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Патент USA US3082235

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United ‘States Patent Oti ice
3,082,225
Patented Mar. 19, 1963
1
2
3,082,225
NGVEL l-l‘tdE'l‘HYL-l,3,5(l0),9(1l)-E§TRATETRA
vIn general to carry out the novel process of my inven
tion a steroidal 3-keto-l,4,‘9i(l'l)-triene of the androstane
or pregnane series is treated with a strong acid catalyst
having a dissociation constant equal to or greater than
ENES AND METHODS FOR THEXR MANU
FACTURE
2><'l0—1, exempli?ed by acids such as p-toluenesulfonic
Hans Reimann, Bloom?eld, N.J., assignor to Sehering
Corporation, Bloom?eld, Null, a corporation of New
‘acid, and trifluoroacetic acid, in a solvent, preferably a
lower alkanoic acid or acid anhydride, at a temperature in
the range of about 20-100” C. for a period extending any-‘
where from one half to 72 hours. The reaction time Will
depend on the temperature of the reaction maintained, the
Jersey
No Drawing. Filed Sept. 15, 1961, Ser. No. 138,270
13 Claims. (Cl. 260-39145)
This invention relates to novel 1-methyl-l,3,5(l0),
9(11)-estratetraenes, valuable as therapeutics and as inter
mediates, and to a novel method for their manufacture.
More particularly, this invention relates to a process
whereby 3-keto-1,4,91(1<1)-trienes in an anhydrous acid
medium undergo rearrangement to the corresponding 1
methyl-3-hydroXy-l,3,5 (1'0) ,9( 1 l )-estratrienes which are
particular activity of the catalyst employed, and the nature
of the speci?c steroid converted. The product recovered
will be found to consist of a l-methylated-1,3,5(1'0),9(\l l)
estratetraene such as are illustrated above.
15
therapeutically active per se, and are valuable as inter
androstatriene-B,l7-dione, 1,4,9i(11) - androstatriene-l7?
mediates in the preparation of other therapeutically active
steroids.
ol~3-one, l,4-,9i(l1 )-pregnatriene-l7ot-ol-3,20-dione, 1,4,9
'( 1-1)-pregnatriene-3,-20-dione, 1,4,'9*( l 1 )-pregnatriene-17a,
Among the novel, 1,3,'5‘(10),'9(11)-estratrienes prepared
2l-diol-3,20-dione 21-acetate, and the like. These start
by my novel process are compounds of the following
structural formula:
ing materials may also be substituted in the nucleus or
in the side chain, for example in the 6 and/ or 16 position,
by halogeno or lower alkyl groups, hydroxy or acyloxy
CH3
0 H3
AI/ZJ
The starting materials for our process are in general
known 3-keto-1,4,9(11)~pregnatrienes or 3-keto-1,4,9(11)
androstatrienes which include, for instance, 1,4,9‘(l'1)
25 groups such as 6a-iluoro-1,4,9(ll)~androstatriene-3,l7-di
I
wherein R is selected from the group consisting of hydro
gen, lower alkyl, lower alkanoyl, Z is selected from the
group consisting of:
one, 6a-fl-uoro-1,4,'9‘( l 1) ~ pregnatriene "‘170t,21-dlO1-3,20‘
dione, i6a-methyl-’l,4,9-'(1l)-androstatriene-3,17-dione and
zéot-methyldl,4,9('1\1)-pregnatriene - 17a-21-diol-3,20-dione
disclosed in copending application Serial No. 817,071, ?led
June 1, 1959, now Patent No. 3,032,664 and the known
l~6-methyl substituted l,4,'9*(1vl)-trienes such as 1‘6a-meth~
~ y1#1,4,9(11)-pregnatriene - 17a,2l-diol - 3,20-dione, 16a
methyl~1,4,9(il l )-androstatriene-3,17-dione, 16cc - methyl
1,4,9(ll) - androstatriene - 17p - ol - 3-one, and other 16
chloro-, l6-?uoro-, l6-hydroxy-, and li6-acyloxy- substi
tuted 1,4,9i('l l)~androstatriene - 3,17 - diones and pregna
triene-3,20-diones well known in the art.
For instance, a suitable starting material selected from
the above for the manufacture of our novel compounds
with R’ representing a substituent selected from the group 40 is 1,4,9( 1l)-pregnatriene-l7a-ol-3,20-dione. Illustrative
ly, the reaction of this compound with tri?uoroacetic an
consisting of hydrogen and lower alkanoyl, and R" repre
hydride in acetic acid accompanied by heating results in
senting a substituent selected from the group consisting
the formation of l-methyl - 175 - acetyl-l,3,5(l0),9(1l)
of lower alkyl and ethinyl.
estratetraene - 3,1704 - diol diacetate ( l-methyl-l9-nor-1,3,
In addition to the foregoing estratrienes, l-methyl
9(ll)-dehydroestrone and the 3-lower alkyl ethers and 3 45 5(10),9(1l)-pregnatetraene-3,l7a-diol-20-one diacetate).
Further treatment of this ester with a reagent such as
ester derivatives thereof may be prepared by the novel
process of my invention.
methanolic potassium hydroxide gives the corresponding
The above de?nition of the novel compounds prepared
3,17-diol. Alternatively, treatment of the 3,17-diacetate
by my new method of derivation should not be strictly
construed, but rather may be considered to admit the
presence of other substituents on the steroid nucleus par
with perchloric acid in methanol will hydrolyze the ester
group on the 3-carbon to a hydroxy group yielding an
other of the novel compounds of this invention, i.e.,
ticularly at positions 6 and 16 such as the 6rx-methyl, ‘6a
1-methyl-175-acety1-l,3,5( l0),9( 11) - estratetraene-3,171»
‘?uoro, 6ot-chloro, l-6ot-hydroxy, l6a-acyloxy, l6-methyl
diol l7-acetate (l-methyl-19-nor-1,3,5( l0) ,9 ( 1 l )-pregna
tetraene-3,l7cx-diol-20-one l7-acetate). This latter prod
and 16-halogen analogs thereof. This modi?cation de
pends solely on the choice of starting material which may
possess the desired substituents in the positions in
cated.
The terms “lower alkyl” and “lower alkanoyl” as they
appear above represent those substituents having from 1
to 6 carbon atoms therein, such as methyl, ethyl, propyl, 60
'butyl, and formyl, acetyl, butyryl, propionyl and the like,
respectively.
The lower alkyl radicals represented by R are exempli
uct may, in turn, be treated with a reagent such as benzoyl
chloride in pyridine to give the corresponding 3-benzoate
ester, i.e., l-methyl-l7,B-acetyl~1,3,5(l0),9(11)-estratetra
ene-3,l7a-diol 17-acetate 3-benzoate (1-methyl-19-nor~
1,3,5(10),9(ll) - preguatetraene-3,l7u-diol-20-one 3-ber1
zoate l7-acetate).
Suitable catalyst-solvent combinations are, for example,
tri?uoroacetic anhydride-acetie acid, p-toluenesulfonic
acid-acetic acid, and the like. Other suitable acid cata~
?ed by methyl, ethyl, propyl, butyl, pentyl, hexyl, and‘ the
lysts include benzenesultonic acid, and anhydrous hydro
branched chain isomers thereof. Some examples of lower
alkanoyl radicals as designated by R’ are formyl, acetyl,
such as propionic acid, propionic anhydride, butyric acid,
propionyl, butyryl, valeryl, caproyl, and the branched
chain isomers thereof, said groups being the acyl radicals
be realized that other variations in catalysts and solvents
chloric and sulfuric acids, while solvents may include
and the like.
These are selected at random and it is to
of alkanoic acids containing up to ‘6 carbon atoms. Halo
will readily occur to those skilled in the art. In the case
gen as employed herein has its conventional scope to em 70 of tri?uoroacetic anhydride, it should be noted that this
brace chlorine, bromine, ?uorine and iodine.
anhydride should be employed with a carboxylic acid. so
3,082,225
a
4
cured from pregnane starting materials, i.e., those having
a corticoid side chain, show anti-corticoid and anti-andro
as to set up an equilibrium whereby tri?uoroacetic acid is
generated in situ in the system.
genic properties.
It has heretofore been unknown to subject a 3-keto
The invention will appear more fully from the exam
ples which follow. These examples are set forth by way
of illustration only, and it is to ‘be understood that the
1,4,9(l1)-triene steroid to an acid-catalyzed rearrange
ment medium such as is disclosed herein. Furthermore,
it is unexpected, under the anhydrous conditions of my
process, that a l~methyl-3-hydroxy-aromatic-A-ring steroid
is obtained from the 3—keto-1,4,9(ll)-triene starting com_
invention is not to be construed as limited to the details
contained therein as many modi?cations in materials and
methods will be apparent from the disclosure to those
pounds of my process. Heretofore, c-ringunsubstituted
skilled in the art. The invention is to be limited only by
3-keto-1,4-dienes devoid of a conjugated double bond at 10
the scope of the appended claims.
EXAMPLE 1
C-6 (e.g., 1,4-androstadiene-3,17-dione) when subjected
to anhydrous, strong acid conditions similar to those of
my process, would convert to a 1-hydroxy-4-methyl steroid
1-Methyl-1,3,5(10) ,9(1 1 )-Estratetraene~3-0l-17-0ne
(e.g., to 1-hydroxy‘4-methyl - 1,3,5 (10) - estratriene - 17
(A) To a solution of 1.0 g. of 1,4,9(11)-androstatri
one). By my process, on the other hand, steroids devoid 15
ene-3,17-dione in 40 ml. of acetic anhydride is added 250
of conjugated double bonds and unsubstituted in the C
mg. of p-toluene-sulfonic acid. The mixture is ?ushed
ring, e.g., 3-keto-1,4,9(l1)-trienes such as l,4,9(11)-preg
with argon and heated on the steam ‘bath for 5 hours, then
n'atriene - 3,20 - dione and 1,4,9( 1 l )-androstatriene-3,l7
poured into ice-water and stirred to hydrolyze any excess;
dione, are catalytically rearranged in an anhydrous, strong
acid medium to the corresponding 1-methyl-3-hydroxy 20 anhydride. The resulting product containing 1-methyl17j8-acetyl-1,3,5(10),9(11) - estratetraene (i.e., 1-methyl~
1,3,5 (l0),9( 11)-estratetraene-3-ol-17-0ne acetate, is dis‘
3-hydroxy-l9 - nor - 1,3,5(10),9(ll) - pregnatetraene-ZO
solved in 20
of methanol, then a solution of 1 g. of
potassium hydroxide in 2 ml. of water is added and the‘
mixture heated under re?ux for 20 minutes. The solution:
one) and 1-methyl-9(l1)-dehydroestrone (i.e., l-methyl
1,3,5 ( 10) ,9( 1 1 ) -estratetraene~3-ol~ l7-one) respectively.
is poured into ice-water and acidi?ed with hydrochloric‘
acid. The resulting precipitate is filtered, washed with‘
water, dried, crystallized from ether-hexane and recrystallization from ether to give 1—methyl-1,3,5( 10),9(l1)
As a general rule, when an anhydride is employed in
my process, the corresponding ester of the phenolic hy
droxyl at the 3-carbon is obtained and any other hydroxyl
groups in the molecule are also esteri?ed. On the other
hand, when an acid is used as the solvent, the correspond
ing free phenol may be obtained.
By my novel process as described herein, 1,4,9(11)
30
estratetraene~3~ol-17-one M.P. 163—165° C;
Anton 215 mu (5 24,100), 253 my (6 12,100)
[a]D +245° C. (CHCl3). This compound is soluble in
mux.
androstatriene-B-one-175-01 and 16a - methyl - 1,4,9(11)
androstatriene-3-One-l'i?-ol upon reaction with p-toluene
sulfonic acid in acetic acid yields respectively l-methyl
dilute aqueous base.
i
(B) To a solution of 1.0 g. of 1,4,9(1l)-androstatriene
3,17-dione in 40 m1. acetic acid is added 250 mg. of p
9(11) - dehydroestradiol and l,16a-dimethyl-9(11)-dehy
droestradiol. Alternatively, the 1-met'nyl~9(11)-dehydro
estradiols of my invention may be derived by utilizing
toluenesulfonic acid. The mixture is heated on the steam
bath for 5 hours, then poured into ice-water. The result
known techniques from 1-methyl-9(11)-dehydroestrone
ing precipitate is ?ltered, dried, and crystallized twice
which, in turn, is obtained by the process of this invention 40 from ether-hexane to give 1-methyl-1,3,5(10),9(11)
estratetraene-3-ol-17-one (i.e., 1-methyl-9(11)-dehydr0
by the action of p-toluenesulfonic acid in acetic acid on
1,4,9(11)-androstatriene-3,17-dione. Thus, for example,
borohydride yields 1-methyl-9(11)-dehydroestradiol which
estrone).
reduction of 1-methyl-9(11)-dehydroestrone with sodium
EXAMPLE 2
may, if desired, be transformed by conventional methods
1 -Methyl estrone
such as with acetic anhydride in pyridine to its ester de
rivatives. Additionally, the 17-keto group of l-methyl
9(11)—del1ydroestrone may be treated with an alkyl Gri~
To a suspension of 60 mg. of 10% palladium on stron
tium carbonate in 5 ml. ethanol, prehydrogenated at room
temperature and atmospheric pressure, is added a solution
of 75 mg. of 1-methyl-1,3,5(10),9(11)-estratetraene-3-ol
17-one in 8 ml. ethanol. The solution is hydrogenated
until no more hydrogen uptake is observed. The palla
dium catalyst is ?ltered off and the ?ltrate concentrated
to a residue which is crystallized from aqueous ethanol,
gnard reagent such as methyl magnesium iodide to give
the corresponding 17u-methyl- 17p‘ - hydroxy compound,
1,17a - dimethyl - 9(11) - dehydroestradiol.
Similarly, 1
methyl-9(1l)-dehydroestrone upon reaction with sodium
acetylide according to known techniques yields the corre
sponding 17u-ethinyl - 17?-hydroxysteroid, 1-methyl~17<z
and recrystallization from methanol to give 1~methyl~
estrone, M.P. 243~247° C.;
AM“ 214 my (6 10,400), 282,287 me (e 1,760)
ethinyl-9(11)-dehydroestradiol. If desired, the phenolic
3-hydroxy group in the estratetraenes prepared by my
process may be esteri?ed in the usual manner, or con
max.
verted to an ether function, for example 3-methoxy, by
The infrared spectrum is identical with that of an authentic 1
means of dimethyl sulfate and base.
_
The 1,3,5 (10),9(1l)-estratetraenes of my invention are 60 sample.
‘ EXAMPLE 3
valuable as intermediates in the synthesis of therapeuti
cally valuable 9,11-disubstituted-1~methyl-aromatic-A-ring
1-Me1hyl-1,3,5(10),9(11)-Estratetraene-3-Ol-17-0112
steroids such as are described in co-pending application
of Reimann and Robinson, Serial No. 138,271 ?led on
even date with the instant application. The 9(11)-double
bond of the estratetraenes of this invention may be utilized
Acetate
To a solution of 250 mg. of 1-methyl-1,3,5(l0),9(1l)
estratetraene-3-ol-17-one in 5 ml. of pyridine is added 1
ml. of acetic anhydride. The mixture is allowed to stand
in the synthesis of 9,11-disubstituted-l~methyl-estrogens
of Reimann et al. by addition of halogens or hypohalous
acids and the like, to yield 9,11-dihalogenated compounds
or 9,11-halohydriris and esters thereof.
In addition to their use as intermediates the novel com
pounds of this invention show useful estrogen-like activity,
such ‘as the ability to lower serum cholesterol while ex
hibiting greatly reduced, undesirable estrogenic side
eftects. On the other hand, the novel derivatives pro
70
at room temperature for 22 hours, then is poured into
ice-water and stirred to hydrolyze any excess anhydride.
A solid separates which is crystallized from ether to give
1-methyl-1,3,5(10)-estratetraene-3-ol-17-one acetate, M.P.
125—126‘’ C.;
A3152“ 212 me (6 27,000), 247 me (6 13,300)
[cc]D +215“ (CI-1G3).
3,082,225
7
5
6
EXAMPLE 4
EXAMPLE 8
1-Methyl-1,3,5(10),9(11 ) -Estratetraene-3-Ol-17-One
1~Methyl-1,3,5 (10) ,9 (11 ) -Estratetraene-3,I 713-Di0l
Dipropionate
Methyl Ether
To a solution of 500 mg. of 1-methyl-1,3,5(10),9(11)- 5
To a solution of 500 mg. of 1,4,9(l1)-androstatriene—
estratetraene-3-ol-17-one in 25 ml. methanol is added a
l7?-ol-3-one in 20 ml. of propionic anhydride is added
solution of 3 g. potassium hydroxide in 5 ml. of water.
125 mg. of p-toluenesulfonic acid. The mixture is re
The mixture is chilled and 2 ml. of dimethyl sulfate is
acted and the resulting product isolated in a manner simi
added dropwise, then the mixture is stirred at room tem
lar to the procedure of Example 7B. The product is then
perature for 1/2 hour. Additional 2 ml. portions of di 10 crystallized from ether-hexane to give 1-methyl-1,3,5( l0),
methyl sulfate are added at the next two 1/2 hour intervals,
9 ( 1 1 ) -estratetraene-3,17B-diol dipropionate.
then the mixture is stirred a ?nal 1/2 ‘hour, and allowed
EXAMPLE 9
to evaporate overnight. The resultant residue is washed ‘
with Water, dried, crystallized twice from ether-hexane to
1 - Methyl - 17,8 — Acetyl - 1,3,5(10),9(11) - Estratetra
give 1-methyl-1,3,5(10),9(11) - estratetraene-S-ol-l7-one
ale-3,] 7 a-Diol Diacetate (1-Methyl-J9-N0r-1,3,5 (10) ,
15
methyl ether, M.P. 100-102° C.; I
9 (11 ) -Pregnatetraene-3,1 7 a~Di0l~2 O-One Diacetate)
MBOH 213 me (6 31,300), 252 my (6 17,300)
A solution of,1.0 g. of 1,4,9(1l)-pregnatriene-l7a-ol
3,20-dione in 10 ml. of acetic acid and 2 ml. of tri?uoro
acetic anhydride is ?ushed with argon and heated on the
[0611) -l-'262o
EXAMPLE 5
20 steam-bath for 50 minutes. The solution is then cooled
max.
and poured into ice-Water. The resulting precipitate is
l-Metlzyl-I7a-Ethinyl-1,3,5 (10) ,9 (1] ) -Estratetraene
?ltered, dried, dissolved in ether and ?ltered through a
short Florisil column. The eluted oil is triturated with
ether-pentane to give a solid which is crystallized from
3,1 7,8-D iol
To a solution of 250 mg. of 1-methyl-1,3,5(10),9(11)
estratetraene-3-ol-17-one in 6 ml. of dimethylsulfoxide, 25 ether-hexane to give 1-methyl-17/3-acetyl-l,3,5 (10),9( ll)
cooled to about 15° C. is added sodium acetylide, o -
tained ‘by centrifugation of 1.5 ml. of a 17% suspension
in xylene, in 2 ml. of dimethylsulfoxide. The mixture is
stirred at room temperature for 25 minutes, then poured
into ice-water and the solution acidi?ed with hydrochloric 30
acid. The resulting precipitate is ?ltered, Washed with
Water, dried and crystallized from acetone-hexane to give
EXAMPLE l0
1 - Methyl - 1713 - Acetyl - ],3,5(10),9(I1) - Estratetra
9 (11 ) -Pregnatetraene-3,17ot-Di0l-20-0ne J 7-A cetate)
To a solution of 530 mg. of l-methyl-17/3-acetyl-1,3,5
(l0),9(ll)-estratetraene-3,l7ot-diol diacetate in 25 ml. of
methanol is added 0.53 ml. of 70% perchloric acid and
AL‘SQH 214, 253 my.
EXAMPLE 6
the mixture allowed to stand at room temperature for 18
1 -Methyl-1,3,5 (10) ,9 (11 ) -Estratetraene-3,17,8-Diol
A solution of 2.5 g. of 1-methyl-l,3,5(l0),9(l1)-estra
tetraene-3-ol-17-one in 50 ml. of methanol is chilled in
ice. To the chilled solution 2.5 g. of sodium borohydride
is added in portions and the resulting solution kept at 0°
C. until foaming subsides. The reaction mixture is then
allowed to stand at room temperature for 1 hour, acidi?ed
with 5% hydrochloric acid and diluted with water. The
resulting precipitate is ?ltered and crystallized from aque
ous acetone to give 1-methyl-1,3,5(10),9(11)-estratetra
ene-3,l7,B-diol, M.P. 148-152° 0.;
mg 211 mil (6 27,000), 248 my (6 13,800)
[a]Df+84° (CHCla).
ate-3,1 7a-Diol 17-Acetate (1-Methyl-19-N0r-1,3,5 (10),
1 - methyl - 17a - ethinyl - 1,3,5 ( l0),9(11) - estratetraene
3,17?-diol,
.
estratetraene-3,17a-diol diacetate, M.P. 143~146° C.;
,
40
‘hours, then poured into ice-water. The resulting pre
cipitate is ?ltered, dried and chromatographed on Florisil.
Suitable fractions, as determined by paper chromatog
raphy, are combined and crystallized from ether-hexane
‘and ether-acetone to give 1-methyl-17;8-acetyl-1,3,5(l0),
9(11)-estratetraene-3,l7ot-diol 17-acetate, M.P. 227-235. °
- 2
AMeOH
mm 215 my (6 24,000), 252 m,u (6 12,300)
[ot]D '+l10° (CHClg).
EXAMPLE l1
50
1 - Methyl - 17B - Acetyl - 1,3,5(10),9(I1) - Estratetra
my 215 m” (6 25,000), 253 me ((-1 13,200)
ene-3,17u~Di0l
[OC]D -l—138c
A solution of 100 mg. of the 3,17-diacetate of Example
9 in 4.5 ml. of 5% potassium hydroxide in methanol and
0.5 ml. of Water is heated under re?ux for 15 minutes.
It is then acidi?ed with dilute hydrochloric acid and
poured into water. The resultant precipitate is ?ltered
and crystallized twice from ether-hexane -to give l-methyl
1-Methyl-1,3,5(10),9(11)-Estratetraene-3,17,8-Di0l
_
(J-Methyl-19 - Nor - 1,3,5(10),9(11)
Pregnatetraene-3,J 7a-D i0l-20-One)
EXAMPLE 7
Diacetate
(A) A solution of 1.5 g. of the l-methylestratetraene
of Example 6 in 15 ml. of pyridine and 2 ml. of acetic 60
17,6-acetyl-1,3,5(10),9(l1)-estratetraene-3,17ot-diol,
anhydride is allowed to stand at room temperature for
197-205° C
18 hours. The solution is then poured into ice-water and
the resulting precipitate is ?ltered, dried, and crystallized
twice from ether-hexane to give 1-methyl-1,3,5(10),9(11)
estratetraene-3,17B-diol diacetate, M.P. 128-129“ C.;
[LX113 {-78o
(B) To a solution of 1.0 g. of 1,4,9(1l)-androstatri
ene-17?-ol-3-one in 40 ml. of acetic anhydride is added
250 mg. of p~toluenesulfonic acid. The ?ask is ?ushed
M.P.
my 215 my (6 27,800), 254. my (a 13,900)
[06113 ‘+860 ('CHClg).
65
'
Alternatively, the 17-monoacetate compound of Ex
ample 10 is hydrolyzed according to the above procedure
to give the desired product, identical with that prepared
from the diacetate as above.
‘EXAMPLE 12
> with argon and the mixture is heated on the steam-bath 70
for 5 hours, then poured into ice-water, and stirred for
I ~ Methyl - 17;? - Acetyl - 1,3,5 (10) ,9 (1]) - Estratetra
V2 hour to hydrolyze any excess anhydride. The result
ene-3-Ol (1-Methyl-19-N0r-I,3,5(10) ,9 (1] ) -Pregnatet
ing precipitate is ?ltered, washed with water, dried, and
crystallized from ether-hexane to give 1-methyl-1,3,5(10),
9(11)-estratetraene-3,17;8-diol diacetate.
‘
raene-3-0l-20-One)
‘A sample of 500 mg. vof 1,49(11)-pregnatriene-3,20
75 drone is allowed to react with acetic anhydride and p
3,082,225
7
acid anhydrides.
2. A process according to claim 1 wherein the strong
acid catalyst is p-toluenesulfonic acid and the solvent is
give 1-methyl-17?-acetyl-1,3,5(10),9(11)-estratetraene-3
acetic anhydride.
o1,
3. A process according to claim 1 wherein the strong
acid catalyst is p-toluenesulfonic acid and the solvent is
m 215 ma (6 25,200), 253 mg (6 12,000)
X11203
acetic acid.
4. A process according to claim 1 wherein the strong
[0.]3 +2040 (CHCl3).
EXAMPLE 13
8
the group consisting of carboxylic acids and carboxylic
toluene-sulfonic acid according to the procedure of Ex
ample 1A and the product hydrolyzed and isolated as
described, then crystallized twice from ether-hexane to
10 acid catalyst is tri?uoroacetic anhydride and the solvent
1 - Methyl - 17/3(/3' - Acetoxyacetyl) - 1,3,5(10),9(11)~
is acetic acid.
Estratetraene-3,17a-Di0l-20-One Diacetate (I-Methyl
‘
5. In the process for the production of compounds
having the following structural formula:
19 - Nor - 1,3,5(10),9(11) - Pregnatetraene - 3,17u,21
Tri0l-20-0ne Triacetate
Five g. of 1,4,9(11)-pregnatriene'17u,21-diol-3,20-di 15
tr
one 21-acetate is allowed to react with acetic anhydride
CH3 \
Ml
and p-toluenesulfonic acid according to the procedure of
Example 7B to give 1methyl-17B(;8’-acetoxyacetyl)-1,3,5
(10) ,9( 1 1 ) -estratetraene-3, 17oc-diol-20-one diacetate
20
M552“ 213 mu (6 23,300), 247 Inn (6 10,300)
EXAMPLE l4
wherein R is selected from the group consisting of hy
drogen, lower alkyl and lower alkanoyl; Z is selected from
1 -Methyl-1 7/3-Acetyl-1,3,5(10),9(1 1 )-Estratetraene
3,1 7a-Di0l 3-Benz0ate 1 7-Acetate
To a solution of 800 mg. of l-methyl-17/8-acetyl-1,3,5
the group consisting of:
(10),9(11)-estratetraene-3,17a-diol 17-acetate (the com
pound of Example 10) in 10 ml. of pyridine is added 1
ml. of benzoyl chloride. The mixture is allowed to stand
at room temperature overnight and then is poured into 30
R’ being selected from the group consisting of hydrogen
ice water and stirred for 20 minutes. A solid separates
and lower alkanoyl', R” being selected from the group
which is ?ltered, dried, and crystallized from acetone
consisting of lower alkyl and ethinyl; the step which com
hexane to give l-methyl-17?-acetyl-1,3,5(10),9(11)-estra
prises heating a compound of the formula:
tetraene-3,17a-diol S-benzoate 17-acetate.
35
on,
EXAMPLE 15
CH3
1,1 7ot-Dimethyl-1,3,5 (1 0) ,9 (11 ) -Estratetraene-3,1 7,8-D iol
To a solution of 1 gram of 1-methyl-1,3,5(10),9(11)
/\
estratetraene-3-ol-17-one (the compound of Example 1) 40
0:0
in 50 ml. of tetrahydrofuran is added dropwise with stir
ring to an ethereal solution of methyl magnesium iodide
(prepared from 3 grams of magnesium metal and 7.5 ml.
of methyl iodide in 200 ml. of anhydrous ether). The
wherein Z is as de?ned above, with a strong acid catalyst
reaction mixture is diluted with 150 ml. of tetrahydro ~15 in a ‘solvent of the group consisting of carboxylic acids
furan then distilled until 200 ml. of distillate has been
and carboxylic acid anhydrides.
collected. The reaction mixture is then re?uxed for 1
6. A compound of the structural formula:
hour, cooled and poured slowly into 200 m1. of cold
CH;
10% aqueous ammonium sulfate solution. The mixture
is extracted with methylene chloride and the organic 50
extracts are combined, washed with water, and concen
, trated to a residue which is crystallized. from acetone
hexane to give 1,17a-dimethy1-1,3,5(10),9(11)-estratetra
ene-3,17?-diol.
By substituting other Grignard reagents, such as ethyl '
magnesium bromide for methyl magnesium iodide in the
above procedure, there is obtained the corresponding 17a
wherein R is selected from the group consisting of hy
drogen, lower alkyl‘and lower alkanoyl; Z is selected from
the group consisting of:
alkyl derivative, e.g., 1-methyl-17u-ethyl-1,3,5(10),9(11)
estratetraene-3,17?-diol.
EXAMPLE 16
1,16ot-Dimethyl-1,3,5(10),9 (11 )-Estratetraene-3,17?-Di0l
(1 ’16d'Dl-m€thyl'9 (1 1 ) -Delzy droestradiol)
16a-Methy1-1,4,9(11)-androstatriene-17,6-ol-3-one is re
acted with p-toluenesulfonic acid in acetic acid in the
manner described in Example 1B. The resultant product
is isolated as described to give 1,16a-dimethy1-1,3,5(l0),
R’ being selected from the group consisting of hydrogen
and lower alkanoyl; R” being selected from the group
consisting of lower alkyl and ethinyl.
9(11)-estratetraene-3,17,6-dio1.
I claim:
1. A process ‘for the production of I-methyl-hydroxy
1,3,5(10),9(11)-estratetraenes which comprises heating a
3-keto-1,4,9(11)-triene taken from the ‘group consisting
of 3-keto-1,4,9(11)-androstatrienes and 3-keto-1,4,9(l1)
pregnatrienes with a-strong acid catalyst ‘.in a solvent of
70
7. 1 - methyl - 17a - ethinyl - ‘1,3,5(10),9(11)-estra
tetraene-3,17B-diol.
8. 1,170; - dimethyl . 1,3,5(10),9(1l) - estratetracne
3,17i3-diol.
9. 1 - methyl - 175 - acetyl - 1,3,5(10),9(11) - estra
tetraene-3,17<x-diol diacetate.
3,082,225
10
10. l - methyl - 17/3 - acetyl - l,3,5‘(10),9(11) - estra
tetraene-3,17a-diol 17-acetate.
11. 1 - methyl - 17B - acetyl - 1,3,5(l0),9(11) - estra
tetraene-3,17a-diol.
12. 1 - methyl - 17B - acetyl - l,3,5(10),9(11) - estra
tetraene-B-ol.
13. 1 - methyl - 17,8(5’ - acetoxyacetyl) - 1,3,5(10),
9(l1)-estratetraene-3,17a-diol 3,17-diacetate.
I.
References Cited in the ?le of this patent
Elks et al.: Proceeding of the Chemical Society, Janu
ary 1959, pp. 6 and 7‘
Mills et al.: J.A.C.S. 82 5882-5889 (Nov. 20, 1960)
(p. 5883 depended upon).
Kirk 61: 211.: ].C.S. (1960), pp. 4664—4667.
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No‘. 3,082,225
March 19, 1963
Hans Reimann
It is hereby certified that error appears in the above numbered pat
ent requiring correction and that the said Letters Patent should read as
corrected below.
Column 7, line 71' for "l—methyl—hydr0xy—" read —— l
methyl~3—hydroxy— ——.
Signed and sealed this 8th day of October 1963.
(SEAL)
Attest:
EDWIN L. REYNOLDS
ERNEST W. SWIDER
Attesting Officer
'
AC t i 11 Q5
Commissioner of Patents
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