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Patented Nov. 5, 1946
2,410,463
UNITED STATES PATENT OFFICE
2,410,463
METHODS OF- PREPARING ‘STILBENE
DERIVATIVES
Otto Schwarzkopf, New York, N. Y., assignor to
Burton T. Bush, Incorporated, Delawanna, N. .L,
a corporation of New Jersey
No Drawing.v Application November 19, 1943,
Serial No. 510,976
5 Claims. (Cl. 260-613)
1
2
The invention relates to the preparation of stil~
bene derivatives and particularly hydroxy-stiL.
bene compounds of the general formula:
dialkyl-stilbene within Formula I above, the hy
droxy radicals being in the para positions.
no-canl-c=c~c?nl—on
R1 R2
(I)
The starting material for this invention may
be any substance within Formula II. R1, R2, R3,
and R4 in all cases represent the same or different»
alkyl radicals. Such formula, II, shows that two
wherein R1 and R2 are identical or different alkyl
radicals, preferably of four or less carbon atoms,
diastereo-isomeric racemates may exist, but for
this invention itis unimportant which of the two
and the hydroxyl radicals are in any positions on
is present or whether both are present. '
the benzene nuclei, but preferably the para posi 10
Solutions, containing one or both of such race
tion, and including both the cis and the trans
mates, have also been used by Braker (U. S._Pat
isomers with regard to the positions of the radi
ent No. 2,252,696) in the same way as Dodds, also
cals R1 and R2, this patent being a continuation
by Fieser (U. S. Patent No. 2,248,019).
in-part of my application, Serial No. 424,474, ?led
Said starting substance may be obtained by the
December 26, 1941.
‘
These substances are important because of
their estrogenic activity, particularly the highly
15 Dodds process, or by the action of a Grignard
reagent, for example methyl-magnesium-iodide,
ethyl-magnesium-bromide, etc., upon the carbi-v
active form thereof which is trans-4,4'-dihy
nol such as obtained by Dodds (whereby, the
droxy, alpha,alpha'-diethyl—stilbene, and to
Grignard reagent reacts with the hydroxy group
which ‘this invention more specially relates. 20 forming methane, ethane, etc.) or it may be pre
They are known substances, described by Dodds
pared according to said application, Serial No.
(Nature, vol. 141, page 248 (1938) and Proc. Royal
424,474, by the action of a Grignard reagent,
Society, vol. 127, page 140 (1939)), but the proc
such as
esses by which they have heretofore been made
are expensive to practice and the yields are not 25
high. By this invention these products are more
economically obtained by a process which avoids
upon a ketonic compound Rs0-—CeH4—CO—Rz.
the successive steps of hydrolysis and dehydra- '
In all cases the structural forms of the reagents
tion necessary in prior proposals, and yields the
selected to make the starting material are prefer
more desirable trans isomer in predominating 30 ably such as have their alkoxy radicals in para
ratio.
' positions, thereby producing a starting substance,
Referring to the Dodds’_ process, the starting
Within Formula II, in which such radicals are
material was a. ketone of the formula:
similarly located and a, ?nal product in which the
hydroxy radicals also occupy the para positions,
35 which isdesired.
,
RI
~ ' Broadly stated the new process comprehends
and by reaction with a Grignard reagent
the treatment of solutions containing any one or
(RzMgHal) was converted to an oxymagnesium
more of the-starting substances included within
halide compound, of the general formula
Formula II above with one or more members of
40 the group consisting of acid halides and» acid
anhydrides, organic or inorganic, and then de
alkylating the product to substitute hydroxyl for
(II)
which was hydrolized to a carbinol, of the gen
eral formula
-
Among the inorganic acid halides found’most
,
practical for the new process are phosphorus tri
OH
chloride, phosphorus oxychloride, phosphorus
tribromide, pentachloride, pentabromide, sul
50 furyl chloride, thionylchloride, etc.; among the
R40—C5H4—CH—-b-CaH4-O R3
1
2
and then dehydrated to a dialkoxy-dialkyl-stil
bene, viz:
'
the alkoxy groups, as by means of an alcoholic
solution of an alkali metal hydroxide, as herein
45 explained, or otherwise.
"
R40—C6H4—~C(R1) =c<Ri> —CsI-I4—OR3
‘ inorganic acid anhydrides are phosphorus pent
oxide, sulfur trioxide, etc. On the organic side,
among the acid halides, are acetyl chloride,
stearyl chloride, benzoyl chloride, propionyl chlo
which was dealkylated to form a’ dihydroxy- 5s ride, and the like, and among the organic acid
3
4
anhydrides, are propionic anhydride, acetic an
hydride, phthalio anhydride, etc.
I am aware that acid halides as well as acid
anhydrides have been used in the prior art proc
esses, but they were there used only for dehy
drating carbinols and not for'direct conversion
(without hydrolysis and subsequent dehydration)
of any such oxymagnesium halide compound as is
represented by Formula II above.
'
It can be assumed that the primary result of '
the reaction of the selected agent on a substance
of Formula II is the formation of an ester of
the formula
220 cc.
This is a solution of an oxymagnesium
halide compound within Formula II, being
‘
wherein Ac is the radical of the acid derivative
employed.
.
temperature between 0° C. and 35° C. to a Gris?
nard reagent prepared in known way from 3.5
g. magnesium covered with 70 cc. of ether and
15.6 gr. of ethyl bromide (or corresponding
amount of other halide) dissolved in 90 cc. of
ether. The solution was allowed to stand over
night and then decanted from the unreacted
magnesium. The volume was then brought to
'
These esters are transitory and decompose im
mediately to yield the stilbene derivative
v"To 220 cc. of a solution prepared as above there
was added at room temperature a solution of 11
g. phosphorus oxychloride, POC13, in 25 cc. ether.
The mixture remained over night and the ether
was then distilled on and after standing for a
day at room temperature, 90-100 cc. of ethanol
was added while stirring the batch. After cool
_ If organic acid halides are used, it is possible
ing, trans-4,4’—dimethoxy-alpha,alpha’-diethyl
under vappropriate conditions-such as low re
stilbene (21-25 g.) crystallized and was ?ltered,
action temperature, use of equimolecular quan
washed and dried (yield ‘72%-86%) melting
titles of the acid halide and short reaction time,
point 122° C. The dealkylation was made by
to isolate these esters from the reaction mixture
heating this substance with a solution of KOH
(which in any event will contain some of the
(41-50 g.) in diethylene glycol (180-220 g.) at
compound of Formula IV). They can be subse 30 180-215” C. for twenty hours atmospheric pres
quently converted, as intermediates, to the stil
sure. Before heating the air was displaced by
bene derivative (IV) by different ways, accord
nitrogen. After the dealkylation was completed,
ing to the stability of the particular ester. Some
of_ them, by simply standing at room temperature
crude
trans-4,4’ - dihydroxy - a1pha,alpha’ - di
ethylstilbene was precipitated with HCl (150 cc.
will be split and others must be heated to tem 35 conc. I-ICl diluted With 150 cc. H2O). The pre
peratures between ISO-200° C., or be distilled at
cipitate was ?ltered, redissolved in a solution of
this temperature, to yield the stilbene derivative.
20 g. KOH in 100 cc. H20 which solution was ?l
The isolation of these intermediates and their
tered and the substance was again precipitated
subsequent conversion to the stilbene is included
with HCl as before. The material was then dis
in this invention although the direct conversion 40 solved in ether, washed with sodium bicarbonate
is preferred and is generally su?’iciently accom
(saturated solution), the other solution was
plished ‘by using moderate temperature and some
dried, the ether distilled OE and the residue re
excess, say 30% of the acid halide or the anhy
. crystallized from 5 times its weight of 50% eth
dride, disposing of the excess afterwards by
anol. 16-17 g. pure trans-4,4'-dihydroxy,alpha,
treatment with ethanol, for example.
al'pha'-diethylsti1behe (M. P. 169-171° C.) were
The alkoxy substance of Formula IV is next
thus obtained, yield 80 %.
dealkylated to yield the product dihydroxy-di
In. another case trans-4,4’dimethoxy,alpha
alkyl-stilbene of Formula I, and this is preferably
alpha'-diethylstilbene, prepared as above (29.6
done by reacting it with a solution of alkali
g. ) was added to a solution of 60 g. KOH in 240
metal hydroxide in one of the polyhydric also~
cc. of ethylene glycol and heated to 180-2150 C.
50
hols at a temperature between 180° and. 250° C.
for 20 hours in the protection of nitrogen. After
and at atmospheric pressure, and then liberating
cooling, the solution was acidi?ed with 200 cc.
the hydroxy-compound from the alkaline solu
of hydrochloric acid diluted with 200 cc. of water.
tion by treatment ‘with any acid stronger than
Trans-44' - dihydroxy,alpha,alpha’ - diethylstil
the hydroXy-compound, e. g. HCl, vH2804, CO2
bene precipitated and was ?ltered, redissolved
etc. The polyhydric alcohols suitable for this 55 and again ?ltered and 18-20 grams were ?nally
purpose are those in which the alkali metal hy
crystallized from ethylene dichloride (M P.
droxide is soluble either at room or elevated tema
167-169“ 0.).
perature and which have boiling points above
Example 2
150° C. and preferably above; 180° 0., for ex—
ample, ethylene glycol, diethylene glycol, propyl
ene glycol, glycerol.v
Such alkaline dealkylation is equally effective
whether the alkoxy group occurs in only
one or both sides of theformula and it is also
possible to obtain dealkylation of only one of the
two alkoxy groups, which can be done by simply I
terminating the treatment at the appropriate
point, as indicated by test of samples.
In further explanation of the invention, the
following illustrative examples are given:
To prepare the starting material used in the
following examples, 28.4 g. ethyl de'soxyanisoin
<oH3o-o@Hl—co-<:H(c2H51) -——C6H4-——OCH3)
To 220 cc. of the solution as above, there were
added 19 g. of p-nitro benzoyl chloride at room
temperature. The mixture stood for twenty-four
hours, andwas then poured into 100 cc. of cold
water. The water was extracted with ether, and
65 the ether washed with sodium carbonate and wa
ter. The solution was then dried, the ether re
moved, the, residue crystallized from ethanol
yielding the ester,’ p-nitrobenzoate' of 3,4-di
,anisyl-hexane-3-ol, of melting point 122‘0 C.
which is convertible by heating into dimethoxy
diethylstilbene, as above pointed out.
Example 3
To 220 cc. of the solution as above, there was
dissolved in 50 cc. of ethyl ether was added at a 75 added dropwise a solution of 18 g. sulfuryl chlo
3144.02.46?
ride dissolved in 100 cc. of ;ether. The mixture
stood over night at room temperature. Then the
ether was distilled off and the residue stood for
one day.
Then 120 cc. of ethanol were added
with stirring until the mass cooled'to room tem-_
perature.
Trans - 4,4’ 4 dimethoxy,alpha,alpha’
diethylstilbene crystallized and was ?ltered, and
?nally dried (yield 15 g._, M. P. 122-4° C., 50%)
being convertible to trans-4,4’ dihydroxy,alpha,i
alpha-diethylstilbene by dealkylation as before. 10
'
'
Example-4
'
'
,
'
6
g.’ of trans-4,4’-dimethoxyealpha,alpha’-dieth£
'ylstilb'ene’ crystallized out. After. evaporating the
alcohol, the liquid ‘ residue contained essentially
the acetate of 3,4-dianisyl-hexane-3-ol. This
was converted into trans-4,4’-dimethoxy-alpha,
alpha'-diethylstilbene by prolonged standing,
also by distillation in vacuo, and thereafter de
methylated. In a similar way other esters,
stearates, for example, can be formed and then
converted into'the desired stilbene derivative. '
From the above examples it'will be apparent
that the members of the group referred to are
effective reagents for producing the unsaturated
To 220 cc. of the solution as above was added at
stilbene form from a starting material of the
room temperature dropwise a solution of 16 g.
acetyl chloride in 50 cc. of ether. The mixture 15 kind mentioned, and that they tend to yield the
trans isomer in preference to the other. The
stood for 4 days at the same temperature. Then
reaction is found to be indifferent to the par
the ether was distilled off; the residue kept for
ticular positions on'the benzene nuclei of the
1 day. Then 120 cc. of ethanol were added.
methoxy (or alkoxy) groups in the starting ma
stilbene crystallized (yield 21 g., M. P. 122-4° C‘. 20. terial, and as might be expected, the original
position persists through to the stilbene product.
72%) and was dealkylated and worked up as de
Also, and as the case with other stilbene processes
scribed above.
’
the reaction pattern is the same regardless of the
‘Example 5
identity of the alkyl groups (R1, R2‘, R3, and R4) ,
To 220 cc. of the above solution was added
the‘ same" or different.’ Thus, 4,4’
dropwise a solution of 20 g. of benzoyl chloride 25 whether
dimethoxy-alpha,alpha"-dimethylstilbene
(M. P.
(CeHsCOC'l) in 100 cc. of ether. After standing
128° C.) can be produced according to this inven
Trans - 4,4’ - dimethoxy - alpha,alpha' - diethyl
for 1 hour at room temperature, the ether was
distilled o?. The residue stood over night, then
100 cc. of ethanol were added. Trans-4,4’-di—
methoxy - alpha,alpha’-diethylstilbene crystal
lized (yield 21 g., M. P. 122~3° C., ‘72%) and was
dealkylated and worked up as described above.
Example 6
tion from a solution containing the homolog
prepared by the reaction of methyl magnesium
iodide and methyl desoxyanisoin, to be then de
methylated as above described to the correspond
ing dihydroxy compound (M.YP. 195° 0.); and
4,4’-dimethoxy - alpha - methyl,alpha’-ethylstil
bene (B. P. 160° C./0.1 mm.) can be produced
To 220 cc. of the above solution was added a 35 from the homolog prepared from ethyl magne
sium iodide and methyl desoxyanisoin, and other
solution of 24 g. propionic anhydride in 200 cc.
alkyl radicals such as propyl-, isopropyl, butyl,
xylene, at room temperature. The ether was dis
isobutyl, etc. can be introduced in the side chain
tilled off until the boiling point rose to 130° G.
in positions R1, R2 in the stilbene derivative if
Then the liquid was re?uxed for 1 hour. Then
the xylene and the propionic acid formed were 40 that should be desired, or in the positions R3
distilled off. To the residue was added 100 cc. of
ethanol, and trans-4,4'-dimethoxy-alpha,alpha’
diethylstilbene was crystallized (M. P. 121-4° C.)
and was dealkylated as before.
and R4.
’
I claim as my invention:
1. The process for preparing the trans-com
pound having the structural formula:
Example 7
To 25 g. of P205 with 300 cc. of xylene, there
was added 220 cc. of the above solution. The
ether was distilled off and suspension heated to
130° C. under vigorous stirring for 4 hours. Then
the xylene was distilled off and the residue stood
over night. 100 cc. of ethanol were then added
, and after cooling trans-4,4’-dimethoxy-alpha,
CHsO
which comprises mixing the compound having
the structural formula:
.
0 M gHalogen
H
l
alpha’-diethylstilbene crystallized and was ?l
OCH;
tered and treated as said before (M. P. 122-4° C.) .
Example 8
To 220 g. of the solution as above was added a
solution of 17 g. of thionyl chloride in 100 cc. of -
with a compound selected from‘ the group con
sisting of acid halides and acid anhydrides; and
isolating the said trans-compound thus produced.
ether. It stood over night, the ether was distilled 60 2. The process for preparing the trans-com
o? and to the residue were added immediately
pound having the structural formula:
100 cc. of ethanol. Trans-4,4’-dimethoxy,alpha,
alpha'-diethylstilbene was obtained (M. P.
122-3° C.) .
Example 9
CzHn
OMOaEQOOH.
which comprises mixing the compound having
To 220 cc. of the above solution there was
the structural formula:
‘
added dropwise in 2 hours a solution of 11 g. of
OMgBr
acetyl chloride in 100 cc. of ether at room tem
perature. After 30 min. standing, the mass was
poured into 200 cc. of a 5% solution of sodium
bicarbonate. The ether layer was separated,
C2Hs 02115
washed with water and dried over sodium sul
with a compound selected from the group con
fate. The ether was then distilled off leaving a
residue to which was added 100 cc. of ethanol, 4 75 sisting of acid halides and acid anhydrides; and
i‘ i
isolating the said trans-compound thus produced.
,
8
_
which comprises mixing the compound having
3. The process for preparing the 'trans-com-i
the structural formula:
pound having-the structural formula:
OMgBr
III
(L
y
.
C1115 C2115
with phosphorus oxychloride; and isolating the
said trans-compound thus produced.
which comprises mixing the eompoundhaving
the structural formula:
'
.
5. The process for preparing the trans-com
pound having the structural formula:
OCH:
15
which comprises mixing the compound having
the structural formula:
with acetyl chloride; and isolating the said trans
compound thus produced.v
51,, The process for preparing the
pound having the structural‘ tormula:trans-com5 20
CaHa
C 2H5
I?
' 0M Br
i g
(llsHa (12H;
with sulfuryl chloride; and isolating the said
trans-compound thus produced.
25
OTTO SCHWARZKQPF.
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