CA1050966A - STEROIDAL (16.alpha.,17-B) 1,4-DIOXANES - Google Patents

Abstract

STEROIDAL [16a,17-b]1,4-DIOXANES AND
STEROIDAL[16a,17-b]1,4-DIOXINS

Abstract of the Disclosure A series of novel steroidal[l6a,17-b]1,4-dioxanes and steroidal[l6a,17-b]1,4-dioxins having useful anti-inflammatory properties is disclosed herein.

Description

K540a 9~6 Steroidal[16a,17-b]1,4-dioxanes and steroidal[l6~,17-h]-1,4-dioxins have been prepared and found to have useful anti-inflammatory activity. The steroids encompassed by this invention are the 3,20-diketo pregnenes having an ll~-hydroxy group or an ll-keto group and having fused on the 16- and 17-positions a 1,4-dioxane ring or a 1,4-dioxin riny.
F,xemplary of the ~teroids of the above description are steroids having the structural formula I C=0 _ ~ ~ o /~

1 . o : .

Q
In formula I, and throughout the specification, the symbols ~'~ are as defined below. ::
.
Z can be hydrogen, hydroxyl, acyloxy or halogen; :~
Y can be hydrogen and Y' can be hydroxyl or together Y
and Y' can be -0;
X can be hydrogen or halogen;
P can be hydrogen, methyl or chLoro;
: Q can be hydrogen, methyl or fluoro;
, :

:`' ' ' ~

. ., . ~ ~ , . . ~ . .

~S~9~6 K540a l l4 l5 Al can be -CH-CH2-, -C=CH-, -C = C-, R2O-CH-CH2-, -C-CH2- or R3C-O-cH CH2 ;

Rl can be hydrogen, alkyl or aryl;

R2 can be hydrogen, alkyl or arylalkyl;

R3 can be alkyl, cycloalkyl or aryl; and R4 and R5 can be the same or different and can be alkyl or aryl.

Steroids having the formula II C=O

__ - OH

p___ O ':
Q

are useful as intermediates in the preparation of the steroidal[l6a,l7-h]l~4-dioxanes and steroidal[16~,17-b]-1,4-dioxins of formula I. In formula II, and throughout the specification, the symbol A2 can be l-C~ C - CH2, -C-R6, -CH-OH, -CH-O-S-CH3, ~CH(O-R7~2, or -CH2-O ~

. .:
The symbol R6, as used throughout the ~pecification, can be alkyl or aryl. The symbol R7, as used throughout the Sp2Ci-fica*ion, can be alkyl or arylalkyl.

' .

, .

K54Oa Steroids having the formula CH2 z IIa C=O
Y' I
--OH

O-C~

:
are also useful as intermediates in the preparation of the novel steroids of formula I. In formula IIa, and throughout the specification, the symbol A3 can be l(o alkyl) or -C-R4.
The dotted lines in the 1,2- and the 6,7-positions of the steroids of this invention represent the optional presence of double bonds.
, . .
The term "pregnene", as used throughout the specifi-cation, refers to pregnanes having ethylenic unsaturation in one or more positions. Exemplary of pregnànes specifically contemplated are ~4-pregnenes, ~1'4-pregnadienes, ~4'6-pregna-dienes, and ~l'4'6-pregnatrienes. The ~4-pregnenes and the Ql'4-pregnadienes are prefexred.
The expression "1,4-dioxane ring", as used throughout the speciication, refers to unsubstituted and substituted , 1,4-dioxane xings. Exemplary substitueOts are alkyI, ar31-alkyl, aryl, alkoxy, arylalkoxy, alkyl-C-O~, cycloalkyl-C-O-, arylalkyl-C-O-, ar/l-C-O- and oxo gr~up~.

.

., . ' ' . i .

K54Oa ~L~5~ 6~
Th~ 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.
The term "alkyl", as used throughout the specifica-tion, refers to both branched and straight chain alkyl groups having 1 to 8 carhon atoms. Alkyl groups of :L to 4 carbon atoms are preferred, and methyl is the most pre~erred.
The term "cycloalkyl", as used throughout the speci-~0 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 phenyl are the preferred aryl groups.
The term "halogen", as used throughout the specifi-cation, refers to fluorine, chlorine, bromine, and iodine.
The term "alkoxy", as used throughout the specifica-tion, refers to groups having the structure alkyl-O- wherein alkyl is as defined above. Alkoxy groups having 1 to ~
carbon atoms are preerred, and methoxy is the most preferred.
The term "acyloxy", as used throughout the specifi-cation, refers to groups wherein the acyl portion is a physiologically acceptable acid residue derived from an 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, ben~oic, and toluic acids. Exemplary polycarboxylic acids are malonic, _4 ., . ....... .
. , . , ~,. ..

K540a ~S~96~
succinic, glutaric,adipic, pimelic, and phthalic acids.
Exemplary inorganic acid are sulfuric, nitricj and phos-phori~ ~cids.

' The s~eroids of formula I are physiologically active substances which possess glucocorticoid and anti-inflamma-tory activity and hence can be used in lieu of known gluco-corticoids in the treatment of rheumatoid arthritis, for which purpose they can be administered in the same~manner as hydrocortisone, for example, the dosage being adjusted for the relative potency of the particular steroid. In addition, the steroids of this invention can be used topically in lieu of known glucocorticoids in the treatment of skin conditions such as dermatitis, psoriasis, sunhurn, neuro-dermatitis, eczema, and anogenital pruritus.
., .
When given orally, the compounds of this invention 1 may be used in a daily dosage range of O.l to 20n milli-¦ grams 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~
by weight, pre~erably 0.05 to 2.0% by weight, in a conven-, tional cream or lotion. The topical mode of administration ,. . : i8 preferred.
,~ '; - Cycloborate-esters of 16~,17-dihydroxy steroids having ,, ~
he formula ~. .

, 30 ' . .

: '. : . ' ~ "''' ': ' '' ~ . . . ' iios~6i6, K540a . IH2Z
C--O
IIIyl I
Y~ / B-OH
P---^r . , o~

Q
are one of the starting materials for the prepara~ion of the steroids of formula I. The cycloborate esters of formula III are known; see, for examp}e, United States patent

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 organia solvent at re~lux tem- :
perature. .
Exemplary cycloborate ester starting materials of :~
formula III are 1 11~,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, l . 16,17-cycloborate, ~ 9-~luoro-11~,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cyclohorate, I 6~,9-difluoro-11~,16a,17,21-tetrahydroxypregn-4-ene-:~ 3,20-dione, 16,17~cycloborate, ,16a,17,21-tetxahydroxy-6~-methylpregn-4-ene-3,20-dione, 16,17-cycloborate, - ~ ~
21-chloro~ ,16~,17-trihydroxypregn-4-ene-3,20-dione, ;;
16~,17~-cycloborate, :~
I ~ 21-chloro-9-fluoro~ ,lS~,17-trihydroxypregn-4-ene-j 3,20~dione, 16,17-cycloborate, :

. ' 3 0 ..1: .
: -6 K54Oa - ~OS~66 ~ 21-chloro-6~,9-difluoro-11~,16~,17-trihydroxypregn-: 4-ene-3,20-dione, 16,17-cycloborate, 21-chloro-6~-fluoro-11~,16~,17-trihydroxyprec3n-4-ene-

3,20-dione, 16,17-cycloborate, 21-chloro-11~,16a,17-trihydroxy-6~-methylpregn-4-ene-; 3,20-dione, 16,17-cycloborate, 11~,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-d.ione, 16,17-cycloborate, 9-fluoro-11~,16~,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, 6~,9-difluoro-11~,16~,17,21-tetrahydroxypregna~l,A-diene-3,20-dione, 16,17-cycloborate~
6a-fluoro~ ,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, 11~,16a,17,21-tetrahydroxy-6~-methylpregna-1,4-diene-3,20-dione, 16,17-cycloborate, 21-chloro-11~,16~,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, 21-chloro-9-fluoro-11~,16~,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, 21-chloro-6a,9-difluoro-11~,16~,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, ; 21-chloro-6a-fluoro-11~,16a,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloboratej 21 chloro~ ,16a,17-trihydroxy-6a-methylpregna-1,4-diene-3,20-dione, 16~17 cycloboratq, 2-chloro-11~,16a,17,21tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, .

. . . ~ .
: . . .

K540a lOSO9b;B
2-chloro-9-fluoro~ /16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, 9-fluoro-11~,16~,17,21-tetrahydroxypregna-1,4,6-triene-3,20-dione, 16,17-cycloborate.
Diazoalkenes having the formula IV C~2=C ~CHN~

are also used as starting materials for the preparation of Rl OH
theOsteroids of fOrmula I wherein Al is -C=CH- ' --CH-CH2-, R3-C-O-CH-CH2-' -C-cH2-' or CH CH . In formula IV, those diazoalkenes wherein Rl 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 Rl is aryl ~e.g., 2-phenyl-3-diazo-1-propene) is described in the examples of this s~ecification.
Reaction of a cycloborate ester of formula III with a diazoalkene of formula IV yields a steroid having the formula , ' .

C=O
y _ ~ ,,J~ O~I

p_ ~ b-CH2-C=C!12 Q -.:
The reaction can be conducted in an organic solvent, prefer-ably a lower alkanol such as methanol, at a temperature of about -10C ~o +40C for about 30 minutes to 4 hours, ;, :

K540a ~ 5~9G,~i preferably at 0C to 20C 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-perbenzoic acid to yield a steroid having the formula VI C=O
~ -OH

l O-CH2-- C CH2 1'0 p__~ 3/ \0/

o Q

The reaction can be conducted in an organic solvent, prefer-ably a halogenated hydrocarbon such as dichloromethane, at a temperature of from about 0C to 40C for about l.hour to 96 hours, preferably at room temperature for about 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 Rl is alkyl or aryl with a strong oxidizing agent such as periodic acid, yields a steroid having the formula 1~2z C--O

p ~ /~ CN2--C--R6 Q
30`

_9_ :

K540a ~563~
Reaction of a steroid of formula VI when Rl is hydrogen with a strong oxidizing agent yields a cyclic lactol (formula VIII) which is in equilibrium with the corresponding aldehyde (formula VIIIa), i.e., CH~2 I H2 C=O

p _ ~ ~ ~ 2 p ~ -CH2-Q
Q ~
VIII VIIIa These oxidation reactions can be conducted in an organic ~ solvent such as tetrahydrofuran mixed with water at a ; temperature of about 0C to 40C, for about 1 hour to 8 hours, preferably at room temperature for 2 hours to 4 hours.
The steroids of formula VII or VIII can be r~acted 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'-dihydroE16a,17-b]1,4-dioxins having the ormula CH Z
C=O
IX - Y ~ _ O-C-R

. I O-CH
~, p~
.~ ' ~

Q

K540a ~1~5~66 The reaction can be conducted under reflux conditions in an inert atmosphere for about 2 hours to 48 hours, prefer-ably 4 hours to 24 hours.
Reaction of a steroid oO formula VIII with an an-hydride having the formula (R3C~2O yields a steroidal [16~,17-b]1,4-dioxane having the formula CE~ Z
X C=O
~o ~ o_f~l P f ~ --CH2 . .
Q
The reaction can be conduc~ed in an organic solvent such as pyridine at a temperature of about 0C to 40C for about 3n 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 ~An~ew. Chem. Internat. Edit., 8, 444 (1969)) yields a steroid having the formula XI y~ ¦ O - C~

0 ~

Q

.
- . :

K54Oa ~05~966 The reaction can be conducted in an organic solvent such as benzene, toluene, etc. at a temperature of about 80C
to 110C for about 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 I 2 y~ C=o .:

rO y _ ~ -OH

o,~/~ Rl Q :
The reaction can be carried out in an organic solvent, prefer-ably a lower alkanol such as methanol at a temperature of from about -10C to 20C for about 10 to 60 minutes, prefer-ably at about 0C for 10 minutes to 30 minutes.
A 16~-hydroxyethoxy steroid of formula XII can be re-acted with a methanesulfonyl halide ~methanesulfonyl chloride is preferred) to yield a steroid having the formula XIII y~ C=O

O-CH2-CR-O-S-Ci33 Q

` ~ - .
' , .

.

K540a 9~ .
The reaction can be carried out in an organic solvent such as pyridine, in an inert atmosphere, at a tempera~ure of about -10C to 40C for 30 minutes to 4 hours, pre~erably at about 0C for 1 hour to 2 hours.
- Reaction of a steroid of formula XIII with sodium bicarbonate in a dipolar aprotic solvent such as dimethyl-sulfoxide yields a steroidal[l6a,17-b]1,4-dioxane having the formula XIV Y' I
---~0 - CH
y _ _ ~ ~ O--CH2 O'~ ~

Q
The reaction can be conducted at a temperature of from about 60C to 130C for about 1 hour to 24 hours, preferably at about 110C ~or 2 hours to 4 hours.
Steroidal[16a,170b]1,4-dioxanes of formula I wherein Al Os R20-CH-CH2- ~ R3 C~0-CH-C~2-~ -CH=CH-, -CH2-CH2- or -~-CH2~ can be prepared ~rom the cycloborate esters of 16a,17-dihydroxy steroids of formula III and diazoethers having the formula XV ~R7-0)2CHCHN~ .
The diazoethers of formula XV are known; seé, for exampIe, Chem. Ber. 100, 1491 (1967).
Reaction of a cycloborate ester of formula III with a diazoether o~ formula XV yields a steroid having the ~ormula : .

.
: ! ~

K540a ~S~g66 y~ C=O
y ~ ~ OH O-R
p ~ 2 1 ~ :

Q ~.

The reaction can be conducted in an organic solvent, prefer-ably a lower alkanol such as methanol, at a temperature of from about -10C to 40C until nitrogen evolution ceases.
The preferred reaction temperature is from 0C to 20C. :
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 steroidal~l6~,17-b]l/4-dioxane having the formula XVII I C=O ~ O-R7 ~-. 20 ~ ~ -CH2 P~

,. ..
The ~eaction can be carried out at a temperature of about 60C to 140C for about 1 hour to 24 hours, preferably 80C
to 1.10C for 2 hours to 4 hours.
Reaction o a steroid of formula XVI with a mineral acid, e.g., hydrochloric acid, yields a steroidalrl6~,17-b]-1,4-dioxane of formula VIII. The reaction can be carried ., ~ .

-14~ ~

K54~a ~S~ .

out in an organic solvent such as tetrahydrofuran at a temperature of from about 0C to 100C for about 1 hour to 24 hours, preferably 40C to 60C for 2 hours to 8 h~urs.
A steroid of formula VIII can be used to obtain a steroid of formula IX (wherein Rl is hydrogen), ~ steroid of formula X, a steroid of formula XI and a steroid of formula XIV (wherein Rl is hydro~en) follo~ing the proce-dures set forth above.
Steroidal[16~,1?-b]1,4-dioxanes of formula I wherein Al is -CH2-CH2- can also be prepared from the ~yclo~orate esters of 16~,17-dihydroxy sterolds o formula III and 2-(tetrahydropyran-2-yloxy)-1-diazoethane, the preparation of wl~ich is set forth in the examples below.
Reaction of a cycloborate ester of formula III with 2-(tetrahydropyran-2-yloxy)-1-diazoethane yields a steroid having the formula CH Z

C=O
Y' y~ OH
p ~ ~J ~ O-CH2-CH2-'' O~J : .
.
~ ~ Q
The reaction can be carried out in organic solvent, prefer-ably a lower alkanol such as methanol, at a temperature of from about -10C to 40~C, preferably 0C to 20C. The re-action is continued until nitrogen evolution ceases.

3~
;

.~ ' ' ,, K54Oa 1a~5C 1966 A steroid of formula XVIII may be cleaved with an acid to yield a steroid of formula XII (wherein Rl is hydrogen). The cleavage reaction can be conducted in water at a temperature of from about 0C to 40C, preferably at room temperature, for about l 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 Al is -CH2-CH2- from a steroid of formula XII is set forth above. R4 l5 A s~eroid of formula I wherein A1 is -C- C- can be prepared from the cycloborate esters of 16~,17-dihydroxy steroids of formula III and diazoethers having the formula XIX (alkyl-0)2CCIN2 Reaction of a cycloborate ester of formula III with a diazoether of formula XIX yields a steroid having the formula CIH2z C=O
Y' _OH
2Q XX y__ ~ ~ O-alkyl Q
The reaction can be conducted in an organic solvent, prefer-j ably a lower alkanol such as methanol, at a temperature of from about -10C to 40C until nitrogen evolution ceases.
The preferred reaction temperature is from 0C to 20C.
.i , ,.:

'' .

,, , .. . , .. ~ - - . ~ , , , , ., , ~ ............ . .

K54Oa ~5~
Reaction of a steroid of formula XX with a mineral acid, e.g. hydrochloric acid, yields a steroid having the structure Cl 1~2 XXIyl C-=O
y~
~ p _ _ ~ ~ O-CH-C-R

.
1~ Q
The reaction can be carried out in an organic solvent such as tetrahydrofuran at a temperature of from about 0C to 100C for about 1 hour to 24 hours, preferably 40C to 60C
for 2 hours to 8 hours.
, ., A steroid of formula XXI can be reacted with a slurry or solution of an organic acid such as ~-toluenesulfonic acid in an organic solvent such as benzene to yield a steroid having the formula ~ XXII~, C=o ~ ~ - O- C- R4 p ~l~ ~ ~ , O- C - R5 O~J
Q

.
The reaction can be conducted under reflux conditions in an inert atmosphere for about 2 hours to 48 hours, prefer-ably 4 hours to 24 hours.

K540a ~L~5~96~

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 ~II 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-1,4-benzoquinone when used in the presence of an acid. About one molar equivalent of the oxidizing agent is used per molar equivalent of steroid.
The oxidation reac~ion can be conducted in an organic sol-vent such as benzene, toluene, dioxane, etc.; dioxane is preferred. The reaction can be carried out for about 1 hour to 96 hours at a temperature of about 50C to 150C, prefer-ably for about 4 to 24 hours at about 70C to 130C. Alternately a borate containing unsaturation in the 6,7-position can be prepared from the corresponding, kno~n 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 ~kill in the steroid art. For example, those steroids of this invention having a halogen in the 21-- ~ position can be prepared from the correspondin~ 21-hydroxy steroid by reacting the later with an alkyl or aryl sul- -fonyl halide ~e~.g.; methanesulfonyl chloride or ~-toluene-.
sulfonyl chlorlde), in the presence of an organic base such as pyridine, to yield a 21-alkyl ~or aryl) sulfonyl-; oxy steroid. The 21-alkyl (or laryl) sulfonyloxy ;: ~
', ,; ~ ., . : ~ . . . .

K54Oa ~S~9~6 steroid intermediate can be reacted with alkali metal halide (e.g., potassium fluoride, lithium chloride, lithium bromide, sodium iodide, etc.) 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 repre-sented by the various symbols used in fomrula I can be added to the steroid nucleus after the addition of the dioxane or ~ dicxin 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 of this invention.
Steroids of formula I wherein P and Q are hydrogen are preferred.
Steroids of formula I wherein X is halogen are pre-' ferred, and those wherein X is fluorine are most preferred.
Steroids of formula I wherein Y is hydrogen and Y' is hydroxyl are preferred. Rl Steroids of formula I wherein Al is -CH2-CH2-, -C=CH-, O CH CH - -C-CH2-, or R3C-O-C~H CH2 p . OSteroids oO formula I wherein Z is hydrogen, hydroxyl, alkyl-C-O-, aryl-C-O- or halogen are preferred.
The ollowing examples are ~pecific embodiments of this invention.
`

~0 :
' ' ' .

:
,, , , . . . . . .. : . ., :. . :

K5~oa ~S0gl66 Example 1 9-Fluoro-5~ ,21-trihydroxypregn-4-eno[16~,17-b]-[1,4]dioxane-3,20-dione, 21-acetate A. 16~-Al~yloxy-9-fluoro-11~,17,21-tr hydroxypregn-4-ene-3,20-dione 6.6 g of 9-fluoro-11~,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione,16,17-cycloborate i~ added to a solution of vinyl dia~omethane in 1:1 methanol-ether at 0C. After stirring for 1 hour, the solvellt is evaporated and the residue di~olved in chloroorm and chromatographed on a 150-g silica gel column. Elution with 5~ ethyl acetate in chloroforln gives 1.04 g of TLC ~thin layer chromatography) pure material. Two recrystallizations from acetone-hexane give 0.5 g oE 16a-allyloxy-9-fluoro-11~,17,21-trihydroxy-pregn-4-ene-3,20-dione, melting point 199-201C.
iY~ ta c d for C24H33F06: C, 66.04; H, 7.62; F, 4.35.
Found: C, 65.82; H, 7.83; F, 4.24.

B. 16~-Allyloxy-9 fluoro~ ,17,21-trihydroxypre~n-4-__ _ el~e-3,~0-dione, 21-acetate ~ solution of 2.5 g of 16a-allyloxy-9-fluoro-11~,17, 21-trihydroxypregn-4-ene-3,20-dione in 25 ml of pyridine is stirred or 2 hours with 2.5 ml of acetic anhydride and the so3vent i9 then removed ln vacuo. A solution of the resïdue ln chloro~orm is washed with sta~ hydrochloric acid, water, 10~ sodium bicarbonate solution, water, and dried.
~oivent removal in acuo give~ an oil which crystallizes .. . .
from acetone-hexane to yield 2.5 g o 16~-allyloxy-9-fluoro-~ ,17,21-trihydroxypregn-4-ene-3,20-dione, 21-aceta1:e, ~eltin~ point 189-191C.
.. . .

.

;~

K5~0 a ~5~g~6 C. 9-Fluoro-11~,17,21-trihydroxy-16~-(oxiranyl-methox~)-pregn-4-ene-3,20-dione, 21-acetate A solution of 6.44 g of 9-fluoro-16a-allyloxy-11~,17, 21-trihydroxypregn-4-ene-3,20-dione, 2!1-acetate in 15G ml of dichloromethane i5 stirred with 2.88 g of m-chloroper-benzoic acid for 19 hours at room temperature. The re-sulting 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-chloromethane and chromatographed on a 125 g - silica gel column. Elution with chloroform and a chloroform-ethyl acetate mix~ure gives 3.5 g of unreacted starting material in ~racti~ns (100 ml) 25-37 and 1.7 g (25.6%) of TLC pure product in ~ractions 49-61.
The 1.7 g is recrystallized from acetone-hexane to ~iv~ 991 mg o material having a melting point of 191-192.5C.
A 500 mg portion of this material is recrystallized from the same solvent to give 430 ~g of 9-fluoro-11~,17,21-trihyd~roxy-16a-toxiranyl~lnethoxy)pregn-4-ene-3~2o-dione~ 21-aceta-te, melting ~oint 191-192.5C.
Anal~. Calc d for C26H35FO8: C, 63.15; H, 7.13; F, 3.84.
Found: C, 63.17; H, 6.84; F, 3.64.

- D. 9-Fluoro-5'~ 21-trihydroxypregn-4-eno[16~,17-b3-[l!~ldioxane-3,20-dione, 21-acetate A ~olution of 20.1 g of crude 9-fluoro~ ,17,21-trihydroxy-16~-~oxiranyl-methoxy)pregn-~l-ene 3,20-dione, 21-acetat~ in 300 ml of tetrahydroEuran is stirred ~ith a solution of 30 g of-periodic acid in 75 ml o~ t~ater or ~

' ' : ; .
.. . . . . . . .

K54Oa ~5~66 ~, 6 3/4 hours. The solution is diluted with water and ex-tracted with chloroform. The chloroform extract was washed with 5~ sodi~n bicarbonate solution, dried, and evaporated in vacuo to give 18.2 g of crude productO This material is dissolved in 60 ml of dichloromethane and chromatographed ~n a 450 g -silica gel column. Fractions of 250 ml are collected as the column is eluted with 3 liters of dichloro-methane, 3 liters of chloroform, and then 3 liters of 19:1 chloroform-ethyl acetate. Fractions 17-21 are combined and evaporated in vacuo to give 4.4 g of 9-fluoro-160~-allyloxy-11~,17,21-trihydroxypregn-4-ene-3,2-diIIe, 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-Eluoro-5'~;,11~,21 trihydroxypregn-4-eno[160~,-17-b] ~1,4]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, melting point 205-20~C.
Anal-Calc'd forC2SH33F8 C~ 62~10; ~ 7-50; ~ 3-93-Found: C, 62.22; H, 7.28; F, 3.690 ." ' , .
.
Example 2 9-Fluoro-2',3l-dihydro~ ,21-dihydrcxy-5'-methyl-;;
. , pregn-4-eno[16c~,17-b] [1,41dioxin-3,20-dione, 21-acetate A. 9-Fluoro-113,17,21-trihvdroxv-160~ 2-methyl-2-pr penyl)oxylpregn-~-ene-3,20-dione ~
~ solution of 2-methyl-3-diazo-1-propene in 2SO m:l of ether ~prepared from 0.2 mole of N-~Z-methyl-2~propenyl)-ethyl carbama-te by the method o~ J. L. Br~wbAker and H. ~lar t, - ~

.

, ', : :
: , j . , : .
.. . : . ~ . . . .

K54Oa ~ISi096g~i O J. Am. Chem. Soc., 91, 711 tl969)) is d~luted with 300 ml of methanol and cooled to ~C. A total of 6.5 g of 9-fluoro~ ,16~,1t,~1-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions ~ntil the initial red color fad2s and nitrogen evolution ceases.
~he solvent is evaporated ln vacuo and the residue dis-solved 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-11~,17,21-trihydroxy-16~-[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20 dione, melting point 213-215C, softening at 198-200C.
Anal. Calc'd for C25H35F06: C, 66.64; H, 7-83; F~ 4-22-Found: C, 66.41; H, 8.03, F, 4.16.

. 9-Fluoro-11~,17,21-trihydroxy-16~-[(2-methyl-2-pro-penyl)oYv]pregn-4-ene-3,20-dione, 21-acetate A solution of 3 g of 9-fluoro-llg,17,21-trihydro.cy-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 anhydride. l'he solvent is removed ln vacuo and the residue i~ dissolved in chloroform, washed with 5~ hydrochloric acid solution, water, 5% ~sodium bicarbon2te solution, and dried. Solvent removal in vacuo gives a solid which is recryst~llized from acetone-hexane to give 2.82 g of material having a melting point o~ 230-231C. Recrystallization of 0.6 g oE this m~terial from acetone-heYane gives 481 mg oE
9-fluoro~ ,17,21-trihydroxy-16~-[(2-m~thyl-2-propenyl)-oxy]pregn-~-~ne-3,20-dione, 21-ncetate, melting point 230-232~C.
.' : , ~ ~ -23-, K54Oa ~s~g~ .
Anal. Calc'd for C H F07: C, 65.84; H, 7.57; F, 3.86.

Found: C, 65.89; H, 7.56; F, 4.06.

C. 9-Fluoro~ ,17,21-trihydroxy-16a-~(2-methyl-oxiranyl)methoxy] pre~n-4-ene-3,20-dione, 21-acetate ~ slurry of 1.0 g of 9-fluoro-11~,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 of 10~ sodium carbonate solution and 10% sodium sulfite solution, dried, and evaporated to give 1.04 g of oil which solidifie~. Recrystallization from acetone~hexane gives 793 mg of material, melting point 221-224C and 160 mg of material, melting point 219-224C. Recrystallization of a mixture of 390 mg of crop 1 and 160 mg oE crop 2 from acetone-hexane gives 298 mg of 9-fluoro-11~,17,21-tri~
hydroxy-16a-[~2-methyl-oxiranyl)methOxy]pregn-4-ene 3,20-dioner 21-acetate, melting point 223-227~C.

~na~l- Calc d for C27H37F08: C, 63.76; H, 7.33; F, 3~74.

Found: C, 63.96; H, 7.10; F, 3~g3.

The nmr spectrum of this material indicates it is a mixture of epimers ~ca. 2:1 ratio) at the quaternary - ~ epoxide carbon atom.

. .

:
` 3 ' ' :

! . , , . .. . :
'' : ~ ` ' ;. .. ' . ' :

1050966 K540a . D 9-Fluoro~ ,17,21-trihydroxy-16a-(2-oxopropoxy) : pregn-4-ene-3,20-dione, 21-acetate A solution of 1.54 g of 9-fluoro-11~,17,21-tri-hydroxy-16~-[(2-methyl-oxir~nyl)methoxy]pregn-4-ene-3,20-dione, ~l-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 wit:h chloroform. The chloroform solution is ~ washed with 10% sodium bicarbonate solution, dried, and evaporated in vacuo to give an oily residue. This is dissolved ill chloroform and chromatographed on a 40-silica gel column. Elution with chloroform gives 400 mg of slightly .imuure ~roduct follo~ed by 990 mg of TLC homo-geneous solid. The 990 mg is recrystallized twice ~rom acetone-h~xane to give 328 mg of 9-fluoro-11~,17,21-tri~
hydroxy-1~-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate, meltlng point 203-208C.
Anal- C~c'd for C26H35F8 C, 63-15; H~ 7-13; F~ 3-84-Found: C, 63.01; H, 7.04; F, 4.08.

E. 9-Fluoro-2',3'-dihydro-11~,21-dihyclrox~-5'-methyl-pre~ ~4-eno[16~,17-b_[1,4]dioxin-3,20-dione, 21-; acet.ate - .
A .sl.urry of 100 mg of ~-toluenesulfonic acid in 250 . .
ml of ben~ene is refluxed wit~ a Dean-Stark tran. The first 50 ml of l~enzene-water azeotro~e is discarded and Linde t~pe 4A molecular sieves are added to the trap. AEter 30 ~ minutes ~ reflux, the solution is cooled and 1.0 g of .-: 9-fluoro lL,B,17,21-trihydroxy-16a-(2-oxopropoxy)precJn~4-ene-3,2n dione, 21-acetate is added. The resultin~ slurry -~5-.
.. . . ., :
- . .

x54oa is refluxed for 5 hours under nitrogen, cooled, diluted with chloroform, washed with 5% sodium bicarbonate solu-tion, water, dried and evaporated. The crude residue is dissolved in a small amount of chloroform and chroma-~ographed on a 20 g - silica gel column. Elution with chloroform gives 805 mg of material wh:ich is recrystallized from acetone-hexane to give 501 mg of 9-fluoro-2',3'-di-hydro-11~,21-dihydroxy-5'-methylpregn-4-eno[16~,17-b][1,4]-dioxin-3,20-dione, 21-acetate, melting point 233-235C, dec.
Anal. Calc'd for C26H33FO7: C, 65.53; H, 6.98; F, 3.99.
Pound: C, 65.78; H, 6.84; F, ~.14.

: ' ~
9-Fluoro-2',3'-dihydro-11~,21-dihydroxy-5'-methyl-pregn-4 eno[16~,17-b][1!4~dioxin-3,20-dione A solution of 886 mg of 9-fluoro-2',3'-dihydro-11~, 21-dihydroxy-5'-methylDregn-4-eno[16a,17-b][l,~ldioxin-3,20-dione, 21-acetate (prepared as described in Exam~le 2) in 270 ml of methanol is cooled to 0C and 27 ml of 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 chlorofor~ to give 775 mg of TLC pure 9-fluoro-2',3'-dihydro-11~,21-dihydroxy-5'-methylpregn-~-eno[16,17-b][1,4]dioxin-3,20 dione.
::

::
.
- 30 ~
.

-2~
-105iO966 K540 a O Exam~le 4 9-Fluoro-2',3'-dihydro-11~,21-d:LhydrQxy-5'-pllen~l-pregn-4-eno[16~,17-b][1,4]dioxin=3,20-dione, 21-acetate .
A r 9-Fluoro-llg,17,21-trihydrox~-16~-[(2-phenyl-2-pro~enyl)ox~]~regn-4-ene 3,20-dLone, 21-acetate a~ N-(2-phenyl-2-propenyl)phthalImide ~ mixture of 60 g-of potassium phthalimide and 66.4 g of -bromomethyl styrene (prepared by the met-hod of S. F. Reed, Jr., J. Org. Chem., 30, 3258 (1965)) in 150 ml of dimeth~lformamide is refluxed for 2 hours, cooled, and diluted with 400 ml of water. The re-sulting solid is filtered and dried in vacuo to give 83.4 g of N-(2-phenyl-2-propenyl)phthalimide. A small sample that is recrystallized from acetone-hexane has a melting point of 118-121C.

b) N-(2-phenyl-2-propenyl)ethyl carbamate A solution of 83 g of N-(2-phenyl-2-~ropenyl) phthalimide and 30 g of 99% hydrazine-hydrate is refluxed for 270 minutes and cooled. The slurry is treated with 125 ml of conc. hydrochloric acid and filtered. The solid is washed with fo~r 100 ml portions of water and the filtrate is evaporated in vacuo to a volume of 300 ml.
.
Thls solution is cooled and ~ixed with a solution of~60 g of sodil~m hydroxide in 250 ml o, cold ~ater. The re-sultin~ solution is extracted wlth four 200 ml ~ortions o~
ether and the ether solution is dried and eva~orated in ~ vacuo to give 30.7 g of oil. The oil is dissolvecl in ~ -27-K540a ~051D966 250 ml of e~her, cooled to 0C, and 33 g of ethyl chloro-formate is addedO A solution of 12 g of sodium hydroxide in 30 ml of water is added simultaneously with the second half of the ethyl chloroformate solution. After 1 hour at 10C, the ether layer is washed w:ith 5% hydrochloric acid, dried, and evaporated in vacuo to give 41.7 g of oil. Trituration with hexane and fi:Ltration gave 33 g of N-(2-phenyl-2-propenyl)ethyl carhamate, melting point ~;
41-42.5C.

~) N-Nitroso-N~(2-phenyl-2-propenyl)ethyl carbamate A solution of 21 ml (29.4 g) of nitrosyl chloride in 60 ml of pyridine (prepared at -25C) is added over a period of 15 minutes to a solution o 57 g of N-(2-phenyl-2-propenyl)çthyl carbamate in 400 ml of pyridine at -5C.
The solution is stirred for 15 minutes and poured into 4 i liters of cold water. The oil which separates is e~tracted , .
into ether ~three 6Q0 ~1 portions) and the ether ex~ract is washed successively with 1 liter of 10% hydrochloric acid, water, 1 liter of 5% sodium bicarbonate solution, and dried. Solvent removal gives 63 g of red oil that shows only minor .impurities on T~C.

d) 2-Phenyl-3-diazo-1-pro~ene-A solution of 63 g of N-nitroso-N-(2-phenyl-2-propenyl)ethyl carba.~ate in 300 ml of ether is add~d to 300 ml of 3M sodium methoxide in methanol at -1 to -2C
over a period o~ 30 minutes. Tho solution is stirred for a further hour and then poure~ into 2 liters ~ ice water .` : ` , ~2~-: .
.: .

~0$09~6 KS40 a and 100 ml each of ether and pentane. The organic layer is separated and kept at 0C while the aqueous layer is ~ extracted with 300 ml of ether. The combined organic layer is washed with t~Jo 1 liter portions of ice water, dried for 10 minutes at 0C over NaOH pellets, and Eiltered to give 700 ml of red solution.

e) ?-Fluoro~ ,17,21-trih~droxy-16~-~t2-~henyl-2-~ro~nylJoxy]preyn-4-ene-3,20-dione The solution of 2-phenyl-3-diazo-1-propene prepared as described above is diluted with 150 ml of cold methanol and stirred well at 0C as 13 g of 9-fluoro-11~,16~,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions. The slurry is stirred for 1 hour at 0C and filtered to give 9.6 g of the title compound. The filtrate is stirred at room temperature for 1 hour with 4 g of the cycloborate and the resulting solution is cooled to 0C and filtered to ~ive 4.2 g of the tltle co~pound. The filtrate is evaporated in vacuo and the residue is dis-solved in 400 ml of 3:1 ether-methanol and cooled to -10C
to give a ~urther 3.0 g of material. A small sample re-crystallized from acetone hexane has a melting point of 161-163.5C.

' ' , :
' ' ' ~ ' ':

30 ~ ~
. ; . . . .

~ ~ -29- ~
.; .

.

K540 a S~9~6 O B. 9-Fluoro~ ,17!21-trihydroxy-16~-[(2-phenyl-2-propenyl)oxy] pre~n-4 -ene-3, ? 0-dione, 21-acetate - A solution of 3.0 g of 9-fluoro~ ,17,21-tri-hydroxy-l~a-[(2-phenyl-2-propenyl)oxy]pregn-4-ene-3~2o-dione in 30 ml of pyridine is allowed to stand with 3 ml of acetic anhydride for 2 hours at room tem~erature. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with 5% hydrochloric acid, water, 5% sodium bicarbonate solution, and driedO Solvent re-moval gives an oil that crystallizes rom acetone-hexane to give 2.3 g of material. Recrystallization of 600 mg from acetone-hexane gives 510 mg of 9-fluoro-11~,17,21-trihydroxv-16a-[(2-phenyl-2-propenyl)oxy]pregn-4-ene-3,20-dione, 21-acetate, melting point 169-171C
Anal Calc d for C32~39FO7: C, 69.29; H, 7.09; F, 3.42.
Found: C, 69.13; H, 7.11; F, 3.26.
~ .
C. 9-Fluoro-11~,17,21-trihydroxy-16d-E(2-phenyl- ;
. .
oxiranyl)methoxy]pregn-4-ene-3,20-dione,_21-`
_cetate A solution of 555mg of 9-fluoro-11~,17,21-trihydroxy-16a-[~2-phenyl-2-propenyl)oxylpregn-4-ene-3,20-dione, 21-acetate ln 25 ml of dichlo~romethane lS stirred for 330~
minutes with 200 mg of m-chloroperbenzoic acid. The solu-, tion is ~shed with 50 ml each of 5~ sodium sulfite solu-tion and 5~ potassium carbonate solution. The dichloro-methane solution is dried and evaporated to giv~ 58~ mg of `` product. Recrystallizatlon from acetone-hexane gives~360 mg of 9-Eluoro-11~,17,21-trih~droxy-16a-[(2-phenyl-oxira nyl 30 ~ methoxy]pregn-4-ene-3,20-dione, 21-a~cetate.~ ~

.

~ ; -30- -.. . . ~ .. , . , , ; -:, :

`` :
X540a l~S(~9~6 D. 9-Fluoro~ ,17,21-trih~droxy-16a-(2-phenyl-2 oxoethoxy)~reqn-4-ene-3,20-dione, 21-acetate .
A solution of 2.4 g of 9-fluoro-11~,17,21-tri-hydroxy-16a-1(2-phenyl-oxiranyl)methoxy~2regn-4-ene-3,20-- dione, 21-acetate in 75 ml of tetrahydrofuran is stirred with a solut:ion of 5 g of periodic acid in 20 ml of water for 270 mimlte~. The resulting slurry is diluted with 150 ml of watex and the solid is filtered and dried ln vacuo to givo 1.79 g of crude product. This material is L0 chromatographed on a 40 g-silica gel column. Elution with chloroform gives 1.6 g of TLC pure solicl that is re-crystallized rom acetone-hexane to give 1.42 g of 9~fluoro 11~,17,21-trihydroxy-16a-(2-phenyl-2-oxoethoxy)pregn--4~ene-3,20-dione, 21-ace~atet melting point 228-230C.
Anal- C~alcd for C31H37F8 C~ 66-89; H~ 6-70; F~ 3-41-~ ~ Found: C, 67.07; H, 6.69; F, 3.~5.

E. 9-Fluoro-2',3'-dihydro~ ,21-dihydroxy-5'-phenvl- -~ecln-4-eno[16a,17-b][1,4]dioxin-3,20-dione, 2a . 21-a~etate A ~lurr~ of 150 mg of ~-toluenesulfonic acid in ~ 300 ml of benzene i6 refluxed with a Dean-Stark trap.
; The firsl: 50 ml o~ distillate is discarded, Linde 4A
mole~ular sieves added, and the solution is refluxed for 30 minutes. The solution is cooled, 1.25 g of 9-fluoro- -,17,21-trihydroxy-16a-(2-phenyl-2-oxoethoxy)pregn-4- -ene-3,20-dione, 21-acetate added, and the solution re fluxed for 5 hours under nitrogen. The resulting solu-, tion i~ cooled, washed with 5~ sodium bicarbonate solution, . .

: ' ..

~.. ...

.

.. .

K540 a ~S~g~6 dried, and evaporated in vacuo. The residue i5 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 silica gel plates. After 2 developments with 1:1 chloro-form-ethyL acetate the major W -active band is excised and eluted with chloroform to give TLC pure material. Re-cry~tallization from benzene gives 380 mg, of 9-fluoro-2',3'-dihydro~ ,21-dihydroxy-5'-phenylpregn-4-eno-1. ' ' , ! .
[16a,17-bl~1,4]dioxin-3,20-dione, 21-acetate, melting point 145-147C.
Anal. Calcd for C31~35F07: C, 69.13; H, 6.55; F, 3.53.
Foundi C, 68;.90; H, 6.73; F, 3.58.

Ex ple 5 9-~luoro-2~3'-dihydro~ 21-dihydroxypr_gn-4-eno[l6a,17-b][1,4]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 of 9-fluoro-s~ 2l-trihydroxypregn-4-eno[l6a,l7-b]-Cl, 4]dioxane-3,20-dione, 21-acetate (prepared as described in Example 1) is added. The resulting solution is re-fluxed with a Dean~Stark trap filled with 4A molecular - sieves for 24 hours under nitrogen. The solution is ccoled, diluted with chloroform, washed with 5% sodium bicarbonate 1~ ~olution, and dried. The residue obtained on solvent re-moval in vacuo is chromatographed on a 20 g - silica gel ':
column. Elution with 1:1 dichloromethane-chloroform gives ~1 , ~ 30 :, , ' ~ .
. j .
~ -32-.
;

, . , . ~ .... .

K540 a ~6~5~6~
510 mg of pure compound. Recrystallization from aceto~e-hexane gives 325 mq of TLC Pure solid, in two crops. The mother liquor is purified by preparative thin layer chroma-o~raphy on a ~n x 20 cm - 2 mm silica gel plate. After three developments with 9:1 chloroform-ethyl acetate, the major UV-active band is excised and eluted wi-th chloroform-methanol. The residue obtained on solvent removal is crystallized fxom acetone-hexane to give 96 mg of pure material~ This is combined with the 325 my obtained above lQ and recrystallized from acetone-hexane to give 312 mg o 9-fluoro-2',3'-dihydro~ ,21-dihydroxypregn-4-eno[16a,17-b]-[1,4]dioxir.-3,20-dione, 21-acetate, melking point 231-240C, dec.

Anal. Calc d for C25H31FO7: C, 64.92; H, 6.76; F, 4~11.
Found: C, 64.64; H, 6.54; F, 3O90.

. ' ~ .
: :

~E~
9-Fluor_-2',3'-dihydro-11~,21-dihydroxy~re~n-4-eno-[16~,17-b~[1,4]dioxin-3,20-dlone A solution of 700 mg of 9-fluoro-2',3'-dihydro~
21-dihydroxypregn~4-eno[1~,17-b][1,4}dioxin-3,20-dione, 21-acetate (prepared as described in Example 5) in 75 ml ~-of methanol is cooled to O~C and 7 ml of 10% potassium carbonate solution is added. After lS minutes, 20 ml of 20~ aqueous acetic acid is added and the resulting solld is fil-tered and dried in vacuo to give 310 mg of 9-fluoro-2',3~-dihydro-11~,21-dihydroxypregn-4-eno[16~,17-~][1,4]-dio.Yin-3,20-dione, melting point 255-258QC, dec.

:, ~ . . . . . . : . : . :

K540 a 51:)~6~

21-Chloro-9-fluoro-2',3'-dih~dro~ -hyd ~
methylpregna-1,4-dieno[16a,17-b][1,4]dloxin-3,20-dione :
A. 21-Chloro-9-fluorc-11~!16a!17-_rihyd~y~3l~DL~ L~

diene-3t20-dione, 16,17-cycloborate . . .............. . .
A solution o~ 15.0 g of 21-chloro-9-fluoro~ ,16~,17-txihydroxypregna-1,4-diene-3,20-dione and 60 g of boric oxide in 750 ml of methanol is xe~luxed for l hou:e, cooled 1~ to 30C and diluted with 1.5 liters of water. Th,~ re-sulting solid is filtered and dried Ln vacuo to give 13.85 g of 21-chloro-9-fluoro~ ,16~,17-trihydrox~pregna-1,4-diene-3,20-dione, 16,17-cycloborate.

. , , B~ 21-Chloro-9-fluoro-11~,17-dihydroxy-16a-~(2 methyl-. 2-propenyl)oxy]~regna-1,4-diene-3,20-dione . - A solutlon of 2-methyl-3-diazp-1-propene in 150 ml of ether (prepared from 0.1 mole of N-(2-methyl-2-propenyl~-ethyl carbamate by the method of J. L~ Brewbaker and H. Har~, J. Am. Chem., Soc., 91, 711 ~1969)) is diluted with S0 ml o~ methanol and cooled to 0C. A total o 7 g o$ 21-chloro-9-fluoro~ ,16~,17~trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is adde~ in portions un~il ni~rogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved ln chloroform and chromatographed on an 80 g -silica gel column. Elution with chloroform gives TLC pure material which cxystallizes from acetone-hexane to give 5.4 g of 2l-chloro~9-fluoro~ 7-dihydroxy-l6a : [(2-methyl-2~propenyl)oxy]pregna-1,4-diene-3,20-dione, . 30 : : .
' ~34- .

,, " , . . . ~ .

. .. K540 a ~ 5~66 O melting point 238-240Co Anal. Calc'd for C25H32ClFO5: C, 64.30; H, 6.91;
Cl, 7.59; F, 4.06.
Found: C, 64.53; Hl 7.04; Cl, 7.74; F, 4.27.

C. 21-Ch~oro-9-fluoro~ ,17-dihydroxy-16~-[(2-_1ethy~
oxiranyl)methox~pre~na-1,4-diene-3,20-dione . .
A solution of 3.0 g of 21-chloro-9-fluoro~ ,17-dihydroxy~l6a-[~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 210 minutes. The solution :i.s washed with a mixture of 10~ pota.ssium carbonate .~olution and 10~ sodium sulfite solution! dried, and evapor-ated in vacuo to give an oil which solidiEies on standing~ :
Recrysta.LL;.zation from acetone-hexane gives 1.94 g as a ~irst crop, and 820 mg as a second crop. Recrystalli-i zation of 600 mg of crop 1 from acetone-hexane gives 460 - mg of 21-chloro-9-fluoro-113,17-dihydroxy-16~-[(2-methyl-oxiranyl)methoxy]pregna-1,4-diene-3,20-dione, mel-ting ~.

point 193-236C~
AnaL.. Calc'd for C25H32ClFO6: C, 62.16; H, 6.68; . .
Cl, 7.34; F, 3.93.~
Found: C, 62.19, ~, 6.67i Cl, 7.52; F, 4.07.
, -(~he nmr spectrum of this material~indicates that it is ca. a 1:1 mixture of epimers at the quaternary : :~ .oxirane carbon~2tom.~ - :

30.
. ~ ~35-' ~ ' ' K54Oa D. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-(2-oxo-propoxy)pre~na-1,4-diene-3,20-dione A solution of 2.16 g of 21-chloro-9-fluoro-11~,17-dihydroxy-16~-[(2-methyloxiranyl)meth~xy~pregna-1,4-diene-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 ex-tracted with chloroform. The chloroform solution is dried and evaporated in vacuo and the residue is dissolved in chloroform and chromatographed on a 50 g-silica gel column.
Elution with chloroform and collection of 50 ml fractions gives 1.81 g of TLC pure solid in fractions 9-17. Recrystal-lization from acetone-hexane gives 1.15 g of irst crop material and O.SO g in crops 2 and 3. Recrystallization from acetone-hexane of 600 mg of the first crop gives 490 mg of 21-chloro-9-fluoro-11~,17-dihydroxy-16~-(2-oxopropoxy)pregna-1,4-diene-3,20-dione, melting point 226-227C.
Anal. Calc'd for C24H30ClF06: 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-ll~~hydroxv-S~-methy~lpre~na-1,4-dieno~16~,17-b]~1,4]dioxin-3,20-dione . :
A slurry of 100 mg of ~-toluenesulfonic acid in 250 ml of benzene is refluxed with a Dean-Stark trap. The first 50 ml of benzene-water azeotrope is discarded and Linde type 4A molecular sieves are added to the trap.

AEter 30 minutes at reflux, the solution is cooled and ' !

K54Oa - ~5~66 :
980 mg of 21-chloro-9-fluoro-llB,17-dihydroxy 16a-(2-oxopropoxy)pregna-1,4-diene-3,20-dione:is added. The resulting ~lurry is refluxed for 25 hours under nitrogen, cooled, and filtered to give 720 mg of solid. The filtrate is diluted with chloroform, washed wi.th 5% sodium bicar-bonate solution, water, dxied, and evaporated to give 210 mg of material identical by T~C to the 720 mg of solid. ~:
These materials are combined, slur~ied with 50 ml of ~ineral oil, diluted with chloroform, a~d chromatographed 10 on a 100 ~ -.5ilica gel column. Elution with chloroform gives 850 mg of material which is recrystallized from :
acetone to give 487 mg o 21-chloro-9-1uoro-2',3'-di-hydro~ -hydroxy-5'-methylpregna-1,4-dieno[16a,17~b]
11,4~dioxin-3,20 dione, melting point 259-260C.

. -Anal. Calc'd for C24H2805~Cl: 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 5'~-Ethoxy-9-fluoro-llB,21-dihydroxypre~n-4-eno-~16a,17-b][1,4]dioxane-3,20-dione A. 16a-~2,2-Diethoxyethoxy)-9-fluoro~ ,17,21-tri-hydro_y~egn-l-ene ~
A solution of 2,2-di~thoxy-1-diazoethane ~prepared : :
, : .
from 0.0935 mole of N-2,2~diethoxyethyl~:urea by the method of W. Kirmss and M. Buschhoff, Chem. Ber.~100, 1491 (1967)) ~in 3QO ml of 3:~ ether-pentane is diluted~with 100 ml of ., .
methanol and cooled to 0C. A total of 5.5 g of 9~1uoro-30 . llR,16~,17,21-tetrahydroxypregn-4-ene-3~20~dione, .

~37- :-,: .
:' K54Oa ~0~i~1966 16,17-cycloborate is added in portions until ni~rogen evolution ceases. The solvent is removed ln vacuo and the residue is recrystallized from mlethanol to give 3.4 g of slightly impure material. This is dissolved in chloro-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'-diethoxyethoxy)-9 fluoro~ ,17,21-trihydroxy-pregn-4-ene-3,2~-dione, melting point 208-210C.
~nal.Calc'd for C27H41F8 C~ 63-26; H~ 8-07; F~ 3-71-Found: C, 63.03; H, 7.86; F, 3.79.
.
B. 5'~-Ethoxy-9-fluoro~ 21 dihydroxypregn-4-eno~
[lfia,17-b]tl,4]dioxane-3,2Q-dione ' A slurry o 100 mg of ~-toluenesul~onic acid in 250 ; ml of benzene is refluxed with a Dean-Stark trap. The first 50 ml of benzene-water azeotrope is discarded and Linde 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~ ,17,21-tri-hydroxypregn-4-ene-3,20-dione is added. The'resulting slurry is refluxed for 2 hours under nitrQgen, 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 a 100 g - silica gel column.~ Elution ~ith chloroform and

4:1 c1lloroform-ethyl a~etate givea a total of 1.33 c~ o~
TLC pure material. Two recrystallizations from acetone-' hexane (the last with charcoal) give 57'0 mg of 5'~-ethoxy-9-fluoro-11~,21-dih~droxypregn-4-eno[16~,17-b][1,4]--3~-.

.

. , ,: .' ' . . .. . '' ' . ~

Ki40a .~S~
:
dioxane-3,20-dione, melting point 248-250C, dec.
Anal. Calc d for C25H33FO7: C, 64.64; H, 7-16; F, 4-10-Found C, 64.75; H, 7.02; F, 3.95.

, Example 9

5'~-Meth [l6a~l7--b]~l~4ldioxane-3~2o~dione A. 16a-(2,2-Dime xyethoxy)-9-fluoro~ ,17,21-tri-~ oxypregn-4-ene-3,20-dione A solution of 2,2-dimathoxy-1-diazoethane in 100 ml of 6:4 pentane-ether (prepared by the method of W. Rirmse and M. Busahhof, Chem. Ber., 100, 1491 ~19671utllized for the diethoxy analog) i9 diluted with 50 ml of methanol and cooled to 0C. A total of 2 g of 9-fluoro-11~,16~,17,21-- tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate i~
adde~. After nitrogen evolution ceases the solvent is removed in vacuo and the residue is dissolved in chloro-form and chromatographed on an alumina column ~neutral, ~ activity III~. Elution-with chloroorm gives 485 mg of slightly impure material and t~en 1.27 g o~ TLC pure com~ ;
pound. Recrystallization o the 485 mg from acetone-; hexane yives 175 ~g of TLC homogeneous solid which i5 combined with the 1.27 g ~nd recrystallized from acetcne~
hexane to give 1.09 g of 16~-(2,2 - dimethoxyethoxyj-g-~luoro~ ,17,21-trihydroxypregn-4-ene-3,20-dione, melting point 192-194C.
. . ~na Ccllc d for C25H37F08: C, 61.96; H, 7.70; F, 3.94~
Found: C, 62.21; H, 7.79, F, 3.85.
:-., ~ :. .
, ' 30 '. ~

:, , ,. : , ,.. : .

K54Oa B. 5~ Methoxy-9-fluoro-llB~2l-dih~gea~oæ ern-~ -ern-~16a,17-b] ~1,4] dioxane-3 ! 20-dione Following the procedure of Example 8B, but sub-s~itutir.~ 16a- (2, 2-dimethoxyethoxy)~9-fluoro~ ,17,21-trihydroxypregn-4-ene-3,20-dione for the 2,2-diethoxy-ethoxy steroid, the title compound i~; obtainedO

~, eno~l6a~l7-bl[l~4]dioxane-3~2o-dione A. ~ F.thoxy-9-fluoro-llg,21-dihydroxypregn-4-eno-[l6a~l7-b]ll~4]dioxane-3~2o-dione~ 21-mesylate . .
A s~lut~on of 950 mg of 5'~-ethoxy-9-fluoro-11~,21-dihydroxy~regn-4-eno~16a,.l7-b] [1,4~dioxane-3,20-dione (prepareci as described in Example 8~ in 10 ml of pyridine is stirred at 0C wi~h 3 ml of methanesulfonyl chlori~e for lSO minutes. Ice is added and the mixture poured into cold, dilute hydrochloric acid and extracted with chloro-form. The chloroform solution is dried and evaporated in vacuo to give 1.0 g of crude mesylate.

B. 21-Chloro-S'~ethoxy-9-~luoro~ hydroxypregn-4-enoll6~,17-b][1,4]dioxane-3,20-dione~
solution of 1 g of 5'~-ethoxy-9-fluoro~ ,21-di-hyaroxyp~ ec3n-4-enoll6~,17-b311,4]dioxane-3,20-dione, 21-mesylate in 100 ml of dimethylformamide is reflux2d with 4 g of lithium ch~oride for 30 minutes, cooled, and poured into ic~-water. The resultin~ solid is filtered, washed well with water, and ~ried in vacilo to give 782 mg o~ ~

.

~4~-:

lOS0966 KS40a product. This material is dissolved in chloroEorm and chromatographed on a 20 g - silica gel column. Elution wi~h chloroform gives 715 mg of TLC pure solid. Re- -crystallization from acetone-hexane gives 600 mg of 21-chloro-5'~-ethoxy-9~fluoro~ -hydroxypregn-4-eno[16a,~
17-b]l1,41dioxane-3,20-dione, melting point 235-237C, dec.
A~l~ Calc'd for C25H34ClF06: C, 61.91; H, 7.07;

. Cl, 7.31: F, 3.92.
Found: C, 61.75j d, 7.27; Cl, 7.24 ~, 3.85.

"', ' "''' ,-. ', ' - .
, .

' ' ' ' ' :' .1 ~'' .
;3 : ~
.` , . .. . .
.

! ~ :

. :, ~ :
, -41-' .

. ~ , ' ... ,.... .. ' . ~ - . . ' I ~5~
~5~9~6 - Example 11 ..
9-Fluoro-5~,11g,21-trihydroxypregn-4-eno~l6a,17-b]-~1,4~dioxane-3,20-dione - A solution of 1.6 g of 16a-(2,2--diethoxyethoxy)-9-fluoro 11~,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 lM 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. Re,crystallization from methanol gives 350 mg of 9-fluoro-5'~ ,21-trihydroxypregn-4-eno-~16a,17-b]~1,4]dioxane-3,20-dione, melting point 260-26~C, dec.
Anal. Calc'd for C23H31FO7: C, 63.00; H, 7.13; F, 4.33.
Found: C, 62.96; H, 7.07; F, 4.48.

.
Example 12 9-Fluoro-5'~ ,21-trihydroxypr~n-4-eno~16~,17-b]-[1,4]dioxane-3,20-dione, 5',21-diacetate .
To a solution of 1.3 g of 9-fluoro 5'~ ,21-tri-hydroxypregn-4-eno[16~,17-b]tl,4]dioxane-3,20-dione (pre-pared 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 vacuo and the residue dissolved in chloroform, washed with dilute hydrochloric acld~ and dried. The solvent is se-~

` moved 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 ` . ' ~; :

K540 a ~5(~9~;6 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 develop-ments with 1:1 chloro~orm-ethyl acetate, the UV-active band of lowest R~ 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-5'~ ,21-tri-hydroxypregn-4 eno[l6a,17-b][1,4]dioxane-3,20-dione, 5',21-diacetate, melting point 195-197C.
Anal. Calc'd ~or C25H35FOg C, 62.42; H, 6.21; F, 3.66.
Found: C, 62.37; H, 6.44; F, 3.61.

Exam~e 13 9-Fluoro-5'~ ! 21-trihydroxypre~n-4-eno[16a,17-b]-El, 4]dioxane-3,20-dione, 5'-valerate, 21-acetate ~ .
A solution of 9-fluoro-5'~ ,21-trihydroxypregn-4-eno[16~,17-bl[1,4]d oxane-3,20-dione, 21-acetate (prep~red as described in Example 1) in pyridine is stirxed with zo excess valeric anhydride for 2 hours. The solvent is re-moved in VACUO and the residue dissolved in chloro~orm The chloro~orm solution is washed with 5~ hydrochloric acid, waterr 5~ sodium bicarbonate, and dried. Solvent removal yields 9-fluoro-~ ,21-trihydroxypre~n-4-eno~l6~,17-b][1,4]dioxane-3,20-dione, 5'-valerate, 21-acetate.

~54Oa ~5~3~66 O
21-Chloro-9-fluoro-5'~ dihydroxypre~na-1,4-- dieno[l6,17-b]~1,4]dioxane-3,20-dione A. 21-Chloro-16~ (2,2-diethoxyethoxy)-9-fluoro~ ,17-dihydroxypregna-1,4-diene-3,20-dione A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of WO Xirmse and Mo Buschhoff, Chem. Ber., 100, 1491 ~1967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to 0C. A total of 2.5 g of 21-chloro-9-fluoro~ ,16~,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed ln vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g - silica gel column. Elution with chloroform gives 2.16 g of TLC pure material that is recrystallized from acetone-hexane to give 1.75 g of 21-chloro-16~-(2,2-diethoxyethoxy)-9-fluoro-11~,17-dihydroxypregna-1,4-diene-3j20-dione, melting point 200-202C.
20Anal. Calc'd for C27H38ClFO7: C, 61.30; H, 7.2~;
Cl, 6.70: F, 3.59.
Found: C, 61.55; H, 7.24;
Cl, 6.68; F, 3.47.
,, .
-Bo ?l-Chloro-~ fluoro-5'~,11g-dihydrox~pre~na-1_4-dieno[l6~,17-b]11,41dioxane-3,20-d7One A solutioll of 1.6 g of 2l-chloro-l6~-!2~2~diet ethoxy)-9-1uoro-11~,17-dihydroxypregna-1,4-~iene-3,20-dione in 200 ml of tetrahydroEuran is re~luxed with 20 ml .

~, ~
.: . - :

- . . . . - . ~ . : . . ,. ., . ,,, . ~ . - ~ , X540 a .:
1~3SO966 of lN hydrochloric acid for 5 1/2 hours~ The solvent is removed in vacuo and the residue is diluted with water, .. ex~racted with chloroform, and the chloroform solution is wa~h~d witll 5~ sodium bic~rb~nate solution, water, dried, and evaporated. The residue is dissolved in chloroform and chromatographed on a 60 g - silica gel column. Elution with a mixture of 3:2 chloroform:ethyl acetate gives 1.29 g of pure material which is recrystallized from acetonitrile to give 940 mg of 21-chloro-9-fluoro-5'~ dihydroxy-pregna-l~4-dienotl6a~l7-b]~l~4]dioxane-3~2o-dione~ melting point 242-245C, dec.
Anal- Calc'd for C23H286ClF C, 60.72~ H~ 6-20;
. Cl, 7.79; F, 4.:L8.
Found: C, 60.52; H, 5.97; Cl, 7.86; F, 4.03.
: .
Example 15 21-Chloro-9-fluoro- ~ 13-dihydroxy~regna-1,4-dieno~l6u,17-b~[1,4]dioxane-3,20-dione,~5'-acetate To a solution of 887 mg of 21-chloro-9-fluoro-5'~, 11~-dihydroxypregna-1,4-dieno[16~,17-bl~1,4]dioxane-3,20-~ 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 ~ilute hydrochloric:acid, and . dried. The solvent is removed in vacuo and~the residue ~- is dissolved in chloroform and chromatographed on a silica gel column. Elution wlth chloroform gives 748 mg of~
material. Recrystallization from~acetone-hexane gives -~

~ 45 ~ ~ ~

~540a 5~966 ' !
505 mg of slightly impure material. A second recrystalli-zation fxom ~ethanol gives 420 mg of TLC pure 21-chloro-.. 9-fluoro-5'~ -dihydroxypregna-1,4-d~ienoE16,17-b]~1,4]-dioxane-3,20-dione, 5'-acetate, melting point 242-244C, decr Anal. Calc a for C25H307F~l C~ 58041; H~ 6-39;
Cl, 7.50; F, 4.02.
Found- C, 58.23; H, 6.23; Cl, 7.40; F, 4.08.

Example 16 21 Chloro-9-fluoro-2',3'-dihydro~ -hydroxypregna-. 1,4-dienotl6~,17-blEl,4]dioxin-3,20 dione A slurry of 300 mg o~ ~-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 tra~ and the solllt.;.~n. i.q r~fluxed for 30 minutes. The solution is cooled, 2.0 g of 21-chloro-9-fluoro-5'~ -dihydroxypresna-1,4-dieno[16~,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 under nitrogen. The slurry is cool~d and the benzene is removed in vacuo. The residue is dissolved in chloroform and the chloroform solution washed with 5%~sodium bicar-bonate solution, water, dried, and evaporated in vacuo. :
The residue is dissolved .in chloroform and chromatographed .
on a 50 g - silica gel column. Elution with chloroform gives 985 mg of sQlid which is recrystallized from acetone- .~
. hexal~e to give 528 mg of 21-chloro-9-~luoro-2',3'-dihydro- :
113-hydroxypregna-1,4-dienoE16~.,17-b~[1,4]dioxin-3,20-~ ~ ~
; . . . :
- 30 dione, melting point 248-2 0C,:dec.
~ .: -.
~ ~ 4~

~ .. . .. . . . . . .. . ........ .

~osos6~ K54 0 a Anal. Calc dfor C23H26ClF05: C, 63.23; H, 6.00;
Cl, 8.12; F, 4.35.
Found: C, 62.95; H, 5.88; Cll 8.24; F, 4.22.

~ , " ' .
9-Fluoro-llB~2l-dihydroxypregn-4-eno[l5a~l7-b~[l~4 dioxane-3,5',20-trione, 21-acetate , .
A solution of 1.2 g of 9-fluoro-5'~ ,2L-tri-hydroxypregn-4-eno[16a,17-b] E 1,4]dioxane-3,20 dione, 21-!0 acetate (prepared as described in Example 1) in 250 ml of toluene is slurried with Z2 g of Fetizon's reagent tV.
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 12 1/2 hours, cooled, filtered, and the resulting solid is washed well with chloroform. The filtrate and washings are com .
bin~d, evaporated ~n vacuo, and the r~sidue chromatographed on ~ 40 ~ - silica gel co:Lumn. Elution with chloroform g~ves 270 mg of oil which crystallizes from aceton~-hexane to give 181 mg of TLC pure solid. This is combined with 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~ ,21-dihydroxypregn-4-eno[1~,17-b][1,4]dioxane-3,~', 20-trione, 21-acetate, ~ ~-ne1ting point 217.5-220Ct dec.
A~ Calc'd for C2s~l31F8 ~ ~ ~ Found:r~ 62.61; H, 6.53; F~ 3.73. :

'` ' . ' ::
, 30 ;: ~ :
.~
:
47~

X54Oa :IOS~966 xam~
9-Fluoro-llB,21-dihydroxypregn-4-eno[16a,17-b]-~1,4]dioxane-3,20-dione, 21-acetate A. 9-Fluoro~ ,17, 2i-trihydroxy-l6a-[2-(tetr-ahvdr pyran-2-yloxy)ethoxy]pre~n-4-ene-3,20-dione a) Tetrahydropyran-2-yloxy~acetonitrile This material is prepared by the method of J. Davoll and D. H. Laney, ~ Chem. Soc. 2129 (1956~ and has a boil-inq point of 78-79C at 2 ~m.
,:
- b) 2-(Tetrahydropyran-2-yloxy)Qthylamine A solution of 35 g o tetrahydropyran-2-yloxy aceto-nitrile in 100 ml of ether is added dropwise to a slurry of 10 g of lithium aluminum hydride in 300 ml of ether and 100 m~ of tetrahydrofuran. The slurry is refluxed for 210 minutes, cooled, and 25 ml of sat. potassium carb~nate solution is added at;a rate that maintalns gentle reflux. After 90 minutes the sIurry 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- -~
hydropyran-2-yloxy)_thylamine, boiling point 41.5-46C at 0.5-0.8 mm.
. ~ ' c~ 2-lTetrahydropvran-2-ylo~y)ethyl]urea A mixture of 33.2~g of 2-(tetrahydropyran-2-yloxy~
ethylamin~ SO g of lce, and a ~solution oE~35 g of ~- potassium isocyanate in~80 ml of~water is~stirred well as 4;.6 m- of SN~hydrochloric acid~ ~cooled to~ -40C) is added in bne portkA ~bc Fosu~ ting~solution s reEIu~ed for~

~OS096~ K54 oa .

90 minutes, cooled, and extracted with four 150 ml por-tions of chloroform. The chloroform extract is dried and evaporated in vacuo to give 39.6 g of oil.

d) I~-Nl so~ 2-(tetrahydropyran-2-yloxy) ethyl)urea A solution of 39.6 g of N-12-(tetrahydropyran-2-yloxy)urea in 400 ml of ether and 100 ml of methylene chloride is slurried with 50 g of sodium acetate and cooled to -10C with mechanical stirring. A solution of 30 g of nitrogen dioxide in 100 ml of ether is added over a 30 minute period, the slurry is stirred a-t -10C for 20 minutes and then filtered. The filtrate is washed with saturated sodium bicarbonate solution, dried, and evapor-ated 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)ethylJurea in 200 ml of ether and 100 ml of pentane i5 added to 450 ml of lN sodium hydroxide solu-tion at 1-4~C over a 25 minute period. The solution is ~ stirred for an additional 30 minutes and the layers are i separated. The organic layer is dried over sodium hydroxide pellets at 0C for 5 minutes, and then filtered.

, .

K54Oa ~S~g66 f) 9-Fluoro~ ,17,21-trihydroxy-16~-[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 o~ 3:1 ether-pentane is diluted with 100 ml of cold methanol and stirred well as 5.0 g of 9-fluoro~ ,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 filtrate is evaporated ln 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 o~ TLC pure product. A small sample of similar material is recrystallized from acetone-hexane to . :
give 9-fluoro-11~,17,21-trihydroxy-16~-12-(tetrahydro-.
.j pyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione, melting point 196-200C. ;~

- . B. 9-Fluoro-11~,17,21-trihydroxy-16a-~2-(tetrahy~
.
; 20 pyran-2-yloxy)ethox~]pregn-4-ene-3,20-dione, 21-. ~ ... .
acetate A solution of 4.0 ~ of 9-fluoro~ ,17,21-trihydroxy-16a-[2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20~

dione in SO ml of pyridine is allowed to stand with 5 ml :::

of acetic anhydride for 3 hours. The :solvents are re-. moved in vacuo and the residue is dissolved in chloroform -l and washed with 5% hydrochloric acid, water, and 5%
. - . .
sodium:bicarbonate solutionO Drying and solvent removal gives 4~4 g of crude product. Crystallizatlon of a -'! : .
3 0 ~ ' :

50~

: :~
, :
K54Oa ~05096G
similar sample from acetone-hexane gives 9-fluoro-11~,17,~
21-trihydroxy-16a-~2-(tetrahydropyran-2-yloxy)ethoxy]-pregn-4-ene-3,20-dione, 21-acetate, melting point 150-152C.

C. 9-Fluoro-11~,17,21-~rihydroxy-16c~-(2-hydroxyethoxy)-~regn-4-ene-3,20-dione, 21-acetate ., Method A
A solution of 4.4 g of 9-fluoro-11~,17,21-~rihydroxy-}6a-[2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20-lo dione, 21-acetate in 60 ml each of acetic acid and water is stirred for 4 hours and the bulk of the solvent removed ln vacuo. The residue is dissolved in chloroform and washed with 5~ sodium bicarbonate solution. Drying and solvent removal gives an oil whlch crystallizes from acetone- :~
hexane to give 2.4 g of 9-fluoro-ll~l7~2l-trihydroxy-l6a- .
(2-hydroxyethoxy)pregn-4-ene 3,20-dione, 21-acetate, melt- : :
ing pc~int 162-165C. ~ :

, Method B
A solution of 1.98 g of 9-fluoro-5'~ ,21-tri-hydroxypregn-4-eno-[16a,17-h] [1,4]dioxane-3,20-dione, 21-acetate (prepared as described in Example 1) in 100 ml of methanol is cooled ~o 0C and 148 mg of sodlum boro ~iydride is added. After g minutes the solution is poured into a mixture of ice and 5% hydrochloric acid and ex-.
tracted with chloroform to give 1.78 g of oil. This material is chromatographed on a SO~ g~- silica gel column.
Elution with 19:1 chloroform-ethyl~ acetate gi~es 0.45 g of pure 9-fluoro~ 7~2l-trihydroxy-l6o~-t2-hydroxyethoxy) pregn-4-ene-3,20-dione, 21-acetate`and a total of 0.35~ g of impure material.
. . : ~ :
~51- I ~

:
: , . . .

K540 a ~0~
D. 9-Fluoro-16~-(2-mesyloxyethoxy)~ 7~2l-tri hydroxypregn-4-ene-3,20-dione, 21-acetate A solution of 0.80 g of 9-fluoro-16~-(2-hydroxy-ethoxy)-11~,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate in 10 ml of pyridine is stirred with 0.5 ml of methanesulfonyl chloride for 90 minutes at 0C 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-graphed on a 20 g - silica gel column. Elution with chloroform gives 521 mg of TLC pure 9-fluoro-16~-(2-mesyloxyethoxy)-11~,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.

E. 9-Fluoro-llg,21-dihydroxypre~n-4-eno[16~,17-~[1,4]-dioxane-3,20-dione, 21-acetate . . _ .
A solution of 521 mg of 9-fluoro-16~-(2-mesyloxy-ethoxy)~ ,17,21-trihydroxypregn-4-ene-3,20-dione, 21-; acetate in 40 ml of dimethylsulfoxide is stirred at 110C
under nitrogen for 2 hours with 600 mg of sodium bicarbonate (dried at 110C ln 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.
.,.,j .
This material is chromatographed on a 20 g - silica gel column. Elution with chloroform gives 331 mg of TLC pure material which solidifies. Recrystallization from acetone- -hexane gives 215 mg o 9-fluoro-11~,21 dihydroxypregn-4-eno[l6~,17-b][1,4]dioxane-3,20-dione, 21-acetate, melting polng 275-280C, dec.
~, .. .

. . .; : , . .
. : ~. . . . . . . . . .

K540 a Anal. Calc'd for C25H33FO7 C~ 64-64; H~ 7-16; F~ 4-09-E~ound: C, 64.59; H, 7.21; F, 3.98.

Example 19 21-Chloro-9-fluoro-5'~ -dihydroxypreqn-4-eno-` [16~,17-b][1,4~dioxane-3,20-dione A. 16~-~llyloxy-9-fluoro-11~l17,21-trill~droxypreqn-4-ene-3,20-dione, 21-methanesulfonate .. . .. ... . .. .. . . .. . _ _ i A solution of 1.0 g of 16~-allyloxy-9-fluoro-11~, 17,21-trihydroxypregn-4-ene-3,20-dione (prepared as de-scribed in Example lA) in 15 ml of pyridine is stirred at 0C under nitrogen for 150 minutes with Q.35 ml of methane-sulforlyl chloride. The resulting solution is poured into cooled 5~ hydrochloric acid and extracted with chloroform.
The chloroform solution is washed with water, dried, and evaporated ln vacuo to give 1.05 g of residue.

' B. 16~-Allyloxy-21-chloro-9-fluoro-llB,17-dihvdrox~-pregn-4-ene-3,20-clione A solution of 1.05 of 16~-allyloxy-9--fluoro-11~,~
17,21-trihydroxypregn-q-ene-3,20-dione, 21-methanesulonate in 65 ml of dimethylformamide is refluxed for 1 hour under nitrogen with 1.05 g of lithium chloride. The solution is cooled, diluted with 400 ml of water and filtered. The solid is dissolved in chloroform, washed with 5% hydro-chloric acid, water, dried, and evaporated in vacuo to ~ give 800 mg of residue. This material is dissolved in - chloroform and chromatographed on an 18 g - silica gel column. Elution Wi.th chloroform gives 600 mg of TLC pure ~ 30 .

.

~540 a 3i66 material. Two recrystalli2ations from acetone-hexane give 500 mg of 16~-allyloxy-21-chloro 9-fluoro-11~,17-di-hydroxypregn-4-ene-3,20-dione, melting point 224-225C.
Anal. Calc'd for C24H32ClFO5: C, 63.36; H, 7.09;
Cl, 7.79; F, 4.18.
Found: C, 63.53; H, 6.97; Cl, 7.50; F, 4.14.

C. 21-Chloro-9-fluoro~ ,17-dihydrox~-16~-(oxiranyl-methoxy)pregn-4-ene-3,20-dione ., Following the procedure of Example lC, but sub-stituting 16a-allyloxy-21-chlorQ-9-fluoro llB,17-dihydroxy-pregn-4-ene-3,20-dione for 9-fluoro-16a-allyloxy-11~,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate, the title com~
pound is obtained.
D. 21-Chloro-9-fluoro-5'~ -dihydroxypr~n-4-eno-116~,1?-b}[1,4]dioxane-3,20-dione Following the procedure of Example lD, but sub-~-~ stituting 21-chloro-9-fluoro-11~,17-dihydroxy-16~-(oxiranyl-methoxy)pregn-4-ene-3,20-dione for 9-fluoro~ ,17,21-tri-hydroxy-16~-(oxiranyl~methoxy)pregn-4-ene-3,20-dione, 21-~cetate, the title compo~nd is obtained.

~ ,.....

, K540 a Example 20 21-Chloro-9-fluoro-2',3'-dihydro-11~-hydroxy-5'-phenylpreyna-1,4-dieno116~,17~b]~1,4]dioxin-' 3,20-dione A. 21-Chloro-9-fluoro~ ,17-dih~droxy-16~-[(2-phenyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione A solution of 2-phenyl-3-diazo-1-propene (pxepared from 28.5 g of N-(2-phenyl-2-propenyl~ethyl carbamate, prepared as described in Example 4) in 700 ml of ether and 50 ml of pentane is diluted with 150 ml of methanol at 0C and 10 g of 21-chloro-9-fluoro-11~,16a,17 tri-hydroxypregna-1,4-diene-3,20-dione, 16,17~cycloborate is added in portions. After nitrogen evolution ceases the solvents are removed ln vacuo and the residue is re-crystallized from methanol to give 6.1 g of 21-chloro-9-fluoro-llR~l7-dihydroxy-l6a~[(2-phenyl-2-propenyl)oxy3 pregna-1,4-diene-3,20-dione, melting point 212-214C.
Anal. Calc'd. for C30H34 5 C, 68.11; H, 6.48;
Cl, 6.70; ~, 3.59.
Found: C, 68.37; H, 6.75; Cl, 6.92; F, 3.49.

B. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-[(2-phenyl-oxiranyl)methoxyJpregna~1,4-diene-3,~0-dione A solution of 4.0 g of 21-chloro-9-fluoro~ ,17- -dihydroxy-16a-[(2-phenyl-2-propenyl~oxy]pregna-1,4-diene-3,20-dione in 100 ml of dichloromethane is stirred with 1.6 g of m-chloroperben~oic 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 .i ,:
., , .:
' X540a 1~S6)966 5~ sodium bicarbonate solution, dried, and evaporated 1n vacuo to give 4.8 g of crude 21-chloro-9-fluoro-11~,17-dihydroxy-16a-~(2-phenyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione.

C. 21-Chloro-9-fluoro-11~,17-dihy~ (2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione A solution of 4.8 g of 21-chloro-9-fluoro-11~,17-dihydroxy-16~-[(2-phenyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione in 150 ml of tetrahydrofuran is stirred with a solution of 10 g of periodic acid in 40 ml of water for 4 hours. The resultiny slurry is diluted with 1 liter of water and Eiltered. The solid is dried ln vacuo and recrystallized from methanol-chloroEorm to give 2.4 g of 21-chloro-9-fluoro-11~,17-dihydroxy-16a-(2-oxo 2-phenylethoxy)pregna-1,4-diene-3,20-dione, melting point 266-268C, dec.
Anal. Calc'd. for C29H32ClFO6: C, 65.59; H, 6.08; Cl, 6.68;
F, 3.58.
Foond: C, 65.28 H, 6.38; Cl, 6.62; F, 3.i7.

.

. I .

.` .

., ~
.
, K540 a D. 21-Chloro-9-fluoro-2',3'-dihydro-11~-hydroxy-5'-phenylpregna-1,4-dieno[16a,17-b][1,4]_-dioxin-3,20-dione A slurry of 150 mg of p-toluenesulfonic acid in 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~ , 17-dihydroxy-16a-(2-oxo-2-phenylethoxy~pregna-1,4-diene-3,20-dione is added. The resulting slurry is refluxed for 6 hours under nitrogen, cooled, washed with 5% sodium bicarbonate solution, water, dried and evaporated ln vacuo -to yive 955 mg of crude product. This material is dissolved in chloroform and 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.
Recrystall~æation from ethyl acetate-hexane gives 443 mg of 21-chloro-9-fluoro-2',3'-dihydro-11~-hydroxy-5'-phenylpregna-1,4-dieno[16~,17-b][1,4]dioxin-3,20-dione, melting point 195-197C.
Anal. Calcd. for C2gH30ClFO5:
C, 67.89; H, 5.90; Cl, 6.91; F, 3.71.
Found: C, 68.02; H, 5.84; Cl, 6.70; F, 3.59.

, K540 a Example 21 21-Chloro-9-fluoro-11~-hydroxypregna-1,4-dieno-- 116~,17-b][1,4]dioxane-3,20-dione A. 21-Chloro-9-fluoro-11~,17-dihydroxy-16a-[2-(tetra-hydropyran-2-yloxy)ethoxy]pregna-1,4-diene-3,20-dione A solution of 2-(tetrahydropyran-2-yloxy)-l~diazo-ethane (prepared from 0.21 mole of N-[2-(tetrahydropyran-2-yloxy)ethyl~urea as described in Example 18) in 400 ml of 3:1 ether-pentane is diluted with 100 ml each of ether and methanol at 0C and stirred vigorously while 5.0 g of 21-chloro 9-fluoro-11~,16~,17-trihydroxypregna-],4-diene-3,20-dione, 16,17-cycloborate is added. After nitrogen evolution ceases the solvents are removed }n vacuo and the residue dissolved in chloroform and chroma-tographed on a 100 g-silica gél column. Elution with chloroform give 3.6 g of solid. Recrystallization from acetone-hexane gives 3.26 g of 21-chloro-9-fluoro~ ,17-s dihydroxy-16~-[2-(tetrahydropyran-2-yloxy)ethoxy]pregna-1,4-diene-3,20-dione, melting point 168-170C.

B. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-(2-hydroxy-ethoxy)pregna-1,4-diene-3,20-dione A solution of 4.2 g of 21-chloro-9-fluoro-llg,17-dihydroxy-16-[2-tetrahydropyran-2-yloxy)e~hoxylpregna-, 1,4-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 ~iltered and dried in vacuo to give 2.63 g.

.

` -58 `

. . , , ': : , : , ., K54 0 a ~\5û9~6 . `
, -Recrystallization from acetone-nexane gives 2.03 g of 21-chloro-9-fluoro-11~,17-dihydroxy-16~-(2-hydroxy-ethoxy)pre~na-1,4-diene-3~20-dione, melting point 226-228C, dec.
Anal. Calcd. for C23H30ClFO6:
C, 60.46; H, 6.62; Cl, 7.76; F, 4.1~.
Found: C, 60.26; H, 6.49; Cl, 7.88, F~ 4.26.
' .
C. 21-Chloro-9-fluoro-11~,17-dihydroxy-16 .. i .
mesyloxyetho~y)pre~na-1,4-diene-3,20~-dione A . A sol~tion of 1.5 g of 21-chloro-9-fluoro-llB,17-`; dihydroxy-16a-(2-hydroxyethoxy)pregna-1,4-diene~3,20-dione in 25 ml of pyridine is cooled to 0C and 0.6 ml o methanesulronyl chloride is added. After 2 hours the mixture is poured into cold dilute hydrochloric acid and extracted with chloroform. The chloroform solution is driea and evaporated in vacuo to 2.0 g of crude mesylate.

.
Do 21-Chloro-9-fluoro-~ hydroxypregna-l~4-dien ~16,17-b][1,4]dioxane-3,20-dione A solution of 2.0 g of 21-chloro-9-fluoro-11~,17-dihydroxy-16~-~2-mesyloxyethoxy)pregna-1,4-diene-3,20-dione in 100 ml of dimethylsulfoxide is stirred at 110C
.
under nitrogen with 2.0 g of sodium bicarbonate (dried . ~
? at 110C }n vacuo). After 1 hour the slurry is cooled, ., .
poured into 2 liters of 2.5% hydrochloric acid, and 2X-~racted with chloroform. The chloroform solution is , -:
washed twice with dilute hydrochloric acid, dried, and evaporated in vacuo to give 1.4 g of crude product.
- ~ .
. . . : .
'-59-. .

.

K540a ~5~6i6 This material is dissolved in chloroform and chromato-graphed on a 100 g-silica gel column. Elution with chloroform gives 880 mg of material wh~ch crystallizes from methanol-chloroform to give 405 mg of 2~-chloro-9-fluoro-ll~-hydroxypregna-1,4-dieno[16a,17-b][1,4]dioxane-3,20-dione, mel-ting point 320-321C, dec.

Anal. Calcd for C H ClFO :

C, 62.g4; H, 6.43; Cl, 8.08; F, 4.33.
Found: C, 62.73; H, 6.20; Cl, 8.27; F, 4.27.

Example 22 _~,21-Dih~droxyer ~n -1,4-dieno[16~,17-b][l,~]-dioxane-3,20~dione, 21-acetate -A. 16~-[2-(Tetrahydrop~ran-2-yloxy)ethoxy~ ,17,21-trihydroxypregna-1,4-diene-3,20-dione A solution of 2~(tetrahydropyran-2-yl)oxy-1-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 O~C. 14 g of 11~,16~,17, 21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cyclo-borate is added in portions. After nitrogen evolu-tion ceases the solvents are removed in vacuo and the residue is dissolved in chloroform and chromatographed on a 150 g-silica gel column. Eiution with chloroform and then 1:1 chloroform-ethyl acetate gives 4.0 g of TLC
pure 16~-[2-(tetrahydropyran-2~yloxy~ethoxy]~ ,17,21-trihydroxypregna-1,4-diene-3,20-dione.
'.

K540a B. 16~-[2-(Tetrahydropyran-2-yloxy)ethoxyl~11~,17,21-trihydroxypregna~ -diene-3,20-dione, 21-acetate A solution of 3.75 g of 16a-[2-tetrahydropyran-2-yloxy)ethoxy]-11~,17,21-trihydroxypregna-1,4-diene-3,20-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 16~-~2-(tetrahydro~
pyran-2-yloxy)ethoxy]-11~,17,21-trihydroxypregna-1,4-diene-3,20~dione, 21-acetate.

C. 16~-(2-Hydroxyethoxy)~llR,17,21-trihydroxypreqna-1,4-diene-3,20-dione, 21-acetate A solution of 4.9 g of crude 16a-~2-~tetrahydro-pyran-2-yloxy)ethoxyl-11~,17,21-trihydroxypregna-1,4-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 ln vacuo and the residue is 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 1:1 chloro-form-ethyl acetate gives 3.7 g of material which crystallizes from acetone-hexane to give 3.17 of 16~-(2-hydroxyethoxy)-,17,21-trihydroxypregna-1,4~diene-3~20-dione, 21-acetate~ melting point 138-140C.

.

,. - ~.. ~: . .

1050966 KS40a . .
D. 16~-(2-Mesyloxyethoxy)~ ,17,21-trihydroxypregna~
1,4-diene-3,20-dione, 21-acetate A solution of 3.0 g of 16a-(2-hydroxyethoxy)~
17,21-trihydroxypregna-1,4-diene-3,20-dione, 21 acetate in 15 ml of pyridine is stirred with 0.75 ml of methane sulfonyl chloride at 0C for 150 minutes. The mixture is poured into 1.5 liter of cold lN hydrochlorie acid, stirred for a short time, and filtered. The resulting solid is dissolved in chloroform, washed with water, dried, and evaporated in vacuo to give 4.0 g of crude 16a-(2-mesyloxyethoxy~ ,17,21-trihydroxypregna-1,4-diene-3,20 dione, 21-acetate .
. ~ , .
E. 11~,21-Dihydroxypre~na-1,4-dieno[16~,17-b][1,4 dioxane-3,20-dione, 21-acetate A solution of 4.0 g of crude 16~-~2-mesyloxy- -~j ethoxy)-11~,17,21 ~rihydroxypregna-1,4-diene-3,20-dione, .
21-aeetate in 200 ml of dimethylsulfoxide is stirred at 110C under nitrogen, with 4.0 g of sodium bicarbonate , ~ ' 'I . .
for 2 hours. The slurry is cooled, poured into 2 liters . . ~ . ~. .
of cold 2.5% hydrochloric acid, and extracted with c~loroform ~three 250 ml portions). The chloroform solution is washed with two 1 liter portions of 2.5 .
hydroohlorie aeid, dried, and evaporated in vacuo. The .::
residue i5 dissolved in chloroform and chromatographed on a 66 g-silica gel eolumn. Elution with chloroform gives 2.4 g of material which erystallizes from acetone-hexane to give 1.55 g of 11~,21-dihydroxypregna-1,9-dienoll6a,~
- ~ 17 b][l,4]dioxane-3,20-dione, 21-~cetate, melting point 280-282C.
' .
Z -62- ~
., .
.

i.... . . ,, , ,.. , . ... . ~ . . . .~:

; : : ..... .. :.... : .. :: :, . . .: . :. . , , , : ..

105~966 K540a Examples_23-25 Following the proc~dure of Example 1, but substituting the steroid listed in column I for 9-fluoro~ ,16~,17,21-tetrahydroxypregn-4-ene-3 t 20-dione, 16,17-cycloborate, -the steroid listed in column II is obtained.
' 3~

X54 0 a ~15~966 ~`I Q ~),~ .IJ
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Examples 26-28 Following the procedure of Example 15, but sub~
stituting the acid anhydrid~ listed in column I for acetic ' anhydride, the steroid listed in col.umn II is obtained.

1 0 , , ~ .

., : ' . , ' 30 .

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--6 6-- :
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.. ~ . .. . . .

K540a ~L050966 Examples 29-32 .
Following the procedure of Example 20, but sub-stituting the steroid listed in column I for 21-chloro-9-fluoro~ ,16~,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate, the steroid listed in column II is obtained ' -.
, .. . ..

, :1 .
., .:
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o ~ ~ .~.~ ~ ~ ~ ~ c, H ~ I O I I ,~ .~ tt ~ Ll X
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~ 68- ~ .

... , : , . . . .

K540 a 5(~966 Examples 33-35 Following the procedure of Example 22, but sub-stituting the acid anhydride listed in column I for acetic anhydride, the steroid listed in col~mn II is obtained.

. . ~.
.
., .
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,, :
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;~, 20 ~' 1 ' ' '.
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.

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;
, ~ 1050966 K540a O Example 36 .

21-Chloro-5'-(4-chlorophen~1)-9--fluoro-~',3'-- dihydro~ -hydroxypregna-1,4-dieno[16~,17-b]-- [1,4]dioxin-3,20-dione Following the procedure of Example 20, but sub-stituting 2-~4-chlorophenyl)-3-diazo-1--propene for 2-; phenyl-3-diazo-1-propene, yields 21-chloro-5'-(4-chloro-phenyl)-9-fluoro-2',3'-dihydro-11~-hydroxypregna-1,4-dienotl6~,17-b][1,4]dioxin-3,20-dione, melting point 212-214C, dec., softening at 200C.

Example 37 21-Chloro-5'-(1,1-dimeth~lethyl)-9-fluoro-2',3'-- :
dihydro-llB-h~droxypregna-l~4--dieno~l6~l7-~]
11,4]dioxin-3,20-dlone :~
Following the procedure of Example 7, but sub- :
stituting 2-(1,1-dimethylethyl)-3-diazo-1-propene fcr 2- ~ .
methyl-3-diazo-1-propene, yields 21-chloro-5'-(1,1-dimethyl-ethyl)-9-fluoro-2',3'-dihydro-11~-hydroxypregna-1,4-dieno-[16~,17-~]~1,4]dioxin-3,20-dione, melting point 240-242C, dec.

.I . ' ' . ' . ' '; : ~
: :.
'' ~ ' .
' . 30 , ~ , ' '. ' I ~ : ;71- :
. .

....

) K540a ~.~5~
. .
o ~
9-Fluoro~ ,21-dihydroxy-5'~-methylpre~n-4-eno-[16a,17-b][1,4~dioxane-3,20-dione, 21-acetate Ao 9-Fluoro-11~,17,21-trihydroxy-16a-(2~-hydroxypro-~oxy)pregn-4-ene-3,20-dione, 21-acetate A solution of 1.0 g of 9-fluoro-11~, 17,21-trihydroxy-16~-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate (pre-pared as described in Example 2D) in 80 ml of methanol is cooled to 0C and 80 mg of sodium borohydride is added. After 10 minutes the solution is poured into chloroform and ex-tracted with dilute hydrochloric acid. The chloroform solu-tion 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 compound.

B. 9-Fluoro~ ,17,21-trihydroxy-16a-(2~-mesyloxy-propoxy)pre~n-4-ene-3,20-dione, 21-acetate A solution of 7Q0 mg of 9-fluoro-11~,17,21-tri-hydroxy-16a-(2~-hydroxypropoxy)pregn-4-ene-3,~0-dione, 21-acetate in lQ ml of pyridine is cooled to 0C and 0.4 ml of methanesulfonyl chloride is added. After 4 hours the mixture i~ extracted, dried and evaporated to give the title compound.

'; ' ; 3~ ~

:, ~ . , .

. .

K540a ~C~5C~966 .
C. 9-Fluoro~ ,21-dihvdroxv-S~-methvl~regn-4-eno-[16a,17-b][1,4~dioxane-3,20-dione, 21-acetate A solution of 750 mg of 9-fluoro~ ,17,21-trihydroxy-16~ (2~-mesyloxypropoxy)pregn-4-ene-3,20-dione, 21-acetate in 50 ml of dimethylsulfoxide is stirred at llO~C under nitrogen with 1.0 g of sodium bicarbonate. After ~ hours the reaction mixture is extracted, dried and evaporated to yield the title compoundO

-9-Fluoro-11~,21-dihvdroxv-5'~-~henvl~recn-4-eno-~16,17-bl~1,4]dioxane-3,20-dione, 21-acetate A. 9-Fluoro-11~,17,21-trihydroxy-16~-(2-phenyl-?-hydroxyethoxy)pre~n-4-ene-3~2o-dione~ 21-acetate A solution of 1~0 g of 9-fluoro-11~,17,21-trihydroxy-16~(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.0C ànd 80 mg of sodium borohydride is added.
.
After 10 minutes, the solution is poured into chloroform ; 20 and extracted with dilute hydrochloric acid. The chloroform solution is dried and evaporated ln vacuo to yield the title compound.

.; ~ ': .
~ . .

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. .
.

~ -73-: ' . ' :

K540a )9~6 Bo 9-Fluoro~ ,17,~1-trihydroxy-l6a-(2-mesyloxy-2 enylethoxy)pre~n-4-ene-3,20-dione, 21-acetate ~ A solution of 700 mg of 9-fluoro~ ,17,21-trihydrox~-16a- (2-phenyl-2 hydroxyethoxy)pregn-4-ene-3,20~dione, 21-acetate in 10 ml of pyridine is cooled to 0C 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-llB,21-dihydroxy-s~-phenylpreqn-4-en [16~,1 -b][1,4~dioxane-3,20-dione, 21-acetate A solution of 750 mg of 9-fluoro-116,17,21-trihydroxy~
16a-(2-mesyloxy~2-phenylethoxy)pregn-4-ene-3,20--dione, 21-a¢etate in 50 ml of dimethylsulfoxide is stirred at 110C
under nitrogen with 1.0 g of sodium bicarbonate. After 2 hours the reaction mixture is extracted, dried and evapor-ated to yield the title compound.

Ex ~
21-Chloro-9-fluoro-11~-hydroxy-5'-methyl-4'-phenyl-preqna-1,4- dieno[16~,17-b][1,4]dioxin-3,20-dione _ A. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-[(3-oxo-3 henylprop-2-yl)oxy]pregna-1,4-diene-3,20-dione~
, - a. N-[2-~3-oxo-3-phenyl~opyl)~phthalimide ; A solution of 58 g of ~-bromopropiophenone and 50 g of potassium phthalimide in 200 ml~of dimethylformamide is refluxed for 2 hours under nitrogen, cooled, and poured into 500 ml of water. The resulting mlxture is extracted with ether, and khe ether solution is drled and evaporated in vacuo.
A solu ion of the residue in 200 ml of ether gives the title ~ .
3G compound as a solid.

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K540a 5iO966 I b. 2-[1-(N-phthalimidoeth~1)]-2-phenyldioxolane .~
A solution of 49.9 g of ~-[2-(3-oxo-3-phenylpropyl)]
phthalimide in 500 ml of toluene is refluxed for a total of 13 days with S g of ~-toluenesulfonic acid and 150 ml of ethylene glycol. The solution is cooled, diluted with chloroform, and washed with dilute sodium bicarbonate solu-tion. The chloroform solution is dried and evaporated to give, on trituration with ether, 51.5 g of the title com-pound, melting point 127 130C.

c 2~ Aminoethyl)-2-phenyldioxolane A solution of 51.5 g of 2-[1-(N-phthalimidoethyl)]-2-phenyldioxolane in 500 ml of méthanol is refluxed for 6 hours with 5.76 g of hydrazine. The slurry is cooled t f il-tered and the solid washed well with methanol. The filtrate is evaporated in vacuo, and the residue triturated ~ith di-chloromethane and filtered. The filtrate is distilled in vacuo to give 28.25 g of the title compound, boiling point -`1 97-100C at 1.1 mm Hg.

d. 2-Phenyl-2-(1-~ethox~ca~bonylamlnoethyl)-dioxolan_ ~
A solution of 2-~1-aminoethyl)-2-phenyldioxolane (20 mmoles), triethyl amine (24 mmoles), and ethyl chloro- ; -.
ormate (22 mmol~s) in L00 ml of dichloromethane is stirred at 0C for 2 hours, washed wi~h water, dried, and evapor-"
aeed to give the title compound. ~ ~

.
:. "' ' . :

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.

,: ' ' : ' K540a Ei6 e. 2-Phenyl-2~ diazoeth~)dioxolane Following the procedure of Example 4A (parts c and d), hut substituting 2-phenyl-2-~1-ethoxycarbonylamino-ethyl)dioxolane for N-(2-phenyl-2-propenyl)ethyl carhamate, the title compound is obtained.

f. 21-Chloro-9-fluoro-11~,17 ~ ~-[(3 oxo~ henylprop-2-yl)oxy]~regna-1,4-diene-3,20-dione A solution of 2-phenyl-2-(1-diazoethyl)dioxolane in 3:2 ether-pentane is diluted with methanol and cooled to 0C.
21-Chloro-9-fluoro-11~,16~,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed ln vacuo.
The residue is purified and dissolved in tetrahydro-furan. The solution i9 refluxed with hydrochloric acid. The solvent is removed ln vacuo and the residue is diluted with water, extracted with chloroform, and the chloroform solution is washed with 5% sodium hicarbonate solution, water, dried, and evaporated to yield the title compound.

.

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K540a B. 21-Chloro-9-fluoro~ hydroxy-5'-me h phenylpregna-1,4-dieno[16~,17-b][1,4]dioxin--- v . . _ 3,20-dione A slurry of 150 mg of ~-toluenesulfonic acid in 750 ml of benzene is refluxed with a Dean-Stark trap. The first 150 ml of benzene-water azeotrope is discarded and ~inde 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-11~,17-dihydroxy-16~-[(3-oxo-3-phenyl-io prop-2-yl)oxy]pregna-1,4-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 ln vacuo to yield the title compound.

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.
i 30 ~

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., ~ .

Claims (58)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a steroid having the for-mula and the 1,2-dehydro and 6,7-dehydro derivatives thereof, wherein Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y' is hydroxyl or together Y and Y' are =O;
X is hydrogen or halogen; P is hydrogen, methyl or chloro;
O is hydrogen, methyl or fluoro; A1 is , , or ; R1 is hydrogen, alkyl or aryl; R2 is hydrogen, alkyl or arylalkyl;
R3 is alkyl, cycloalkyl or aryl; and R4 and R5 are the same or different and are alkyl or aryl, which comprises:

a) whenever A1 is to be , treating a steroid of the formula with sodium bicarbonate in a dipolar aprotic solvent;

b) whenever Al is to be and R4 and R5 are the same or different and are hydrogen, alkyl or aryl, treating a steroid of the formula with an acid catalyst; or R4 and R5 are the same or different and are alkyl or aryl, subjecting a steroid of the formula to consecutive mineral acid and organic acid treatment;
c) whenever Al is to be R2O-CH-CH2, where R2 is hydrogen, alkyl or aralkyl, treating a steroid of the formula with an acid;
d) whenever Al is to be -CH=CH-, dehydrating a steroid of the formula where R'7 is hydrogen;
e) Whenever Al is to be , oxidizing a steroid of the formula with Fetizon's reagent; and f) whenever Al is to be and R3 is alkyl, cycloalkyl or aryl, acylating a steroid with an acyl group.

2. A process in accordance with claim 1 wherein X is fluoro.

3. A process in accordance with claim 1 wherein Z
is hydroxyl.

4. A process in accordance with claim 1 wherein Z
is acyloxy.

5. A process in accordance with claim 1 wherein Z
is halogen.

6. A process in accordance with claim 1 wherein z is chlorine.

7. A process in accordance with claim 1 for preparing a steroid wherein Al is .

8. A process in accordance with claim 1 for preparing a steroid wherein Al is .

9. A process in accordance with claim 1 for preparing a steroid wherein Al is .

10. A process in accordance with claim 1 for preparing a steroid wherein Al is .

11. A process in accordance with claim 1 for preparing a steroid wherein Al is .

12. A process in accordance with claim 1 for preparing a steroid wherein Al is .

13. A process in accordance with claim 1 wherein Z is acetoxy, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is .

14. A process in accordance with claim 1 wherein Z is acetoxy, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and A1 is .

15. A process in accordance with claim 1 wherein Z is hydroxyl, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and A1 is -CH=CH-.

16. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and A1 is .

17. A process in accordance with claim 1 wherein Z is hydroxyl, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and A1 is .

18. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and A1 is .

19. A process in accordance with claim 1 wherein Z is hydroxyl, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and A1 is .

20. A process in accordance with claim 1 wherein Z is acetoxy, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and A1 is .

21. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydro-gen, Q is hydrogen, and A1 is .

22. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is

23. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is -CH=CH-.

24. A process in accordance with claim 1 wherein Z is acetoxy, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is .

25. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is .

26. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is -CH2-CH2-.

27. A process in accordance with claim 1 wherein Z is acetoxy, Y is hydrogen, Y' is hydroxyl, X is hydrogen, P is hydrogen, Q is hydrogen, and Al is -CH2-CH2-.

28. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is .

29. A process in accordance with claim 1 wherein Z is chloro, Y is hydrogen, Y' is hydroxyl, X is fluoro, P is hydrogen, Q is hydrogen, and Al is .

30. A steroid having the formula and the 1,2-dehydro and 6,7-dehydro derivatives thereof, wherein Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y' is hydroxyl or together Y and Y' are =O; X
is hydrogen or halogen; P is hydrogen, methyl or chloro;
Q is hydrogen, methyl or fluoro; Al is , , , or ; R1 is hydrogen, alkyl or aryl; R2 is hydrogen, alkyl or arylalkyl;
R3 is alkyl, cycloalkyl or aryl; and R4 and R5 are the same or different and are alkyl or aryl, whenever prepared according to the process of claim 1.

31. A steroid in accordance with claim 30 wherein X is fluoro, whenever prepared according to claim 2.

32. A steroid in accordance with claim 30 wherein Z
is hydroxyl, whenever prepared according to claim 3.

33. A steroid in accordance with claim 30 wherein Z
is acyloxy, whenever prepared according to claim 4.

34. A steroid in accordance with claim 30 wherein Z is halogen, whenever prepared according to claim 5.

35. A steroid in accordance with claim 30 wherein Z is chlorine, whenever prepared according to claim 6.

36. A steroid in accordance with claim 30 wherein Al is , whenever prepared according to claim 7.

37. A steroid in accordance with claim 30 wherein Al is , whenever prepared according to claim 8.

38. A steroid in accordance with claim 30 wherein Al is , whenever prepared according to claim 9.

39. A steroid in accordance with claim 30 wherein Al is , whenever prepared according to claim 10.

40. A steroid in accordance with claim 30 wherein Al is , whenever prepared according to claim 11.

41. A steroid in accordance with claim 30 wherein Al is , whenever prepared according to claim 12.

42. A steroid in accordance with claim 30 having the name9-fluoro-5'.epsilon.,11.beta.,21-trihydroxypregn-4-eno-[16a,17--b][l, 4]dioxane-3,20-dione, 21-acetate, whenever prepared according to claim 13.

43. A steroid in accordance with claim 30 having the name9-fluoro-2',3'-dihydro-11.beta.,21-dihydroxy-5'-methylpregn-4-eno[l6a,17-b]11,4]dioxin-3,20-dione, 21-acetate, whenever pre-pared according to claim 14.

44. A steroid in accordance with claim 30 having the name9-fluoro-2',3'-dihydro-11.beta.,21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxin-3,20-dione, whenever prepared according to claim 15.

45. A steroid in accordance with claim 30 having the name21-chloro-9-fluoro-2',3'-dihydro-11.beta.-hydroxy-5'-meethyl-pregna-1,4-dieno[16a,17-b][1,4]dioxin-3,20-dione, whenever pre-pared according to claim 16.

46. A steroid in accordance with claim 30 having the name5'.epsilon.-ethoxy-9-fluoro-11.beta.,21-dihydroxypregn-4-eno-[16a,17-b][l,4]dioxane-3,20-dione, whenever prepared according to claim 17.

47. A steroid in accordance with claim 30 having the name21-chloro-5'.epsilon.-ethoxy-9-fluoro-11.beta.-hydroxypregn-4-eno [16a,17-b][1,4]dioxane-3,20-dione, whenever prepared according to claim 18.

48. A steroid in accordance with claim 30 having the name9-fluoro-5'.epsilon.,11.beta.,21-trihydroxypregn-4-eno[16a,17-b][1,4]
dioxane-3,20-dione, whenever prepared according to claim 19.

49. A steroid in accordance with claim 30 having the name9-fluoro-5'.epsilon.,11.beta.,21-trihydroxypregn-4-eno-[16a,17-b][l, 4]dioxane-3,20-dione, 5',21-diacetate, whenever prepared according to claim 20.

50. A steroid in accordance with claim 30 having the name 21-chloro-9-fluoro-5'.epsilon.,11.beta.-dihydroxypregna-1,4-dieno[16a, 17-b][1,4]dioxane-3,20-dione, whenever prepared according to claim 21.

51. A steroid in accordance with claim 30 having the name21-chloro-9-fluoro-5'.epsilon.,11.beta.-dihydroxypregna-1,4-dieno[16a, 17-b][1,4]dioxane-3,20-dione, 5'-acetate, whenever prepared according to claim 22.

52. A steroid in accordance with claim 30 having the name21-chloro-9-fluoro-2',3'-dihydro-11.beta.-hydroxypregnaa-1,4-dieno[l6a,17-b][1,4]dioxin-3,20-dione, whenever prepared according to claim 23.

53. A steroid in accordance with claim 30 having the name9-fluoro-11.beta.,21-dihydroxypregn-4-eno[16a,17-b][1,4]dioxane-3,5',20-trione, 21-acetate, whenever prepared according to claim 24.

54. A steroid in accordance with claim 30 having the name 21-chloro-9-fluoro-2',3'-dihydro-11.beta.-hydroxy-5'-phenyl-pregna-1,4-dieno[16a,17-b][1,4]dioxin-3,20-dione, whenever prepared according to claim 25.

55. A steroid in accordance with claim 30 having the name 21-chloro-9-fluoro-11.beta.-hydroxypregna-1,4-dieno-[16a, 17-b][1,4]dioxane-3,20-dione, whenever prepared according to claim 26.

56. A steroid in accordance with claim 30 having the name 11.beta.,21-dihydroxypregna-1,4-dieno[16a,17-b][1,4]dioxane -3,20-dione, 21-acetate, whenever prepared according to claim 27.

57. A steroid in accordance with claim 30 having the name 21-chloro-5'-(4-chlorophenyl)-9-fluoro-2',3'-dihydro-11.beta.-hydroxypregna-1,4-dieno[16a,17-b][1,4]dioxin-3,20-dione, when-ever prepared according to claim 28.

58. A steroid in accordance with claim 30 having the name 21-chloro-5'-(1,1-dimethylethyl)-9-fluoro-2',3'-dihydro-ll.beta.-hydroxypregna-1,4 dieno[l6a,17-b][1,4]dioxin-3,20-dione, whenever prepared according to claim 29.