2,455,535
Patented Dec. 7, 1948
UNITED STATES PATENT OFFICE
2,455,535
ESTROGENIC SUBSTANCES
Ralph C. Tallman, Morristown, N. J., and Alfred
H. Stuart, New York, N. Y., assig'nors to
Schieffelin & 00., New York,_N. Y., a corpora
tion of New York
No Drawing. Original application May 30, 1944,
Serial No. 538,089. Divided and this applica
tion November 10, 1945, Serial No. 627,972
4 Claims. (Cl. 260—613)
2
1
estrogenic and bactericidal properties are pos
This application is a division of co-pending
application Serial Number 538,089, ?led May 30,
sessed by compounds having the structure
1944, now U. S. Patent 2,400,033, which in turn
is a continuation-in-part of application Serial
Number 363,669, filed October 31, 1940, and now
abandoned.
This invention relates to estrogenic substances,
in which each X is H, alkyl, acyl of aliphatic or
i. e., substances possessing properties similar to
those possessed by the female ovarian follicular
aromatic type, or an inorganic ester radical such
as SOsH or POsHa Which‘may be obtained by
10 condensing one of these compounds having OH
hormone.
Estrogenic substances are those which bring
terminal groups with an inorganic acid; and R
is H‘ oralkyl, at least one R being alkyl; in which
about the physiological changes known as estrus.
the OXgroups may be symmetrical or not, and
or “heat” periods in female animals, or the
follicular phase of the menstrual cycle in human
. [may be the same or different; and in which each
females. Ordinarily such substances are secreted 15 alkyl B. may- be the same or different. -> -~
by the ovaries and the physiological changes
brought about by the normal functioning of
The invention is‘ further based on the further
discovery that" compounds having _the following
these ovarian secretions in conjunction with
other bodily functions.
type formulae are especially and uniquely bene
->
However, due to disease, illness, surgical in
" 'ficlal, and it is a further object of the invention
20 to utilize said ‘compounds as estrogenic and (bac
tervention or many other causes,v the normal
tericidal compoundsj" “
Type I
functioning of the ovaries, and the consequent
secretion of estrogenic substances, may be abel
sent or impaired.
x0
This condition may, in turn;
give rise to other types of physical and mental
illnesses. In such instances it often becomes ad
visable or necessary to administer therapeuti
H H a
I
.25
cally, for example, by injection or by feeding;
estrogenic substances produced outside the body
ox
I ([3
rec
.
..
H
H
H
I‘
_
.
_ _ in which X is H, alkyl, or acyl, and R is alkyl.
of the patient to substitute for the absent or di-v
minished natural secretions.
'
a
Type II
v-xo"
"H; R
such as the excretions of pregnant female mam
.
'
OX.
| ‘13 I
0'1"?
For industrial elaboration, estrogenic sub
stances may be obtained from natural sources, ‘
H‘
.-
l H H
_
in which X is H, alkyl, or acyl, and R is alkyl.
mals. For example, the urine of pregnant fe 35
Type III
male horses may be collected and subjected to
various ‘processes designed to concentrate and
x0
1'1 Ill. 1}
.
ox
purify the estrogenic substances contained
therein, and thus to isolate them in a condition
suitable for therapeutic administration in the 40
t H l
manners and for the purposes named above.
in which X is H, alkylyor acyl, and each R is
Such procedures are devious, time-consuming,
and expensive.
Type IV
This invention describes arti?cial estrogenic
xo
'
OX
substances which may be prepared from simple 45
chemical compounds. When the products de
alkyl.
scribed in this invention are employed, no re
course to estrogenic substances from natural
sources is necessary. The compounds described
below will induce physiological changes like 50
those brought about by estrogenic substances
from natural sources as outlined above.
These
‘
l.
'
Gel-~60
..
t l t"
in which X is H, alkyl, or acyl, and each R is
alkyl.
Type V
x0
I
R
R
R
OX
compounds may be produced simply and inex
pensively in commercial quantities, and may be
,
n .
i1 is it
used therapeutically for treatment of conditions 55
arising from absence or diminution of the bodily
in which X is H, alkyl, or acyl, and each R is
alkyl.
produced estrogenic substances.
Dir-‘LC?
‘_ This invention is based on the discovery that
The OX radical may be in the ortho, meta, or
.
2,455,535
3
4
para positionineach ofithe foregoing types, and
need not‘be symmetrically positioned; "j
tion ‘oi-crystals ,or by failure of the residue to
boil-at a constant temperature, the same process
Examples of the production of compounds of the
may be repeated until reduction is complete.
above types are as follows:
:~;;.-,_~;= The ?nal product of this step, 1,3-di (p-methoxy
phenyl) -pentane may be puri?ed by distillation,
EXAMPLE 1'_PRODUCTION OF TYPE ‘I: = " "and is ‘a'colo‘rless liquid which boils at l60-165° o.
Speci?c members of the series illustrated, bx‘, _{ ,under 1 mm. pressure. It may be converted into
Type I may be prepared in the renewing‘ man'neri “ .7.‘ {the‘corresponding‘phenolic product as follows:
48 grams of p—methoxyacetophenone and45asrsms
2.0v grains ‘of, the 1,'3-di (p-methoxyphenyD
of anisaldehyde are dissloved in 150 cc. of alcohol. 10 pentane are hydrolyzed by dissolving in 6 cc.
The solution is stirred vigorously, and 150 00, of
glacial acetic acid, to which solution 15 cc. of 57%
10% aqueous sodium hydroxide solution.isgradilQ-Rediiepus .hydriodicjacid is added. The reaction
ally added in Small portions- The‘P1'0>dll¢t'[email protected]:{ ' ‘mixture isunjiaintained under re?ux at the boil
rates slowly from the solution “and becomes ' 'ing"iaoiii,t ‘for 15 minutes, then 4 cc. of glacial
Crystalline 0n the addition of seed- "Stirring . '1‘5: aceti'c'racid and 5 cc. of the hydriodic acid solu
is continued for two hours after the addition
tion are added, and re?uxing continued for a
of ‘sodium hydroxide; is, complete, and the
mixture?s» then ,allowed, to st,and1_2,v to, 24
totalvofn four hours. The mixture is poured into
water, thesolution made alkaline with excess
hours at 0° C. The p,p'-,dimethoxy chalcone
potassium hydroxide, and ?ltered with the aid
thus produced (888 Step I below) . is vremoved 20 ofcharcoal. »_The phenolic product thus obtained
by ?ltration, washed with ice-cold alcohol 7‘ (see Step IV below) is precipitated by acidi?cation
and water, and may be puri?ed by crystallizaof the ?ltrate, extracted with ether, and, after the
tion:from about 400 cc. of alcohol! _from ,which
it separates in bright yellow._ crystals'Q‘M. .P.
100-101" C.v
-
'
a _.
'
‘
"
evaporation of the ether. distilled slowly at. 150°
C; under high vacuum. The distillate is a color
25 less, glass-like product which solidi?es on long
The p,p’-dim_ethoxy_ chalcone is reacteddsee
Step II below) with ethyl magnesium bromideas
standing. This compound is 1,3-di-(p-hydro
xyphenyl_);-_pentane, where R is the ethyl radical.
L ‘onion; ;} anger
cmQ-QE-QmEH-Q-wm
t
omoOg-om-znOocm _-» (reacted cuiwo-omécm-icn-gocm
t
'
i
'
"
Step
.
t
IV‘
,
I
-
'
oH,o-C>-oHi-—.CH=—OH'C>~ocH3-> (hydrolysis) THo—®-om—oHi-oH‘C>-on
follows: Asolution of 31 grams of ethyl magnesium
, ' Any product corresponding to Type I can be
bromide in 450 cc. dry ether is. maintained at 50 produced by following the basic outline of the
—10°' C; and vigorously ‘stirred while 20 grams of
process andequations set forth herein above, using
the chalcone is added; insinall quantities. The
an alkyl- magnesium halide having the desired
cooling bath is then removed, and stirring continued fortwo and one-half hours at room tem-
perature.
number of-carbonatoms in its alkyl group. The
condensation can‘ also be carried out in acid me
The reaction-mixture is-"poured into 55 diuin', using-a mineral acid as the condensing
1200 cc. ice water containing 150 cc. hydrochloric . =
agent_.;
acid, after which the ether layer is separated
and the aqueous layer extracted once with ether.
.
2..—PRODUCTION OF TYPE II
,
The ether is evaporated from the combined 'solu-'
’
tions and the product which remains is puri?ed 60 “speci?c. members of the Series illustrated by
by distillation under high vacuum and crystal- 4-; T3711?" II» may be Prepared in the following man
lization from alcohol. Thewhite crystals of the
W116 grams of anisaldehyde and 22 grams of p‘
product, 1,3-di (p-methoxyphenyl)-pentanone~1
methexvbutvrophenone are thoroughly mixed’
(Where R is the ethyl group) have a melting point
anda'stream of dry hydrogen chloride gas bubbled
of 70°C. ,This compound may be converted-into 65 mtOIth? mixture until the total Weight is in‘
1,3-di (p-methoxyphenyl)-pentane as follows;
51!; ctrjélftse?tby 3-5 grams
9 grams of the pentanone are mixed with so
grams of amalgamated zinc, 45 cc. water, 120 cc.
hydrochloric acid, 35 cc. of toluene, and 2 co.
acetic acid, and the reactionmixture heated under 70
The reaction mixture,
WhlPh_rapid1y becomes very dark red, is shaken
until 1t becomes pasty, due to the separation of
the: Product, and is then allowed to stand for
?fteen; hours. The entire mixture is dissolved
re?ux at the boiling point for twenty-eight hours
. in benzene ' and the benzene solution extracted
(see Step III below), Itlis- then comedy-and eX-
with water, with sodium carbonate solution and
tracted with ether, the ether layer separated,.and
again with water.
all solvents removed therefrom by evaporation.
grated. and the residue maintained at 150° C. until
The benzene is then evap
If reduction is not complete, as shown by separa- 75 evolution of hydrogen chloride has ceased, after
2,455,535.
‘which it is subjected to distillation under 're-
withzethyl magnesium (bromide ‘in the following
duced pressure. After a small amount of lower
manner: A solution ‘of 8 grams of the chalcone
boiling forerun, which is discarded, the desired
in 150 cc. of dry ether is added slowly to a vigor
product distills at 190-200° C. under 1 mm. presously stirred-solution 0f 13-2g1‘amS of ethyl mag
sure. The product, 4,4'-dimethoxy-a-ethyl chal- 5 nesium bromide in 85 cc. of dry ether maintained
cone, where R.v is the ethyl. group, (see Step I
at a temperature of —l0?' C. Stirring is con
below) is a bright yellow oil.
tinued for :three hours at room temperature after
'10 grams of the 4,4'-dimethoxy-u-ethyl chalwhich the reaction mixture is poured into 500 cc.
cone from the previous procedure is dissolved in
of ice water containing 7500- Of hydrochloric acid
50 cc. of absolute alcohol, 1 ‘gram of a copper- 10 The etherv layer is separated, the aqueous solu
ohromium oxide catalyst added, and the mixture
tion extracted once with ether and‘ the ether
submitted to high-pressure hydrogenation at 220°
solutions combined. After evaporation of the
and about 150 atmospheres’ pressure for 5 hours
ether the residue is distilled under high vacuum.
in an appropriate machine. After cooling, the
The distillate, 1,3—di-(P-m6th0XyDhehy1)-2-ethyl
hydrogen pressure is released and the solution re- 15 pentan‘one-l,‘ where. R and. R1 are ethyl radicals,
moved from the hydrogenation apparatus and ?lis a pale yellow oil (See Step H be10W)- This
tered free of the catalyst. On cooling the?ltrate,
may be further converted as follows:
'
the product, 1,3-di-(p-methoxyphenyl) -2-ethyl10 grams of- the ethylpentanone as prepared in
propane, where R is the ethyl group crystallizes
Step II-is dissolved in 50 cc. of absolute alcohol,
as a white solid which may be ?ltered off. It 20 1 gram of a copper-chromium oxide catalyst
has a melting point of 43°. By this method of
added, and the mixture submitted to high pressure
hydrogenation, both the double bond and the
hydrogenation at 220° and about 150 atmospheres’
ketone group in the starting material are compressure for 5 hours in an appropriate machine.
pletely reduced (see Step II below). If desired,
After cooling, the hydrogen pressure is released
the product from this hydrogenation may be 25 and the solution removed from the hydrogena
converted into the corresponding phenolic prod-
tion apparatus and ?ltered free of the ‘catalyst.’
uct as in Example I (see Step III below).
The alcohol is removed from the ?ltrate by evap
Pnonucrron or TYPE II
Step I
’
Et
Step II
CH|0-C>-E-E=CH—O-OCHi+hydrogenation --» ommO-cm-E 11-0300 on,
t
'
’
1;
Step :11
CH;O—O—CHa-EH—CH1—O—OCH3 (hydrolysis) noOcm-on-om-O-on
t
"
Er
.
.
Any compound corresponding to the formula‘
oration and the product (see Step III below),
of Type 11 may be produced by following the ,. which
is l,3-di(p-methoxyphenyl)-2-ethylpen
basic outline of the process set forth above, tak
ing care in Step I to select the proper ketone for
45 tane, where R and R1 are» ethyl radicals is dis-:
tilled at 170 175° C.
ier 1
_ ress 6' It
combination with the aldehyde.
I
'
‘
.
_
8
.
IS. a colorless liquid and may be converted into
EXAMPLE 3'_PRODUCTION OF TYPEIII
Speci?c. members of the series ‘illustrated by
the corresponding phenolic compound as in
Example I (see Step IV below).
PRODUCTION OF TYI'E III
Step
Ill
I
.
I
g
_
‘
0
'
j
I
er‘:
Step II
Step III
I“
I
i
‘
.
_
‘
'
cmoO-o-on-pnO-oom
--» 7(reduction) cmoOoH'récH431100011:
,
t it is
_
i it,
Step IV
1k
11in
,
‘I
v
R‘
Bl
,‘
v.
Type III may be prepared in the following man- 70 R and R1‘ may be the same or different alkyl
her: The ?rst step in this preparation is identical
radicals. In general any desired compound cor
with the ?rst step of Example 2, for the production
responding to thisv type formula may be made by
of 4,4'-dimethoxy-a-ethyl chalcone (see Step I
using. . ,i‘n ‘ Step}, a ketone having the proper
below) .
'
V
alkylradical and, in 'Step II a magnesium bromide
‘ The chalcone as produced above may be reacted 75 compound‘ having vtheiproperallsyl radical.
254542885":
lYElin'c'e‘@the'v carbon‘latoms‘to ‘which the‘ alkyl
distillation water.lisilevolvedriand the}: resulting‘
radicals are'attaohediare asymmetric in this type
ofcompou'ndi, "the product produced may be a
single racemate ora mi'xturevof racemates and
product- I is; 3,5'-di(p=methoxyphenyllreheptene-Zi;
where Rand. R1 are'iethylradicalsazceesteprilll
below). This is vthen treated. accordin'grto'step;
the individual racemates of-such'mixture may be '-
IV as follows:
separated'byany suitable inethod, a preferred
method‘being disclosed- in our copending application Serial No."538,‘090 ?led: May 30,1944, now
4 grams of the‘3;5¢-‘di'tp-methoxyphenyl) -hepl-~
tene-Z is dissolved in 70 cc; of glacial acetlcvacldi
and 0.0.4 gram of platinum oxide catalyst/added.
U; S..Patent 2,400,034.. i For ‘example, when R. and
The container is'then attached; to; a machinejfcr
.-
512,
‘ ~ 3
l
"
.
l T
Y,
;
R1.'arerethylf'groupasthe'intermediate compound 10 catalytic hydrogenation; theqhydrogen applied-i;
pmducedi;as';shown.'in Step II is in the form of
two racemi'c' mixtures; one liquid‘ and one' solid.
andthe, mixture shaken untilione-moleculan'equive,
ale'nt of hydrogen has beenconsum'edw Theimixs:
Thesermixtur'es may be‘ separated by dissolving
ture isithen decantedrfromlthewcatalyst,_'d?utcd:
them; in a solvehtsuchas alcohol and crystallizing
with water, neutralized with NaOILcandtthe prod:
thesolid-racemic mixture fromthe solution. By ‘5 uct extracted withretherg-The, 'etherlzisr-eyopoe;
evaporating the“. solvent fromithe mother liquid,
rated at room temperature, andnthe'iresidue'dism
the liquid racemic .mixture may be recovered.
tilled. under reduced. pressurelvit‘hei product thus:
Either the solid or the'liquid-racemic mixture may
obtained . (see Step‘ IV; below) ,‘is a colorle‘isi oily:
then besubjected to the reactions shown in Steps‘
liquid and vis- 3,5,-di(pfmethoxyphenyhrheptane;
III and IV. ‘As alsoestatedin that application, .20 where;R.and;R.1 are;ethyli radicalsrandnnay, be;
an individual .racemic mixture of two stereoconverted intox'thea corresponding; phenolic com-F
isomeric ‘forms of thistypeof compound may
pound as in‘ Exampleil (-seeStep .V'belowlm
“
"
'- "
T
PRODUCTION or'T's'z‘Pa IV
‘
'
i
'
‘1
.i
2,
.
‘
l
GEOGGHé-‘CHPCHOOCH:
"' ‘
‘ ~
~ '_
I I Step HO
v.14v
I!!!
have greater‘ estrogenic' potency than‘ that‘of the
,.
:45 . wk)
‘4
‘
"it
2
R and R1 maybe. the sewer different all;
radicals. Ingeneral, any compoundconforming
conglomerate of"s'tereoi_s'omers._ v
‘'
to this type formula may be‘ made by’u'si'n‘g'in
EXAMPLE 4.—PRODUCTION OF TYPE IV
5O Steps
lIgand III magnesium bromide compounds
Speci?c members of the series illustrated in 2 having alkyl radicals of the constitution desired
Type IV may be prepared in the following man
' in the ?nal product.
ner: p,p’-dimeth'oxychalcone is prepared in ex
Since the carbonatoms to whichtfié~ alkyl radi-_
actly the‘ manner described‘ in "Example I (See
CI. Cl cals are attached are asymmetric in this typeo:
Step I below). This is then treated as follows:
compound, the product may be a single racemate
Following exactly the same directions as de-y. .or a mixture of racemates and the individual
scribed in Example 1, Step II, the p,p'-dimethoxy
phenyl)
chalcone-pentanone-1.
is converted into
(See 1,3-di(p-methoxyStep‘ 11 below.)
racemates of such mixture may be separated.
EXAMPLE
_
-‘ .- 5'_PR0DUCTION
I,
I
.l
t
, 'V
'
This is then treated according to Step III as‘ 6Q . Speci?c members of the ‘series illustrated by
follows:
Type V may be prepared in the following man
A solution of 10 grams of the pé‘r'itanone in 130
ccfdry ether may be added'slowlywith vigorous
v ner: The ?rst two's‘teps in this processiare identi
ea] in all respects with the ?rstl'two lsteps'iynk'lil'x-f
stirring to a solution of 8.9 grams of ethyl mag: '
ample 3 for the production of 1‘,‘3-di(p-methoxy~
nesium bromide in 60 cc. dry ether. After the] 65 phenyD-2-ethyl pentanone-l (see Steps I and II
addition-of ‘the pentanone has been completed,
below). This may be converted into other prod
the mixture is warmed on a’ steam bath for five "
ucts as’ follows:
hoursfafter which the mixture'is ‘poured into a
mixture 01700 cc- ice Water. and 100 cc.- hydrO- ,
8.0 grams of the ethyl pentanoné obtained in
SteplI are dissolvedindry ether and added slowly
t.
I
. > \
I
‘- ;_ :
chloriclac'id? Theethér‘la'yer is, separated; and 7° tdasoluti'on off'ethyl magnesium bromide me.
the‘ ether removed. The residue. is‘subjected t0
pared from 5.0' grams of ethyl bromide and1l.2
vacuum distillation, and‘ obtained as a‘ color_grams or magnesium‘tu‘riungs lii'aiihydrous ether."
melting‘aft'er‘purl?cationat
at2mii'lyéiiidwhich‘solidines'
less oil which ha‘si‘a boiling point
to
s'r'c;
aisoli'd
of ‘During
‘183-18?
compound
this
C. ‘"5
,, when
asteamtath
completed,‘
the adaiticir’o'r
the ior‘nvencu’rs
reactionthe
mixture
peritanor'ié'has'
eft'er'wiub?i’it
is warmedb‘ is
2,4555%
9.
10
poured into a mixture of r700 cc. ice water and 100
cc. hydrochloric acid. The ether layer is sepa-
mide was used in each of the foregoing reactions
and excellent results are obtained by its use,'but
rated, dried, and the ether removed. The residue
it can be replaced by any alkyl magnesium halide
is subjected to vacuum distillation, and is ob-
except the ?uoride.
tained as a colorless oil., During this distillation, 5
‘
The compounds ofthis invention are preferably
water is evolved, and the resulting unsaturated
administered by intramuscular injection and show
product is 4-ethy1- 3,5 - di(p - methoxyphenyl) -
the reaction of the ovarian follicular hormone.
heptene-Z, Where R1 and R2 are ethyl groups.
See Step III below.
The
I
I
'
In the present speci?cation and claims the sym
-
bol
,
4-ethyl~3,5-di(p - methoxyphenyl) -_hep- 10
tene-2 from the previous step is dissolved inTIO
cc. glacial acetic acid- and subjected to catalytic
-
,
.
..
.
_
signi?es the benzene nucleus.
hydrogenation as described in Example 4, Step
IV, until no more hydrogen is consumed . The
mixture is then decanted from the catalyst,~dil~ 15
uted with water, neutralized with sodium hy-
The dihydroxy compounds of this invention
have the general formula
H0
‘R R R
0H
The
droxide,
etherand
is the
evaporated
product atextracted
room temperature,
with-ether
Fir Ill 1k
,
v a
and the remaining liquid distilled under reduced
pressure. The product thus obtained (see Step '20 where R is selected from the group consisting of
IV below) is a colorless oily liquid and is 4-ethylhydrogen and alkyl radicals, at least one of‘ said
3,5-di(p-meth0XyDheny1)—heptane, Where R, R1
R substituents being an alkyl radical. " The hy
and R2 are ethyl radicals, and may be converted
droxy substituents may be in the ortho, meta, or
into the corresponding phenolic compound, as in
para-position, and symmetrical or unsymmetrical.
Example 1.
g
.
25 The invention also includes generically the'ether
PRODUCTION
or
TYPE
V‘
I
Step I
'
v
I
a ‘V
*7‘
‘
oH.o-<:>_o=o
+ omo-Qgucmm
——> omoOc?AaqmQ-oom
H
O
0 £1 “
,
Step II
_
cmo-<:><lll-o=on_<:>_oom
+.'R:MgBr --» omoQe-bm-cn-Qoolh
0 R1
’
w
" , g lit‘; lit:
‘_
onloOr?-onnon-ofoom + RMgBr
Step III
---» crime-Georgi:r
011000113
Gino-Oo
0 R1
R1
Step IV
'
‘
_ 1
g “ R;
it,’
" ‘ " '_ "
~ 5 7 "
H- oil-O0 CH5 hydrogenation _» cmoOoH- 403- 0110-0 om
6R1
R7
Step
:
v
I
.'
v‘I!!!
lit:
'
’
CHaO-OoH-JIJH-CHOOCE
'_-> HQ-QoH-,-cI:H--GH_C>-OH
R R1 1kg
R R1 1L1: ‘
R, R1 and R2 may be the same or different alkyl
radicals. In general, any compound corresponding to this type formula may be made by employing in Step I a ketone having the desired alkyl
radical, and in Steps II and III by employing 55
and ester derivatives of these hydroxy compounds.
Either or both of ‘the hydroxy substituents may
exist in the form of their functional derivatives,
that is, ether and ester derivatives, and those cor
responding ether and ester compounds may‘ also
magnesium compounds having the desired alkyl
be symmetrical or unsymmetrical.“
radicals. Mixtures of the racemates produced
may be separated into the individual racemates.
Further support for this generic statement, in
addition to that already set forth, is provided- by
e. g. by the method disclosed in the copending
application hereinabove referred to.
the following:
.60
‘
-
‘ , ' -'
'
‘
"
Example 1 shows the production of
In the above reactions the terminal groupv was
,_
methoxy, but it may be any alkoxy group, and
'
H
.
may be obtained in the ?nal product, by the use
C H‘ '
..
.
"I ll’. g 5
‘
HOOG'CTI 00H
of appropriate starting compounds in Step I or
'
H
by converting the OH groups in the ?nal phenolic '65 ' vBy substituting meta-methoxyacetophenone for
compqund- when a terminal! acyl group is desired m the ?nal compound It may be iconven"
iently obtained by converting the OH groups in
the para compound in Example 1‘ in ‘column 3
and proceeding exactly as prescribed in that ex
amme’there is obtained
the ?nal phenolic compound into RCOO groups.
(A)
: .
The terminal groups may be in the ortho, meta 70
HO- .
.
,
3,3, 3,11,
or
terminal
para position,
groups symmetrical
which are esters
or not.‘ofTo
inorganic
produce
acids,
theiphenolicterminal
group is
condensed
with an appropriate inorganic acid, such as phos-
'
.
_"
(ulna. {IIOOH
| .
. '
‘ ,
-
‘
:
‘H v
a
'
.
.- I
"By substituting ortho-imetho'xy-acetophenone
phoric and sulfonic acid. Ethyl magnesium bro- .75 for the para compound in Example'l and proceed
0,450,085
11
12
ing otherwise exactly as in that example, there is
seeding exactly as in said example, there is ob‘
tsined
Obtained
'
‘
HO
B
t )
H: H: CzHi
Q
A Q
v Mil.“ s.
tam
‘B! substituting orthm'methoxybeiisaldehyde
This compound possesses estrogenic activity
for the para compound in Example 1 and n-propyl
of the same order of magnitude as the corre
magnesium bromide for ethyl magnesium bro- '
sponding (ii-para compound.
chemists; and the invention includes generically
the ester derivatives of organic acids. Support
for this genetic statement will be foundv in the
following illustrative species of ester derivatives:
- Example 3 shows the production of
H: 01H:
a
be obtained, in general, by esterifying one or
both of the hydroity groups in accordance with
the esteri?catlon technique known to organic
example, there is obtained
. i
I l
In so for as the esters are concerned, they may
mide and proceeding otherwise exactly as in that
GzHt
.
1'1! 16:1 H
GtHtGO
-C
C OOaHs
By substituting orthuemethoxybenzaldehyde
for ‘the para compound in Example 8 and other 25
wise proceeding exactly as in that example, there
is obtained
'
'
0H
(D)
CzHs
.-.
(l:
H0
G:Hs-' ‘1 "
g
l
30
>
II
dll?né 00-041}- ‘i- - - 0-0 0 0 Cum:
C ..
“in; -
H:
H:
H: H
.
2H5
7
Example 4 shows the production of
.
I
.
ilii'?i
bail v
OH;
03111
H 1%‘:
By substituting oithmmethoxybenbélllehyde
ouiqc 00:0
for the para compound and proceeding otherwise
exactly as shown in that example, there is ob-.>
tained
(l)
agile-i0
east ‘cat-6H a
H:
I GHHuQOQOCL- - ~(JJ- - ~E-O-ooocmu
Example 5 shows the production of
ts. its,
so
Hi
HiHiH
H
H
I By substituting ortho-methoxyben‘zsidehyde
“for the para compoundaml-methyl'inagnesiuin
iodide for ethyl magnesium bromide in Step III
bi that example and otherwise proceeding exactly
as shown in Eiiample ‘5, there ‘IS obtained
(F)
H0
‘
/_
l
B2
_
..
‘
1'11 H (Ii,
omoooQ-t
C H; Q :Hi CaHs
,
wzoooQé» ‘EEC-000cm;
_
‘
B:
'
400-00 0cm
éIHT
Esteis such as those listed above may be pre
The above identi?ed compounds‘ (in to (F) 08 pared by any of the usual esteri?cation methods.
The following procedures are ‘representative ex
inclusive have‘been tested by subcutaneously in‘
jecting oil solutions thereof into castrated ice
male rats and said compounds have been found
one gram of 1,3-di- (‘p-hydroxy p'henyl) -n7
to possess estrogenic activity comparable to
hexane is dissolved in"5 cc. of b-enz'oy'l chloride
amples‘:
compounds shownvin Examples l_ to L5 differing
from compounds (A) to (F1) inclusive only in the
position of the OH ‘groups.
,
v
p
“
By substituting in ‘Example 4 the ortho
memoxy substituted compounds
phi! substituted
off the
1110*. 178
'
’
‘
and to this solution one ‘drop of ‘concentrated
sulmrlc acid is added. After standing several
‘the mixture is diluted with water, made
‘alkaline vwith potassium hydroxide and extracted
with ether. The ether solution is separated and
boiling oi! the other, the residue is crystal;
2,465,585
14
13
lized from alcohol.
support for these generic statements will be found
in the following speci?c examples:
The dibenzoate is a white
crystalline solid melting at 65° C.
One gram of 1,3-di-(p-hydroxy phenyl) -2
ethyl pentane is re?uxed for four hours with a
mixture of 10 cc. of acetic anhydride and 0.5
gram of fused sodium acetate. After dilution
with water, the mixture is made alkaline with
potassium hydroxide, and extracted with ether.
The ether solution is separated, the ether boiled
off and the residue distilled under high vacuum. 10
It is a thick, pale yellow oil.
Three grams of palmityl chloride is added
dropwise to a solution of 1 gram of 2,4-di-(p-hy
droxy phenyl)-S-ethyl-hexane in 10 cc. of pyr
idine.
After standing overnight, the reaction 15
mixture is worked up in the usual manner. The
dipalmitate, after crystallization from alcohol, is
a white crystalline solid melting at 36-38° C. All
of the above esters have estrogenic properties.
As for the ether derivatives, the invention in
cludes generically the mono- or di-alkyl ether
It is preferred that the number ‘of carbon
20 atoms in each of the alkyl substituents on the
propane bridge be not greater than ?ve, although
the activity of such compounds having longer
substituent chains has been proved by many ex
going description, in which it is pointed out that
instead of employing in Step I methoxy com 25 periments, numerous examples of which are found
herein.
pounds, alkoxy compounds in general may be
We claim:
substituted, and that these alkoxy groups
1. Alpha, gamma-di(alkoxyphenyl) propanes
may be in the ortho, meta, or para position
in which all of the propane carbon atoms are
in relation to the other substituents, thus pro
ducing as a ?nal step prior to hydrolysis, alk 30 substituted by alkyl groups of less than six car
bon atoms, and in which the alkoxy groups have
oxy or ether derivatives in general, symmetrical
less than six carbon atoms.
and unsymmetrical. Instead of producing alkoxy
2. 3-ethyl-2,4-di(p-alkoxyphenyl) hexane hav
or ether derivatives by starting with appropriate
ing less than six carbon atoms in the alkoxy
alkoxy compounds, it is entirely possible to con
vert the ?nal dihydroxy derivatives into their 36 groups.
3. A racemic mixture of two stereoisomeric
corresponding ethers by known etheri?cation
forms of the substance 3-ethyl-2,4-di(p-alkoxy
methods. Various illustrative speci?c examples
phenyl) hexane in which the alkoxy groups have
of ether derivatives are shown; as follows:
less than six carbon atoms, said mixture having
derivatives of the hydroxy compounds. Support
for this generic statement is found in the fore
Garbo-Og- l1:- ipo c3111
40
an estrogenic potency higher than the con
glomerate of the eight possible stereoisomers of
this substance.
4. 3-ethyl-2,4-di(p-methoxyphenyl) hexane.
O C4Hn
0.11.0
G j:(t l
2115
0511110
i
H] H H,
RALPH C. TALLMAN.
ALFRED H. STUART.
45
|
02115
REFERENCES CITED
The following references are of record in the
?le of this patent:
50
UNITED STATES PATENTS
0051111
I
Gal-O
Number
As previously pointed out, there is an R sub
stituent at one or more of the three carbon atoms
of the propane bridge connecting the benzene
radicals, and that R substituent is an alkyl radical
in general, and those R substituents are the same
or different alkyl radicals in general.
Further
2,317,607
2,400,033
Name
Date
Harvey __________ _.. Apr. 27, 1943
Tallman et al. ____ __ May 7, 1946
OTHER REFERENCES
Richardson et al.: “Journal American Chem
ical Society,” vol. 62, (1940), pages 413-415.
Certi?cate of Correction
" Patent No. 2,455,535.
December 7,1948.
RALPH C. TALLMAN ET AL.
It is hereby certi?ed that errors appear in the printed speci?cation of the above
numbered patent requiring correction as follows:
Columns 5 and 6, “Production of Type III, Step I,” for that portion of the formula
read
c
0
columns 9 and 10, “Production of Type V, Step III,” right-hand portion of the
formula, for
"-C--CH--CH—"
||
|
O
1
read
-_c--cg..-cg._
|
|
RI
1
R1
"Step IV,” for
"-C- -CH- -CH—"
|
0
L
R1
1'68.
d
1
--c-.cn-..cg_
||
R R1
1
column 11, lines 44 to 48 inclusive, for
“(I-JIHI CIHI"
—C- -C--
are
--
CIHI 013i
read
--C--
‘A the
-
column 12, lines 28 to 32 inclusive, for
H, H
H,
.41-- ._.__l';_
(LB;
H] H
read
H,
_,5'_._,5___L
élHl
and that the said Letters Patent should be read with these corrections therein that
the same may conform to the record of the case in the Patent O?ice.
Signed and sealed this 5th day of April, A. D. 1949.
[amen]
THOMAS F. MURPHY,
Assistant G'ommz'ssz'oner of Patents.