TRIPHENYLALKENE DERIVATIVES AND PROCESS FOR PREPARING SAME

PREPARATION DE DERIVES DU TRIPHENYLALKYLENE

English Abstract

ABSTRACT
Novel triphenyl-alkene derivatives and
process for preparing same
The invention relates to novel triphenylalkene
derivatives of the general formula I
<IMG> (I)
wherein R denotes a C1-4 alkyl group and X stands for a
halogen atom, with the restriction that when R denotes a
methyl group, then X may denote only a halogen atom other
than chlorine, and their geometrical isomers. Furthermore,
the invention relates to a process for the production of
these compounds.
The compounds according to the invention can be
used for the preparation of Tamoxifen, a known agent against
???illary ??ncer, and of related compounds. Furthermore,
they possess a valuable biological activity.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a triphenylalkene derivative of the
general formula:
<IMG> (I)
wherein R denotes a C1-4 alkyl group and X stands for a halogen atom, with
the proviso that when R denotes a methyl group, then X may denote only a
halogen atom other than chlorine, and their geometrical isomers, which
process comprises dehydrating a triphenylalkanol derivative of the general
formula II
<IMG> (II)
wherein R and X have the meanings defined above, and R1 and R2 are
different from each other and represent a hydrogen atom or a hydroxyl group,
and, if necessary, separating the /Z/ and /E/ isomers of the triphenylalkene
derivative of the general formula I, by chromatography or by subjecting the
mixture of these isomers in an organic solvent or solvent mixture to
fractionated crystallization.
2. A process as claimed in claim 1, wherein the dehydration is
carried out in the presence of an acid.

3. A process as claimed in claim 2, wherein the acid
is hydrochloric acid, hydrogen bromide, phosphoric acid, tri-
fluoroacetic acid or formic acid.
4. A process as claimed in claim 1, wherein the reaction
is carried out in an inert diluent or solvent.
5. A process as claimed in claim 4, wherein the solvent
is an alkanol or aqueous alkanol.
6. A triphenylalkene derivative of the general formula
I as defined in claim 1 or a geometrical isomer thereof, when-
ever produced by the process defined in claim 1, 2 or 4, or by
an obvious chemical equivalent thereof.
7. A process for producing 1,2-diphenyl-1-(p-bromophenyl)-
1-butene, which comprises dehydrating 1,2-diphenyl-1-(p-bromo-
phenyl)-1-butanol.
8. 1,2-Diphenyl-1-(p-bromophenyl)-1-butene, whenever
produced by the process claimed in claim 7, or by an obvious
chemical equivalent thereof.
9. A process for producing 1,2-diphenyl-1-(p-fluoro-
phenyl)-1-butene, which comprises dehydrating 1,2-diphenyl-1-
(p-fluorophenyl)-1-butanol.
10. 1,2-Diphenyl-1-(p-fluorophenyl)-1-butene, whenever
produced by the process claimed in claim 9, or by an obvious
chemical equivalent thereof.
11. A process for producing 1,2-diphenyl-1-(p-chloro-
phenyl)-1-butene, which comprises dehydrating 1,2-diphenyl-1-
(p-chlorophenyl)-1-butanol.

12. 1,2-Diphenyl-1-(p-chlorophenyl)-1-butene, whenever
produced by the process claimed in claim 11, or by an obvious
chemical equivalent thereof.

Description

1~872~2
The invention relates to novel triphenylalkene derivatives of the
general formula I
X - ~ ~ - C = C - ~ (I)
~,
wherein R denotes a Cl 4 alkyl group and X denotes a halogen atom, with the
restriction that if R is a methyl group then X may denote only a halogen atom
other than chlorine, and to their geometrical isomers. Furthermore the inven-
tion relates to a process for the production of these compounds.
The compounds according to the invention possess a valuable bi-
ological activity. Further they can be used for the preparation of Tamoxifen
[/Z/-1,2-diphenyl-1~ p-[2-(dimethylamino)-ethoxy]-phenyl}-1-butene], a known
agent against mammillary cancer, and of related compounds (see British Patent
Specifications 1,013,907 and 1,064,629) as well.
The 1,2-diphenyl-1-(p-chlorophenyl)-1-propene has been described by
G.E. Nousa et al. ~J. Appl. Chem. 1970, 256) but its biological activity has
not been investigated. Besides, also some ethylene derivatives with a struc-
ture related to that of the compounds of the general formula I had been de-
I scribed already ~Ng. Ph. Buu-Hoi, J. Chem. Soc. 1948, 1080; W. Tadros, J.
,; Chem. Soc. 1949, 439; Ng. Ph. Buu-Hoi, J. Org. Chem. 22, 1057 /1957/ ; A.
g Boris et al., Arch. int. Pharmacodyn. 151, 475 /1964/ ; H.N. Fox et al.,
r 20 J. Med. Chem. 8, 250 /1965/ ). These known compounds mentioned above have
been prepared by the method generally used for the synthesis of alkene
derivatives, by elimination of water from the corresponding tertiary alkanol
derivative.
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8721Z
The novel triphenylalkene derivatives of the general formula I
and their geometrical isomers can be prepared by dehydrating a novel tri-
phenylalkanol derivative of the general formula II
X - ~ 1l 12 ~ II
wherein R and X have the same meaning as above, and Rl and R2 have different
meanings, and stand for a hydrogen atom or a hydroxyl group. This means that
when Rl stands for a hydrogen atom ~hen R2 denotes a hydroxyl group and vice
versa. The dehydration, i.e. the elimination of water, is carried out in the
presence of an inorganic acid, e.g. hydrochloric acid, hydrobromic acid, phos-
phoric acid, or of an organic acid, such as trifluoroacetic acid or formic
acid, in a diluting agent or in a solvent, e.g. in aqueous ethanol. The
geometrical isomers can be separated by fractionated crystallization or by
chromatography.
The triphenylalkene derivatives according to the invention inhibit
to a significant extent the growth of hormone-dependent experimental tumors
induced in animals by DMBA.
The compounds according to the invention can be used for the produc-
tion of pharmaceutical preparations by converting at least one compound of
; the general formula I into a pharmaceutical preparation together with non-
toxic, therapeutically suitable diluents and/or carriers. The preparation can
be given orally or parenterally.
The compounds and the process according to the invention are further
illustrated by the aid of the following Examples, without, however, restrict-
ing in any way the scope claimed.
- - 3 -
,,' ~ '

~L~8721Z
Example 1
The solution of 135.0 g. (0.355 moles) of 1,2-diphenyl-1-~p-bromo-
phenyl)-l-butanol in 1400 ml. of ethanol is boiled for 5 hours with 300 ml
of 36 % hydrochloric acid. Ethanol is distilled off in vacuo, and the aque-
ous residue is extracted in several portions with a total of 1500 ml. of
methylene dichloride. The org~nic phase is washed with water until neutral,
then dried. On evaporating the solvent, the crude crystalline product is re-
crystallized from ethanol, affording 120.0 g (93%) of 1,2-diphenyl-1-(p-
bromophenyl)-l-butene; m.p. 64 - 82C; the ratio of the ~Z/ isomer to the /E/
isomer is 1:1. On recrystallizing the product thrice from isopropanol, the
/Z/ isomer having a m.p. of 112 - 115C is obtained. The mother liquor is
evaporated to dryness, and the residue is recrystallized twice from methanol,
affording the /E/ isomer of m.p. 89 - 92C.
1,2-Diphenyl-l-(p-bromophenyl)-l-butanol serving as starting sub-
stance is obtained as follows:
A solution of 20.6 g. (0.90 moles) of sodium in 600 ml. of an-
hydrous ethanol is combined with 165.0 g. (0.60 moles) of 4-bromodeoxybenzoin
~I.L. Kotlyarevskii and N.I. Popova, Izv. Aked. Nauk SSSR, Ser. Khim. 1967,
208). The cooled solution is combined with 140.0 g. (0.90 moles) of ethyl
iodide and boiled for 5 hours. On pouring the reaction mixture into ice-
water, the oily product which solidifies within a few hours is filtered and
dried. The obtained 4-bromo-a-ethyl-deoxybenzoin is purified by distillation.
Yield: 155.5 g. (85.5 %); m.p. 50 - 53C; b.p.: 173 - 180C at 0.7 torr.
14.6 g. (0.60 moles) of magnesium in 600 ml. of anhydrous ether are
:
allowed to react, under stirring, with the solution of 94.2 g. (0.60 moles)
of bromobenzene in 100 ml. of anhydrous ether. To the cooled solution of the
formed Grignard reagent a solution of 151.5 g. (0.50 moles) of 4-bromo-a-
,, ethyl-deoxybenzoin in 300 ml. of anhydrous ether is added, and the mixture is
boiled for an hour. Then 600 ml. of 1.0 _ hydrochloric acid are added to the -
cooled reaction mixture, and the organic phase is separated. The aqueous
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108721Z
phase is extracted several times with ether, then the combined ethereal
phases are shaken with a 10% solution of ammonium chloride and with water.
After drying the solvent is removed by distillation, and the crude cTystal-
line product is recrystallized from 90% ethanol, affording 152.0 g. t79.6%)
of 1,2-diphenyl-1-(p-bromophenyl)-1-butanol; m.p.: 138 - 140C.
Example 2
To a solution of 320.0 g. (1.0 mole) of 1,2-diphenyl-1-(p-fluoro-
phenyl)-l-butanol in 3800 ml. of ethanol, 850 ml. of 36% hydrochloric acid
are added and the mixture is boiled for an hour. The crystals precipitated
from the cooled solution are filtered and washed with several portions of
water until neutral. On evaporating the mother liquor to the half of its
initial volume, further amounts of the product are obtained. On recrystal-
lizing the crude product (290 g.) from 90% ethanol an isomer mixture of 1,2-
diphenyl-l-(p-fluorophenyl)-l-butene is obtained, with a yield of 257.0 g.
(84.9%); m.p. 65 - 70C; ratio of the /Z/ isomer to the /E/ isomer: 1:1.
The mixture of isomers is separated on a column of silica gel having a grain
size of 0.063 - 0.20 mm. impregnated with silver nitrate, by elution with an
apolar solvent tsuch as petroleum ether or cyclohexane). From 5 g. of the
mixture 2.46 g. t49.3%) of /Z/-isomer having a m.p. of 77 - 80C and 1.21 g.
~24.2%) of /E/-isomer having a m.p. of 78 - 81C are obtained.
1,2-Diphenyl-l-tp-fluorophenyl)-l-butanol used as starting sub-
; stance is prepared as follows:
29.2 g. tl.20 moles) of magnesium in 150 ml. of anhydrous ether
are allowed to react under stirring with the solution of 210.0 g. tl.20
moles) of l-bromo-4-fluorobenzene in 420 ml. of anhydrous ether, then the
solution is cooled and treated with a solution of 224.3 g. tl.O mole) of
~-ethyl-deoxybenzoin tT.E. Zalleskaya and O.A. Netsetskaya, Zh. Org. Khim.
5, 1076 /1969/) in 1~00 ml. of ether. The reaction mixture is boiled for 4
hours, then cooled and decomposed by 1000 ml. of a 10% solution of ammonium
chloride, the ethereal part is separated, then the aqueous phase is extracted
:~.
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7212
with further portions of ether, and the combined ethereal solutions are
evaporated to dryness. The 1,2-diphenyl-1-(p-fluorophenyl)-1-butanol ob-
tained in this way ~314.0 g. /98%/; m.p.: 80 - 88C) in crystalline form can
be converted into the appropriate butene derivative without any further puri-
fication. After recrystallization from 90% ethanol the m.p. of the product
is 94 - 96C.
Example 3
The solution of 33.7 g. (0.10 moles) of 1,2-diphenyl-1-~p-chloro-
phenyl)-l-butanol in 400 ml. of ethanol is boiled for 2 hours with 85 ml. of
36% hydrochloric acid, The solution is cooled, and the precipitated crystals
are filtered, washed with water and then recrystallized from 90% ethanol,
affording 28.3 g. (88.8%) of a mixture of 1,2-diphenyl-1-(p-chlorophenyl-1-
butene isomers; m.p. 67 - 87C; ratio of /Z/ isomer to the /E/ isomer: 1:1.
The 1,2-diphenyl-l-(p-chlorophenyl)-1-butanol serving here as
starting substance can be prepared as follows:
4.38 g. (0.18 moles) of magnesium in 25 ml. of anhydrous ether are
allowed to react with a solution of 34.4 g. (0.18 moles) of 1-bromo-4-chloro-
benzene in 70 ml. of anhydrous ether under stirring, then a solution of
33.6 g. (0.15 moles) of ~-ethyl-deoxybenzoin in 140 ml. of anhydrous ether
is added to the cooled solution, and the mixture is boiled for 4 hours. On
decomposing the cooled mixture with a solution of ammonium chloride, the
aqueous phase is shaken with further amounts of ether. The crude crystalline -~
product obtained after the removal of the solvent by distillation is re-
crystallized from ethanol, affording 44.0 g. (87.1%) of 1,2-diphenyl-1-(p-
chlorophenyl)-l-butanol; m.p.: IOg - III~C.
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