CA1142916A

CA1142916A - STEROIDAL [16.alpha., 17-B]NAPHTHALENO AND CYCLOHEXENE-21-CARBOXYLIC ACID ESTERS

Info

Publication number: CA1142916A
Application number: CA000328182A
Authority: CA
Inventors: Ravi K. Varma
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1978-06-26
Filing date: 1979-05-23
Publication date: 1983-03-15
Also published as: IT1162746B; PT69818A; CS208160B2; GR72244B; DK267079A; CS208159B2; PL216614A1; IE49178B1; DE2925552A1; AU524173B2; FR2429796B1; NL7904510A; GB2023608B; LU81420A1; GB2023608A; AU4748179A; ES481875A1; FR2429796A1; CH642087A5; FI791934A

Abstract

K570 ABSTRACT STEROIDAL[l6.alpha.,l7-b]CYCLOHEXENE AND NAPHTHALENO-21-CARBOXYLIC ACIDS AND ESTERS Steroids having the formula and esters thereof wherein X is hydrogen or halogen; Y is hydrogen, methyl or fluorine; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached form a benzene ring; R6 are R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, , phenyl or cyano and in addition hydroxy, halogen carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or wherein R9 and R10 are the same or different and are hydrogen or alkyl have useful antiinflammatory activity.

Description

3~6 STEROIDAL E16~l 17-b]CYCLOHEXENE AND NAPHTHAL~NO-21-CARBOXYLIC ACIDS AND ESTERS
. . _ . _ _ Steroids having the formula . . O

J~

and esters thereof are useful as topical anti-inflammatory agents. In formula I, and throughout the specification, the symbols are as defined below:
X is hydrogen or halogen;
Y is hydrogen, fluorine or methyl;
R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O;
R2 and R3 are the same or difPeren-t and are hydrogen, alkyl or aryl or taken -together with the double bond -to which they are a-t-tached, form a benzene ring;
R6 and R7 are the same or different and are hydrogen,~ alkyl, alkoxy, formyl, alkyl-~-O-, phenyl or cyano and in addition, hydroxy, halogen, carbo-alkoxy and alkylcarbonyl when R2 and R3 are separate with the prov.iso that when R6 and R7 are di-Eferent, one of R6 and R7 is hydrogen; and R8 is hydrogen or CH-RgRlo wherein Rg and Rlo are the same or different and are hydrogen or alkyl.

' ~

~ X5~0 The dotted lines in the 1,2-position of khe steroids of this invention represent the optional presence of ethylenic unsaturation.
The terms "alkyl" and "alkoxy", as used throughout the specification (unless otherwise defined), refer to both straight and branched chain groups having 1 to 6 carbon atoms.
The term "aryl", as used throughout the sp~cification, refers to phenyl or phenyl substituted with one or more halogen, alkyl and alkoxy groups.
The term "halogen", as used throughout the specification, refers to fluorine, chlorine, bromine and iodine.
The esters contemplated are the Cl-C10 alkyl, aryl and aralkyl esters.
The steroids of formula I can be prepared from the corresponding 21-hydroxy-steroidal[16~, 17-b]-cyclic-enes having the structural formula fH2H R
II

wherein the symbols are as previously defined. The steroids of formula II are generally known in the art;
see, for example, United States patents 3,927,720 issued February 10, 1976; 3,994,935 issued November 30, 1976 and 3,944,584 issued March 16, 1976.
A steroid of formula II can be oxidized to the corresponding aldehyde having the formula ~ K570 _~_ HC=O
III ~ 2 using a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presence of oxygen (e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula III, the corresponding steroidal-21-acetal formed with the alcohol solvent (Rl-O~I); i.e., a steroid having the formula ~~~- ~ CH~OR ) IV C=O ,''< / R2 O ~ J 3 The oxidation reaction will generally be comple-ted within a relatively short period of time, i.e., about 1 hour.
If the above-described reaction is allowed to proceed for an extended period of time. e.g., more than about 24 hours, the major product will be the 2Q
hydroxy-21-carboxylic acid ester having the formula o V C-ORl R
HC~oH, ~ R2 ¦ L i ` ~ 3 If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for an extended period of time, in addition to the 20-hydroxy-21-carboxylic acid ester of formula V, the corresponding 20-hydroxy-21-carboxylic acid will be produced. i.e., a s-teroid havinq the -formula O ~

C-O~I R
HC~OH,''< / 2 VI ¦ ~ J ~ ~

, 8 ~he steroids of formulas V and VI exist as mixtures of the 20~- and 20~-hydroxysteroids. Reacting a steroid of formulas III or IV or a mixture thereof with an inorganic cyanide catalys~, an oxidizing agent, an inert solvent, an alcohol and an organic acid yields the product of formula I. More specificallyj a product of formula I can be obtained by reacting a steroidal-21-aldehyde of formula III or the corresponding steroidal-21-acetal of formula IV or a mixture thereof with a mixtuxe of (i) an inorganic ~, . . . . . .. . . . . ..

~5--cyanide catalyst (e.g., an ~lkali metal cyanide such as potassium cyanide); (ii) an oxidlzing agent, e.g., I a heavy metal oxide such as activated manganese dioxide or lead dioxide, (iii) an inert solvent, e.g., a halogenated hydrocarbon solvent such as dichloro-methane or chloroform; (iv) a primary or secondary alcohol, Ri-OH (throughout the speci~ication Ri is any primary or secondary Rl group); and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula o (~

VII R ~~~ ~ ~3 O ~ ~ R
Y
The 20 ~ and 20~-hydroxysteroids of Eormulas V
and VI can be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas O O
V II I a and ~42~1~ K570 6 __ ______ _ O O
~-COH R
VIIlb l ' ~ ,l~2 H

Y
Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20~- and 20~-hydroxysteroids being oxidized have an ll~-hydroxy substituent, the products of Eormulas I and VIII will be mixtures of ll~-hydroxy and ll-keto steroids.
The esters of formula I can also be prepared byesterification of the corresponding steroidal-21-oic acid of formula ~III. (A steroid of formula VIII can be prepared as described above, or alternatively, by saponification of a corresponding steroidal-21-oic ! acid ester of formula I.) Still another route for the preparation of the products of ~ormula I wherein Rl is a non tertiary alkyl group of l -to 10 carbon atoms or aryl i9 the transesterification of another ester of formula I.
The starting steroid is reacted with the appropirate alcohol in the presence oE a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide) or, preferabIy, a source of cyanide ion (e.g. r an alkali metal cyanide such as sod um cynaide or potassium cyanide to yield the transesterification product.

.... .

~57 The steroids oF formula I are llseful tol)ical antiinflammatory agents which can b~ uso(l ill lio~l ol~
known glucocorticoids in the treatment of conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and anogenital pruritus. The steroids may be administered in a conventional cream, ointment, lotion, or spray in the range of 0.01 to 5.0~ by weight, preferably 0.025 to 2.0% by weight.
In an alternative process, steroids of the formula I can be prepared from the corresponding 21-hydroxy-~16 steroids having the formula 4 ~=o lS IX 8 Y
by first converting the 21-hydroxy group to a 21-carboxylic acid group and then fusing the cyclo-hexane and tetrahydronaphthalene groups in the 16,17-position.
The 21-hydroxy-~16-steroids of formula IX, which form the starting point for -the alternate process, or the corresponding 21-acyloxy steroids, are known in the art. The 21-acyloxy steroids are readily converted to the corresponding 21-hydroxy steroids using conventional techniques.
A steroid of formula IX can be oxidized to the corresponding aldehyde having the formula 4 ~ 9 ~ ~ K570 , . _ , HC=O
X R

5 0~

using oxygen (or air) and a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presencs of oxygen ~e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula X, the corresponding steroidal-21-acetal formed with the alcohol solvent (Rl-OH); i.e., a steroid having the forrnula . . .
CH(ORl~2 XI

0~;

Y
The oxidation reaction will generally be completed within a relatively short period of time, i.e.,about 1 hour.
If the above described reaction is allowed to proceed for an extended period of time, e.g., more than about 24 hours, the major product will be the 20-hydroxy-21-carboxylic acid ester ~aviny the formula , . .. .

~Z916 K570 _9_ XII l-ORl HCrVOH

X
'.:- O' ~
, . . I
-., y If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for .~ an extended period of time, in addition to the 2 O-.~,- : .
~-~ hydroxy-21-carboxylic acid ester of formula XI, the _ . corresponding 20-hydroxy-21-carboxylic acid will be .~--` producea, i.e., a steroid having the formula C-OH
XIIII -. R HCrVOH .
R5 ~
. ~ ` ;`
,~ ;,~
The stervids of formula~ XlI and XIII exi3~ as I ~ .D~
25 mixtures of the 20a- and ~0~-hydroxy-steroids.~ .3 Reacting a steroid of formu.las ~X. or XI or a mixture thereof with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid yields the product of formula I. A
product of formula I can be.obtained by reacting a steroidal-21-aldehyde of formula X or the corresponding steroidal-21-acetal of formula XI or a mixture thereof with a mixture of (i)an inorganic cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); ~ii) an oxïdizing agent, e.g., a heavy metal oxide such as .,~' -' ~ Y~70 activated manganese dioxide or lead dioxide; ~iii) an inert solvent, e.g., a hal~genated hydrocarbon solvent such as dichloromethane or chloroform; (iv~
a primary or secondary alcohol, Rl-OH (throughout the specification Ri is any nontertiary Rl group);
and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula O p -- ,,. . ,_ R ~-~ORi XIV R ~
.' ~ ' '.
O ~
Y , ,.
The 20~- and 20~-hydroxysteroids of formulas XII
and XIIIcan be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas XVR --- ~ OR
' ~,~
~ ~ ~ ~

Y and _ _ XVI5 ~ ~
f~
O ~

. ~ ,. ,~b, S ~ ~ .
~ . . .

l6 Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20~ and 20~-hydroxysteroids being oxidized have an ll~-hydroxy substituent, the steroids of formulas XV and XVI will be mixtures of ll~-hydroxy and 11-~keto steroids.
The intermediates of formula XV can also be prepared by esterification of the corresponding steroidal-21-oic acid of formula XVI. (A steroid of formula XV can be prepared as described above, or alternatively, by saponification of a corresponding steroidal 21-oic acid ester of formula XV).
Still another route for the preparation of the intermediates of formula XV wherein Rl is a non-tertiary group is the transesterification of anotherester of formula XIV or XV. The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide), or preferably, a source of cyanide ion (e.g., an alkali me-tal cyanide such as sodium cyanicle or potassium cyanide) to yield the transesteri:Eication product.
A steroid of formulas XIV, XV or XVI can be converted to -the correspond.ing product of formula I
by reacting it with a benzocyclobutene having the formula XVII

~ R;

or with a butadiene having the formula R ~C- C - C- CHR8 using the Diels Alder reaction~
_ _ _ _ . _ .. . .. _ _, .. _ _ . .. _ _,, .. _, ., . . . , . _ . .. . , .,, . ,,, _, . ..
In the case of the XVII reactant, the reaction can be run neat or in an inert solvent, eOg., o-dichlorobenzene or diethylbenzene. Preferably the reaction will be run neat, in an inert atmosphere, at temperatures up to the boiling point of the solution.
A free radical inhibitor may be added to the mixture.
In the case of the XVIII reactant, the preferred catalysts for the reaction are anhydrous aluminum chloride and anhydrous aluminum bromide. The reaction can be run in an organic solvent, e.g., a halogenated hydrocarbon such as dichloromethane. The above described Diels-Alder reaction is highly selective and takes place exclusively at the double bond in the 16-position, even in the presence of the ~ ' -3-keto-function. In those instances wherein the butadiene isunstable in the presence of a Lewis acid catalyst, the Diels-Alder reaction is run in the presence of a free radical inhibltor at elevated temperatures.
If the steroid of formula XIV/ ~V or ~VI contalns an ll~-hydroxy group, it is desirable to first protect the group before running the Diels-Alder reaction.
While many means of protecting the ll-functional group will be apparent to a person skilled in the steroid - art, one particularly desirable method is the acylation of the group. The acylation reaction can be run using an acid anhydride, e.g., acetic anhydride in the presence of a Lewis catalyst, e.g., boron tri-fluoride etherate. After the Diels-Alder reaction has been run, the protective group can be removed using a conventional technique.

2~

Example 1 9-Fluoro-1',2'3'4'-tetrah~o~ -hydrox~-3,20-dioxo regna-l 4-dieno~ ,17-hJna hthalene-21-oic P ~ P
acid, methyl ester 9-Fluoro-1',2',3',4'-tetrahydro-11~,21-dihydroxy pregna -1,4 dieno[l6a,17-b]naphthalene-

3,20-dione (1.0 g) is dissolved in anhydrous methanol (170 ml) by warming and the solution is cooled to room temperature. Cupric acetate hydrate (250 mg) is added and under stirring, a slow stream of air is passed into the solution.
Within 10 minutes, the starting steroid disappears to give essentially a single less polar material, as judged by thin-layer chrornatography (TLC).
The methanol is mostly evaporated in vacuo at room temperature; some steroid precipitates out. The concentrate is diluted with water and extracted with chloroEorm~ The chloroform solution is washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to leave 0.98 g of 9-fluoro-1',2',3',4'-te-trahydro~ -hydroxy pregna-1,4-dieno[16a,17-bl naphthalene-21-al-3,-20-dione. This material shows a single spot on TLC (chloroform-methanol, 93:7; silica gel) and an IR spectrum consistent with the structure.
However, the NMR spectrum shows that it is contaminated with a small amount of the corresponding 21~dimethyl acetal.

~2~6 -14- K57~

A mixture of the impure aldehyde t950 mg), anhydrous methanol (50 ml), dry dichloromethane (50 ml), glacial acetic acid (Q.9 ml), potassium cyanide (200 mg) and active manganese dioxide (2.1 g) is stirred at room temperature for 10 hours. It is then fil-tered through a bed of diatomaceous earth. The cake is resuspended in chloroform which is refluxed and filtered again. The filtrates are comhined, washed with a dilute sodium hicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated ~o afford 0.86 g of a solid. This is dissolved in a mixture of dichloromethane and methanol. The dichloromethane is removed under reflux to precipi-tate 675 mg of a solid. This is again subjected to purification as abo~e to afford 630 mg of the title compound, melting point 319-321C (dec., discoloration starts from about 260C) with consistent spectral data.
Anal- Calc'd for C30H33F5 C, 73-15;
~1, 6.75;
F, 3.86 Found: C, 72.85;
H, 6.95;
F, 3.65 Example 2 9-Fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3,20-dioxopregna-1,4-dieno[16~,17-b]naphthalen-21-oic acid, l-methylethyl ester A suspension of 9-fluoro-1',2',3',4'-tetrahydro-ll~-hydroxy-3,20-dioxopregna 1,4 dieno[l6a,17-b]naphthalen-21-oic acid, me-thyl ester (490 mg., see Example 1) in dry isopropanol (30 ml, freshly distilled from magnesium turnings) containing sodium cyanide (10 mg) is refluxed under an atmosphere of nitrogen for 20 minutes when a clear solution results. A TLC examination at this point shows complete conversion of the starting steroid into a less polar compound. The mixture is then evaporated ln vacuo, the residue is dissolved in chloroform, washed with dilute brine and water, dried over anhydrous magnesium sulfate and evaporated to afford 516 mg of the title compound. One crystallization from ethyl acetate affords the analytical specimen of the title compound as colorless needles (410 mg), melting point 269-271C (dec., discoloration starts from about 250 C) wi.th consistent spectral dataO
Anal. Calc'd for C32 H37FO5: C, 73.82;
H, 7.16;
F, 3.~5 Found: C, 73.45;
H, 7.11;
F, 3.47 xample 3 9-Fluoro-1',2',3',4'-tetrahydro~ -h~droxy, 3,20-dioxopregna-1,4-dieno~16a,17-b]naphthalen-21-oic acid, butyl ester 9-Fluoro-1',2',3',4'-tetrahydro~ ,21-39 dihydroxypregna-1,4-dieno[16a,17-blnaphthalene-3,20-dione (800 mg) is dissolved in n-butanol 'h916 ~150 ml) by warming. The solution ls cooled to room temperature, cooper acetate hydrate (250 mg) is added and air is buhbled into the solution with sitrring for 30 minutes. Mos-t o the n-butanol is then removed b~ evapora-tion _ vacuo at 40-42C. The concentrate is dlluted with water and extracted with chloroform. The chloroform extracts are combined, washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to afford 850 mg of 9-fluoro~
2',3',4'-tetrahydro-11~-hydroxypregna-1,4-dieno[16a,17-b]naphthalene-21-al-3,20-dione.
(This material is characterized spectroscopically.
A TLC examination shows the presence of one major compound, traces of starting material and traces of another impurity, less polar than the starting materlal, and believed to be 9-fluoro-1',2',3',4'-tetrah~dro~ hydroxy-21~21-di-n-butoxy-pregna-1,4-dienol16~,17-b~na~hthalene-3,20 dione).
The above crude mlxture (840 mg) is dissolved in a mixture of dry n-butanol (20 ml) and dichloromethane (50 ml). Acetic acid (0.8 ml), potassium cyanide (200 mg)and active manganese dioxide (2.0 g) are added and the mixture is stirred at room temperature for 60 hours. (A
shorter reaction time would he adequate). The mixture is then filtered through a bed of diatomaceous earth. The solids are washed with chloroform, the filtrate and the washings are ,.. , ~

-17~ K57n combined, washed with water, dried over anhydrous magnesium sulfate and evaporated to afford the crude product as a gum. From this the major component is isolated by preparative TLC (four, 5 2.Omm silica gel plates developed with chloro-form-ethyl acetate 1:1) and identified as the title compound (487 mg). One crystallization from ethyl acetate gives 381 mg of the analytical specimen of the title compound, meltiny point 245-246C with consistent spectral data.
Anal. Calc d for C33H3gFO5 C, 74-13;
~I, 7.35;
F, 3.55 Found: C, 74.37;
H, 7.41;
; F, 3.46 Example 4 9-Fluoro-1',2',3',4'-tetrahydro-11~-hydroxy~3 _ dioxopregna 1,4-dieno[16a,17-b]naphthalene-21-oic acid, l,l-dimethxleth~1 ester A) 9-Fluoro-1',2',3',4'-tetrahydro-ll~h~droxy-3,20-dioxo~regna-1,4-dieno~16a,17-blnaphthalene-21-oic acid ~ solu-tion o~ luoro-1',2',3',4'-tetrahydro-11~-hydroxypregna-1,4-dieno[16~, 17-b]naphthalene-21-al-3,20-dione (3.ny, see Example 1) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) containing acetic acid (3.0 ml) and water (4.0 ml) is stirred with activated manganese dioxide (6.0g) and potassium cyanide (700 mg) for 20 hours. The mixture is then filtered and the solids are washed with warm chloroform-methanol ~7:3~. The filtrate and the washings are combined and evaporated in v~cuo.
The residue is washed with wa-ter, dried, purified by chromatogra~hy, crvstalliz~d fr~m methanol~chIoroform to afford the title compound, melting point 280-281C (dec.).
B) 9-Fluoro-1',2',3',4'-tetrahydro~ hydroxy-3,20~dioxopregna-1,4-dieno[1_~,17-b]naphthalene 21-oic acid, l,l-dimet ylethyl -ester To a suspension of g-fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3,20-dioxopregna-1,4-dieno 116a,17-b]naphthalene-21-oic acid(325 mg.) in dry dioxane (60 ml) containing sulfuric acid-phosphoric acid catalyst (0.4 ml.; prepared by the addition of the calculated amount of phosphorous pentoxide to 96~ sulfuric acid to react with all of the water) in a pressure reaction vessel is passed a stream of isobutylene (until about 6 ml is added). The reaction vessel is closed and maintained at ambient temperature for 30 hours with stirri.ng. The mixture is poured into a solution of sodium ace-tate hydrate (5.0g) in water (500 ml) and extracted successi.vely with chloroform and ethyl acetate. The extracts are washed with brine, combined, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel to afford 145 mg. of the -title compound, melting point 293-296C (dec., discoloration starts from about 275~C) after crystalliza-tion from acetone-hexane.

,. . .

Example 5 ~-Fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3, 20-dioxopre~na-1,4-dienol16a,17-~]naphthalen-21-oic acid, 2,2-dimethylpropyl ester A solution of 9-fluoro-1',2',3',4'-tetrahydro-ll~-hydroxy-3,20-dioxopregna-1,4-dieno~l6a,17-b3naphthalene-21-oic acid, methyl ; ester in dry dioxane (20 ml, distilled over sodium) and dry pyridine (15 ml) is refluxed with neopentYl alcohol (2.2 g) and sodium cyanide (100 mg) under a nitrogen atmosphere for 18 hours. The resulting solution is evaporated ln vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with dilute sodium chloride solution and water, dried over anhydrous sodium sulfate and evaporated ln vacuoO The residue is dissolved in chloroform-hexane (9:1) and ~ 20 chromatographed on a 35 g-silica gel column.
; Elution with chloroform-hexane (9:1) gives 540 mg of material. Crystallization :Erom acetone-hexane give~ 460 mg of an analytical specimen of the title compound, melting point 329-331C (dec.).
Anal. Calc d for C34 41 5 ; H, 7.53;
F, 3.46.
Found: C,- 74.39;
H, 7.73;
F, 3.37.

_20- K570 Example 6 9-Fluoro~ -hydroxy-3,20-dioxopregna-1,4-dieno-[16~!17-d]cyclohexen-21-oic acid meth 1 ester A solution of 1.2 g of 9-fluoro-11~,21-dihydroxypregna-1,4-dieno~16a,17-d]cyclohexene-3,20-dione and 3no mg of copper acetate in 150 ml of methanol is stirred at room temperature for 1 hour while a stream of air is hubbled through the solution. The solvent is evaporated in vacuo at 30C. The residue is diluted with water and extracted with chloroform, ana then, ethyl acetate. The chloroform solution and ethyl acetate solution are washed with aqueous ammonium chloride solution (ln~ and water, dried over anhydrous sodium sulfate, evaporated in vacuo and combined to give 1.3 g of a solid. The NMR
spectrum of the solid shows that it is an approxi-mately equimolar mixture of the 21-aldehyde and 21-dimethylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.3 g) is stirred in a mixture of 50 ml dry me-thanol and 50 ml dry dichloromethane at room temperature for about 16 hours with activated manganese dioxide (2.0g), glacial acetic acid (1.0 ml) and potassium cyanide (2~0 mg) The suspension is filtered through a bed of Hyflo and washed with chloroform.
The filtrate and washings are comhined, washed with water and dried over anhydrous magnesium sulfate.
; 30 The solvent is evaporated in vacuo to give 1.1 g of a solid. Th~ is dissolved in chloroform and chromatographed on a 35 g-silica gel column.
Elution with chloroform gives 93~ mg of material.

* Trade Mark .

~2~

Crystallization from acetone-hexane gives 650 my of the title compound, melting point 256-258C, with consistent spectra data.
n ysis Calc d for C28H31FO5: C, 70.57;
H, 7.06;
F, 4.29 Found: C, 70O66;
H, 7.11;
F, 4.02 Example _ 9-Fluoro~ -hydroxv-3,20-dioxopregna-1,4-dieno-.... .. ..
[16a,17-d~cyclohexen-21-oic acid, l-meth~le-thyl ester A solution of 480 mg of 9-fluoro-11~-hydrox~-3,2~-dioxopregna-1,4-dieno[16a,17-d]
cyclohexen-21-oic acid, methyl ester (see Example 1) and 85 mg of sodium cyanide in 65 ml of dry isopropyl alcohol is stirred under a nitrogen atmosphere at 100C for about 16 hours.
The resulting solution is evaporated in vacuo and the residue is dissolved in chloroform ancl washed with 25 ml of water. The aqueous layer is saturated with sodium chloride and ex-tracted with chloroform. The chloroform solutions are z5 combined, dried over anhydrous sodium sulfate and evaporated ln acuo. The residue is dissolved in chloroform-hexane (7:3) and chromatographed on a 25 g-silica gel column.
Elution with chloro~orm-hexane (7:3)gives 370 mg of material. Cr~stallization from acetone~
hexane gives 3no mg of the title compound, melting ~z~

point 226-228C, with consistent spec~ral data.
~nalysis calc'd. for C28ll35FO5 H, 7.50;
F, 4.04 Found: C, 71.47;
H, 7.44;
F, 3.82 Example 8 . 9-Fluoro-ll~-h~droxy-3,20-dioxopregna-1,4-dieno-~.6a,17-d]cyclohexen-21- ic aci_, b~tyl ester A mixture of 1.0 g of 9-fluoro-11~,21-dihydroxypregna-1,4-dieno[16~,17-d]cyclohexene-3,20-dione.and 250 mg of copper acetate in 50 ml of dichloromethane and 30 ml of n-butanol is ; 15 stirred at room temperature for 1 hour while a slow stream of air is bubbled through the solution.
Since the rate of oxidation is extremely 510w, the dichloromethane is evaporated and replaced with 50 ml of n-butanol. Another 200 mg of copper acetate is added and the reac-tion is continued for 1.5 hour when the starting material disappears. The sol~ent is then evaporated .ln vacuo at 35-40C and the residue is diluted with 200 ml of water and extracted with dichloromethane, and then ethyl acetate. The dichloromethane solution and ethyl acetate solution are washed with ammonium chloride solution (10%) and water, combined, dried over anhydrous sodium sulfate and evaporated 1n vacuo to.give 1.2 g of solid. The NMR spectrum of the ,, _ solid shows that it is an approximately equimolar mixture of the 21-aldehyde and 21-di-n-butylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.2 g) is dissolved in 50 ml of dry dichloro-methane and 30 ml of dry n-hutanol and stirred at room temperature for ahout 16 hours with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. A dry calcium chloride tube is attached to the flask to avoid contact with moisture.
After 20 hours another 2.0 g of activated manganese dioxide and 200 mg of potassi~n cyanide are added. The suspension is stirred at room 1~ temperature for 7 hours, filtered through a bed of Hyflo, and washed thoroughly with dichloro-methane. The filtrate and washings are combined and washed with a saturated sodium ~icarbonate solution and water, dried over anh~drous sodiwn ~o sulfate ana evaporated ln vacuo. The title compound in the residue cannot be success~ully separated from impurities on precoated silica gel TLC plate. It can, however, be successully purified on E. Merck precoated silica gel TLC
plate (2 mm, 2.5:97.5 methanol~chloroform) to yive 400 mg of a foam Crystallization from ethyl acetate-hexane gives 330 mg of the title compound, melting point 203-209C, with consistent spectra data Analysis calcld for C29H37FO5: C, 71.87;
H, 7.70;
F, 3.92 Found: C, 71.98 H, 7.73 F, 3.62 Example 9 9-Fluoro~llo~Ao~ L~ thYl-3~2o-diox~E~regna~1,4-dieno~16a,17-d]cyclohexen-21-oic acid, met~l ester A solution of 4.9 g of q-fluoro-11~,21-dihydroxy-1',2'-dimethyl-3 r 20~dioxopregna-1,4-dieno[16a,17-d~ c~clohexene and 1.1 g of copper acetate in 800 ml of methanol is reacted with air following the procedure described in Example 1 (first paragraph) to yield 5.0 g of an approximately equimolar mixture of the 21-; aldehyde and 21-dimethylacetal derlvatives of the starting s-teroid~
~ The solid product of the above reaction (4.5 g) is stlrred in a mlxture o~ 250 ml dry methanol and 250 ml dry dichloromethane at room temperature for abouk 16 hours under a nitrogen atmosphere with activated manganese dioxide (7.0 g), glacial acetlc acid (4.0 ml) and potassium cyanide (700 mg). The resulting suspenslon is filtered through a bed of diatomaceous earth and washed with chloroform-methanol (~
The flltrate and washlngs are comblned and evaporated ln vacuo to give 5O6 g of a solld.
This is dissolved in chloroform-hexane (9:1) and chromatographed on a 100 g silica gel column.
Elution with chloroform-hexane (9:1) yields

4.2 g of material, 1.5 g of whlch ls crystallized from acetone-hexane to give 900 mg of an analytical specimen of the title compound, melting point 256-258C.
Analysis Calc'd for C28H35FO5: C, 71.46;
H, 7.50;
F, 4~04 Found: C, 71.38;
H, 7.50;
F, 3.95 Example 10 9-Fluoro-~ hydroxy-ll~2l-dimethyl-3~2o-d-loxo-pregna-1,4-dieno[16a,17-d]cyclohexen~21-oic acid, ethyl ester A? 9-Fluoro-ll~-hydrox~-1' ! 2'-dimethy~-3,20-dioxop_e~na,l,4-dieno[16 _17-d]cyclohexen-21-oic acid ~ solution of 9-fluoro~ -hydroxy-1',2', dimethyl--3,20-dioxopreyna-1,4-dieno[16a,17-d]
cyclohexen-21-oic acid, methyl ester (2.5 g) in a mixture of methanol (110 ml) and tetrahydro:Euran (200 ~1) is stirred with a solution of potassium hydroxide (640 mg) in water (10 ml) for 1.0 hour under a nitrogen atmosphereO The reaction mixture is then acidified with 5% hydrochloric acid and is evaporated in vacuo. The resulting slurry is mixed with water and filtered to afford 700 mg of the title 3~ compound, melting point 234-238C.
The filtrate is evaporated in vacuo and washed with chloroform-methanol (4:1). The solvents are evaporated to afford 1.4 g of the hydrated form of the title compound, melting point 215-240oc.

~26_ K570 B) 9-Fluoro~ hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d] cyclohexen-21-oic acid, ethyl ester To a suspension of 235 mg of 9-fluoro-11~-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno [16a,17-d]cyclohexen-21-oic acid in 5.0 ml of dry dichloromethane is added successively, 0.5 ml of triethylamine and 0.068 ml of pivaloyl chloride. After the resulting solution is stirred at room temperature for 15 minutes, 0.116 ml of absolute ethanol is added. After 3.0 hours, the mixt~re is acidified with 50%
hydrochloric acidj poured into water and extracted with çhloroform. The chloroform extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and evaporated.
The residue is subjected to preparative thin-layer chromatography to isolate 97 mg of the title compound, melting point 198-200C.
Exam~le 11 9-Fluoro-ll~-hydroxy-1',2'-dimethyl-3L~ o-pregna-1,4-dieno [16a,17-dlcyclohexen-21-oic acid, l,l-dim ~ ester A solution of 700 mg of 9-fluoro-11~-hydroxy-1',2'-dimethyl-3,20~dioxopregna-1,4-dieno ~16a,I7-d]cyclohexen-21-oic-acid (see Example lOA) in 60 ml of dry dioxane containing 12 ml of isobutylene and 0.7 ml of a sulfuric acid/
phosphoric acid catalyst (prepared hy adding phosphorous pentoxide to 96% sulfuric acid) is maintained in a pressure reaction vessel at room temperature for 24 hours. A stream of dry nitrogen is then passed through the solution to remove the excess isokutylene and the mixture is poured into a saturated sodium bicarbonate solution. The steroid is isolated by ex-traction with chloroform and the chloroform solution is washed with water, dried over anhydrous magnesium sulfate and the solvents are evaporated. The residue (7~0 mg) is subjected to chromatography on a column of silica yel to isolate 500 mg of the title compound, melting pount 2~9-21~C after crystal-lization from acetone hexane.
Example 12 9-Fluoro-~ hydroxy-3t2o-dioxopregna-lt4-dien [16a,17-d]cyclohexen-?1-oic acid, 2,2-dimeth~lJ~o~
_ . .
ester A solution of 9-fluoro~ hydroxy-3,2n-dioxopregna-1,4-dieno-[16a,17-d]cyclohexen-21-oic acid, methyl ester (25 mg) in dry dioxane (2,0 ml) containing dry neopentyl alcohol (400 mg) and sodium cyanide (5.0 my) is refluxed under anhydrous conditions for 2. n hours. The mixture is then cooled, aclded to water, and extracted with chloroform. The ch].oroform extract is washed with water, dried over anhydrous maynesium sulfate, evaporated and the residue is crystallized from ethyl acetate-chloroform to afford 23 mg. of the title compound, melting point 288C (dec., discoloration starts ~efore melting point)~

9 ~ ~ K570 ~xample ~3 9-Fluoro-1',2i,3',4'-tetrahydro-llB-hydrox~ 3,20-dioxopregna-1,4-dieno[16a~,17-b]naphthalene-21-oic acid,methyl ester ~ ... . .

A) 9-Fluoro-ll~-hydroxy-3,20-dioxopregna-1,4,16-triene-21-carboxaldehyde and 9-fluoro-11~-hydroxy-21-dimethoxypregna-1,4,16-triene-3, 20~dione , A solution of 9-fluoro~ ,21-dihydroxypregna-- 1,4,16-triene-3,20-dione (1.7gj is dissolved in methanol (30Oml) by warming and the solution is cooled to room temperature. Copper ace-tate (lOOmg) is added and a stream of air is passed into the solution under stirr1ng. In about 20 minutes the starting material disappears to give less polar compounds as indicated by thin layer chromatography. The solution is then evaporated ln vacuo, -the residual solid is washed successively with a dilute ammonium chloride solution and water and is dried to a~ford an essentially equimolar mixture (1.9g) of the title aldehyde (as iks hydrate) and the title acetal as indica-ted by the NMR spectrum. When dried in vacuo (125-130C, 005mm of Hg) for 2.0 hours, this material is converted into an essentailly equimolar mixture (1.77g~ of the title aldehyde and acetal as shown by NMR and IR spectra.

,.~ ,~

11 4Z ~ 1 ~ K570 s) 9-Fluoro-llB-hydroxy-3,20-dio o~re~na-1,4, 16~trieno-21-olc acld, met~yl ester To a stirred solution oE the mixture of aldehyde and acetal prepared in part A (1.75g), in a mixture of anhydrous dichloromethane (lOOml) and anhydrous methanol (20ml) is added successively activated manganese dioxide (4.0g), potassium cyanide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting mat~rials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a ~ed of 1~ diatornaceous earth and the fi.lter cake is washed with several small portions of a warm mixture of dichloromethane~methanol. The iltrate and the washings are combined and evaporated to a solid residue which is washed with water and dried. Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichloromethane) yields 1.4g oE khe title compound, melting point 28~-286C.
C) 9-Fluoro-1',2',3',4'-tetrahydro~ h~ydroxy-3~
20-dioxopregna-1,4-dieno[16a,17-b]naph-thalene-. . _ . _ . . .
21-oic acid, methyl:ester A solution of 9-fluoro~ -hydroxy-3, 20-dioxopregna-1,4,16-trieno-21-oic acid, ~42916 K570 methyl ester (lOOmg) in benzocyclobutene (5.Oml) containing 4,4'-thiobis-6-t-butyl-m-cresol (6.Omg) is reEluxed under an atmos-phere o~ nitrogen for 10 hours; a solid separates from the solution. The unreacted ben~ocyclobutene is recovered by vacuum distillation and the pot residue is crystallized from methanol-dichlorome-thane (by evaporative removal of the dichloromethane) to yield the title compound, melting point 325-326C
(discoloration starts from about 295 C).

Exam~le 14 15 9-Fluoro~ hydroxy-3,20-dioxopre~na-1,4,16-trieno 21-oic acid .

A solution of 9-Eluoro-ll~-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-oic acid, methyl ester (lOOmg; see Example lB) in a mixture of methanol (15ml) and tetrahydrofuran tl5ml) is stirred with 3~ sodium hydroxide (l.Oml) under a nitroyen atmosphere for 2.0 hours. The mixture i.s then acidified with 5% hydrochloric acid and evaporated to a residue. The residue is washed with water and crystallized from chloroform-methanol to yield the title compound. This material turns black when heated to 400C, but does not melt.
The steroid of this Example can be esterified using conventional techniques and then reacted with a benzocyclobutene as described in Example 13C
to yield a product of formula I.

~31-~ 5 9-Fluoro~ -hydroxy-1 , 2'-dimethyl-3,20-dioxopr--egna-1,4-dieno[16~,_17-d]cyclohexene-21-oic acid, n-butyl ester A) 9-Fluoro-113-hydroxy-3L20~ opre~na-1,4,16-triene-21-carboxaldeh~e and 9-fluoro-11~-hydroxy-2l-dimethoxy~vreqn~a-l~ 4 L 16-triene-3 20-dione A solution of 9-fluoro-ll~J21-dihydroxypregna-1-,4,16-triene-3,20-dione (1.7g) is dissolved in - methanol (300ml) by warming and the solution is cooled to room temperature. Copper acetate (lOOmg) is added and a stream of air is passed into the solution under stirring. In about 20 minutes the startiny material disappears to give less polar compounds as indicated by thin layax chromatography. The solution is then evaporated ln vacuo, the residual solid is washed successively with a dilute ammonium chloride solution and water and i5 dried to afford an essentially equimolar mixkure (1.9g) oE the title aldehyde (as its hydrate) and the title acetal as indicated by the ~R spectrum. When dried ln vacuo (125-130C, 0.5mm of H~) for 2.0 hours, this material is converted into an essentially equimolar mixture (1.77g) of the title aldehyde and acetal as shown by NMR and IR spectra.

~1.4 Z9 ~ ~ K570 B) 9-Fluoro~ -hydroxy-3,20-dioxopregna-1,4 16-trieno-21-oic acid, me-thyl ester , To a stirred solution of the mix-ture of ~d~hyde and acetal prepared in part A, in a mix-ture of anhydrous dichloromethane (lOOml) and anhydrous methanol (20ml) ls added successively activated manganese dioxide (4.0g), potassium c~anide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting materials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. The filtrate and the washings are combined and evaporated to a solid residue which is washed with water and dried.
Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichlorornethane) yields 1.4g of the title compound, melting point 284-286C.

C) ll~-~Acetyloxy)-9~f _ oro-3,20-dioxo~re~na-~5 1,4,16-trieno-21-oic acid! methyl f~ster A solution of 9-fluoro-11~-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-oic acid, methyl ester (400mg) in a mixture of glac~ial acetic acid ~9.Oml) and acetic anhydride ~9 n Oml) containing p-toluenesulfonic acid (200mg) is stirred at room temperature for 24 hours. Sodium acetate (300mg) is added and the mixture is pour2d into ice water ~200ml) with stirring.
The solid that separates is isolated by filtration, washed with water and dried to yield 400mg of the title compound that is contaminated with only trace amount impurities as judged by thin layer chromatography. Crystallization of this material from ethyl acetate-hexane yields 350mg of the title compound, melting point 235-236C.

D) ll~-(Acetyloxy)-9-fluoro-1'~ 2'-dimethyl-3,20-dioxopregna-1,4-dieno-[16~, 17 d]cyclohexen-21-oic acid, methyl ester To a stirred solution of ll~-(acetyloxy)-9-fluoro-3 t 20-dioxopregna 1,4,16-trieno-21-oic acid, methyl ester (320mg) in anhydrous dichloromethane (25ml) containing aluminum chloride (lOOmg) is added 2,3-dimethyl-1,3-butadiene (0.25~1).
The mixture is stirred at room -temperature for 1.5 hour, poured into water and extractéd wl-th dichloromethane. The dichloromethane extract is washed with ~later, dried over anhydrous magnesium sulfate and evaporated to a residue (300mg). This is subjected to chromatography on a column of silica gel (lOg) to isolate the title compound (265mg). Crystallization from ethyl acetate-hexane gives need]es (160mg), melting point 172-173C.

~34-E) 9-Fluoro-ll~-hydroxy-1',2'-d1methyl-3,20-dioxopre~na-1,4-dieno~16~,17-d]cyclohexen-21-oic acid A solution o~ -(acetyloxy)-9-fluoro-1', 2'-dimethyl-3,20-dioxopregna-1,4-dieno[16~,17-d]
cyclohexen-21-oic acid, methyl ester (235mg) in a mixture of 90% methanol (lOOml) and tetrahydrofuran (lOml) containing 3M sodium hydroxide (2.Oml) is stirred under an atmosphere of nitrogen in a bath at 60-70C for 2-3 hours. The mixture is acidified with the minimum amount of 5~ hydrochloric acid and evaporated in vacuo. The residue is worked up with water and dried to yield 195mg of the title compound. Crystalliaation from a mixture of chloroform-methanol gives the analytical s~ecimen of the title compound, melting point 236-239C.

F) 9-Fluoro-11~-hydroxy-1',2'-dimethyl-3,20-dioxopre~na-1,4-dieno[16~tl7_d]c~clohexen-21-oic acld, n-butyl ester.

To a solution of 9-fluoro~ -hydroxy-1', 2'-dimethyl-3,20-dioxopregna-1,4~dieno[16~tl7-d]
cyclohexen-21-oic acid (175mg) in dichloromethane (40ml) containing a few drops of methanol is added an excess of an ethereal solution of diazobutane.
After 5 minutes, the excess diaxobutane is destroyed by the addition of a few drops of acetic acid.
The solution is evaporated to dryness and the residue is crystallized from acetone-hexane to yield 127mg of the title compound melting point 209-~11C.

~z~

Example 16 16~)-9-Fluoro-1~2',3'~4'-tetrahydro-ll-hydroxy ... . _ _ .
3,20-dioxopregna-1,4-dienol16,17-b]naphthalen-21-oic _ _ . . .. .. _ acid, octyl ester A solution of 500 mg (0.96 mmole) of 11~,16~-9-fluoro-1',2',3',4'-tetra-11-hydroxy-3,20-dioxopregna-1,4-dieno[16,17-b]naphthalen-21-oic acid, l-methylethyl ester and 40 mg of sodium cyanide in 40 ml of dry octanol-l (distilled over calcium hydride) was stirred at 130 under nitrogen atmosphere for 1.5 hour. The resulting solution was evaporated in vacuo. The residue was dissolved in dichloromethane, washed wi-th water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a residue which was dissolved in chloroform-hexane (7:3) and chromatographed on a 20g silica gel column. Elution with chloroform-hexane (7:3) gave 485 mg (97%) of product. Crystallization from acetone-hexane gave 370 my (74%) of product, m.p.
215-216.
Anal~ Calcd- ~or c37H47FO5: C~ 75-22; El~8-02 F, 3,22 Found: C,75.34; H,8.23;
F,3.21

Claims

What is claimed is:

1. A process for preparing a steroid of the formula and esters thereof, or the 1,2-dehydro derivative thereof, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached, form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, phenyl or cyano and in addition hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or -CH-R9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl, characterized by oxidizing the corresponding 21-hydroxysteroid of the formula or by oxidizing the 21-hydroxy group of a steroid of the formula to a 21-carboxylic acid group and then fusing the cyclo-hexane and tetrahydronaphthalene group having the formula in the 16,17-position.

2. A process according to claim 1 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl.

3. A process according to claim 1 wherein R2 and R3 taken toyether with the double bond to which they are attached form a benzene ring.

4. A process according to claim 1 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl;
R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydroyen, methyl or fluorine and R6, R7 and R8 are hydrogen.

5. A process according to claim 1 wherein R2 and R3 taken together with the double bond to which they are attached form a benzene ring; R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydrogen, methyl or fluorine and R6, R7 and R8 are hydrogen.

6. A process according to claim 1 wherein X is fluorine and R6, R7 and R8 are hydrogen.

7. A process according to claim 1 wherein R4 is hydroxy, R5 is hydrogen and R6, R7 and R8 are hydrogen.

8. A process according to claim 1 wherein R4 is hydroxy; R5 is hydrogen, R6, R7 and R8 are hydrogen;
and X is hydrogen or fluoroine.

9. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalene-21-oic acid, methyl ester is produced.

10. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, 1-methylethyl ester is produced.

11. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, butyl ester is produced.

12. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalene-21-oic acid, 1,1-dimethylethyl ester is produced.

13. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, 2,2-dimethylpropyl ester is produced.

14. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.,l7-d]cyclohexen-21-oic acid, methyl ester is produced.

15. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.,17-d]cyclohexen-21-oic acid, 1-methylethyl ester is produced.

16. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.,17-d]cyclohexen-21-oic acid, butyl ester is produced.

17. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, methyl ester is produced.

18. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, ethyl ester is produced.

19. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.-17-d]cyclohexen-21-oic acid, 2,2-dimethylpropyl ester is produced.

20. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, 1,1-dimethyl-ethyl ester is produced.

21. A steroid having the formula and esters thereof, or the 1,2-dehydro derivative thereof, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 toyether are =O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached, form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, , phenyl or cyano and in addition hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or -CH-R9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl, whenever prepared by the process of claim 1.

22. A compound according to claim 21 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl, whenever prepared by the process of claim 1.

23. A compound according to claim 21 wherein R2 and R3 taken together with the double bond to which they are attached form a benzene ring, whenever prepared by the process of claim 3.

24. A compound according to claim 21 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl; R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydrogen, methyl or fluorine and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 4.

25. A compound according to claim 21 wherein R2 and R3 taken together with the double bond to which they are attached form a benzene ring; R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydrogen, methyl or fluorine and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 5.

26. A compound according to claim 21 wherein X
is fluorine and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 6.

27. A compound according to claim 21 wherein R4 is hydroxy, R5 is hydrogen and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 7.

28. A compound according to claim 21 wherein R4 is hydroxy; R5 is hydrogen, R6, R7 and R8 are hydrogen;
and X is hydrogen or fluorine whenever prepared by the process of claim 8.

29. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b] naphthalene-21-oic acid, methyl ester, whenever prepared by the process of claim 9.

30. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.-17-b]naphthalen-21-oic acid, 1-methylethyl ester, whenever prepared by the process of claim 10.

31. The steroid in accordance with claim 21 having the name 9-fluoro-1'2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, butyl ester, whenever prepared by the process of claim 11.

32. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalene-21-oic acid, 1,1-dimethylethyl ester, whenever prepared by the process of claim 12.

33. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-b]naphthalen-21-oic acid, 2,2-dimethylpropyl ester, whenever prepared by the process of claim 13.

34. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, methyl ester, whenever prepared by the process of claim 14.

35. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, 1-methylethyl ester, whenever prepared by the process of claim 15.

36. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, butyl ester, whenever prepared by the process of claim 16.

37. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, methyl ester, whenever prepared by the process of claim 17.

38. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, ethyl ester, whenever prepared by the process of claim 18.

39. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, 2,2-dimethylpropyl ester, whenever prepared by the process of claim 19.

40. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, 1,1-dimethylethyl ester, whenever prepared by the process of claim 20.