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Патент USA US3093676

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United vStates Patent ‘O
3,093,664
I‘ ' ‘Patented June 11‘, 1963
1
3,093,664
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4-HALO-6-DEHYDRO AND 4-HALO-1,6-BIS DEHY
DRO DERIVATIVES 0F 17u-HYDROXY PROGES
TERONE
'
‘
_
‘
~
John A. Edwards, Howard J. Ringold, and Fred A. Kincl,
Mexico City, Mexico, assignor‘s, by mesn'e assignments,
‘I338 ‘
0=°
5
No Drawing. Filed Nov. 30, 1959, Ser. N0.'19,438
Claims priority, application Mexico, Nov. 28, 1958 >
p
,
15 Claims.
10
(Cl. 260-3974)
> This invention relates to certain new Icyclopent-a'no
phcnanthrene
derivatives.
‘
a
'
'
i
-
‘
-
‘
"
V
' dehydro-
I/lxo?
I
genatiou
'
-
———->
'0_.
I
on,
h=o
‘
| ‘iv-OH
to Syntex Corporation, a corporation of Panama
t
r
‘
chloranil
O__
‘More particularly, it relates to the ‘novel ~4-halo-6-dei
hydro and 4-halo-1,6-bis‘dehydro' derivatives of 17u-hy
Y
droxyprogesterone, and their esters, represented by the
following formula:
'7
X
_
.15
HI‘
X
‘
I
. "
IV
A
esteri-.
?cation
20
_
CH’
'
'
0H,
--OAcyl ' ‘
i—-OAcyl
dehydro‘
/
'
a.
genatlon
I
*———-—-—-->
'
(
dehydro-
No. 647,503, ?led on March 21, 1957, their 17-esters de
The new compounds according to the invention were
produced by meausof a process illustrated in the reaction
l
.
I
>
_
I
' .O
7
t
I
I
VA
I
‘TIC
'
I
VIA,
lsapom?éation
OH;
7
s (3H,
h=0
I _
| "OH
‘ I
02?‘
V
*
‘w ’ '
0Q, '
V
X
VI
As preparatory steps in the above-illustrated process,
the well known and conventional starting compound I,
65 17a-hydroxy-poogesterone, is epoxidized with the aid of
hydrogen peroxide and sodium hydroxide to the epoxide
II and the latter is then halogenated in its acetonic or the
i
___..____>
o___
l __OAcy1
' /
‘a
X
55
“
I lj-on
'l
I
( xylene
I
,
I "OH
'60
on,
$=0
epoxidation
CH1
~é=0
diagram given below and described thereafter in detail.
‘
(A) or (G)
\l
genation‘
50
scribed by Edwards, Ringold rand Rosenkranz, in patent
application Serial No. 811,019, ?led on May 5, 1959, or
the l-dehydro derivatives of such compounds, also de
scribed in the latter patent application.
‘
dehydrogenation
amyl alcohol
525,313: l yesteri?catlon
chloro- and 4-bromo-17a-hydroxyprogesterone described
I jh-orr'f I
(0) Ohloranil
genatiou
-———~——--——>
'
by Ring-old and Rosenkranz, in patent application Serial
5:0 I
IVA
dehydrd-
dehydro-
‘
o1k/
'
' The new compounds which vare the object of the present I
invention, are valuable drugs which inhibit ovulation, ,
For their preparation, we used as starting materials 4
_1
‘
~
B) Chloranil
'
t
V
CH3
’
45
‘
'
V
(\I
cinate, caproate, henzoate, ltrirnethylacetaite, phenoxy
acetate, phenylpropionate, cyclopentylpropionate and 13
on,
O“
I "OAcyI
alkoxy (of 1 .to 8 carbon atoms) or halogen (?uorine,
chlorine or bromine). Among others, typical esters of
such acids are the acetate, propionate, butylrate, hernisuc
'
'
-
of straight, branched, cyclic or mixed straight (branched)
cyclic chain, optionally substituted with functional groups
such as hydroxyl, acyloxy (of 1 to ‘12 carbon atoms),
"
xylene
1111\-
wherein Z is a‘ member of the group consisting of a single
and a double carbon-to-carbon bond, X is a member of
genation;
the group consisting of chlorine and bromine,‘ and Rise.
8,11%;
member of the ‘group consisting of hydrogen and the acyl
Oxide
radical of a hydrocarbon earboxylic acid having from-'1 35
to 12 carbon atoms andbeing saturated or unsaturated,
chloropropionate.
B) Chloranil
I
like solution with the aid of concentrated hydrochloric
or hydrobromic acid to the corresponding 4-chloro or 4
HnOaNaOH 0_
bromo compound III, in which X represents either chor-ine
\0
.I
_
a,
a
I
n,
,3‘; or ‘bromine as the case may be.
1
Esteri?oation ‘of compound III is‘ carried out in a con;
3,093,664:
4
3
respective acid and p-toluenesulfonic 'acid, and esters of
A mixture of 5 g. of 4-chloro-17a-hydroxyprogesterone
prepared in the above manner, 10 g. of chloranil, 75 cc.
the general Formula IIIA are obtained.
The esters VA of the A1-4-dienes are obtained from
under an atmosphere of nitrogen for 96 hours. The
compounds IIIA by dehydrogenation with selenium di
cooled mixture was washed with cold aqueous 10% so
oxide, t-butanol and pyridine, as described in patent ap
dium hydroxide solution until the washings were color
less, the solution was dried over anhydrous sodium sul
fate and the ethyl acetate was evaporated. Chromatog
raphy of the residue on neutral alumina afforded 4-chlo
ventional manner, ‘for instance with the ‘anhydride of the
of ethyl acetate and 25 cc. of acetic acid was re?uxed
plication 811,019 supra, and the -free Alv‘i-‘dienes V by
conventional saponi?cati-on from esters VA.
In order to introduce a single ‘additional double bond
at C-6,7 into 4-halo-17a-hydroxyprogesterone III or its 10 ro-ti?-pregnadien-17a-ol-3,20-dione.
esters IIIA to 'obtain compounds IV and IVA, the steroid
Example II
is re?uxed with chloranil in mixture with ethyl acetate
To a solution of 1 g. of 4-chloro-17a-hydroxy-proges
acetic acid or in mixture with xylene; in order to intro
terone prepared as described in Example I, in 50 cc. of
duce two double bonds vat C-1,2 and C-6,7, the esteri?ed
A‘i-compouud is re?uxed with chloranil in mixture with 15 anhydrous benzene there was added 2 cc. of acetic an
hydride and 200 mg. of p-toluenesulfonic acid and the
n-amyl alcohol to obtain directly the esteri?ed ALM
compounds VIA and upon conventional saponi?cation the
mixture was 'kept at room temperature for 24 hours and
free compounds VI.
then diluted with water; the benzene layer was separated
Alternatively, we obtained the 1,4,6qtrienes VIA by re
and washed with aqueous 5% sodium carbonate solu
?uxing the above-mentioned 1,4-dienes VA, that is, the 20 tion and with water to neutral, dried over anhydrous so
l-dehydro-derivatives of the 4-‘halo-l7a-hydroxy-proges
dium sulfate and evaporated to dryness. The residue
terones, with chloranil in mixture with the solvents men
crystallized from acetone-hexane to yield 4-chloro-17a-hy
tioned above, or by re?uxing the 4,6-dienes IVA with
droxy-progesterone 17-acetate, M.P. 177-179” C.
selenium dioxide, preferably in mixture with t-butanol,
The latter ester was further treated in the same man
in the presence of catalytic amounts of pyridine, or by 25 ner as described when using the free 4-chloro compound
re?uxing the same 4,6»dienes with chloranil in mixture
in Example I. The 17-acetate of 4-chloro-A‘i-6-pregna
with n-amyl alcohol.
dien-l7a-o1-3,20-dione was obtained.
Although the object of the present invention is the prep
aration of the novel 4-chloro and 4~bromo-A4-6-pregnadi
en-17a-ol-3,20-diones and ‘AWG-pregnatrien-I7a-ol-3,20
Example III
30
diones and their 17-esters, the above-described process
may also be applied to the preparation of the 6-dehydro
and 1,6-bis-dehydro derivatives of other 4-halo(chloro or
Example I was repeated, but hydrobromic acid solu
tion was substituted for the hydrochloric acid and there
was obtained 4~bromo-17a-hydroxy-progesterone.
The latter compound was esteri?ed to its 17-acetate by
the ?rst step described in Example II.
bromo)-A4-3-ketones, for example of the 4-halo analogs
of cortexone (or desoxycorticosterone), of cortexolone 35 A mixture of 5 g. of they resulting 4-bromo-l7a-hy
(or Reichstein’s substance “S”), of cortisone and of hy
droxyprogesterone 17-acetate, 10 g. of chloranil and 50
drocortisone, which compounds may be optionally halo
cc. of xylene was re?uxed for 16 hours under an atmos
genated at 09 and/or substituted at C-16 (a-hyd-roxyl,
phere of nitrogen, cooled, washed with 5% aqueous so
u-methyl or ?-methyl, a-alkoxy or a-?uorine) and/or at
dium bicarbonate solution and water, dried over anhy
C-2 (a-alkyl), and/or at C-2l (?uorine) and/ or have at 40 drous sodium sulfate and the xylene was evaporated un
C-1‘6,17 a cyclic acetal or ketal group, as well as to the
der reduced pressure. By chromatography of the residue
preparation of such dehydro derivatives of the esters of
on neutral alumina there was obtained the l7-acetate of
the above-enumerated compounds.
4-bromo-A4'6-pregnadien-17a-ol-3,20-dione.
’
The reactions involved in the above-described process
may be modi?ed within wide limits. For example, the
reaction time may be varied without much in?uence in 45
the result; for introducing the third double bond into the
4,6-dienes with selenium dioxide, a solvent different from
t4butanol may be employed, such as acetic acid or anoth
Example IV
4-chloro-17a-hydroxy-progesterone was esteri?ed with
caproic anhydride by following the procedure described
in Example II.
A mixture of 5 g. of the resulting 17-caproate of 4
chloro-l7a-hydroxyprogesterone, 0.4 g. of selenium di
er lower tertiary alcohol; pyridine may be substituted 50
oxide and 0.3 cc. of pyridine was re?uxed under an at
by another basic catalyst; the introduction of the double
mosphere of nitrogen for 72 hours and then ?ltered
bond at C-1 may also be achieved by biochemical meth
through celite, washing the ?lter with hot butanol; the
ods, for example by incubation with Corynebacterium
?ltrate ‘and washings were combined and evaporated to
simplex ATCC 6946.
The following speci?c examples serve to illustrate but 55 dryness under reduced pressure; the residue was dissolved
in acetone, treated with decolorizing charcoal, re?uxed
are not intended to limit the present invention.
for half an hour, cooled, ?ltered and evaporated to dry
Example I
ness. The residue was puri?ed by chromatography on
A solution of 10 g. of 17a-hydroxy-progesterone in 300
neutral alumina. There was thus obtained 4-chloro-A1-4
cc. of methanol was cooled to 0° C. and mixed with 20 60
pregnadien-17a-ol-3,20-dione 17-caproate.
tion and 50 cc. of a 4% sodium hydroxide solution.
3,20-dione 17-acetate with 10 cc. of a methanol solution
cc. of previously cooled 32% hydrogen peroxide solu
The
A mixture of 1 g. of \4-chloro-A1A-pregnadien-17a-ol~
of sodium methoxide, prepared from 160 mg. of sodium
mixture was kept standing for 48 hours at 0° C., poured
and absolute methanol, was stirred at 20° C. under an
into water, extracted with methylene dichloride, the di
chloride solution was evaporated to dryness and the resi 65 atmosphere of nitrogen for 72 hours. It was then poured
into 50 cc. of aqueous saturated sodium chloride solution
due crystallized from acetone~hexane. There was thus
containing a few drops of acetic acid and the precipitate
obtained 7.8 g. of 45,5[3-epoxido-pregnane-17a-ol-3-20
formed was collected by ?ltration, washed with a little
dione.
cold water, dried and recrystallized from acetone-hexane.
1 g. of this compound was dissolved in 20 cc. of ace
There was thus obtained the free 4-chloro-A1-4-pregna—
tone and mixed with 1 cc. of concentrated aqueous solu 70
dien-17a-ol-3,20-dione.
tion of hydrochloric acid. The mixture was kept for 4
A mixture of 6 g. of the free 4-chloro-AL4-pregnadien
hours at room temperature and then poured into water.
17a-ol-3,20-dione, 100 cc. of anhydrous benzene, 10 g. of
The product was ?ltered, washed to neutral, dried under
cyclopentylpropionic anhydride and 3 g. of p-toluene
vacuum and crystallized from acetone-hexane, thus giv
sulfonic acid was kept at room temperature for 3 days
75 and then diluted with water. The benzene layer was
ing 800 mg. of 4-chloro-17a-hydroxy-progesterone.
3,093,664
5
6
separated, washed several times with 5% aqueous sodium
wherein Z is a member of the group consisting of a single
and a double carbon-to-carbon bond, X is a member of
the group consisting of chlorine and bromine, and R is a
member of the group consisting of hydrogen and the
carbonate solution and water, dried over anhydrous so
dium ‘sulfate and the benzene was evaporated. Crystal
lization of the residue from acetone-hexane yielded the
cyclopentylpropionate of 4-chloro-A1'4-pregnadien-17a-ol
3,20-dione.
acyl radical of a hydrocarbon carboxylic acid having from
5 g. of the above compound was treated with chloranil
2. 4-chioro-A4ys-pregnadien-17uJol-3,20-dione.
3. An ester of 4-chloro-A4?-pregnadien-l7a-ol-3,20-di
one having an hydrocarbon carboxylic acyl group which
1 to 12 carbon atoms.
in mixture with xylene, exactly as described in Example
II, .thus producing the cyclopentylpropionate of 4-chloro
Ald-s-pregnatrien-17a-o1-3,20-dione.
10 contains up to 12 carbon atoms.
4. 4-chloro-A1res-pregnatrien-17a-ol-3,20~dione.
Example V
By following the method of esteri?cation described in
5. An ester of 4-chloro-Ali‘i'?-pregnatrien-17a-ol-3,20
dione having an hydrocarbon carboxy-lic acyl group which
the preceding example, 4-bromo-17a-hydroxy-pnogester
contains up to 12 carbons atoms.
one prepared as described in Example III was converted
6. 4-br0mo-A416-pregnadien-l7a-ol-3,20-dione.
into its iso-butyrate by reaction with the anhydride of
iso~butyric acid; in turn, this iso-butyrate was converted
into the iso-butyrate of 4-bronro-A4'6-pregnadien-17a-ol
3,20-dione by the reaction with chloranil described in
Example I.
5 g. of the above compound was re?uxed with sele
7. An ester of 4-bromo-A4I6-pregnadien-17a-ol-3,20-di
one having an hydrocarbon carboxylic acyl group which
contains up to 12 carbon atoms.
8. 4-bromo-A1?l?-pregnatrien-17u-ol-3,20-dione.
20
ni-um dioxide, essentially ‘following the method of Exam
9. An ester of 4-bromo-A1'4’6-pregnatrien-17a-ol-3,20
dione having an hydrocarbon carboxylic acyl group which
contains up to 12 carbon atoms‘
ple IV, to produce the isobutyrate of 4-bromo-A1'4'6-preg
10. A compound as described in claim 1 wherein R
natrien-17ot-ol-3,20~dione.
is the acyl group of propionic acid.
25
11.
is the
12.
3,20~dione obtained as described in Example II was re
is the
?uxed with chlorani-l in mixture with n-amyl alcohol, in
13.
accordance with the procedure described in Example IV, 30 is the
thus furnishing the acetate of 4-chloro-A1'4»6-pregnatrien
14.
17a-ol-3,20-di'one.
is the
We claim:
15.
1. A compound of the general formula:
is the
Example VI
5 g. of the acetate of 4»ch1oro—A416-pregnadien~17a-ol
CH:
A compound as described in claim
acyl group of acetic acid.
A compound as described in claim
acyl group of isobutyric acid.
A compound as described in claim
acyl group of hemisuccinic acid.
-A compound as described in claim
acyl group of caproic acid.
A compound as described in claim
1 wherein R
1 wherein R
1 wherein R
1 wherein R
1 wherein R
acyl group of cyclopentylpropionic acid.
35
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,883,379
2,895,969
Moreland et a1. _______ __ Apr. 21, 1959
Ringold et a1 __________ __ July 21, 1959
OTHER REFERENCES
Kirk et al.: “Journal Chemical Soc.” (1956), pages
1184-6.
45
,
Kirk et al.: “Journal Chemical Soc." (1956), pages
627-9.
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