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Патент USA US3079418

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United States Patent O?ice
3,979,498
Patented Feb. 26, 1953
1
2
=bromo ; 3 - methoxyestra-1,3,5(10)-trien-l6a-ol, respec~
.
tively.
3,079,458
3,16-BISOXYGENATED 17-HALOESTRA
The 175-halo l6-ketones of this invention can be manu
factured also by epimer-ization of the corresponding 17w
halo compounds. This process is speci?cally illustrated
by the reaction of 17d-bromo-3-methoxyestrae1,3,5(16)
trien-16-one with p-toluenesulfonic acid to afford 17a
1,3,5 (1@)-TR§EI\TE§
George P. Mueller, Park Ridge, Ilh, assiguor to G. D.
Searle & (30., Chicago, Ill, a corporation of Delaware
No Drawing. Filed Apr. 17, 1961, Ser. No. 103,267
7 Claims. (Cl. 2é€i—397.4)
bromo-3-methoxyestra-1,3,5(10)-trien-l6-one.
The present invention relates to novel 17-halogenated
Although the 16,17 - epoxy-3-hydroxyestra-1,3,5(10)
steriods, and especially to 3,16-bisoxygenated 17-halo 10 trfenes can be used as such to achieve the instant 3-hy
estra-1,3,5(10)-trienes, which can be represented by the
droxy compounds, the phenolic moiety is preferably pro
structural formula
tected by a lower alkanoyl group in order to prevent any
possible oxidative decomposition. Thus, 16a-bromo-3
(if;
ROI I
hydroxyestra-1,3,5(10)-trien-l75-ol is reacted with meth
15 anolic potassium hydroxide to afford 165,175 - epoxy-3
hydroxyestra-1,3,5(10)-triene, which is treated with a low;
er alkanoic ac'd anhydride in pyridine to afford the cor
responding 3-(lower alkanoate). This ester can be, of
course, treated as described in detail supra, to afford the
wherein R is ‘selected from the group consisting of hydro
3-hydroxy compounds of this invention.
The instant 3,16-di-(lower alkanoates) are preferably
manufactured by reaction of the corresponding 3,16-diols
gen, lower alkyl, and lower alkanoyl radicals; X is a
halogen atom; and Z is selected from the group consist
with a lower alkanoi-c acid anhydride in pyridIne. As a
speci?c example, 175 _ bromo-3-hydroxyestra-1,3,5(l0)
20
ing of carbonyl, hydroxymethylene, and (lower alkanoyl)
25
trien-l65-o1 is treated with acetic anhydride in pyridine
oxy-methylene radicals Lower alkyl radicals represented
by R are exempli?ed by methyl, ethyl, propyl, butyl,
pentyl, hexyl, and the branched-chain isomers thereof.
to yield 3,165 ~ diacetoxy - 175-bromoestra - 1,3,5(10)-'
caproyl, and the branched-chain isomers thereof; said
groups being the acyl radicals of alkanoic acids contain
ing fewer than 7 carbon atoms.
3-(lower alkanoate).
triene.
On the other hand, treatment of a 3,16-diol of this in
vention with a limited quantity of a lower alkanoic acid
The lower alkanoyl radicals encompassed by R and Z are,
for example, formyl, acetyl, propionyl, butyryl, valeryl, 30 anhydride in pyridine results in production of an instant
This application is a continuation-in-part of my co
pending application, Serial No. 835,416, ?led August
24, 1959, and now abandoned.
7
Suitable starting materials for the manufacture of the
instant compounds are the appropriately 3-oxygenated
16,17 - epoxyestra - 1,3,5 (10) - trienes. , Dehydrobromi
The compounds of this invention are useful as result
of the'r valuable pharmacological properties. They are,
for example, estrogens in consequence of their ability to
35 promote uterine growth and to produce characteristic
changes in the vaginal epithelium.
The invention will appear more fully from the exam
ples which follow. These examples are set forth by Way
of illustration only and it will be understood that the
nation of the 3-oxygenated l6a,175_-halohydrins, prepared
40 invention is not to be construed as limited in spirit or
by the method disclosed at J. Org. Chem. 23, 1190
(1958), affords the 5-epoxides, as typi?ed by the reaction
of 16a-bromo-3-methoxyestra-1,3,5(10) - trien-l75 - 01
in scope of the details contained therein, as many modi
?cations in materials and methods will be apparent from
this disclosure to those skilled in the art. In these ex
respectively.
3 -_yrnethoxyestra - 1,31,5(10) - triene,
With methanolic potassium hydroxide to afford 3-meth 45 amples temperatures are given in degrees Centigrade
(°' C.). Quantities of materials are expressed in parts
oxy - 165,l75-epoxyestra-1,3,5(l0) - triene. Reaction of
by weight except where otherwise noted.
these 5-epoxides with a hydrohalogen acid results in the
instant l7a,~l65-halodydrins. One the other hand, reac
Example I
tion of the u-epoxides, prepared by epoxidation of the cor
A
solution
of
6
parts
of potassium hydroxide and 4.3
responding l6-dehydro derivatives with perbenzoic acid, 50
parts of l6ct-bromo-3-methoxyestra-1,3,5(10)-trien-l75-ol
with a hydrohalogen acid produces 175,l6cx-halohydrins
in 150 parts of methanol is heated at re?ux for about 19
of this invention. Speci?c examples of these processes
hours. The solution is cooled and diluted with water, and
are the reaction of hydrogen ?uoride in tetrahydrofuran
the resulting crystalline product washed Well with water
with 165,175-epoxy-3-methoxyestra-1,3,5 ( 10) - triene or
with 160:,l7a-6POXY - 3 - methoxyestra~1,3,5(10)-triene 55 and dried. This substance is puri?ed by adsorption on
silica gel, elution with 25% benzene in hexane, and re‘
to a?ord 17a-?uoro-3-methoxyestra-1,3,5(10)-trien-165
crystallization from ether to afford pure 1,65,,175-ep0xy
01 and l75-tluoro~3-methoxyestra-1,3,5(10)-trien-16u-ol,
Oxidation of the aforementioned halohydrins, typical
MP.
116-1l6.5°;
[a]D=+1l5° (chloroform).
By substituting an equivalent quantity of 3-n-propoxy
ly with chromium trioxide in pyrid'ne, results in the cor 60
165-bro1noestra-1,3,5 (10)-trie‘n-175-ol or 3-acetoxy-l6oc
responding 17-halo 16-ketones. For example, the reac
brornoestra-l,3,5(lO)~trien-175-ol ‘ and otherwise pro
tion of l7a-bromo-3-methoxyestra-1,3,5(10)-trien - 165
01 with chromium trioXide in pyridine, affords 17a-bromo
3-rnethoxyestra-l,3,5 ( 10) -trien-l6-one.
ceeding according to the herein described processes, 165,
175-epoxy-3-n-propoxyestra-l,3,5(10)-triene and 165,175
Reaction of the aforementioned 17-halo l6-ketones with 65 epoxy-3-hydroxyes‘tra-1,3,5(10)-triene are obtained.
a suitable reducing agent produces the halohydrins of
Example 2
this invention wherein the con?gurations of the halogen
To a solution of vone part of 165,175-epoxy-3-methoxy
and hydroxy substituents are the same. Thus, treatment
estra-1,3,5(10)~triene in 38 parts of chloroform is added
of 17u-bro-mo-3-methoxyestra-1,3,5(10)-trien - 16 - one or
at 0—5°, 15 parts of 48% aqueous hydrobromic acid, and
175 - bromo-3-methoxyestra-l,3,5(10)-trien-16-one with
the mixture stirred for about 5 minutes‘. The chloroform
lithium aluminum hydride in tetrahydrofuran affords 17a 70 layer
is separated, washed with water, dried over anhy
bromo-3-methoxyestra-1,3,5(l0) - trien-l6a-ol and 175
drous magnesium sulfate and evaporated to dryness in
8,079,408
tract clari?ed by centrifugation, then evaporated to dry:
ness in vacuo to yield l7a-bromo-3-methoxyestra-1,3,J
pentane yields pure 17tx-bromo-3-methoxyestra-1,3,5 ( 10)
tl‘iEIl-l6cx-Ol, MP. 125-126.5°; [a]D=—|—7.9° (chloro
('10)-trien-l6,6-ol. This bromohydrin displays an infra-'
red maximum at 2.77 microns.
By substituting equivalent quantities of 16,8,17/8-epoxy
form).
3-hydroxyestra-1,3,5 ( l0)-triene or 165,1713-epoxy-3-n
propoxyestra-l,3,5(10)-triene and otherwise proceeding
3,5(l0)~trien-16-one, 5 parts of p-toluenesulfonic acid,
10 and 100 parts of acetic acid is heated at re?ux for about
propoxyestra-1,3,S(l0)-trien-l6,8-ol are obtained.
Example 3
To a solution of one part of 163,17B-epoxy-3-methoxy
estra-l,3,5(10)~triene in 38 parts of chloroform is added,
at 0-5 °, 24 parts of concentrated hydrochloric acid and
the mixture shaken for about 15 minutes. The chloro
form layer is separated, washed with Water, dried over an
hydrous magnesium sulfate and evaporated to dryness in
vacuo.
Example 7
A mixture of 2 parts of 17a-bromo-3~methoxyestra-1,
according to the herein described processes, 17a-bromo-3
hydroxyestra-l,3,5 ( 10) -trien-l6,8-ol and 17a-bromo-3-n
4
sorbed on fuller’s earth and eluted with 40% benzene in
heptane. Evaporation of the eluate a?ords an oil which
crystallizes on standing. Recrystallization from acetone
vacuo. The residue is extracted with ether and the ex
The residue is extracted with ether and the ex
68 hours. The reaction mixture is diluted with water and
extracted with benzene. The organic layer is separated,
washed with water, dried over anhydrous sodium sulfate,
and concentrated to dryness at reduced pressure. A ben
zene solution of the residue is chromatographed on silica
gel. Elution of the column with 1% ethyl acetate in ben
zene and concentration of the eluate to dryness aifords a
solid residue which is recrystallized ?rst from methylene
chloride-methanol, then from methanol to afford 17,3
tract clarified by centrifugation, then evaporated to dry
ness in vacuo to yield 17a-chloro-3~methoxyestra- 1,3,5
(10) -trien-l6}3-ol, which exhibits a maximum in the in—
irared at 2.77 microns.
bromo-3-methoxyestra-1,3,5( lO)-trien-16-one, M.P. about
226-229"; [a]D=—100“.
Example 8
The substitution of an equivalent quantity of 17a:
By substituting an equivalent quantity of concentrated 25 chloro-3-methoxyestra—l,3,5(lO)-trien - 16 - one in the
hydriodic acid and otherwise proceeding according to the
process of Example 7 results in 17?-chloro-3-methoxy
herein described processes, 17a-iodo-3-methoxyestra-l,3,
estra-l,3,5(l0)-trien-16-one, Ml’. about 211-213";
5(l0)-trien-16§-ol, which displays an infrared maximum
[a]D=‘—-92°.
at 2.77 microns, is obtained.
Example 9
30
Example 4
To a stirred solution of 7 parts of lithium aluminum
To a solution of 3 parts of anhydrous hydrogen fluoride
in 7.5 parts of tetrahydrofuran is added at —70°, with
stirring, a solution of one part of l6;8,l7?-epoxy-3-meth
oxyestra-l,3,5 (10)-triene in 40 parts of chloroform. Stir
ring is continued at -—70° for about 30 minutes, then
at —30° for about one hour. The reaction mixture is
treated with excess aqueous potassium carbonate and the
organic layer separated, washed with water, dried over
anhydrous magnesium sulfate, and concentrated to dry
hydride in 700 parts of ether is added, at —5° over a
period of several minutes, a solution of 15 parts of 175
bromo-3-methoxyestra-1,3,5(10)-trien-l6-one in 355 parts
of tetrahydrofuran. The reaction mixture is treated suc~
cessively with 50 parts of water and 10 parts of 10%
aqueous sodium hydroxide, ?ltered through a bed of
anhydrous magnesium sulfate containing a ?lter aid and
evaporated to dryness at reduced pressure. The result
ness in vacuo, to yield l7a-?uoro-34methoxyestra-1,3,5
ing residue is recrystallized from acetone-petroleum ether,
then from petroleum ether to produce 1713-bromo-3
(10)-trien-16;S-ol, M.P. about 146-149".
methoxyestra-l,3,5(l0)-trien-l6;9-ol, M.P. about 150
151"; [a]D=+7O°.
Example 5
To a suspension of 2.4 parts of chromium trioxide in
24 parts of pyridine is added, with stirring, a solution of 45
1.2 parts of 17wbromo-3-methoxyestra-1,3,5(10)-trien
165-01 in 12 parts of pyridine. Stirring at room tempera
Example 10
A mixture of one part of 17a-bromo-3-hydroxyestra
1,3,5 (10)-trien-l6p’-ol, 10 parts of acetic anhydride, and
20 parts of pyridine is warmed on the steam bath to
achieve homogeneity, then allowed to stand at room
temperature for about 16 hours. The reaction mixture
rated, washed successively with water, dilute hydrochloric 50 is diluted with water and extracted with ether. The
organic solution is washed successively with aqueous
acid, water and saturated aqueous sodium chloride; then
sodium bicarbonate and water, dried over anhydrous
dried over anhydrous magnesium sulfate and concentrated
magnesium sulfate, and evaporated to dryness in vacuo
to an oil in vacuo. This oil is adsorbed on silica gel,
ture is continued for about 3 hours, then water added and
the mixture extracted with ether. The ether layer is sepa
eluted with chloroform, and the eluate evaporated to yield
to yield 3,16,8-diacetoxy-l7ot-bromoestra-l,3,5 (10)-triene.
(10)-trien-l6-one,
butyroxy-17a-bromoestra-1,3,S(10)-triene.
Substitution of an equivalent quantity of n-butyric
an oil which crystallizes on standing. Recrystallization 55
anhydride in the instant process results in 3,l6?-di-n-.
from ether affords pure 17a-bromo-3-methoxyestra-1,3,5
MP.
133.5-l36.5°;
[a]D=—5°
Example 11
(chloroform) .
The substitution of an equivalent quantity of 170:
chloro-3-methoxyestra-l,3,5(10)-trien-l6B-ol in the in 60 To a solution of 6 parts of l7a-bromo-3-hydroxyestra
1,3,5(l0)~trien-l6;8-ol in 800 parts of acetone is added
stant process results in pure 17cc-chloro-3-methoxyestra
dropwise, at 10-15", 5.5 parts by volume of an aqueous
1,3,5(10)-trien-l6-one, M.P. 11l.1-1l2.5°; [a]D=—49°
solution containing 1.47 parts of chromium trioxide and
(chloroform) .
2.34 parts of concentrated sulfuric acid. The reaction
Example 6
mixture is stirred for about 5 minutes, then diluted with
water and extracted with benzene. The benzene solu-.
To a stirred solution of one part of lithium aluminum
tion is washed successively with water and aqueous po
hydride in 70 parts of dry ether is added, at 0° over a
tassium bicarbonate, dried over anhydrous magnesium
period of about 10 minutes, a solution of 6.45 parts of
17a-bromo-3-methoxyestra-1,3,5(10)-trien-16-one in 54
sulfate and evaporated to dryness in vacuo. Recrystal
parts of tetrahydrofuran. The reaction mixture is treated
lization from acetone-hexane altords pure 17a-bromo-3
successively with water and excess dilute hydrochloric
hydroxyestra-1,3,5(l0)-trien-16-one, which exhibits in
acid, then extracted with ether. The organic layer is sepa
frared maxima at 2.77 and 5.70 microns.
rated, washed successively with water and aqueous sodium
Example 12
bicarbonate, dried over anhydrous magnesium sulfate,
and evaporated to an oil in vacuo.
The residue is ad 75
A mixture of 2 parts of 17a-bromo-3-hydroxyestra
5
3,079,408
6
1,3,5(10)-trien-16-one, 10 parts of acetic anhydride, and
Example 17
20 parts of pyridine is allowed to stand at room tem
perature for about 15 hours. The reaction mixture is
diluted with water and extracted with benzene. The
The substitution of an equivalent quantity of 17a
?uoro-3-methoxyestra-1,3,5(10) - trien - 16,3 - 01 or 17/3
?uoro-3-methoxyestra-1,3,5(10)-trien~16a—o1 in the pro
cedure of Example 4 affords 17a-?uoro-3-methoxyestra
1,3,5 (10)-trien-l6-one, M.P. about 148—l49°
organic layer is separated, washed successively with water
and aqueous potassium bicarbonate, dried over anhydrous
magnesium sulfate, and concentrated to dryness in vacuo.
The crude product can be recrystallized from aqueous
ethanol to produce pure 3-acetoxy-l7a-brornoestra-1,3,
5(10)-trien~l6-one. This substance displays maxima in 10 and 17B-?uoro-3-methoxyestra-1,3,5 (10)-trien M.P. about 155-156°, respectively.
the infrared at 5.70 microns.
Example 13
A mixture of 3.5 parts of 17tx-bromo-3-hydroxyestra
1,3,5 (10)-trien-16?-ol, one part of acetic anhydride, and 15
What is claimed is:
1. A member selected from the group consisting of
compounds of the structural formulae
13 T
Ki
20 parts of pyridine is allowed to stand at room tem
perature for about 16 hours. The reaction mixture is
diluted with water and the resulting mixture extracted
with benzene. The benzene solution is washed succes
sively with aqueous potassium bicarbonate solution and 20
water, dried over anhydrous magnesium sulfate, and
evaporated to dryness in vacuo. The residue is adsorbed
on silica gel and eluted with chloroform to aiford 3
acetoxy-17a-bromoestra-1,3,5(10)-trien-l6B-ol which dis
plays infrared maxima at 2.77 and 5.70 microns.
and
Ito-(l3
25
Example 14
By substituting an equivalent quantity of 17/8-chlor0~
3-methoxyestra-1,3,S(10)-trien-l6-one and otherwise pro
ceeding according to the procedure of Example 9, 17/8 30
chloro-3-methoxyestra-1,3,5(10)-trien-16?-ol is obtained.
Example 15
Rods/‘j
wherein R is selected from the group consisting of hy
drogen, lower alkyl, and lower alkanoyl radicals; X
The substitution of an equivalent quantity of 17a:
bromo-3-methoxyestra-1,3,5 (10) - trien - 165 - 01 or 175
is a halogen atom, and Z is selected from the group con
chloro-3-methoxyestra-1,3,5(10)-trien-16B-ol in the proc
sisting of carbonyl, hydroxymethylene, and (lower alka
noy1)-oxymethy1ene radicals.
7. 17~bromo-3-methoxyestra-1,3,5 ( 10) -trien-16-one.
ess of Example 10 results in l6?-acetoxy-l7u-bromo-3
methoxyestra-l , 3, 5 ( 10)-triene and 16B-acetoxy-17/3-chlo
ro-3-methoxyestra-1,3,5(10)-triene.
Example 16
16 - one,
40
The substitution of one part of 16a,17a-epoxy-3-meth
oxyestra-l,3,5(10)-triene in the process of Example 4
results in 17,6-?uoro-3-methoxyestra-1,3,5(10)-trien-l6a
45
ol, M.P. about 74-76"; [a]D=+18°.
. 1 7-ch1oro'3-methoxyestra-1,3,5 ( 10 ) -t.rien-1 6-one.
. 17-bromo-3-methoxyestra-1,3,5(10)-trien-l6-o1.
. 17-chloro-3-methoxyestra-1,3,5 ( 10) -trien~1 6-01.
. 17-f1uoro-3-methoxyestra-1,3,5 ( 10) ~trien-16-one.
17-?uoro-3-rnethoxyestra-1,3,5 ( 10 ) -trien- 1 6-01.
No references cited.
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