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Патент USA US3086024

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United States Patent 0 "cc
1
3,086,014
Patented Apr. 16., 1963
1
2
The novel compounds of the present invention are pre
pared by the process exempli?ed as follows:
3,086,014
16,16-D1FLUOR0 ESTROGENS
Albert Bowers and Pierre Crabbé, Mexico City, Mexico,
assignors, by mesne assignments, to Syntex Corpora
rl '0
tion, a corporation of Panama
No Drawing. Filed Mar. 1, 1962, Ser. No. 176,824
19 Claims. (Cl. 260-23955)
The present invention relates to novel cyclopentano
phenanthrene derivatives and to a process for the produc~ 1O
tion thereof.
More particularly the present invention relates to novel
min
16,16-di?uoro-9,1 1-oxido-A1’3’5Km) _ estratriene,16,16> - di
?uoro - A1»315-(1°)'8 - estratetraen - 11B 01 and 16,16-di
?uoro - A1-3’5(1"')8 - estratetraen-ll-one derivatives.
i
15
Whi-
The novel compounds of the present invention are rep
resented by vthe following formulas:
I
as
OLL
“O1,
OR’
‘6
F
ROQJ
OLL
Ari;
o
(?g;
-
v1
F
25
-
RO__
0
011
i
/\I
|___Rz
_F
r
/\
~\_
‘R I
xii/U‘?
/
3.11,,
30
MU?
R0
, ‘L
0% F
?
v11
groups are the acetate, propionate, enanthate, benzoate, 55
at
"B3
HO-A
—~F
F
R may be hydrogen, lower alkyl or a hydrocarbon car
boxylic acyl group of less than 12 carbon atoms; R1 rep
resents hydrogen or a hydrocarbon carboxylic acyl group
of less than 12 carbon atoms; R2 may be hydrogen, lower
alkyl, lower alkenyl or lower alkynyl. The Wavy lines of 45
the 9,1l-oxide group indicate that the said group may be
in the 9a,11ot or 918,11?-steric con?guration.
The acyl groups are divided from hydrocarbon car
boxylic ocids containing less than 12 carbon atoms which
may be saturated or unsaturated, of straight, branched,
cyclic or cyclic-aliphatic chain, aromatic and may be
substituted by functional groups such a hydroxy, alkoxy
containing up to 5 carbon atoms, acyloxy containing up to
12 carbon atoms, nitro, amino or halogen. Typical ester
»
r
In the above formulas X represents keto or B-hydroxyl; 40
pentylpropionate, aminoacetate and ,B-chloropropionate.
0% F
35
no
trimethylacet-ate, t-butylacetate, phenoxyacetate, cyc1o~
R0
III
_,
7
F
/
7
RO—
no
IV
VIII
.0
HOTA
.
/
R0
‘
‘RR’
7
F
F
"R2
=
F
r
‘
/
R0——
v
IX
In the above formulas R, R1 and R2 have the same
meaning as previously described.
The compounds represented by the above formulas ex
In practicing the process outlined above, the starting
hibit negligible estrogenic activities but are very valuable
compound (I) which is selected from the group consisting
in arresting calcium excretion in certain bone diseases 60 of A9<11)-dehydro estrone, the 3-lower alkyl ethers and the
such as osteoporosis. In addition they lower the blood
3-acylates thereof, is treated with ethyl formate in the
and adrenal cholesterol level, are useful in the treatment
presence of sodium methoxide to produce the correspond
of artheosclerosis and reduce abnormal bleeding con
ing 16-hydroxymethylene derivative which upon reaction
siderably, for example, hemorrhages after dental extrac
with perchloryl ?uoride in a suitable solvent such as ter
tions and tonsillectomies.
65 butanol, in the presence of potassium terbutoxide yields
3,086,014
4
fate and the solvent was evaporated under reduced pres
the corresponding 16,l6-di?uoro-A9(11)- dehydro estrone
compound (II).
sure; the residue was chromatographed on a column
charged with 20 g. of silica. Recrystallization of the
solid fractions from acetone-hexane yielded 16,16-di
The latter 16,16-di?uoro-17-keto compound ((II) is
treated with a lower alkyl mangnesium halide in an inert
?uoro-3methoxy-A9(11>-dehydroestrone.
solvent, thus affording the corresponding 17a-lower alkyl
1713-alcohol (VI; R2=lower alkyl). The same 16,16
Example III
di?uoro-17-ketones (II) upon reaction with a l-lower
alkine such as acetylene in the presence of potassium
A solution of 2.5 g. of the steroid produced in Example
II in 100 cc. of chloroform was cooled to 0° C. and
ter-amyloxide, yield the corresponding 17a-lower alkynyl
17/3-alcohols (VI: R2=lower alkynyl) which are hydro
10
genated in the presence of a suitable catalyst such as 2%
palladium on calcium carbonate to give the corresponding
mixed with 1.1 molar equivalents of monoperphthalic
acid in ether solution.
The mixture was kept at room
temperature for 20 hours, diluted with water, the organic
layer was separated, washed with aqueous sodium bi
carbonate solution and then with water to neutral, dried
The 16,16-di?uoro-A9(11)-17-ketones (II) are reduced
preferably with sodium borohydride in order to produce 15 over anhydrous sodium sulfate and evaporated to dry
17a-lower alkenyl-17?-alcohols (VI; R2=lower alkenyl).
the Not-unsubstituted Uri-alcohols (VI; R2=H).
The 16,l6-di?uoro-A9(11J-l7-ketones (II) and 16,16
di?uoro-A9(11)l7?-alcohols with a hydrogen, lower alkyl
or lower alkynyl at C~17m (VI), upon reaction with an
organic peracid such as monoperphthalic acid yield the 20
corresponding 9a,11a-oxides and the corresponding
95,11p-oxides (III and VII). The 9/3,11B-oxido com
pounds are treated with hydrogen bromide in a suitable
ness.
The residue was chromatographed on neutral
alumina, thus affording 16,16-di?uoro-3-methoxy-9a,11a
oxido A1'3,5<1°)-estratrien-l7-one and 16,16-di?uoro-3
methoxy-9,8,11?-oxido A1-3'5(1°>-estratrien-17-one.
Example IV
To 1a solution of 4 g. of 16,l6-di?uoro~3-methoxy-9B,
1‘1B-oxido-A1’3’5(lol-estratrien-Ueone in 40 cc. of anhy
drous chloroform, was added, over a period of 35 min
solvent such as chloroform, to produce the corresponding
9a-lbromo-lll8-hydroxy derivatives which upon dehydro 25 utes, 30 cc. of a 0.45 N solution of dry hydrogen bromide
in chloroform, under continuous stirring and maintaining
lsromination with a convenient agent such as calcium
the temperature around 0° C. The mixture was then
carbonate in dimethylformamide yield the corresponding
stirred at 0° C. for 1 hour further, diluted with water
Ag-ll?-alcohols (IV and VIII). The latter M-llp-aleo
and the chloroform layer was separated, washed with
hols are oxidized preferably with Jones reagent to give
30 aqueous sodium bicarbonate solution and then with water,
the ll-keto derivatives (V and IX).
dried over anhydrous sodium sulfate and evaporated
When there is present a Uri-secondary hydroxyl
under reduced pressure. Crystallization of the residue
(R2=H) the A8-ll?,l7l3-diols are ?rst selectively acylated
from acetone-hexane gave 9a-bromo-l6,16-di?uoro-3
in pyridine with an acylating agent, such as acetic an
methoxy-A1315(1°>-estratrien-11p-ol-17-one.
h-ydride, at 0° C., to give the corresponding 17B-acylates
35
Example V
which thereafter are oxidized to the ll-ketones as pre
viously set forth.
2 g. of the ?nal compound of ‘Example IV in 40 cc.
The tertiary 17?-alcohols of the present invention are
of cold dimethylforamide was added over 15 minutes to a
conventionally acylated in the presence of p-toluene
suspension of 5 g. of ?nely divided calcium carbonate in
sulfonic acid with an acylating agent such as an anhydride
15 cc. of re?uxing dimethylformamide. The mixture
derived from a hydrocarbon carboxylic acid of the type 40 ws re?uxed for 30 minutes further, cooled and ?ltered.
hereinbefore set forth, thus a?ording the corresponding
The ?ltrate Was diluted with water and extracted with
Nix-substituted 17?-acylates.
ethyl acetate. The extract was washed with dilute hy
The following speci?c examples serve to illustrate but
drochloric acid, water, aqueous sodium bicarbonate solu
are not intended to limit the scope of the present inven
tion and water, then dried over anhydrous sodium sulfate
tion:
and evaporated to dryness. Silica gel chromatography
Example I
and recrystallization afforded 16,16-di?uoro-3-methoxy
There was added 1.4 g. of sodium methoxide and 1.9
ml. of anhydrous ethyl orthoformate to a solution of 1.9
A1-3»5<1°)-8-estratetraen—1113-01-17-one.
Example VI
g. of 3-methoxy-A9(11>-dehydroesterone (Magerlein et al., 50
A solution of 1 g. of the compound obtained in Ex
ample V in 10 cc. of acetone was cooled to 0° C. and
hydrous benzene.
treated under an atmosphere of nitrogen and with stirring,
The mixture was stirred at room temperature and under
with a solution of 8 N chromic acid (prepared by mixing
an atmosphere of nitrogen for 15 hours. Then 200 ml.
of cold water was added, the strongly alkaline aqueous 55 26 g. of chromium trioxide with 23 cc. of concentrated
sulfuric acid and diluting with water to 100 cc.), until the
phase was separated and acidi?ed with an excess of 10%
color of the reagent persisted in the mixture. It was
hydrochloric acid solution; the precipitate formed was
stirred for 5 minutes further at 0-5" C. and diluted with
collected, washed and dried. Recrystallization from
methanol afforded 3 - methoxy - l6 - hydroxymethylene
water. The precipitate was collected, washed with water
A9<11)dehydroestrone.
60 and dried under vacuum, thus a?ording a crude product
which upon recrystallization from acetone-hexane gave
Example II
J. Am. Chem. Soc. 80, 2220 (1958)), in 40 ml. of an
16,16 - di?uoro - 3 - methoxy - Alia-5am - estratetraene
To a solution of 3 g. of 3-methoxy-16-hydroxymethyl
11,17-dione.
cue-A9(11)-dehydroestrone in 100 ml. of anhydrous ter
butanol was added 40 ml. of a solution of potassium ter 65
butoxide (prepared from 3 g. of potassium and 40 ml. of
Example VII
A solution of 5 g. of 16,16-di?uoro-3-methoxy A901)
dehydroestrone in 250 cc. of thiophene-free benzene was
treated with 27.5 cc. of 4 N methylmagnesium bromide in
A slow stream of perchloryl ?uoride was introduced
ether and the mixture re?uxed with the exclusion of mois
into the resulting solution for 5 hours at room temper
ature; the container was then stoppered and kept over 70 ture for 3 hours. The cooled mixture was cautiously
treated with excess aqueous ammonium chloride solution
night also at room temperature.
and the product isolated by ethyl acetate extraction. The
The mixture was cautiously poured into ice water, ex
extract was washed with water, ‘dried over anhydrous
tract'ed with ethyl acetate and the organic layer was
sodium sulfate and evaporated to dryness. Recrystalliza
washed with 10% sodium carbonate solution and then
tion from methylene chloride-hexane afforded 16,16
with water to neutral, dried over anhydrous sodium sul
anhydrous ter-butanol).
5
3,086,014.
6
di?uoro - 17a - methyl - 3 - methoxy - A1,3,5(1°)9<11>
Example XIV
estratetraen—17B-ol.
A solution of 1 g. of sodium borohydride in 3 cc. of
Example VIII
water was added to an ice-cooled solution of 1 g. of
The ?nal product of Example VII was treated by the 5 16,16-di?uoro-3—methoxy-A1’3:5(1°),8-estratetraen - 11/3 - ol
l7-one in 120 cc. of methanol and the mixture was allowed
procedure described in Example III, thus yielding 16,16
difluoro- 17a-methyl-3-methoxy-9a,11'a-oxido-A1'3,5(1°)-es
tratrien-l7?-ol and 16,16-di?uoro-l7a-methyl-3-methoxy
to stand for 16 hours at room temperature. The excess
reagent was decomposed by addition of acetic acid, the
Example IX
solution concentrated to small volume in vacuo and di
luted with water. The product was extracted with ethyl
acetate, the extract was Washed with water, dried and
The latter oxide of Example VIII was successively
treated ‘by the methods of Examples IV, V and VI, thus
evaporated. The solid residue was puri?ed "by crystalliza
tion from acetone-hexane to give 16,16-di?uoro-3-meth
9p, 1l?-oxido-Al?dum-estratrien-17B-ol.
respectively yielding 9a-bromo-l6,l6-di?uoro-l7a-methyl
3-methoxy-A1,3-5<1°)-estratriene-115,17?-diol, 16,16-difluo
oxy-A1131Mwhs-estratetraene-11,8,17;3~diol.
Example XV
A
mixture
of
1
g.
of
the ?nal product of Example XIV,
17?-diol, and 16,16-di?uoro-17a-methyl - 3 - methoxy
4 cc. of pyridine and 2 cc. of acetic anhydride was kept
A1'3'5(1°)is-estratetraene-175-014l-one.
at 0° C. overnight, poured into ice water, the formed
Example X
precipitate was ?ltered, washed with water and dried.
20 Crystallization from acetone-hexane gave the 17-acetate of
A solution of 1 g. of 16,16-di?uoro-3-methoxy
16,16-di?uoro~3-methoxy-A11315(1W3-estratetraene - 11,6,
A9(11)-dehydroestrone in 30 cc. of anhydrous benzene
17/8-diol.
was added, under nitrogen, to a solution prepared by dis
The latter compound was treated in accordance with
solving 1.4 g. of potassium in 3Ov cc. of t-amyl alcohol.
A slow current of puri?ed acetylene was passed through 25 Example VI, thus yielding the 17-acetate of 16,16-di
?uoro-3-methoxy-A1,3,5<1°) ?-estratetraen- 175-01-1 l-one.
the solution for 40 hours, whereupon the solution was
ro-17a-methyl-3-methoxy - A1,3-5(1°)8 - estratetraene - 1118,
15
diluted with water and extracted with benzene. The or
ganic extracts were then washed to: neutral and dried
Example XVI
To a solution of 5 g. of 16,16-di?uoro-17a—methyl-3
over anhydrous sodium sulfate. Evaporation of the
solvent and chromatography of the residue on 70‘ g. of 30 methoxy-Alylmlm?-estratetraen-1713-01-1l-one in 100 cc.
tions a product, which upon recrystallization from acetone
of anhydrous benzene there were added 1 g. of p-toluene
sulfonic acid and 10 cc. of propionic anhydride and the
liexane aiforded the pure 16,16adi?uoro-17a-ethinyl-3
mixture was allowed to stand for 24 hours at room tem
alkaline alumina gave in‘the hexane-benzene (2:3) frac
methoxy—A1'3'5(1°)-9(11>-estratetraen-175-01.
Example XI
perature, poured into ice and water, and the resulting mix
35 ture stirred to elfect hydrolysis of the excess anhydride.
The benzene layer was separated and washed with 10%
sodium carbonate solution and water. Drying, evapora
tion and crystallization of the residue from ether-hexane
The ?nal product of Example X was treated by the
procedure described in Example III, thus affording 16,16
produced ‘the propionate of 16,16-di?uoro-l7a-methyl-3
di?uoro-17u-ethinyl-3-methoxy-9a-1lot-oxido - A1-3'5(1°)-es
methoxy-Al'3-5(mm-estratetraen-17?-ol-1 1-‘one.v
tratrien-l7?-ol and 16,16-di?uoro-17a-ethinyl-3-methoxy
Following the above procedure were treated 16,16edi
919-11p-oxido-A1’3»5(1°)-estratrien-175-01.
?uoro - 17a - ethinyl - 3 - methoxy - Alia-“10),” - estratet
raen-17?-ol-11-one, and 16,16-di?uoro-17a-vinyl-3-meth
Example XII
oxy-Al?d?o)?-estratetraen-17?-ol-1l-one, thus aifording
The latter oxide of Example XI was successively treated
by the procedures described in Examples IV, V and VI, 45
giving respectively, 9a-bromo-16,16-difluoro-17a-ethinyl
3-methoxy-A113'5(1°)-estratrien-1l?,l7?~diol, 16,16-di?uoro
The starting compounds of Example XVI were treated
in accordance with that example, but using caproic an
17a-ethinyl-3-n1ethoxy-A1315a")i.8 - :estratetraene ~ 11 5,1713
diol, and 16,16-di?uoro-17a~ethinyl-3-methoxy-A1~3,5<1°)'8
estratetraene- 1 718-01-1 l-one.
the corresponding propionates.
Example XVII
50
hydride and cyclpentylpropionic anhydride, instead of
propionic anhydride, thus affording the corresponding
caproates and cyclopentylpropionates of said starting com
Example XIII
pounds.
'
Example XVIII
A solution of 1 g. of 16,16-di?uoro-l7a-ethinyl-3
methoxy-Al's?(mLa-estratetraen-17,8-01-1l-one in 40 cc. of 55
A9(11)-dehydroestrone, (Magerlein et al., op. cit.) was
pyridine was hydogenated at 25° C. and 570' mm. in the
successively treated in accordance with Examples I, II
presence of 400 mg. of pro-hydrogenated 2% palladium
and III, yielding respectively, 16-hydroxymethylene-A9(11)
calcium carbonate catalyst.
'
dehydroestrone, 16,16-difluoro-A9Q1)-dehydroestrone, and
When 1 molar equivalent of hydrogen had been ab
sorbed, the reaction Was stopped, the catalyst separated 60 ?nally, 16,l6-di?uoro-9a,1la-oxido-Al??(10)-estratrien-3
ol-18-one, and 16,16-di?uoro-9?,1l?-oxido-Amr?(“D-estra
by ?ltration through celite, washed with ethyl acetate and
trien-3-ol-17~one.
the combined solutions evaporated to dryness in vacuo,
Example XIX
yielding the crude vinyl derivative. This crude product
was dissolved in ethyl acetate, the organic solution Washed
16,16 - difluoro - 9,8,115 - oxido - A1350“) - estratrien
with dilute hydrochloric acid and water to neutral, dried 65 3-ol-l7-one was consecutively treated by the methods of
and evaporated to dryness. Recrystallization from ace
Examples IV, V and VI, furnishing respectively, 90:
tone gave 16,16-di?uoro-17a-viny1-3-methoxy-A1'315(1°>-8
brorno
16,16 - di?uoro - A11315(1°) - estratrien - 3,11,8
estratetraen-17/3-ol-1l-one.
diol - 17 - one,
By the same procedure, there ‘were treated 16,16-di
?uoro-17a-ethinyl-3-methoxy-9,8,1113 - oxido - A1'3'5(1°>-es
tratrien-17,B-ol and 16,16-di?uoro-17a-ethinyl-3-methoxy
70
en-3-ol-11,17-dione.
16,16-di?uoro-17a-vinyl-3 - methoxy - 95,1118 - oxido~
16,16-di?uoro-A9u1>~dehydroestrone was treated in ac
A1'3,5(1°)-estratrien-173-01 and 16,16-di?u0ro-17a-vinyl-3
methoxy-Al??lmls-estratetraene-115,17,3-diol.
'
Example XX
AL“(1°)'8~estratetraene-11,8,17/3-diol, yielding respective
ly:
16,16 - di?uoro - A1,3»5(1°),8 _ estratetraen
3,11B-diol-17-one, and 16,1G-di?uoro-Al??uo)Is-estratetra
cordance with Examples VII and X, thus giving respec
75
tively,
16,16 - di-fluoro - 17oz - methyl - A1'3’5(1°),9(11)-es
aoeegole
53
tratetraene-3,l75-diol, and 16,16 - di?uoro - 17a - ethinyl
gen, lower alkyl and a hydrocarbon carboxylic acyl group
A1'3'5(1°)-9111)-estratetraene-3,175-diol.
of less than 12 carbon atoms.
2. 16,16 - di?uoro - 3 - methoxy - 90:,1loc - oxido
Example XXI
A1,3'5(1°>-estratrien-l7-one.
3. 16,16 - di?uoro - 3 - methoxy - 95,115 - oxido
16,16 - ?uoro - 17a - methyl - A1'315(1°>19(11) - estratetra
A1,3'5<1°>-estratrien-17-one.
ene-3,175-diol was treated in accordance with Example
4, A compound of the following formula:
III, thus yielding 16,16-dI?UOI'O-17OL-H1CllIlYl-9OL,1lot-OXldC
A1,3»5(1°)-estratrien-3,l75-diol, and 16,16-di?uoro- 17a
methyl-9a,115-oxido-A1'3'5(1°>-estratrien-3 ,175-diol.
10
Example XXII
The 95,115-oxido compound of Example XXI was suc
cessively treated in accordance with Examples IV, V and
VI, producing respectively 9a-bromo-16,16-di?uoro-17a—
methyl - New") - estratriene - 3,115,175 - triol,
16,16
di?uoro - 17oz - methyl - A1'315(1°)-3 - estratetraene - 3,115,
175-triol, and 16,lé-di?uoro-l7a-rnethyl-A1'315(mm-estra
tetraene-3 , l 75-diol-l l-one.
wherein R is selected from the group consisting of hydro
gen, lower alkyl and a hydrocarbon carboxylic acyl group
Example XXIII
l6,16-di?uoro-A9<lll-dehydroestreone was treated fol
20 of less than 12 carbon atoms; and X is selected from the
group consisting of keto and 5-hydroxyl.
lowing the procedure of Example XVI, thus affording the
3-propionate of 16,16-di?uoro-A9(11>-dehydroestrone.
Example XXIV
5. 16,16 - di?uoro - 3-methoxy-A113'5(1°>ts-estratetraen
115-ol-17-one.
6. 16,16 - di?uoro - 3-rnethoxy-A113?mXB-estratetraene
11,17-dione.
The ?nal product of Example XXIII was treated in
7. A compound of the following formula:
accordance with Example III, thus yielding the propio
nate of 16,16-di?uoro-9a-11a-oxido-Am'“ml-estratrien-3
ol-17-one, and the propionate of 16,l6-di?u0ro-95,1l5
oxido-.A1,3-5<1°>~estratrien~3-ol-17-one.
Example XXV
The propionate of 16,l6-di?uoro-95,115-oxido-A1’3'5um
lestratrien-3-ol-17»one was consecutively treated by the
"methods of Examples IV, V and VI, furnishing respec 35
tively, the 3-propionate of 9a-bromo-l6,l6-di?uoro
/
R0
i
A1'3'5(1°)-estratrien-3,115-diol-17-one, the 3-propionate of
wherein R is a member of the group consisting of hydro
gen, lower alkyl and a hydrocarbon carboxylic acyl group
of less than 12 carbon atoms; R1 is selected from the
group consisting of hydrogen and a hydrocarbon car
boxylic acyl group of less than 12 carbon atoms; and
R2 is a member of the group consisting of hydrogen,
16,16 - di?uoro - A1’3'5(1°)'8 - estratetraen - 3,115 - diol
17-one, ‘and the 3-propionate of 16,16-di?uoro-A1'3»5(1°)18
estratetraen-Zi-ol-l 1,17-dione.
Example XXVI
The 3-propionate of 16,16-di?uoro-A1-3'5(1°>ys-estratet
lower alkyl, lower alkynyl and lower alkenyl.
raene—3,115-diol-17-one was consecutively treated in ac
8. 16,16 - di?uoro-17w-methyl-3-methoxy-9a,1la-oxido
cordance with Examples XIV, XV and VI, yielding, re
spectively, the 3-propionate of 16,16-di?uoro-A11315(1°)-8— 45 A1,3,5(1°)-estratrien-175-01.
estratetraene - 3,115,175 - triol,
acetate of
the
9. 16,16 - di?uoro - 17a - methyl - 3-methoxy-95,l15
3 - propionate - 17
oxide-A1350“)-estratrien-175-ol.
16,16-di?uoro-A1'3’5(1°)18-estratetraene-3,ll5,
10. 16,16 - di?uoro - 17a - ethynyl-3-rnethoxy-9a,l1a
175-triol, and the 3-propionate-l7-acetate of 16,16-di?u
oxido-A1’315(1°)-estratrien-175-01.
ore-A1315(10%8-estratetraene-3,175-diol-1 l-one.
50
11. 16,16 - di?uoro - 17oz - ethynyl-3-methoxy-95,ll5
Example XX VII
oxide-A1315(m-estratrien-175-01.
12. A compound of the following formula:
16,16 - di?uoro - 17oz - methyl - A1'3-5(1°)'9(11> - estra
tetraene-3,175-diol was treated in accordance with Exam
ple XVI, thus affording the dipropionate of 16,16-difluoro 55
17oz - methyl - A1’3'5<1°)19(11) - estratetraene - 3,175 - diol,
which upon treatment by the procedure of Example III
furnished the dipropionate of l6,16-di?uoro-17a-methy1
9a,11a-oxido-A113'5(1°>-estratriene-3,175-diol and the di
propionate of 16,16-di?uoro-17a-methyl-95,l15-oxido
A135<1°>-estratriene-3,175-diol.
60
We claim:
1. A compound of the following formula:
wherein R is selected from the group consisting of hydro
{All};
a
65 gen, lower alkyl and a hydrocarbon carboxylic acyl group
of less than 12 carbon atoms; R1 is a member of the
group consisting of hydrogen and a hydrocarbon car
boxylic ‘acyl group of less than 12 carbon atoms; R2 is
selected from the group consisting of hydrogen, lower
70 alkyl, lower alkynyl and lower alkenyl and X is a mem
ber of the group consisting of keto and 5-hydroxyl.
wherein R is a member of the group consisting of hydro- 75
13. 16,16 - di?uoro - l7a-methyl-3-methoxy-A1»3'5(1°),8
estratetraene-l15,175-diol.
14. 16,16 - di?uoro-17a-ethynyl-3—methoxy-A13590),“
estratetraene-l15,175-diol.
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