B 0 0 0 000 xii-io ccx ecx 00--4 J3-00 1-00 1 C Id I >-"d o ^1-4 σιΟ·Ρ o> .G -Ο οίΛΟ ! H I ΓΊ >i - I I X r- ο o ο - Ή (M U tt) - ·* “ Ό fi wro m So vn J 0) 110) jS ·Η H 0) +) H d)4J •HM -CD M C id M4J Cflfl)^ * 0) H 4J I Η I 0 Γ·* I 0 l o *-i Λ H ^ Λ r-H rsj I l Ο ** I O H Cs»*-a) 4-t CJ rH CJFJf-H - .H +> S tP O VO tJ> O G Xl OS H dJ >1 £ " U 4-M-i 0 * U O 3 0 0) Οι I r-t rl I Λ ft Si'*· H Sr» 0 vo 0 I Ή r-)XH U H iJH f) ο " I 0 - i 0) 0 VO U VD r-A u VO Ο I S I Drl >itj H i4 *t O 0 S s Oil f · Λ - 4J - Η C r·» Q cd 0) 0) I U VO I 0) *H « φ -H m OiH σν +) Ό N 4)¾ 0) H 0.

E rj ** in flj X ω m o γΊ ..... ~ 65 - 43427 λ e J® «! ® c1 ci β c £« £ O' O O' o O' 0 55 .¾ οι h «) -η μ τ) WO w 13 Oil Λ I O· >,o i>.o >1° X° X (M X ™ 0 - o - P ίί n W m W m £7 -0 1 Ό I ><« ^1¾ Λ β Λ β Λ C •ri rt »rl (0 Ή flj i1 -OX -OX 1 ο I o 10 m ·Η «η -w m "W Htl Η Ό β) ΗΉ „ r^JJ H-.

M 1«1· --¾1 Id ' ^ Uf - >«Γ 'r-t 1 ci -.-. -^hS 1 1-· p in — m-'X m 1— Ei I ,_, I i— 0 I — rW Ο Λ ΟΛΛ ΟΛ0) O W I W I W W I Λ rj ο r~ Ο Γ1- H ·. .-.-41 Λ ' N M-ia iwac m a β | «ο I UJ Id I VD a) oiri Ql σ> η X σΐΗΛ i 4J i <—· ai i ·— o oo1 ΛΌ1. o i λ o i ο υιοί 1-^ I I -r I I Ί· I f~t -- «-Ι -- ή -- Μ Η ΙΟ ΓΜ Η ΙΟ <Ν r-t in 01 Ό •Η υ w Ο) ·Η Ό Ό Η >1 •rl >1 Λ w χ S *β ο ίο Η Ν Λ Λ w U β β id ·Η e id υ ο 3 0) Ν r-t υ β β ο -rl of a) ο) ο Ο X Έ) Λ Ν 01 ·Η ο β λ w ε 0) Ο τ) Ο -Ο Λ S W υ λ Λ >1 β I , υ m ol «1 ιΗ Ω, Ρ VXD γ- co <3 Ν Γ4 <Μ X w m ο r-· - 67 - · I .1. Ί, · ..... 42437 Following the procedure of Example 20, but sub stituting the steroid listed in column I for 21-chloro-9- fluoro-ll(5,16a,17-trihydroxypregna-l,4-diene-3,20-dione, Examples 29-32 5 16,17-cycloborate, the steroid listed in column IX is obtained E - 68 - 43437 >ι , Λ -ο- 4 , ^ ft ' !. ?8. 8£ Ν 8 Η8 I ' ’g* £ 1 «—I ΟΗ -4 θ -Λ So «Ο NX) 7 ^ <Ί S 2 >ι R X I 1 ' * 7 5 Ϊ1Ι 0 1- * S 7 ο -rt (1) ·Η ·Η 41 ^ Ή η £ I 2 Ό C Ό Ό G Ό ' . S\S ό 1 ο 'Λ5 £>2 (m u x H S-1^· -H '*** t J lOin M :SH'V -r^y i-β 0^.3 C -e7i - I 6 H 0 R UNO | ' g" 7 cS 7 S ° § 5? £ Sft? S S’T 83? ΰο·ΐ 5 nS,.5 §W Jis ^ •t* ti-ig d;« 07f M C5-.H Sm'H 7 irt G O $?S as* 7J8S - d-5 2 0 ·.

S 0.¾1 i-i (h*r ri &> X ? ii ,¾ Cj I ^ N I > '00 I I „ _J w ·. ,—| - μ ·Η r4 >irH ^ ID UJ (Tt ΙΛ *—1 ΓΜ D4»d -i c K o i r· I ·Η «* M N *0 '1 V , s7 II i-4 o »· o - -ho U r- o μ di μ rs» frit) h fM tj β -P * C >i " "* sL n In tr D an 3\2 r- I Si Ό i *μτ3 M G) Μ Γ-* H Q| -P μι ·· R ο η * g p ίο aQ) s - «141 M | CM VO -H X VO r4*rj Q Γη* ho OH HtJi h n ** I μ *io w|Q) CfVVtt) »0 *· Ο ^ H Η «Μ Η * P NO μ * υ φ c Hi rl H nj fdR 0H>1 c non iiu ug 3*9 ε '·Η0 04)0 M -H —I 2 I g ΜΌΛ u c i3 P Ό V fil- t—I r4 I 0 0 tp ο I I I tPrH o 3 0) S ΓΌ <* p> ' υ i'0 .-) u o on i μ ω 0H>1 iwOiN '' Ο Ρ<Ή UIO -UNO 8 n β N 0«l ΌΧΙ ® I · Ο X ' "· 3 G P-. I Ο I- HUD uoo o^i-h »—I U -H ' G n) -Q M R Mjd)' NO' oil O U ΙΌΟ iuvo 'Nip r4-r4 0 *-l N‘H cn SiH CPJSH ΝΌΛ ΝΛΌ 41 a ε σ> o h X ω - 69 - Examples 33-35 Following the procedure of Example 22, but sub stituting the acid anhydride listed in column X for acetic anhydride, the steroid listed in column II is obtained. 434 37 - 70 - 424‘47 I ^ JL, 3 XI Λ I . I * r- r·- Γ"- ,Η r-4 - - - a) 0 0 8' o 8 +) VX) 4J VO -P VO ίΰ rH ιβ H 10 H p — U *—* C >-Ή OH) ON 0 0 g H c c c +> o) ro in o a) i . ·Η > ·Ή Λ -Η ο, TJ I 73 I 73 I 1 1-4 I »-4 I γ-4 7(7 Ν· Μ «· Γ7 r-l - tH r-l *· ΙΟ ΙΟ I o h me m c ο c h co co co tp-M tP-M O'·'-) c o 73 O 73 o 73 1 Ml Ml Ml 5 cuo Oio no r4 >H« >1(N >1« O X * X ~ X * U ο m Ο (Ό On M I M I M I 73 O 73 Ο 73 >|C >i C NC 33 l« 33 7) 33 O •Μ X ·Η X ·Η X 73 Ο 73 Ο 73 Ο I ·Μ I ·Μ I ·Μ ιΗ 73 ιΗ 73 .-1 73 W “ 'C' ca ·* ca *» eft *· Η Η Η Η H rl rl1-1 r-ί ^ H ·—' a) 0) QJ Ό 73 73 ·Η •Μ ·Η M Μ M 73 H u t I C 33 33 C g C C id a id id h O OO Ο ·Μ υ ·μ ·μ 8 Μ Ο Η ΟΝΟ Η C 43 Id Ο I , > Λ CU 0) ιΗ Q. Ε m rf in (¾ ΓΟ ro fft tf w m - 71 - . Example 36 42427 21-Chloro-5'-(4-chlorophenyl)-9-fluoro“2',3'-dihydro-llB-hydroxypregna-l,4-dieno[16g,17-b]- [1.4] dloxin-3,2 O-dione 5 Following the procedure of Example 20, but sub stituting 2-(4-chlorophenyl)-3-diazo-l-propene for 2-phenyl-3-diazo-l-propene, yields 21-chloro-5'-(4-ehloro-phenyl)-9-fluoro-2',3'-dihydro-llg-hydroxypregna-1,4-dieno[16a,17-b][1,4]dioxin-3,20-dione, melting point l’O 212-214°C, dec., softening at 200°C.

Example 37 21-Chloro-5'-(l,l-dimethylethyl)-9-fluoro-2',3'-dihydro-llB-hydroxypregna-1,4-dieno[16a,17-b]- [1.4] dioxin-3,20-dione · 15 Following the procedure of Example 7, but sub stituting 2-(l,l-dimethylethyl)-3-diazo-l-propene for 2-methyl-3-diazo-l-propene, yields 21-chloro-5'-(1,1-dimethyl-' ethyl)-9-fluoro-2',3'-dihydro-llB-hydroxypregna-l,4-dieno-[16a,17-b][l,4]dioxin-3,20-dione, melting point 240-242eC, 20 dec. - 72 - . Example 38 42427 9-Fluoro-llB,21-dihydroxy-51g-methylpregn-4-eno-[16g,17-b] [l,4]dioxane-3,20-dionp, 21-acetate A. 9-Fluoro-llB,17,21-trihydroxy-16a-(2g-hydroxypro- 5 poxy)pregn-4-ene-3,20-dione, 21-acetate A solution of 1.0 g of 9-fluoro-llB,17,21-trihydroxv-16a-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate (prepared as described in Example 2D) in 80 ml of methanol is cooled to 0°C and 80 mg of sodium borohydride is added. After 10 10 minutes the solution is poured into chloroform and ex tracted with dilute hydrochloric acid. The chloroform solution is dried and evaporated in vacuo to give the crude product. Chromatography on a 30 g-silica gel column» eluting with 9:1 chloroform-ethyl acetate, yields 730 mg of the title IS compound.

B. 9-Fluoro-llB,17,21-trihydroxy-16a- (2f,-mesyloxy-propoxy)pregn-4-ene-3,20-dione, 21-acetate A solution of 700 mg of 9-fluoro-llB,17,21-tri-hydroxy-16a-(2C*-hydroxypropoxy)pregn-4-ene-3,20-dione, 21-20 acetate in 10 ml of pyridine is cooled to 0°C and 0.4 ml of methanesulfonyl chloride is added. After 4 hours the mixture is extracted, dried and evaporated to give the title compound. - 73 - 4842? • C. 9-Fluoro-llg,21-dihydroxy-5'g-methylpregn-4-eno- [16a,17-b][l,4]dioxane-3,20-dione, 21-acetate A solution of 750 mg of 9-fluoro-llp,17,21-trihydroxy-16a-(2C-mesyloxypropoxy)pregn-4-ene-3,20-dione, 21-acetate 5 in 50 ml of dimethyl .sulfoxide is stirred at 110 °C under nitrogen with 1.0 g of sodium bicarbonate. After ? hours the reaction mixture is extracted, dried and evaporated to yield the title compound.

Example 39 10 9-Fluoro-llg,2l-dihydroxy-5'g-phenylpregn-4-eno- [16ot,17-b1 [l,41dioxane-3,20-dione, 21-aCetate A. 9-Fluoro-llg,17,21-trihydroxy-16a-(2-phenyl-2- hydroxyethoxy)pregn-4-ene-3,20-dione, 21-acetate A solution of 1.0 g of 9-fluoro-118,17,21-trihydroxy-15 16a-(2-phenyl-2-oxoethoxy)pregn-4-ene-3,20-dione, 21-acetate (prepared as described in Example 4D) in 80 ml of methanol is cooled to 0°C and 80 mg of sodium borohydride is added. After 10 minutes, the solution is poured into chloroform and extracted with dilute hydrochloric acid. The chloroform 20 solution is dried and evaporated i£ vacuo to yield the title compound. - 74 - 42427 • Β· 9-Fluoro-llg,17,21-trihydroxy-16a-(2-mesyloxy-2- phenylethoxy)pregn-4-ene-3,20-dione, 21-acetate A solution of 700 mg of 9-fluoro-llB,17,21-trihydroxy-16a-(2-phenyl-2-hydroxyethoxy)pregn-4-ene-3,20-dione, 21-5 acetate in 10 ml of pyridine is cooled to 0°C and 0.4 ml of methanesulfonyl chloride is added. After 4 hours the mixture is extracted, dried and evaporated to give the title compound.

C. 9-Fluoro-ll8» 21-dihydroxy-51g-phenylpregn-4-eno-[16g,17-b][1,4]dioxane-3/20-diQtie, 21-acetate 10 A solution' of 750 mg of 9-fluoro-116,17,21-trihydroxy- 16«-(2-mesyloxy-2-phenylethoxy)pregn-4-ene-3,20-dione, 21-acetate in 50 ml of dimethylsulfoxide is stirred at 110°C under nitrogen with 1.0 g of sodium bicarbonate. After 2 hours the reaction mixture is extracted, dried and evapor-15 ated to yield the title compound.

Example 40 21-Chloro-9-fluoro-11β-hydroxy- 6-methyl-5'-phenyl-preana-l.4- dieno[16g,17-b][l,41dioxin-3,20-dione A. 21-Chloro-9-fluoro-llg,17-dihydroxy-16g-[(3-oxo-3-2(> phenylprop-2-yl)oxy]pregna-l,4-diene-3,20-dione a. N- [l-roathyl^-oxo-g-phenylethyi? phthalimide A solution of 58 g of α-bromopropiophenone and 50 g of potassium phthalimide in 200 ml Of dimethylformamide is refluxed for 2 hours under nitrogen, cooled, and poured into 25 500 ml of water. The resulting mixture is extracted with ether, and the ether solution is dried and evaporated in vacuo. A solution of the residue in 200 ml of ether gives the title compound as a solid. - 75 - V-- 42437 ' b· 2-ri-phthalimldoethy1]~2-phenyldioxolane A solution of 49.9 g of N-[I-methyl-2-oxo-2-phenylethyl3~ phthalimide in 500 ml of toluene is refluxed for a total of 13 days with 5 g of £-toluenesulfonic acid and 150 ml Of 5 ethylene glycol. The solution is cooled, diluted with chloroform, and washed with dilute sodium bicarbonate solution. The chloroform solution is dried and evaporated to give, on trituration with ether, 51.5 g of the title compound, melting point 127-130°C. c. 2-(1-Aminoethyl)-2-phenyldioxolane A solution of 51.5 g of 2-[l-phthalimidoethyl]-2-phenyldioxolane in 500 ml of methanol is refluxed for 6 hours with 5,76 g pf hydrazine. The slurry is cooled, filtered and the solid washed well with methanol. The filtrate 15 is evaporated in vacuo, and the residue triturated with di- chloromethane and filtered. The filtrate is distilled in vacuo to give 28.25 g of the title compound, boiling point 97-100°C at 1.1 mm Hg. d. 2-Phenyl-2-(1-ethoxycarbonylaminoethyl)-20 dioxolane A solution of 2-(1-aminoethyl)-2-phenyldioxolane (20 mmoles), triethylamine (24 mmoles), and ethyl chloro-formate (22 mmoles) in 100 ml of dichloromethane is stirred at 0°C for 2 hours, washed with water, dried, and evapor-25 ated to give the title compound. - 76 - 42427 • e. 2-Phenyl-2-(l-diazoethyl)dioxolane Following the procedure of Example 4A (parts c and d), but substituting 2-phenyl-2-(1-ethoxycarbonylamino-ethyl ethyl)dioxolane for/N-(2-phenyl-2-propenyl) carbamate, 5 the title compound is obtained. f. 21-Chloro-9-fluoro-llg,17-dihydroxy-16a-[(3-oxo-3-phenylprop-2-yl)oxy]pregna-l> 4-diene- 3,20-dione A solution of 2-phenyl-2-(l-dia20ethyl)dioxolane in 10 3:2 ether-pentane is diluted with methanol and cooled to 0°C. 21-Chloro-9-fluoro-ΙΙβ,16a,17-trihydroxypregna-l,4-diene- 3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo.

The residue is purified and dissolved in tetrahydro-15 furan. The solution is refluxed with hydrochloric acid. 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, dried, and evaporated to yield the title compound. - 77 - 42427 Β. 21-Chloro-9-fluoro-llB-hydroxy-6'-methyl- 5 '-phenYlpreqna-l,4-dieno[16ot,17-b] [1,4]dioxin- 3,20-dione A slurry of 150 mg of £-toluenesulfonic acid in 5 750 ml· of benzene is refluxed with a Dean-Stark trap. The first 150 ml of benzene-water azeotrope is discarded and Linde type 4A molecular sieves are added to the trap. After 30 minutes at reflux, the solution is cooled and 1.0 g of 21-chloro-9-fluoro~llB,17-dihydroxy-16a-[(3-oxo-3-phenyl-10 prop-2-yl)oxy]pregna-l,4-diene-3,20-dione is added. The mixture is refluxed for 6 hours under nitrogen, cooled, washed with 5% sodium bicarbonate solution, water, dried and evaporated in vacuo to yield the title compound.

Claims (61)

1. 42427 CLAIMS:-

2. 1. A 3,20-diketo pregnene having an 1]^-hydroxy group or an 11-keto group and having fused on the 16 and 17 positions a 1,4-dioxane ring or a 1,4-dioxin ring. 5 2. A steroid in accordance with claim 1 having fused on the 16 and 17 positions a 1,4-dioxane ring.

3. A steroid in accordance with claim 1 having fused on the 16 and 17 positions a 1,4-dioxin ring.

4. A steroid in accordance with claim 1 wherein 10 the fused 1,4 dioxane ring or 1,4- dioxin ring has the structural formula ~C—CL i > HC---Cr wherein A^ is Rη R- Rj, Rc — CH-CH2-»—C = CB-' -C =C- ' 0 0 II II

5. 10 R^O-CH-CHj-, — C—CH— or R.^C-0-CH.—CH - ' wherein R^ is hydrogen, alkyl or aryl; R2 is hydrogen, alkyl or arylalkyl; R3 is alkyl, cycloalkyl or aryl; and R^ and R5 are the same or different and are alkyl or aryl, the terms "alkyl", "aryl" and "cycloalkyl" being as hereinbefore 20 defined and the first free bond of A, being attached to the oxygen at the 17-position.

6. 5. A steroid in accordance with claim 4 wherein Αχ is _CH2_CH2—' - 79 - l ............- ί1 -C = CH— , R20-

7. 6. A steroid having the formula ν' 5 and the 1,2-dehydro, 6,7-dehydro and 1,2; 6,7-bisdehydro derivatives thereof, wherein £ is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y1 is hydroxyl or together Y and Y' are = 0; X is hydrogen or halogen; P is hydrogen, methyl or chloro; Q is hydrogen, methyl or fluoro; 10 is R R R, R 11. i4 μ — CH-CH2— , — C = CH—, —C = C—, 0 0 II II R.O—CH—CH_—, — C-CH.- or R.C —0— CH —CH —.; 2 |- 2 . 2 j | 2 R^ is hydrogen, alkyl Or aryl; R2 is hydrogen,' alkyl or arylalkyl; R^ is alkyl, cycloalkyl or aryl; and R^ and R^ 15 are the same or different and are alkyl or aryl, the terms "alkyl", "aryl", "cycloalkyl" and "acyloxy" being as hereinbefore defined and the first free bond of being attached to the oxygen at the 17-position. - 80 - 42427

8. 7. A steroid in accordance with claim 6 wherein Α^ is _CH—CH2—

9. 8. A steroid in accordance with claim 6 wherein

10. 5 A^ is —C — CH— .

11. 9. A steroid in accordance with claim 6 wherein A^ is R. Rc -J-aL. 10 10. A steroid in accordance with claim 6 wherein A1 is R 0 -CH -CH-- 2 , 2

12. 11. A steroid in accordance with claim 6 wherein A^ is 0 II

13. 15. C-CH2-- - 81 - 42437

14. 12. A steroid in accordance with claim 6 wherein A^ is 0 RC— O—CH— CH„— 3 | 2

15. 13. A steroid in accordance with claim 6 wherein 5. is fluoro.

16. 14. A steroid in accordance with claim 6 wherein Z is hydroxyl.

17. 15. A steroid in accordance with claim 6 wherein Z is acyloxy. 10 16. A steroid in accordance with claim 6 wherein Z is halogen.

18. 17. A steroid in accordance with claim 6 wherein Z is chlorine. 18. 9 - Fluoro - 5'ξ,116,21 - trihydroxypregn 15 - 4 - eno D-6a,17-iOP-/43dioxane-3,20-dione, 21 - acetate. 19. 9 - Fluoro - 2',3' - dihydro - 118,21 -dihydroxy - 5' - methylpregn - 4 - eno- Cl6a,17-b3 Cl,4] dioxin - 3,20 - dione, 21 - acetate. 20. 9 - Fluoro - 2',3' - dihydro - 118,21 - 20 dihydroxypregn - 4 - eno Cl6a,17-b3 Cl,43 dioxin - 3,20 - dione 21. 21 - Chloro - 9 - fluoro - 2',3' - dihydro 118. hydroxy - 5' - methylpregna- 1,4 - dieno Cl6a,17-b3 Cl,43 dioxin - 3,20 - dione. 22. 5'ζ - Ethoxy - 9 - fluoro - 118,21 - 25 dihydroxypregn - 4 - eno 0.6a,17-b3L1,43- dioxane - 3,20 - dione - 82 - 42427 23. 21 - Chloro - 5'C - ethoxy - 9 - fluoro -IIP - hydroxypregn - 4 - eno [16a , 17-b] [1,4] dioxane - 3.20 - dione. 24. 9 - Fluoro - 5'ξ,lie,21 - trihydroxypregn - 4 - 5 eno [16a,17-b][l,4] dioxane- 3,20 - dione. 25. 9 - Fluoro - 5'ξ ,116,21 - trihydroxypregn - 4 -eno [l6a,17-bD Cl,4] dioxane- 3,20 - dione, 5',21 - diacetate. 26. 21 - Chloro - 9 - fluoro - 5'€,116-dihydroxypregna - 1,4 - dieno [16“ , 17-b][l, 4.1 dioxane - 3,20 - 10 dione. 27. 21 - Chloro - 9 - fluoro - 5'?,ll6 -dihydroxypregna - 1,.4 - dieno 0.6a, 17-b] 0.,4] dioxane - 3,20 -dione, 5' - acetate. 28. 21 - Chloro - 9 - fluoro - 2',3' - dihydro - 15 116 - hydroxypregna - 1,4 - dieno - 0.6οι, 17-h] 0,4] dioxin - 3.20 - dione. 29. 9 - Fluoro - 116,21 - dihydroxypregn - 4 -eno [16“, 17-b] 0.,4] dioxane- 3,5',20 - trione, 21 - acetate. 30. 21 - Chloro - 9 - fluoro - 2',3' - dihydro - 20 116 - hydroxy - 5' - phenylpregna - 1,4 - dieno [16a,17-b][l,4] dioxin - 3,20 - dione. 31. 21 - Chloro - 9 - fluoro - 116 - hydroxypregna 1,4 - dieno [16a,17-b][1,4] - dioxane - 3,20 - dione. 32. 116,21 - Dihydroxypregna - 1,4 - dieno 25 [16a,17-b][l,4] dioxane - 3,20 - dione, 21 - acetate. 33. 21 - Chloro - 5' - (4 - chlorophenyl) - 9 - fluoro - 2',3' - dihydro - 116 - hydroxypregna - 1,4 - dieno [16a,17-b] [1,4] dioxin - 3,20 - dione. 34. 21 - Chloro - 5' - (1,1 - dimethylethyl) - 30 9 - fluoro - 2',3' - dihydro - 116 - hydroxypregna - 1,4 - _ 63 - 4 343Ύ dieno Cl6a, 17-bll,4ll dioxin - 3,20 - dione,

19. 35. A process for preparing a 3,20 - diketo pregnene having an 116 - hydroxy or an 11-keto group and having fused on the 16 and 17 positions a 1,4 - dioxane or 5 1,4 - dioxin ring which comprises cyclizing the corresponding steroid having a hydroxy group in the 17 position and a 16-alkoxy group having an oxo, acetal or methanesulfonyloxy group on the beta carbon atom.

20. 36. A process according to claim 35 wherein a 10 steroid of the formula CH.Z. V L_~oh y y |'o-ch-C—Ru 4 or a ,1,2-dehydro, 6,7-dehydro or 1,2;6,7-bisdehydro derivative thereof, wherein Z is hydrogen, hydroxyl, acyloxy (as hereinbefore defined) or halogen; Y is hydrogen and Y’ is 15 hydroxyl, or together Y and Y' are = 0; X is. hydrogen or halogen; P is hydrogen, methyl, or chloro; Q is hydrogen, methyl or fluoro; and R4 and R,. are the same or different and are hydrogen, alkyl or aryl (as hereinbefore defined), is treated with an organic acid to form a product of the 20 formula VI C= 0 γ I' o-c- Rs 4 - 84 - or a 1,2-dehydro, 6,7-dehydro or l,2;6,7-bisdehydro derivative thereof. 48427

21. 37. A process according to claim 35 wherein a CHXZ steroid of the formula | v* C— O r~. i, OH o-R^

22. 5 VT Γ'0-«,-ςΗ '>“f^VxTy o-r, Q i or a 1,2-dehydro, 6,7-dehydro 1,2;6,7-bisdehydro derivative thereof,.- wherein Z is hydrogen, hydroxyl, ^cyloxy (as hereinbefore defined) or halogen; y is hydrogen and Y‘ is hydroxyl or together Y and Y’ are = 0; X is hydrogen or 10 halogen; P is hydrogen, m&thyl or chloro; Q is hydrogen, methyl or fluoro; and R? is alkyl or aralkyl (as hereinbefore defined) is treated with an acid to form a product of the formula CH^Z O-R-j. Y pO-CH xSr a 15 wherein R?’ is hydrogen, alkyl or aralkyl (as hereinbefore defined) or a corresponding dehydro derivative thereof.

23. 38. A process according to claim 37 wherein the product (when R^1 is hydrogen) is dehydrated to form a product of the formula - 85 - 42427 a^z , c=0 Υ' - L—O-C-H y—A ii 'O-CH 0. or a 1,2-dehydro, 6,7-dehydro or l,2;6,7-bisdehydro derivative thereof.

24. 39. A process according claim 35 wherein a CH,Z 5 steroid of the formula I OH o - Ί-- pO-CH-C-fci, i—_ i i k or a 1,2-dehydro, 6,7-dehydro or l,2J6,7-bisdehydro derivative thereof. Wherein Z is hydrogen, hydroxyl, acyloxy (as hereinbefore defined) or halogen; Y is 10 hydrogen and Ϋ' is hydroxyl or together Y and Y1 are = 0; X is hydrogen of halogen; P is hydrogen, methyl or chloro; Q is hydrogen, methyl or fluoro; and and are the same or different and are alkyl or aryl (as hereinbefore defined), is subjected to consecutive treatments with a 15 mineral acid and an organic acid to form a product of the CH J. formula ., I or a corresponding dehydro derivative thereof. - 36 - 42427

25. 40. A process according to claim 35 for preparing a steroid of the formula R( V-fTV- CHi ρ-·ηιγ Q or a 1,2-dehydro, 6,7-dehydro or l,2;6,7-bisdehydro 5 derivative thereof, wherein Z is hydrogen, hydroxyl, acyloxy (as hereinbefore defined) or halogen; Y is hydrogen and Y' is hydroxyl or together Y and Y' are = 0; X is hydrogen or halogen; P is hydrogen, methyl or chloro; Q is hydrogen, methyl or fluoro; and R is hydrogen, alkyl or 10 aryl (as hereinbefore defined), which comprises treating C H,Z a steroid of the formula I * y oh Y"‘ltl'‘0-'CHrCH-0-S-CH, I_ i ii -5 p --rrtr R| ° Q. or a corresponding dehydro derivative thereof with sodium bicarbonate in a dipolar aprotic solvent. 15 41. A process for preparing a steroid of the rv formula yl C= 0 * pO-CH» p" Q - 87 - 42427 1 or a 1,2-dehydro, 6,7-dehydro or l,2;6,7-bisdehydro derivative thereof, wherein Z is hydrogen, hydroxyl, acyloxy {as hereinbefore defined) or halogen; Y is hydrogen and Y’ is hydroxyl or together Y and Y' are = 0; X is hydrogen 5 or halogen; P is hydrogen, methyl or chloro; Q is hydrogen, methyl or fluoro; which comprises oxidizing a steroid of CH Z the formula a OH V1 c=0 r' X---0-CH ^CHa ί Q. or a corresponding dehydro derivative thereof with Fetizon's 10 reagent.

26. 42. A process for preparing a steroid of the CHaZ o formula ' I .., C= 0 11' y ι-o— ch-oc-r3 Y " 0— CHa. qA/\/ Q. or a 1,2-dehydro, 6,7-dehydro or 1,2;6,7-bisdehydro 15 derivative thereof, wherein Z is hydrogen, hydroxyl, acyloxy (as hereinbefore defined) or halogen; Y is hydrogen and Y' is hydroxyl or together Y and Y1 are = Ο; X is hydrogen or halogen; P is hydrogen, methyl or chloro; Q is hydrogen, methyl or fluoro; and is alkyl, cyclpalkyl or 20 aryl (as hereinbefore defined) which comprises aeylating a steroid of the formula - 88 - 43437 CjHjZ 0H / c=o r' y_" j "0— CHa 4 or a corresponding dehydro derivative thereof with an anhydride of formula (R^CO^O.

27. 43. A process in accordance with any of claims 35 5 to 42 wherein X is fluoro.

28. 44. A process in accordance with any of claims 35 to 42 wherein 2 is hydroxyl.

29. 45. A process in accordance with any of claims 35 to 42 wherein Z is acyloxy. 10 46. A procees in accordance with any of claims 35 to 42 wherein Z is halogen.

30. 47. A process in accordance with any of claims 35 to 42 wherein z is chlorine.

31. 48. A process in accordance with any of claims 35 15 to 42 wherein the product is 9- fluoro - 5’ξ,ΙΙβ, 21 - trihydroxypregn - 4 - eno - Cl6o,17-13 [l,43dioxane - 3,20-dione,21 - acetate.

32. 49. A process in accordance with any of claims 35 to 42 wherein the product is 9 - fluoro - 2',3' - dihydro - 20 116,21 - dihydroxy - 5’ - methyl - pregn - 4 - eno [l6ot,17-b3- 0.,43 dioxin - 3,20 - dione, 21 - acetate.

33. 50. A process in accordance with any of claims 35 to 44 wherein the product is 9 - fluoro - 2',3' - dihydro -113,21 - dihydroxypregn - 4 - eno [16a,17-b3 [1,43 dioxin - 25 3,20 - dione. - 89 - 42427 51« A process in accordance with any of claims 35 to 42 wherein the product is 21 - chloro - 9 - fluoro - 2',3' -dihydro - lie - hydroxy - 5' - methylpregna - 1,4 - dieno-C16a, 17-b3Cl,43 dioxin - 3,20 - dione, 5 52. A process in accordance with any of claims 35 to 42 wherein the product is 5'ξ - ethoxy -.-9- fluoro -lie, 21 - dihydroxypregn - 4 - eno 0.6a, 17-0 0,43 dioxane- . 3.20 - dione.

34. 53. A process in accordance with any of claims 35 10 to 42 wherein the product is 21 - chloro - 5'f - ethoxy - 9 - fluoro - lie - hydroxypregn - 4 - eno C16a,l7-b3C1,43-dioxane - 3,20 - dione.

35. 54. A process in accordance with any of claims 35 to 42 wherein the product is 9- fluoro - 5'ξ,lie,21 - 15 trihydroxypregn - 4 - eno - p.6ct,17-blC1,43 dioxane - 3,20 - dione.

36. 55. A process in accordance with any of claims 35 to 42 wherein the product is 9- fluoro - 5'ξ,11B,21 -trihydroxypregn - 4 - eno - Cl6a,17-b3C1,43 dioxane - 3,20 - 20 dione, 5',21 - diacetate.

37. 56. A process in accordance with any of claims 35 to 42 wherein the product is 21- chloro - 9 - fluoro - 5'ξ,lie - dihydroxypregna - 1,4 - dieno [16a ,17-13 Cl,43 dioxane- 3.20 - dione. 25 57. A process in accordance with any Of claims 35 to 42 wherein the product is 21- chloro - 9 - fluoro -5'ξ,118 - dihydroxypregna - 1,4 - dieno Πΐ6α,17-ώ Cl,43 dioxane- 3,20 - dione, 5' - acetate.

38. 58. A process in accordance with any of claims 35 30 to 42 wherein the product is 21- chloro - 9 - fluoro - 2',3' - 90 - - dihydro - 116 - hydroxy - pregna - 1,4 - dieno Cl6a,17-li] - Cl,4*1 dioxin - 3,20 - dione. 424-a ?

39. 59. A process in accordance with any of claims 35 to 42 wherein the product is 9- fluoro - 116,21 - 5 dihydroxypregn - 4 - eno Cl6“,17-hl Cl,43 dioxane - 3,5',2θ - trione, 21 - acetate.

40. 60. A process in accordance with any of claims 35 to 42 wherein the product is 21- chloro - 9 - fluoro - 2',3 - dihydro - 116 - hydroxy - 5' - phenylpregna - 1,4 - dieno-

41. 10 Cl6a , 17-bll,4] dioxin - 3,20 - dione.

42. 61. A process in accordance with any of claims 35 to 44 wherein the product is 21- chloro - 9 - fluoro - 2',3 -dihydro - 116 - hydroxy - 5' - phenylpregna - 1,4 - dieno-dione. 15 62. A process in accordance with any of claims 35 to 42 wherein the product is 116,21 - dihydroxypregna - 1,4 -dieno Cl6a, 17-t3Q.,43 dioxane - 3,20 - dione, 21- acetate.

43. 63. A process in accordance with any of claims 35 to 42 wherein the product is 21- chloro - 5' - (4 - 20 chlorophenyl) - 9 - fluoro - 2',3' - dihydro - 116 - hydroxypregna- 1,4 - dieno C16“,17-h3E1,43 dioxin - 3,20 dione.

44. 64. A process in accordance with any of claims 35 to 42 wherein the product is 21- chloro - 5' - 25 (1,1 - dimethylethyl - 9 - fluoro - 2',3' - dihydro - IIP - hydroxypregna- 1,4 - dieno Q.6a,17-b3Cl,43 dioxin - 3,20 -dione.

45. 65. A steroid in accordance with claim 1 as named in any of Examples 3-5,9,13,18,19,23-35 and 38-40. - 91 - α « * β «

46. 66. A steroid in accordance with claim 1 when prepared by a process in accordance with any of claims 35 to 47 and 63 to 64.

47. 67. A'steroid in accordance with claim 1 when 5 prepared by a process in accordance with any of claims 48 to 62.

48. 68. A steroid having the formula CHjZ y‘ Q and the 1,2-dehydro, 6,7-dehydro and l,2;6,7-bisdehydro 10 derivatives thereof,wherein Z is hydrogen, hydroxyl,

49. 0. Ik l__C—0— l_c_o— or halogen; Y is hydrogen and Y' is hydroxyl or together Y and Y' are = 0; X is hydrogen or halogen; A^ is-CH^- CH—, R1 — C = CH—, R 0-CH-CH—, i I ^ 0 0 II II

50. 15. C—CH.—, or R,C—0-CH-CH.—, 2 3 | 2 the first free bond being attached to oxygen at the 17-position; is hydrogen, alkyl, or aryl; R^ is hydrogen, alkyl or aryl-alkyl; R^ is alkyl, cycloalkyl or afyl (as hereinbefore defined); and P and Q are independent of 2o each other and each is hydrogen or methyl. - 92 - 42427 '•,-

51. 69. A compound in accordance with claim 68 wherein A^ is -CHj— CH2~ ·

52. 70. A compound in accordance with claim 68 wherein A^ is I1

53. 5. C = CH- .

54. 71. A compound in accordance with claim 68 wherein A^ is r2o-

55. 72. A compound in accordance with claim 68 ]0 where;in A^ is 0 H - C—CH2— ,

56. 73. A compound in accordance with claim 68 wherein A^ is 0 II R,C — 0— CH— CH-— . 3 | 2 15 74. A compound in accordance with claim 68 wherein X is fluoro.

57. 75. A compound in accordance with claim 68 wherein Z is hydroxyl.

58. 76. A compound in accordance with claim 68 20 wherein Z is acetoxy.

59. 77. A compound in accordance with claim 68 wherein Z is halogen.

60. 78. A compound in accordance with claim 68 wherein Z is chlorine.

61. 25 MACLACHLAN & DONALDSON Applicants1 Agents 47 Merrion Square Dublin 2. - 93 -