Novel, topically-active anti-inflammatory steroids are represented by the formula ##STR1## wherein X is fluoro, chloro or hydrogen; X.sup.1 is fluoro, chloro, bromo, or hydrogen; X.sup.2 is hydroxy or may be chloro when X.sup.1 is chloro; and X.sup.3 and X.sup.4 are independently fluoro, chloro or bromo. These steroids are prepared by formylating at the 21-position a 16.alpha.,17.beta.-isopropylidenedioxypregna-1,4,9(11)-triene-3,20-dione or the corresponding 21-fluoro compound, halogenating at the 21 position, deformylating, then reacting to add the desired components at the 9.alpha. and 11.beta. positions.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a new class of 16.alpha.,17.alpha.-acetonide 
steroids which are 21,21-dihalo substituted. More specifically they are 
compounds which are 21,21-dihalo-16.alpha., 
17.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-diones and the 
corresponding pregn-4-enes which may have a 6.alpha.-halo substituent, a 
9.alpha.-fluoro or chloro substituent, and an 11.beta.-hydroxy substituent 
or 11.beta.-chloro substituent. The compounds of the invention are useful 
as topical anti-inflammatories. The invention also relates to a process 
for making the compounds of this invention which comprises formylating at 
the 21 position a .DELTA..sup.1,4,9(11) steroid having either one halo 
substituent or no halo substituents at the 21 position, halogenating, 
subsequently deformylating, and reacting at the 9(11) double bond to form 
the compounds of the invention. 
2. Prior Art 
It is known from U.S. Pat. No. 3,236,866 to Ringold and Edwards that 
21,21-difluoro-.DELTA..sup.1 -pregnenes are useful as progestational 
agents and as such exhibit anti-androgenic, anti-estrogenic and 
anti-gonadotrophic activity. It is also known from U.S. Pat. No. 3,681,405 
patented Aug. 1, 1972 to Laurent et al. that certain 21,21-dichloro 
steroids have anti-inflammatory activity. The compounds are represented by 
the formula 
##STR2## 
wherein R.sup.1 is hydrogen or chlorine; 
R.sup.2 is hydrogen, fluorine or methyl; 
R.sup.3 is hydrogen or methyl; 
R.sup.4 is hydrogen or a free or esterified hydroxy group; and 
C.sub.1 c.sub.2 represents a single or double bond joining carbon atoms at 
the 1 and 2 position. 
It is further known that 21,21-diiodo, -dibromo, and dichloro steroids are 
useful as intermediates in preparation of certain steroid compounds. See 
for example Canadian Pat. No. 769,025; French Pat. No. 1,243,528; U.S. 
Pat. No. 2,715,621; U.S. Pat. No. 2,752,366; and German Pat. No. 
DT2225658, the latter patent disclosing the 21,21-diiodo compounds which 
are useful for the preparation of triamcinalone, fluocinolone, 
dexamethasone, betamethasone, and paramethasone. 
SUMMARY OF THE INVENTION 
One aspect of this invention is a compound selected from those represented 
by the formula 
##STR3## 
wherein X is fluoro, chloro or hydrogen; 
X.sup.1 is hydrogen, fluoro, chloro or bromo; 
X.sup.2 is hydroxy or may be chloro when X.sup.1 is chloro; 
X.sup.3 and X.sup.4 are independently fluoro, chloro, or bromo; and 
the broken line between C-1 and C-2 indicates that the bond between C-1 and 
C-2 is a single or a double bond. Of the compounds encompassed by the 
generic formula, the preferred compound is selected from those represented 
by formula (I) wherein X.sup.3 and X.sup.4 are independently fluoro or 
chloro and X, X.sup.1, X.sup.2 and the broken line are as previously 
defined. 
Another aspect of this invention is a method of treating an inflamed 
condition in mammals which method comprises topically applying at least 
one compound to the inflamed condition. 
Still another aspect of the invention is the anti-inflammatory combination 
of at least one compound of this invention with a suitable, 
pharmaceutically acceptable carrier. 
Another aspect of this invention is a process which comprises 
a. reacting a formylating agent with a compound represented by the formula 
##STR4## 
wherein X is fluoro, chloro or hydrogen, to form a compound represented by 
the formula 
##STR5## 
wherein X is previously defined; 
b. reacting the compound represented by formula (III) with a halogenating 
agent to form a compound represented by the formula 
##STR6## 
wherein X is previously defined and X.sup.3 is chloro or bromo 
c. reacting the compound represented by formula (IV) with a deformylating 
agent to form a compound represented by the formula 
##STR7## 
wherein X and X.sup.3 are defined previously 
d. treating the compound of formula (V) with a suitable reactant or 
reactants, as described hereinafter, to form a 21-fluoro-21-halo compound 
of this invention represented by formula (I) wherein X, X.sup.1, X.sup.2 
and X.sup.3 are previously defined; and 
e. optionally, if the .DELTA..sup.4 steroids of the invention are desired, 
reducing the C.sub.1 - C.sub.2 double to a single bond. 
Alternatively, the .DELTA..sup.4 steroids may be obtained by proceeding 
through steps (a)-(d) but substituting and ethylene ketal derivative for 
the compound represented by formula (II), namely a compound represented by 
##STR8## 
then hydrolyzing the ketal to form a 21-fluoro-21-halo-.DELTA..sup.4 
steroid of formula (I). The .DELTA..sup.1,4 steroid of formula (I) is 
thereafter obtained by forming an unsaturated bond between C.sub.1 and 
C.sub.2 as discussed hereafter 
The 21,21-difluoro steroids of the invention are obtained by reacting a 
compound represented by formula (IV) with a fluorinating agent to 
substitute a fluoro for the X.sup.3 group at the 21 carbon. 
The 21,21-dichloro or 21,21-dibromo steroids of the invention are prepared 
by 
a. formylating an appropriate 
16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene-3,20-dione 
to form the corresponding compound having a hydroxymethylene group at the 
21 position; 
b. halogenating the product from the previous step to form the 
corresponding 21,21-dihalo-21-formyl-steroid; 
c. deformylating to form the corresponding 21,21-dihalo compound; 
d. treating the resulting product to add the desired substituents at 
9.alpha.-and 11.beta.-positions; and 
e. optionally, reducing the .DELTA..sup.1 bond. 
The 21-bromo-21-chloro steroids are similarly prepared except that in step 
(b) immediately above, the compound is chlorinated (or brominated) to give 
the 21-chloro (or 21-bromo)-21-formyl steroid then brominated (or 
chlorinated) to give the 21-chloro-21-bromo-21-formyl steroid. 
FURTHER DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 
Compounds of the Invention 
Compounds falling within the scope of the invention are those represented 
by formula (I) wherein 
X is hydrogen, fluoro, or chloro; 
X.sup.1 is hydrogen, fluoro, chloro or bromo; 
X.sup.2 is hydroxy or may be chloro when X.sup.1 is chloro; 
X.sup.3 and X.sup.4 are independently fluoro, chloro or bromo; and 
the broken line between C-1 and C-2 represents a single or a double bond. 
Thus compounds failling within the scope of the claims include the 
following compounds which are named as 
16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-diones or 
16.alpha.,17.alpha.-isopropylidenedioxypregn-4-ene-3,20-diones, with the 
substituents on the 6.alpha.-,9.alpha.-,11.beta.-,21-positions being named 
in alphabetical order: 
66.sup.1,4 Steroids 
6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden 
edioxypregna-1,4-diene-3,20-dione; 
21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropy 
lidenedioxypregna-1,4-diene-3,20-dione; 
21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-21-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-iso 
propylidenedioxypregna-1,4-diene-3,20-dione; 
21,21-dibromo-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropy 
lidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,9.alpha.,21,21-tetrafluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-is 
opropylidenedioxypregna-1,4-diene-3,20-dione; 
21-chloro-6.alpha.,9.alpha.,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-6.alpha.,9.alpha.,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha 
.-isopropylidenedixoypregna-1,4-diene-3,20-dione; 
21,21-dichloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-21-chloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
21,21-dibromo-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.-chloro-6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.,21-dichloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-9.alpha.-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.,21,21-trichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,21,21-trifluoro-9.alpha.,11.beta.-dichloro-16.alpha.,17.alpha.-iso 
propylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.,11.beta.,21-trichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha.-iso 
propylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-9.alpha.,11.beta.-dichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha 
.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.,11.beta.,21,21-tetrachloro-16.alpha.,17.alpha.-isopropylidenedioxy 
pregna-1,4-diene-3,20-dione; 
6.alpha.-chloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,21-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-6.alpha.-chloro-21-fluoro-11.beta.-hydroxy- 
16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,21,21-trichloro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden 
edioxypregna-1,4-diene-3,20-dione; 
6.alpha.-chloro-9.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,21-dichloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregna1,4-diene-3,20-dione; 
21-bromo-6.alpha.-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,21,21-trichloro-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,9.alpha.-dichloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,9.alpha.,21-trichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-6.alpha.,9.alpha.-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,9.alpha.,21,21-tetrachloro-11.beta.-hydroxy-16.alpha.,17.alpha.-is 
opropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,9.alpha.,11.beta.-trichloro-21,21-difluoro-16.alpha.,17.alpha.-iso 
propylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,9.alpha.,11.beta.,21-tetrachloro-21-fluoro-16.alpha.,17.alpha.-iso 
propylidenedioxypregna-1,4-diene-3,20-dione; 
21-bromo-6.alpha.,9.alpha.,11.beta.-trichloro-21-fluoro-16.alpha.,17.alpha. 
-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
6.alpha.,9.alpha.,11.beta.,21,21-pentachloro-16.alpha.,17.alpha.-isopropyli 
denedioxypregna-1,4-diene-3,20-dione; 
9.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden 
edioxypregna-1,4-diene-3,20-dione; 
21-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregna-1,4-diene-3,20-dione; 
21,21-dichloro-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.,11.beta.-dichloro-21,21-difluoro-16.alpha.,17.alpha.-isopropyliden 
edioxypregna-1,4-diene-3,20-dione; 
9.alpha.,11.beta.,21-trichloro-21-fluoro-16.alpha.,17.alpha.-isopropylidene 
dioxypregna-1,4-diene-3,20-dione; 
9.alpha.,11.beta.,21,21-tetrachloro-16.alpha.,17.alpha.-isopropylidenedioxy 
pregna-1,4-diene-3,20-dione; 
9.alpha.-bromo-6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha 
.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.-bromo-6.alpha.-chloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxy-1,4-diene-3,20-dione; 
9.alpha.-bromo-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropy 
lidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.-bromo-21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.-bromo-21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
9.alpha.-bromo-6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha 
.-isopropylidenedioxypregna-1,4-diene-3,20-dione; 
21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxypreg 
na-1,4-diene-3,20-dione; 
9.alpha.-bromo-21-chloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-iso 
propylidenedioxypregna-1,4-diene-3,20-dione; 
21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregna-1,4-diene-3,20-dione; 
.DELTA..sup.4, Steroids 
21,21-dichloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregn-4-ene-3,20-dione; 
21-bromo-21-chloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,21,21-trifluoro-9.alpha.-chloro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregn-4-ene-3,20-dione; 
21-bromo-9.alpha.-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregn-4-ene-3,20-dione; 
9.alpha.,21-21-trichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,21,21-trifluoro-9.alpha.,11.beta.-dichloro-16.alpha.,17.alpha.-iso 
propylidenedioxypregn-4-ene-3,20-dione; 
9.alpha.,11.beta.,21-trichloro-6.alpha.-21-difluoro-16.alpha.,17.alpha.-iso 
propylidenedioxypregn-4-ene-3,20-dione; 
21-bromo-9.alpha.,11.beta.-dichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha 
.-isopropylidenedioxypregn-4-ene-3,20-dione; 
9.alpha.,11.beta.-21,21-tetrachloro-16.alpha.,17.alpha.-isopropylidenedioxy 
pregn-4-ene-3,20-dione; 
6.alpha.-chloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,21-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.-chloro-9.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,21-dichloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregn-4-ene-3,20-dione; 
21-bromo-6.alpha.-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-4-ene-3,20-dione; 
6.alpha.,21,21-trichloro-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedixoypregn-4-ene-3,20-dione; 
6.alpha.,9.alpha.-dichloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,9.alpha.,21-trichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregn-4-ene-3,20-dione; 
21-bromo-6.alpha.,9.alpha.-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,9.alpha.,21,21-tetrachloro-11.beta.-hydroxy-16.alpha.,17.alpha.-is 
opropylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,9.alpha.,11.beta.-trichloro-21,21-difluoro-16.alpha.,17.alpha.-iso 
propylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,9.alpha.-11.beta.-21-tetrachloro-21-fluoro-16.alpha.,17.alpha.-iso 
propylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.-bromo-21-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 
.alpha.-isopropylidenedioxypregna-4-ene-3,20-dione; 
6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden 
edioxypregn-4-ene-3,20-dione; 
21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregn-4-ene-3,20-dione; 
21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop 
ylidenedioxypregn-4-ene-3,20-dione; 
6.alpha.,9.alpha.-21,21-tetrafluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-is 
opropylidenedioxypregn-4-ene-3,20-dione; 
21-chloro-6.alpha.,9.alpha.,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph 
a.-isopropylidenedioxypregn-4-ene-3,20-dione; and other .DELTA..sup.4 
steroids corresponding to the .DELTA..sup.1,4 steroids named hereinbefore. 
Of the compounds broadly set forth above, the group that is particularly 
valuable and therefore preferred includes the compounds represented by 
formula (I) wherein X.sup.3 and X.sup.4 are each independently chosen from 
fluoro or chloro and X, X.sup.1, X.sup.2 and the broken line between 
C.sub.1 and C.sub.2 are as described in this section hereinbefore. An 
especially preferred subgroup is that wherein X is fluoro; X.sup.1 is 
fluoro or chloro; X.sup.3 is fluoro; X.sup.4 is fluoro or chloro; and 
X.sup.2 is as previously described. 
Process For Preparation 
The essence of the process aspect of this invention is premised on the 
discovery that certain known 
16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene-3,20-diones 
compounds which are substituted by one fluoro atom at the 21 position or 
have no fluoro at the 21 position can be 21-formylated, halogenated and 
deformylated to form novel intermediates from which the novel 
anti-inflammatory compounds of this invention are obtained. Reaction 
Scheme A exemplifies one facet of the process for preparing the compounds 
of this invention. In this reaction scheme the wavy line indicates that 
the rest of the steroid molecule remains unchanged. 
##STR9## 
One aspect of the process of this invention comprises (a) treating a 
compound (II) which is substituted with a fluorine atom on the 21 carbon 
of the steroid chain with a formylating agent to form a compound of 
formula (III), (b) treating the compound of formula (III) with a suitable 
halogenating agent to form a 21-fluoro-21-halo compound (IV) also having a 
formyl group attached to C.sub.21 ; and (c) deformylating the compound, 
i.e., the formyl group is removed to form a compound indicated as formula 
(V). 
The compound of formula (V) may be treated with a suitable chlorinating 
agent to form a compound of formula (Ia), or may be treated to form a 
9.alpha.,11.beta.-bromhydrin of formula (Ib) which in turn is epoxidized 
then hydrofluorinated to form a 9.alpha.,11.beta.-fluorhydrin of this 
invention represented by formula (Ic). 
a. In the first step of the process of this invention the starting 
material, a 
16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene-3,20-dione 
which is substituted at the 21 position with a fluoro substituent, and 
preferably with a 6.alpha.-fluoro or 6.alpha.-chloro substituent, and 
preferably with a 6.alpha.-fluoro or 6.alpha.-chloro substituent is mixed 
with a suitable hindered base such as 
N-isopropyl-N-lithium-cyclohexylamine (formed by reacting 
isopropylcyclohexylamine with n-alkyl lithium in an appropriate aprotic 
solvent such as a mixture of tetrahydrofuran and hexametylphosphoric 
triamide or other suiable ethers such as glyme, dioxane, tetrahydropyran 
(THP), and the like), N-lithium-diisopropylamine, N-lithium 
bis-1,1,1-trimethylsilylamine. The reactants are stirred together 
preferably in an inert atomosphere such as nitrogen or argon at 
temperatures from about 10.degree. to 50.degree. C preferably at about 
20.degree.-25.degree. C for 5 to 24 hours. A suitable formylating agent 
such as ethyl formate is added and the reaction continued for a time 
sufficient to form a compound represented by formula (III). Generally this 
will be about 2 to 10 hours, preferably about 4 or 5 hours. The resulting 
product can then be extracted and crystallized using methods well known in 
the art for this particular process. 
b. Once a reaction product represented by formula (III) is obtained, it is 
reacted with at least an equimolar amount of a halogenating agent, i.e. 
(i) a suitable chlorinating agent such as copper chloride with lithium 
chloride, t-butyl hypochlorite, sulfuryl chloride and the like, (ii) a 
suitable brominating agent such as cupric bromide and the like or (iii) a 
suitable fluorinating agent such as trifluoromethyl hypofluorite, 
perchloryl fluoride, and the like, in a suitable solvent such as DMF, 
chloroform, THF, and the like. Generally the reaction will take place at a 
temperature of about 25.degree. to 100.degree. C, preferably about 
40.degree. to 50.degree. C for the first part of the reaction then 
70.degree. to 90.degree. C for the latter part of the reaction. The 
reaction will be completed in about 2 to 10 hours, preferably about 3 
hours at the lower temperature and 1 hour at the upper temperature. 
c. The resulting 21-fluoro-21-chloro (21-bromo or 21-difluoro)-21-formyl 
steroid (IV) is reacted with a molar excess of a deformylating agent such 
as an alkali metal hydroxide (e.g. sodium or potassium hydroxide), an 
alkaline earth hydroxide (e.g. barium hydroxide), and the like in a 
suitable solvent such as ethanol, methanol, ether, water, and the like or 
mixtues thereof. This reaction will take place generally at about 
-10.degree. to +10.degree. C, preferably at 0.degree. C for a period of 
time sufficient to complete the reaction which is generally about 1 to 5 
hours, preferably about 2 to 3. Purification and recrystallization can be 
done using procedures known in the art. 
An alternative method for preparing a 21,21-difluorosteroid such as (Id), 
(Ie) or (If) is to treat the resulting product if a 21-bromo or 21-chloro 
is present, with a suitable fluorinating agent such as tetramethylammonium 
fluoride in an appropriate solvent such as sulfolane at the appropriate 
tenperature, for example about 40.degree. to 120.degree. C, preferably 
about 70.degree. to 90.degree. C for a period of time sufficient to 
complete the reaction, i.e. generally about 2 to 10 hours, preferably 
about 2 to 3. After purification the resulting 21,21-difluoro compound 
(VI) (or the 21,21-mixed halogen compound) is further treated to form the 
corresponding 9.alpha.,11.alpha.-dichloro compound represented by formula 
(Id) (or formula (Ia) in the case of the 21,21-mixed halogen compound) by 
chlorinating across the double bond between C-9 and C-11. The chlorination 
step may be carried out using procedures known in the art, e.g. see 
"Steroids" 5, 615-35 (1965) by Heller et al. Generally chlorine gas is 
bubbled through a solution of the reactant in a chlorinated hydrocarbon 
such as methylene dichloride in the presence of a suitable base catalyst 
such as pyridine. Generally the addition takes no more than a few minutes 
at about 20.degree.- 30.degree. C. 
A 9.alpha.-fluoro-11.beta.-hydroxy compound represented by formulae (Ic) or 
(If) is formed by epoxidizing the bond between the C-9 and C-11 carbons in 
formulae (V) or (VII). The epoxidation is a two step procedure wherein a 
compound of this invention represented by formulae (Ib) or (Ie) is 
prepared by reacting (V) or (VII) with dibromantin along with a dilute 
perchloric acid solution. In this step, an intermediate having 
9.alpha.-bromo-11.beta.-hydroxy substituents on the steroid structure (Ib) 
or (Ie) is first formed which may be readily purified using procedures 
well known in the art. This material (either crude or pure) is then 
dehydrobrominated using for example isopropyl alcohol and potassium 
acetate at reflux temperature for a time sufficient to form the epoxide as 
indicated in formulae (VI) and (VIII). 
The resulting epoxide compound is purified then reacted with a 
hydrohalogenating agent such as hydrofluoric or hydrochloric acid to form 
a 9.alpha.-halo-11.beta.-hydroxy compound of this invention. Such 
hydrohalogenating procedures are well known in the art. See for example 
Organic Reactions In Steroid Chemistry, Vol. I, edited by J. Fried and J. 
Edwards, Chap. 8, Van Nostrand Rheinhold (1972), which is incorporated 
herein by reference. 
By reacting the compounds represented by formulae (Ib) and (Ie) with, e.g., 
tributyltin hydride in a suitable solvent such as THF, other compounds of 
the invention represented by the following formulae may be respectively 
obtained: 
##STR10## 
Generally the conversion is implemented by irradition in the presence of 
azobisisobutyronitrile. 
The 21,21-dichloro, 21-bromo-21-chloro and 21,21-dibromo steroids of the 
invention are prepared by a process similar to that set forth in Reaction 
Scheme A, but instead of a 21-fluoro steroid as a starting material, a 
16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene-3,20-dione 
is employed as set forth in Reaction Scheme B. In this reaction scheme the 
wavy lines in formulae (IIIB), (IIIC), (IVB) and (VB) indicate that the 
remainder of the steroid structure (i.e. positions 1-19) is the same as 
that depicted in formula (IIB). 
##STR11## 
The starting material represented by (IIB) is formylated under 
substantially similar conditions described for the first step in Reaction 
Scheme A, supra, except that the reaction is carried out at reflux 
conditions. The 21-formylated steroid (IIIB) is then halogenated, that is 
chlorinated or brominated, by reacting the compound represented by formula 
(IIIB) with a suitable halogenating agent in an appropriate inert solvent 
at temperatures of about 0.degree. to 100.degree. C, depending on the 
reactants and solvents, to give the 21,21-dihalo steroid of formula (IVB). 
Suitable chlorinating agents include cupric chloride with lithium 
chloride, sulfuryl chloride, t-butyl hypochlorite, and the like, 
preferably cupric chloride with lithium chloride, while suitable 
brominating agents include cupric bromide, N-bromosuccinimide, bromine, 
and the like, preferably cupric bromide. Appropriate solvents include 
dimethylformamide, ethyl acetate, chloroform, carbon tetrachloride, and 
the like and may be used for either the chlorination or bromination. 
If the 21,21-dichloro or 21,21-dibromo steroid is desired, then at least 
two molar equivalents of the chlorinating agent or brominating agent must 
be respectively used to give a compound represented by formula (IVB) 
wherein X.sup.3 and X.sup.4 are both chloro or both bromo. If, on the 
other hand, the 21-bromo-21-chloro-steroid is desired, the halogenation is 
carried out stepwise by first reacting about an equimolar amount of a 
chlorinating (or brominating) agent with a compound represented by formula 
(IIIB) to give a 21-chloro (or bromo) compound represented by formula 
(IIIC) and thereafter brominating (or chlorinating) the resulting compound 
of formula (IIIC) to give (IVB) wherein X.sup.3 is chloro and X.sup.4 is 
bromo. The resulting 21,21-dichloro-21-formyl; 21,21-dibromo-21-formyl; or 
21-bromo-21-chloro-21-formyl steroids may be purified by methods known in 
the art such as solvent extraction and evaporation, filtration, 
recrystallization, and the like. 
The steroid represented by formula (IVB) is then deformylated according to 
the procedure discussed hereinbefore in relation to Reaction Scheme A to 
form a 
21,21-dihalo-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-trien 
e, 3,20-dione represented by formula (VB). This in turn is reacted 
according to procedures set forth supra to form .DELTA..sup.1,4 steroids 
of this invention represented by formula (I) wherein X.sup.3 and X.sup.4 
are independently chloro or bromo; the broken line between C.sub.1 
-C.sub.2 represents a double bond; and X.sup.1 and X.sup.2 are previously 
defined. 
The .DELTA..sup.4 steroids of this invention are then easily obtained by 
reducing the C.sub.1 -C.sub.2 double bond of the .DELTA..sup.1,4 steroids 
using a suitable reducing agent such as hydrogen with an appropriate 
catalyst such as tris-(triphenylphosphine)chlororhodium in an acceptable 
inert solvent such as a mixture of benzene and ethanol. Such a reaction 
readily takes place at 0.degree. to 50.degree. C, with 20.degree. to 
25.degree. C being preferred. 
Alternatively, the .DELTA..sup.4 steroids of this invention represented by 
formula (I) wherein the bond between C.sub.1 and C.sub.2 is a single bond 
may be prepared by first forming an ethylene ketal derivative of the 
.DELTA..sup.4,9(11) analog of a compound represented by formula (II) or 
(IIB), viz 
##STR12## 
then going through the steps discussed hereinbefore in relation to 
Reaction Schemes A and B to arrive at the ethylene ketal derivatives 
represented by the formula 
##STR13## 
X, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are defined previously. These 
compounds are then hydrolyzed to form compounds of this invention. The 
hydrolysis takes place under acidic conditions and is a procedure well 
documented in the art. See for example chapter 1 by J. F. W. Keana in 
"Steroid Reactions," edited by C. Djerassi, Holden Day (1963). 
The .DELTA..sup.1,4 steroids may be prepared through the 3-ethylene ketal 
route by reacting the .DELTA..sup.4,9(11) -3-ethylene ketal with 
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) according to the procedure 
discussed in chapter 6 or "Organic Reactions of Steroid Chemistry", supra, 
which is incorporated in pertinent part by reference herein. 
The starting materials for the process aspects of this invention, namely 
those compounds represented by formulae (II), (IIB), (IIa) and (IIb), are 
known in the art and may be prepared according to representative 
preparations given hereafter. 
Pharmaceutical Composition 
The novel steroids of this invention may be formulated with suitable 
pharmaceutical vehicles known in the art to form particularly effective 
topical, anti-inflammatory compositions. Generally about 0.001 to about 
10%w of the steroids defined hereinbefore are combined with about 90 to 
about 99.999%w suitable excipients which may include a pharmaceutically 
acceptable solvent and other pharmaceutically acceptable additives to form 
a pharmaceutical formulation which may be applied topically. 
A pharmaceutically acceptable solvent is one which is substantially 
non-toxic and non-irritating under the conditions used and may be readily 
formulated into any of the classical drug formulations such as creams, 
ointments, lotions, gels, or the like. Particularly suitable solvents 
include water, glycerine, propylene carbonate, and glycol such as 
1,2-propylene diol (i.e. propylene glycol), 1,3-propylene diol, or 
mixtures thereof; polyethylene glycol having a molecular weight of from 
100 to 20,000; dipropylene glycol; etc.; and mixtures of the 
aforementioned with each other. 
A cream, topical, anti-inflammatory mixture may be prepared as a semi-solid 
emulsion of oil in water or water in oil. A cream base formulation by 
definition is an emulsion which is a two phase system with one liquid (for 
example fats or oils) being dispersed as small globules in another 
substance (e.g. a glycol-water solvent phase which may be employed as the 
primary solvent for the novel steroids of this invention). Typically the 
cream formulation may contain other than the solvent with the steroids 
therein, fatty alcohols, surfactants, mineral oil or petrolatum and other 
typical pharmaceutical adjuvants such as anti-oxidants, antiseptics, or 
compatible adjuvants. A typical cream base formulation is given in the 
following table. 
______________________________________ 
Water/glycol mixture 50 - 99 
(15% or more glycol) 
Fatty alcohol 1 - 20 
Non-ionic Surfactant 0 - 10 
Mineral Oil 0 - 10 
Typical pharmaceutical adjuvants 
0 - 5 
*Active Ingredients 0.001 - 10 
______________________________________ 
The fatty alcohol, non-ionic surfactant, and other adjuvants are discussed 
in copending application U.S. Ser. No. 551,811 filed Feb. 21, 1975 and as 
much of that application as is pertinent is incorporated herein by 
reference. 
The novel steroids of this invention may also be formulated as ointments. A 
"classical" ointment is a semi-solid anhydrous composition which may 
contain mineral oil, white petrolatum, a suitable solvent such as a glycol 
and may include propylene carbonate and other pharmaceutically suitable 
additives such as surfactants, for example Span and Tween or wool fat 
(lanolin), along with stabilizers such as antioxidants and other adjuvants 
as mentioned before. Following is an example of a typical "classical" 
ointment base: 
______________________________________ 
White petrolatum 40 - 94 
Mineral Oil 5 - 20 
Glycol solvent 1 - 15 
Surfactant 0 - 10 
Stabilizer 0 - 10 
Active Ingredients 0.001 - 10.0 
______________________________________ 
Other suitable ointment base formulations which contain propylene carbonate 
are described in a copending U.S. Pat. applications Ser. No. 85,246, filed 
Oct. 29, 1970 by Shastri et al. entitled "Propylene Carbonate Ointment 
Vehicle" and 201,997, filed Nov. 24, 1971 by Chang et al. entitled "Fatty 
Alcohol-Propylene Carbonate-Glycol Solvent Cream Vehicle". As much of 
those applications as is pertinent is incorporated herein by reference. 
Following is an ointment base formulation containing propylene carbonate 
found to be particularly effective for the compositions of this invention: 
______________________________________ 
Active Ingredients 0.001 - 10.0 
Propylene Carbonate 1 - 10 
Solvent 1 - 10 
Surfactant 1 - 10 
White Petrolatum 70 - 97 
______________________________________ 
Suitable solvents, surfactants, stabilizers, etc. are discussed in U.S. 
Ser. No. 551,811 and such discussion is incorporated herein by reference. 
A suitable "non-classical" anhydrous, water washable "ointment type" base 
is described in U.S. Pat. No. 3,592,930 to Katz and Neiman, and as much of 
that disclosure as is pertinent is incorporated herein by reference. A 
representative composition of this invention utilizing such a base is as 
follows: 
______________________________________ 
Glycol solvent 40 - 85 
Fatty alcohol 15 - 45 
Compatible plasticizer 
0 - 15 
Compatible coupling 0 - 15 
Agent 
Penetrant 0 - 20 
Active Ingredients 0.001 - 10.0 
______________________________________ 
The fatty alcohols which are suitable have been previously disclosed above 
in this specification and in U.S. Pat. No. 3,592,930. As much of those 
disclosures as is pertinent is incorporated herein by reference. 
Method of Treatment 
Generally an inflammed condition in animals, particularly humans, is 
treated by contacting the inflamed area with an effective amount of the 
novel steroids of this invention, i.e. an amount sufficient to effect 
improvement of the inflamed condition. Preferably the steroids are first 
formulated to prepare a suitable pharmaceutical formulation, as discussed 
hereinbefore, which is then placed in contact with the inflammed area. An 
effective amount will depend upon the particular condition and the animal 
receiving the treatment but will vary between 0.001 to 5% by weight of the 
pharmaceutical composition and preferably will be between 0.01 and 1% by 
weight of the formulation. Using these levels in the formulation, a 
therapeutically effective and non-toxic amount, i.e. enough to effect an 
anti-inflammatory response, but not enough to harm the recipient, is 
applied to the inflamed area. 
PREATION A 
This Preparation sets forth a process for making a starting material of 
formula (II) wherein X is H. The Preparation is based on the method set 
forth in U.S. Pat. No. 3,053,838 to Fried. The compound 
21-hydroxy-16.alpha.-17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene- 
3,20-dione (a known compound, see M. Heller, R. H. Lenhard, S. Bernstein, 
"Steroids" 5, 615-35, 1965) is reacted with mesyl chloride in the presence 
of an organic base such as pyridine to form the corresponding 21-mesyl 
steroid. This, in turn, is heated with potassium fluoride in ethylene 
glycol to form 
21-fluoro-16.alpha.-17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene-3 
,20-dione. 
PREATION B 
A starting material of formula (II) wherein X is fluoro is known and may be 
prepared as taught in U.S. Pat. No. 3,409,613 issued Nov. 5, 1968 to J. H. 
Fried. 
PREATION C 
A starting material of formula (II) wherein X is chloro is prepared by 
following the procedure set forth in Preparation A but starting with 
6.alpha.-chloro-21-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxypregna-1 
,4,9(11)-triene-3,20-dione. This compound is prepared from 
21-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxypregna-4,9(11)-diene-3,2 
0-dione (a known compound which may be prepared by hydrogenating 
21-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene- 
3,20-dione with tris-(triphenylphosphine)chlororhodium in benzene and 
ethanol) according to a method described by Ringold et al. in J.A.C.S. 80, 
6464 (1958). In the Ringold et al method, the corresponding 21-acetate of 
the 
3-ethoxy-16.alpha.,17.alpha.-isopropylidenedioxypregna-3,5,9(11)-trien-20- 
one is first prepared which is then reacted with N-chloro succinimide to 
form the 6.beta.-Cl-.DELTA..sup.4,9,(11) steroid. This, in turn, is 
converted to the 6.alpha.-chloro .DELTA..sup.4,9(11) steroid using 
hydrochloric acid/acetic acid. This compound is then reacted with selenium 
dioxide to give the corresponding .DELTA..sup.1,4,9(11) steroid. The 
21-acetate is hydrolyzed to give the desired 21-hydroxy 6.alpha.-chloro 
.DELTA..sup.1,4,9(11) steroid. 
PREATION D 
The starting material of formula (IIB) wherein X is H is a known compound 
and may be prepared as taught in U.S. Pat. No. 3,167,546 issued Jan. 26, 
1965 to Bernstein et al. or in J. Am.Chem. Soc. 81, 4962 (1959). 
PREATION E 
The starting material of formula (IIB) wherein X is F is prepared by 
reacting 
6.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-4,9(11)-dien 
e-3,20-dione (a known compound, see U.S. Pat. No. 3,197,470 issued July 27, 
1965 to Deghenghi et al.) with selenium dioxide as taught in Ringold et 
al. J.A.C.S. 80, 6464 (1958). 
PREATION F 
The starting material of formula (IIB) wherein X is Cl is prepared by 
reacting 
16.alpha.,17.alpha.-isopropylidenedioxypregna-4,9(11)-diene-3,20-dione (a 
known compound, see British Pat. No. 881,501 issued Nov. 1, 1961 to 
American Cyanamid Corp.) according to the Ringold et al. process of 
Preparation C. 
PREATION G 
The starting 3-ethylene ketals represented by formulae (IIa) and (IIb) are 
readily prepared by reacting the starting material made according to 
Preparation A-F with hydrogen in the presence of tris-(triphenylphoshine) 
chlororhodium in a solvent of benzene and ethanol. The resulting 
3-keto-.DELTA..sup.4,9(11) steroid is then reacted with a mixture of dry 
benzene, ethylene glycol and p-toluenesulfonic acid monohydrate at reflux 
conditions using a water separator. The reaction mixture is then washed 
with aqueous sodium bicarbonate solution and water, dried and evaporated 
to dryness to yield a compound represented by formulae (IIa) or (IIb) 
which is recrystallized from acetone:hexane.

The following non-limiting examples are set forth to more fully describe 
the process and compounds of the invention and to teach one of skill in 
the art how to make representative compounds. These examples are 
illustrative only and are not presented to limit the scope of the 
invention in any way. 
EXAMPLE 1 
This example illustrates a process for preparing 
9.alpha.,11.beta.-dichloro-21,21-difluoro-16.alpha.,17.alpha.-propylidened 
ioxypregna-1,4-diene-3,20-diones. 
a. Formylation 
A compound of formula (1) was formylated according to the following 
reaction scheme and procedure 
##STR14## 
To an ice-cooled three neck flask equipped with a mechanical stirrer and 
charged with 5 milliliters (ml.) of freshly distilled 
isopropylcyclohexylamine and 50 ml. of dry tetrahydrofuran (THF), was 
added 20 ml. of 1.5 molar n-butyl lithium followed by a solution of 5.0 
grams (g.) of the steroid (1) in 10 ml. of dry THF and 10 ml. of 
hexamethylphosphoric triamide (HMPA). After stirring under nitrogen at 
room temperature overnight, 5.0 ml. of purified ethyl formate was added 
and stirring continued for 4 more hours at room temperature. The contents 
of the flask were poured into 250 ml. of water and extracted with three 50 
ml. portions of CH.sub.2 Cl.sub.2. The combined CH.sub.2 Cl.sub.2 layers 
were extracted with three 50 ml. portions of 1. N. NaOH solution which was 
combined with the previous aqueous layer. The combined aqueous basic 
layers were acidified with concentrated HCl in the presence of ice, and 
the white precipitate was extracted with CH.sub.2 Cl.sub.2 (5.times.30 
ml.). The combined CH.sub.2 Cl.sub.2 extracts were washed with water, 
brine, dried over MgSO.sub.4 and evaporated to give a yellow solid (6.25 
g.). Recrystallization from acetone-hexane gave a crystalline sample, mp. 
136.degree.-138.degree. C. 
b. Chlorination 
and 
c. Deformylation 
The compound of part (a), above is chlorinated and deformylated according 
to the following reaction scheme and procedure. 
##STR15## 
To a flask charged with 625 milligrams (mg.) of CuCl.sub.2 (3.6 millimole), 
76.4 mg of LiCl (1.8 millimole) in 0.9 ml. of DMF was added 500 mg of the 
hydroxymethylene steroid (2). The solution was heated with stirring to 
40.degree.-50.degree. C for 3 hours under N.sub.2 then to 80.degree. C for 
1 hour. The solution was partitioned between CH.sub.2 Cl.sub.2 (30 ml.) 
and water (50 ml.). After extracting the aqueous layer with CH.sub.2 
Cl.sub.2 (3.times.20 ml.) the combined organic layers were washed with 
water, dried over MgSO.sub.4 and evaporated to give a solid (546 mg). 
This crude solid was dissolved in ethanol (5 ml.) and cooled to 0.degree. 
C. Barium hydroxide (500 mg) was added and the mixture was stirred at 
0.degree. C for 2 hours then partioned between 50 ml. ice cooled 0.1 N. 
HCl and CH.sub.2 Cl.sub.2 (30 ml.). After extracting the aqueous layer 
with CH.sub.2 Cl.sub.2 (2.times.20 ml.) the combined organic layers were 
washed with water, brine, dried over MgSO.sub.4 and evaporated to dryness 
to give a solid (496 mg.). Recrystallization from CH.sub.2 Cl.sub.2 
cyclohexane gave a crystalline sample, mp. 218.degree.-222.degree. C. 
d. Fluorination 
The compound of formula (3) was fluorinated to form the corresponding 
6.alpha.,21,21-trifluoro compound according to the following reaction 
scheme and procedure: 
##STR16## 
To a flask charged with 1.17 g of N(CH.sub.3).sub.4 F and 15 g of sulfolane 
and heated to 75.degree. C was added with stirring 550 mg of the 
21-chloro-21-fluoro steroid (3). The solution was stirred under nitrogen 
(N.sub.2) for about 1/2 hour maintaining the temperature at 75.degree. C. 
The contents of the flask were poured into 50 ml. water, and extracted 
with three 50 ml portions benzene. The combined benzene layers were washed 
with water, brine, dried over MgSO.sub.4 and evaporated to give 600 mg of 
a brown solid which was purified by chromatography on 50 g of silica gel 
with ethyl acetate and hexane as eluting solvents, giving 314 mg. of the 
pure crystalline product, mp. 223.degree.-224.degree. C. 
e. Dichlorination at 9.alpha./11.beta. 
The compound of formula (4) was dichlorinated to form a product of formula 
(5) according to the following reaction scheme and procedure: 
##STR17## 
The 21,21-difluoro steroid (4) (45 mg) was dissolved in 2 ml of a solution 
made by adding 1 ml of pyridine to 10 ml of CH.sub.2 Cl.sub.2. A stream of 
chlorine gas was bubbled through this solution for 4 minutes. After 
diluting with 20 ml of CH.sub.2 Cl.sub.2 this solution was washed with 
dilute HCl, water, brine, dried over MgSO.sub.4 and evaporated to give a 
solid (52 mg). The product was purified by preparative thick layer 
chromatography on silica gel with ethyl acetate in hexane as developing 
solvent. Recrystallization from acetone hexane gave the analytical sample 
(24 mg), of 
9.alpha.,11.beta.-dichloro-6.alpha.,21,21-trifluoro-16.alpha.,17.alpha.-is 
opropylidenedioxypregna-1,4-diene-3,20-dione; mp. 240.degree.-245.degree. C 
(decomposed). 
Similarly, by following steps (a) through (e) in this example but 
substituting 
6.alpha.-chloro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-tri 
ene-3,20-dione and 
21-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene-3, 
20-dione for 
6.alpha.,21-difluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(1 
1)-triene-3,20-dione (formula 1) in step (a) the corresponding 
6.alpha.-chloro and 6.alpha.-hydrogen compounds of this invention may be 
obtained. 
EXAMPLE 2 
This example illustrates the preparation of 
9.alpha.,11.beta.,21-trichloro-21-fluoro-16.alpha.,17.alpha.-isopropyliden 
edioxypregna-1,4-diene-3,20-diones. 
a. Formylation, 
b. Chlorination, 
and 
c. Deformylation 
The procedure set forth in Example I, step (a)-(c) was followed to obtain 
21-chloro-6.alpha.,21-difluoro-16.alpha.,17.alpha.-isopropylidenedioxypreg 
na-1,4,9(11)-triene-3,20-dione. The resulting compound is treated according 
to the procedure of Example I, step (e) to give 
9.alpha.,11.beta.,21-trichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha.-is 
opropylidenedioxypregna-1,4-diene-3,20-dione. 
Similarly, by following the above procedure of this example but 
substituting 
6.alpha.-chloro-21-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4 
,9(11)-triene-3,20-dione and 
21-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-triene-3, 
20-dione for 
6.alpha.,21-difluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(1 
1)-triene-3,20-dione (formula 1) of step (a), the corresponding 
6.alpha.,-chloro and 6.alpha.-hydrogen compounds of this invention may be 
obtained. 
EXAMPLE 3 
This example sets forth a process for preparing 
21-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopro 
pylidenedioxypregna-1,4-diene-3,20-dione of this invention. 
The compound represented by formula (3) was prepared as in Example I, steps 
(a)-(c). The compound, 
21-chloro-9.beta.,11.beta.-oxido-6.alpha.,21-difluoro-16.alpha.,17.alpha.- 
isopropylidenedioxypregna-1,4-diene-3,20-dione, was prepared according to 
the following reaction scheme and procedure: 
##STR18## 
A solution of the 21-chloro-21-fluoro steroid (3) (106 mg) in dioxane (1.2 
ml) was cooled to 10.degree. C. Dibromantin (160 mg) was added, followed 
by 0.09 ml of a solution made by diluting 3 ml of 30% HClO.sub.4 to 27 ml 
with water. The temperature was maintained at 10.degree. C for 4 hours 
with stirring. 
To the above solution was added 2.3 ml of isopropyl alcohol followed by 
255.6 mg of potassium acetate (KOAC). The solution was heated at reflux 
overnight. The reaction mixture was then poured into 100 ml of water, 
extracted with 80 ml of benzene and chloroform (3.times.10 ml). The 
combined organic layers were washed with water (100 ml), NaHCO.sub.3 (50 
ml) and brine (50 ml), dried over MgSO.sub.4 and evaporated to dryness. 
The crystalline residue (176 mg) was recrystallized from methanol to give 
the 9.beta.,11.beta.-oxido derivative (6.alpha.), mp. 208.degree. C. 
The 9.beta.,11.beta.-oxido compound represented by formula (6) was then 
hydrofluorinated to give a compound of this invention according to the 
following reaction scheme and procedure. 
##STR19## 
Eight-tenths (0.8) ml. of a hydrogen fluoride-urea complex was added to a 
sample of the epoxy steroid (6) (52 mg.) in a polyethylene bottle. The 
reaction mixture was stirred at room temperature for 3 hours and then 
poured into an ammonium hydroxide solution, (0.1 N., 20 ml.). The product 
was extracted with three 120 ml. portions of CH.sub.2 Cl.sub.2 and the 
combined CH.sub.2 Cl.sub.2 extracts were washed with water, brine, dried 
over MgSO.sub.4 and evaporated to give a solid (35 mg.). Recrystallization 
from ethanol gave 
21-chloro-6.alpha.,9.alpha.,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alp 
ha.-isopropylidenedioxypregna-1,4-diene-3,20-dione, mp. 303.degree. C 
(decomposed). 
Similarly by following the procedure of this example but substituting for 
the compound represented by formula (3), the following compounds: 
6.alpha.,21-dichloro-21-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregn 
a-1,4,9(11)-triene-3,20-dione; 
21-chloro-21-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11) 
-triene-3,20-dione, the corresponding compounds of this invention may be 
obtained. 
EXAMPLE 4 
This example sets forth a process for preparing 
9.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylide 
nedioxypregna-1,4-diene-3,20-diones. 
The compound represented by formula (4), namely 
6.alpha.,21,21-trifluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4 
,9(11)-triene-3,20-dione, was prepared as in Example 1, steps (a)-(d). The 
9.beta.,11.beta.-epoxidation and subsequent hydrofluorination procedure 
set forth in Example 3 was followed to prepare 
6.alpha.,9.beta.,21,21-tetrafluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-is 
opropylidenedioxypregna-1,4-diene-3,20-dione. 
Similarly, by following the process of this example but substituting 
6.alpha.-chloro-21,21-difluoro-16.alpha.,17.alpha.-isopropylidenedioxypreg 
na-1,4,9(11)-triene-3,20-dione and 
21,21-difluoro-16.alpha.-17.alpha.-isopropylidenedioxypregna-1,4,9(11)-tri 
ene-3,20-dione, for the compound represented by formula (4), the 
corresponding 6.alpha.-chloro or 6.alpha.-hydrogen compounds of this 
invention may be obtained. 
EXAMPLE 5 
This example sets forth a procedure for preparing the 
9.alpha.-bromo-11.beta.-hydroxy .DELTA..sup.1,4 steroids of this 
invention. In this process, the procedure for preparing a compound 
represented by formula (6) is followed, and after the compound represented 
by formula (3) was reacted with dibromantin and HClO.sub.4 for 4 hours at 
10.degree. C, the reaction mixture is poured into ice water then extracted 
with methylene chloride. The organic phase is washed with water, aqueous 
NHCO.sub.3 and dried over MgSO.sub.4. The solvent is then evaporated and 
the product is recrystallized from ethanol to give 
9.alpha.-bromo-21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,1 
7.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione m.p. 
218.degree.-220.degree. C (decomposed). 
Similarly by following the above procedure but substituting 
6.alpha.,21-dichloro-21-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypreg 
na-1,4,9(11)-triene-3,20-dione and 
21-chloro-21-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11 
)-triene-3,20-dione for the compound of formula (3), the corresponding 
6.alpha.-chloro and 6.alpha.-hydrogen compounds are obtained. 
EXAMPLE 6 
By following the procedure of Example 5 but substituting 
6.alpha.,21,21-trifluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4, 
9(11)-triene-3,20-dione, 
6.alpha.-chloro-21,21-difluoro-16.alpha.,17.alpha.-isopropylidenedioxypregn 
a-1,4,9(11)-trine-3,20-dione, 
21,21-difluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-trie 
ne-3,20-dione for the compound represented by formula (3), other 
corresponding compounds of this invention may be obtained. 
EXAMPLE 7 
This example sets forth a procedure for preparing a 9.alpha.-H-11.beta.-OH 
.DELTA..sup.1,4 steroid of this invention according to the following 
reaction scheme and procedure: 
##STR20## 
To a flask charged with 31 mg. of tributyltin hydride in 15 ml. of freshly 
distilled THF is added 50 mg. of the steroid (6). A trace amount of 
azobisisobutyronitrile is added to the vigorously stirred solution and the 
reaction flask is irradiated with a lamp. After 1/2 hour the solvent is 
removed under vacuum and the product is extracted with 50 ml. of CH.sub.2 
Cl.sub.2. The organic solution is washed with water, brine, dried over 
MgSO.sub.4 and evaporated to dryness to give a solid. Recrystallization 
from MeOH gave a crystalline product of 
21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopro 
pylidenedioxypregna-1,4-diene-3,20-dione. 
Similarly, by substituting other 9.alpha.-Br-11.beta.-OH-.DELTA..sup.1,4 
steroids prepared according to Example 5 and Example 6, for the compound 
represented by formula (6), other 9.alpha.-H-11.beta.-OH-.DELTA..sup.1,4 
compounds of this invention may be prepared which correspond to the 
respective starting compounds. 
EXAMPLE 8 
The 9.alpha.-chloro-11.beta.-OH-.DELTA..sup.1,4 steroids of this invention 
may be prepared by reacting a 9,11-oxido compound prepared according to 
Examples 3 and 4 with hydrogen chloride by well known procedures and 
isolated by procedures discussed hereinbefore. 
EXAMPLE 9 
This example sets forth a process for preparing the 
9.alpha.,11.beta.,21,21-tetrachloro-.DELTA..sup.1,4 steroids of this 
invention according to the following procedure. Five g. of 
6.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4,9(11)-tr 
iene-3,20-dione is formylated according to the procedure set forth in 
Example 1 except that once the ethyl formate is added stirring is 
continued at refluxing temperature for four more hours. After extraction 
and isolation, recrystallization from acetone gave the corresponding 
21-hydroxymethylene compound, m.p. 201.5.degree.-203.degree. C. This 
product was chlorinated and deformylated according to the procedure of 
Example 1 to give 
21,21-dichloro-6.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxypreg 
na-1,4,9(11)-triene-3,20-dione having a m.p. of 199.degree.-200.degree. C. 
By following the dichlorination step of part (e) in Example I, 
9.alpha.,11.beta.,21,21-tetrachloro-6.alpha.-fluoro-16.alpha.,17.alpha.-is 
opropylidenedioxypregna-1,4-diene-3,20-dione, m.p. 225.degree.-235.degree. 
C (dec.), is prepared. 
Similarly, by substituting the appropriate 6.alpha.-chloro or 6.alpha.-H 
starting material for the 6.alpha.-F-.DELTA..sup.1,4,9(11) steroid in this 
example, other corresponding compounds of this invention are prepared. 
EXAMPLE 10 
This example sets forth a process for preparing the 
9.alpha.-fluoro-11.beta.-hydroxy-21,21-dichloro-.DELTA..sup.1,4 steroids 
of this invention. The formulation, chlorination and deformylation steps 
of Example 9 are followed and the 21,21-dichloro-.DELTA..sup.1,4,9(11) 
steroid thus obtained is reacted according to the sequence of Example 3 to 
give the corresponding 21,21-dichloro 9.alpha.,11.beta.-bromohydrin and 
subsequent 9,11-oxido steroid (m.p. 212.degree. C-dec.) which in turn is 
reacted with hydrogen fluoride as taught in Example 3 to give 
21,21-dichloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.al 
pha.-isopropylidenedioxypregna-1,4-diene-3,20-dione, m.p. 
270.degree.-285.degree. C (dec.). 
Similarly, the corresponding 6.alpha.-chloro and 6.alpha.-hydrogen compound 
are prepared by employing the appropriate starting material. 
The intermediate 21,21-dichloro-9.alpha.,11.beta.-bromohydrins are prepared 
according to the process of Example 5 while the 
9.alpha.-hydrogen-11.beta.-hydroxy compounds are prepared according to 
Example 7. The corresponding 
21,21-dichloro-9.alpha.-Cl-11.beta.-OH-.DELTA..sup.1,4 steroids are 
prepared by following the procedures of Example 8. 
EXAMPLE 11 
The 21,21-dibromo compounds of this invention may be prepared by following 
the procedures of Examples 9 and 10 but dibrominating at 21 instead of 
dichlorinating. 
EXAMPLE 12 
The example sets forth a process for making the .DELTA..sup.4 steroids of 
this invention. 
##STR21## 
A solution of 25 mg. of tris-(triphenylphosphine) chlororhodium in 6 ml. of 
benzene and 15 ml.. of ethanol is stirred under hydrogen for 60 min. The 
above steroid (244 mg.) is added and the resulting solution is stirred 
under hydrogen at room temperature and atmospheric pressure. After 
hydrogen uptake is complete, the solution is evaporated to dryness and the 
residue taken up in a mixture of petroleum ether and methylene chloride. 
The pure product corresponding to the .DELTA..sup.1,4 compound (7), above, 
is isolated by column chromatography on silica gel. 
Similarly, by substituting other .DELTA..sup.1,4 steroids of this invention 
made according to Examples 1-11 for the compound of formula (7), other 
corresponding .DELTA..sup.4 steroids are prepared.