Note: Descriptions are shown in the official language in which they were submitted.
~C~'7%~3 ~ ~
The in~ention relates to a process for the produc~ion o-f triphenyl-
alkene derivatives of the general formula I
RlR ~ -CH~-CH2 ~ 0 } ~ (I)
wherein Rl and R2 may denote identical or different Cl ~ alkyl groups or ;-
together with the adjacent nitrogen atom they may denote a piperidine or ~;
morpholine group, whereas R3 denotes a Cl 4 alkyl group, and their salts and
/Z/ and /E/ isomers.
1~ ;.. ' i'
Compounds of the general formula I are known to possess an anti-
estrogen effect; one of them: the /Z/-1,2-diphenyl~ p-[2-(dimethylamino)-
ethoxy~-pheny~ -l-butene (Tamoxifen, see Hungarian patent specifications
Nos. 151,747 and 154,086) has been applied also therapeutically for the
treatment of hormone-dependent mammillary cancer under the name Nolvadex .
The above-mentioned Hungarian patent specifications describe for
the production of this type of compounds two different ways of synthesis;
they do not indica~e, however, the yields of the steps of the processes.
According to one of the processes described in Example 2 of the H~mgarian
patent specification No. 151,747, the /Z/- and /E/-1,2-diphenyl-1-(p-hydroxy-
phenyl)-l-propene isomer mixture is alkylated with 2-(diethylamino)-ethyl
chloride and the citrate of the obtained /Z/- and /E/-1,2-diphenyl-1-~p-[2-
(diethylamino)-ethoxy]-phenyl~-l-propene is isolated. The starting substance
is prepared in three steps: ~-meth~ldeoxybenzoin is treated with a Grignard
reagent prepared from p-methoxyphenyl bromide, then the obtained l~2-diphenyl- ! ;
l-(p-methoxyphenyl)-l-propanol is dehydrated with an acid, and the obtained
; 1,2-diphenyl-1-¦p-methoxyphenyl)-1-propene is decomposed by ether splitting.
According to the other method described in Example 9 of the
Hungarian patent specification No. 151,747, 1,2-diphenyl-1-lp-[2-(dimethyl-
29 amino)-ethoxy]-phenyl~-l-butanol is dehydrated by an acid to give the mixture
-1- ~
t
~7~ )g3
of /Z/- and /E/-lt2-diphenyl-1-~p-[2-~dimethylamino)-ethoxy]-phenyl~
butene. Subsequently the isomers are separated by the fractionated crystal-
lization of their citrates. In this case the starting substance is prepared
in three steps as well: c~-ethyl-4-methoxydeoxyben~oin is at ~irst subjected
to ether splitting, the formed ~ethyl-4-hydroxydeoxybenzoin is O-alkylated
with 2-(dimethylamino)-ethyl chloride and then allowed ~o react with a
Grignard compound prepared from bromoben3ene.
The Hungarian patent specification No. 154,086 describes the
separation of the isomers of compounds of the general formula I and of their
salts. This can be carried out both by fractionated crystalli~ation from
an organic sol~ent or solvent mixture, and by way of chromatography.
The technique of the above-mentioned synthesis variants and the
yields of the individual steps were studied in case of Tamoxifen, a drug of
prominent therapeutic effect, and it was established that the industrial
applicability of both methods i~ inhibited by the cumbersome technique and
unfavourable yield of the individual intermediates, such as the reactions of
ether splitting and O-alkylation. This drawback is further increased by the
strong inclination to polymerization of 2-(dimethylamino)-ethyl chloride,
a compound whose handling is rather difficult.
The elimination of these deficiencies has been attempted by the
method described in the published German patent application (Offenlegungs-
schrift) ~o. 2,252,879. According to this method, Tamoxifen is obtained in
the terminal step of the synthesis, by splitting hydrogen cyanide of the
compound 2-tp-[2-(dimethylamino)-ethoxy]-phenyl~-2,3-diphenyl ~aleronitrile,
followed by the separation of the isomers. On carrying out the reaction in
N,N-dimethyl formamide with sodium amide, the /Z/ isomer was separated from
the reaction mixture in a yield of 3 9 ~, whereas on separating it in liquid t
ammonia with potassium amide the yield was 9.4 %. The starting substance is
29 prepared from ~(4-tosyloxy)-phenyl-acetonitrile similarly in three steps:
-2-
'
:
~C~72~3
on treating the starting compound with phenol, the ~-(p-hydroxyphenyl)-
phenylacetonitrile, and on alkylating this latter with 2-(dimethylamino)- -~
ethyl chloride the ~-~p-[2-(dimethylamano)-ethoxy]-phenyl~-phenylacetonitrile
is obtained which, when reacted with l-chloro-l-phenylpropane, affords the
desired valeronitrile. The practical application of this process is made
difficult mainly by the cumbersome technique of the terminating step, i.e.
the use of potassium or sodium amide, liquefied ammonia and a temperature of
-40 C, and besides also by the poor yields of several steps of the synthesis
Now we have found that the triphenylalkene derivatives of the
10 general formula I, wherein Rl and R2 may have identical or different meanings `
and may denote a Cl 4 alkyl group or together with the adjacent nitrogen
atom they may denote a nitrogenous heterocyclic group carrying possibly also
another heteroatom, whereas R3 denotes a Cl ~ alkyl group, and their salts,
further their /Z/ and /E/ isomers can be produced by reacting the /~/ or /E/
isomer or the mixture of these isomers of an aryl halide of the general
formula II
R
X ~ C = C ~ (II~
wherein R3 has the above-given meaning and X denotes a halogen atom, with an
aminoethanol derivative of the general formula III
RlR2N ~ CH2 ~ CH2 ~ OM (III)
wherein Rl and R2 have the above-given meanings whereas M denotes hydrogen
or an alkali metal, preferably a sodium or potassium atom. No data of
literature are known for the alkoxylation of phenethylphenyl halides, and
thus the above-described alkoxylation of compounds of the general formula II
is a fully new method. On the basis of literature data (Methoden der
29 organischen Chemie VI/3, 75, G. Thieme Verlag, Stuttgart /196S/; Saul Patai:
:
i~7~ 3
The Chemistry of Ether Linkage, John Wiley and Sons, London-New ~ork-Sydney
/1967/ p. 450) a favourable progress of this reaction could not be expected
because the aromatic halide derivatives can be exchanged with an alkoxy
group only in the presence of a strongly electron-attractive o- or p-posi-
tioned group or groups, such as nitro, sulphonic acid, nitrile or carboxyl
groups. In our case, in turn, the presence of the p-positioned phenethenyl
group affects the electron distribution of the aromatic ring to a significantly
weaker extent. Thus, the occurrence of the reaction was surprising.
We have found that among the aryl halides of the general formula
II the chloro and bromo derivatives react with the aminoalcohols of the
general formula III at 160-200 C in 5-150 hours whereas the fluorine deriva-
tives react at 110-170 C within ~-40 hours. Of the halogen derivatives, the
fluorine derivatives excel not only by their higher chemical reactivity but
also by the selectivity of the discussed reaction. A further advantage of
the -fluorine derivatives is that, owing to their higher reactivity, the
ether-forming reaction can be carried out also at lower temperaturesg and so
the temperature-dependent transisomerization of the geometrical isomers can
be avoided. Thus e.g. on carrying out the discussed reaction with a /Z/ OI`
/E/ fluorine derivative of structure II at a temperature below 170 C, the
corresponding homogeneous isomer o~ structure I is obtained in a yield of
80 bo 85 %.
In this reaction the alkali salts, e.g. the sodium or potassium
salts, of the compounds of the general formula III are applied in at least
an equimolar amountg expediently in an excess. The reaction is carried out
in a solvent, preferably in an excess of an alcohol derivative of the general
formula III, wherein M denotes a hydrogen atom, or in aprotic solvents, such
as dimethyl sulphoxide, NgN-dimethylacetamide, or phosphoryl tris-(dimethyl-
~; amide). I the reaction is not carried out with a separated isomer of the
29 compounds of the general formula II, an isomer mixture is obtained.
--4--
~6:1 7'~3
Furthermore we have found that the separation of the isomers can -~
be carried out with an efficiency higher than that described in the Canadian -~
patent specification No 271,086 (crystallization from an organic solvent or
chromatography,~, if their mixture in the form of their salts, preferably of ~;
their halides, e.g. of their hydrochlorides, is subjected to fractionated
crystallization from the aqueous solution of the salt-Eorming acid. In this ;~
way any desired isomer can be separated in a pure form in yields of 80 to
~3 ~.
The compounds of the general formula II used as starting materials
10 can be produced in excellent yields according to the Hungarian patent applica~
tion No. G0-1328 by dehydrating with an acid the 1,2-diphenyl-1-(p-halogen-
phenyl)-l-alkanol obtained by reacting an ~~alkyldeoxybenzoin with a 4-
halogenphenyl magnesium bromide.
An advantage of the process according to the invention is that it
makes possible the preparation of compounds of the general formula I in a
smaller number of operational steps, by a simpler technique and in better
yields than the methods known thus far. Its further advantage is that any -
isomer of the compounds of the general formula I can be produced immediately
from the separated appropriate isomer of the compounds of the general formula
20 II~ The efficiency of the separation of the mixture of isomers, i.e. of the
fractionated crystalli~7ation of their salts from an aqueous solution, is
higher and thus the yield is more favourable than that of the known methods.
The process according to the invention is fur-ther illustrated by
the aid of the following ~3xamples.
Example 1
After dissolving 9020 g. (0.4 moles) of sodium in 71.20 g. (0.8
moles) of anhydrous 2-(dimethylamino)-ethanol, the solution is cooled and
combined with 72.66 g. (0.2 moles) of 1,2-diphenyl-1-(p-bromophenyl)-1-
29 butene and stirred for 10 hours at 200 C. The reaction mixture is cooled,
--5--
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diluted with 500 ml. of water, extracted with 1000 ml. of ether, then the
aqueous phase again extracted with further amounts of e~her and the combined
ethereal phases are washed with water until neutral. The ethereal extract
obtained in this way is extracted with 1200 ml. of 0.5 N hydrochloric acid.
The needle crystals of /Z/-1,2-diphenyl-1-~p-[2-(dimethylamino)-ethoxy]-
phenyl~ butene hydrochloride precipitated from the aqueous phase are iso-
lated, washed with water and dried in vacuo over phosphorus /V/ oxide. Yield:
8.40 g. (10.3 %); m.p. 190-193 C. The base is liberated from the salt with
an excess of 1.0 N sodiwn hydroxide; yield: 7.50 g. (10.1 ~0); m.p. 96-98 C.
Exam~
; After dissolving 2.3 g. (0.1 mole) of sodium in 17.80 g. (0.2 moles)
of anhydrous 2-(dimethylamino)-ethanol, the solution is cooled and combined
with 16.0 g. (0.05 moles) of 1,2-diphenyl l-(p-chlorophenyl)-l-butene, and
stirred for 20 hours at 190 C. The reaction mixture is cooled, then decom-
posed with ether in the way specified in Example 1 and extracted with ether.
The ethereal solution is washed until neutral, dried oYer sodium sulphate,
filtered and saturated with dry gaseous hydrochloric acid. The precipitated
isomer mixture of the hydrochlorides is filtered by suction, washed with
ether, dried and repeatedly recrystallized from dilute (0.06 to 0.6 %)
hydrochloric acid. From the obtained 1.94 g. (9.50 ~) of /Z/-1,2-diphenyl-1-
tp[2-(dimethylamino)-ethoxy]-phenyl~ butene hydrochloride the base is
liberated by mixing with loO N sodium hydroxide; yield 1.73 g. (9.30 ~);
m.p. 96-98 C.
Example 3
6.90 g. (0.3 moles) of sodium are dissolved in 53.40 g. ~0.6 moles)
of anhydrous 2-(dimethylamino)-ethanol. The obtained solution is cooled,
combined with 45.40 g. (0.15 moles) of 1,2-diphenyl-1-(p-fluorophenyl)-1
butene and stirred for 2-2.5 hours at 170 C. The cooled solution is diluted
29 with 500 ml. of water and extracted with 1500 ml. of carbon tetrachloride
.
~L~7;2~3 ; ~
added in portions. The combined organic phases are washed with water until ~`
neutral, then dried. The filtered carbon tetrachloride solution is treated
with gaseous hydrochloric acid The precipitated isomer mixture of 1,2-
diphenyl-l-~p-[2-(dimethylamino)-ethoxy]-phenyl~-1-butene hydrochloride is
filtered by suction and dried in vacuo over phosphorus /~/ oxide. Yield
51.0 g. (82.5 %); m.p. 164 to 167 C. The isomer mixture of hydrochlorides
is repeatedly recrystalli~ed fram 0.06 % hydrochloric acid, then the salt of
the /Z/ isom0r is isolated. Yield: 26.5 g. (~2.7 %); m.p. 190-192 C. On
dissolving the hydrochloride in some methanol, it is mixed up with 1.0 N ~-
hydrochloric acid. The precipitated /Z/-1,2-diphenyl-1- ~-[2-¦dimethylamino)-
ethoxy]-phenyl~-l-butene is filtered, washed with water and dried over calcium
chloride. Yield: 23.0 g. ~41.~ %~; m.p. 96-98.5 C.
$xa~p_e 4
After dissolving 0.46 g. (0.02 moles) of sodium in 3.56 g. (0.4
moles) of anhydrous 2-(dimethylamino)-ethanol, the solution is cooled, com-
bined with 3.02 g. ~0.01 moles) of /Z/~1,2-diphenyl-1-(p-fluorophenyl)-1-
buter~e and stirred for 8 hours at 150 C. The reaction mixture is cooled,
decomposed with some water and extracted with carbon tetrachloride. m e
organic phase is washed with water until neutral, dried, the solvent removed
by distillation and the crystalline residue dried in vacuo~ affording 3.05
g. (82.0 %) of /Z/-1,2-diphenyl-1-~p-[2-(dimethylamino)-ethoxy]-phenyl~
butene; m.p. 96.5-98 C.
Example 5
1.38 g. (0.06 moles) of sodium are dissolved in 15.5 g. (0.12 moles)
of anhydrous N-[2-(hydroxyethyl)]-piperidine. m e reaction mixture is cooled,
then combined with 9.06 g. (0.03 moles) of an isomer mixture of 1.2-diphenyl-
l-(p-fluorophenyl)-l_butene and stirred for 2 hours at 170 C. On proceeding
according to Example 3, 13.0 g (98 %) of an isomeric mixture of 1,2-diphenyl-
29 1-[p-(2-piperidinoethoxy)-phenyl]-1-butene hydrochloride is obtained; m.p.
~7
~72~3
136-140 C. On repeatedly recrystallizing the isomer mixture of hydrochlorides
from dilute hydrochloric acid and liberating the base, 5.26 g. (~2.3 %) of
/Z/-1,2-diphenyl-1-[p-(2-piperidinoethoxy)-phenyl]-1-butene are obtained;
m.p. 112-113 C.
Examp~e 6
On dissolving 0.46 g. (0.02 moles) of sodium in 5.24 g. ~0004 moles)
of anhydrous ~-~2-(hydroxyethyl)]-morpholine, the cooled solution is com-
bined with 3.02 g. (0.01 moles~ of /Z/-1,2-diphenyl-1-(p-fluorophenyl)-1-
butene and stirred for 8 hours at 150 C. On proceeding according to Example
4, 3.4~ g. (83.5 %) of /Z/-1,2-diphenyl-1-[p-(2-morpholinoethoxy)-phenyl]-1-
butene are ob~ained; m.p. 131-133 C.
xample 7
e mixture of 17.40 g. (0.12 moles) of anhydrous 2-(diisopropyl-
amino)--ethanol and 60 ml. of anhydrous phosphoryl-tris (dimethylamide) is
heated with 2.30 g. (0~10 moles) of sodium at 100-120 C until complete
dissolution. On combining ~he reac~ion mixture with 24.20 g. (0.08 moles)
of 1,2-diphenyl-1-¦p-fluorophenyl)-1-butene~ it is stirred for 10 hours at
160 C. The cooled solution is diluted with water, extracted with ether,
then the combined ethereal solutions are washed with water ~til neutral and
dried over sodium sulphate. On leading gaseous hydrochloric acid into the
filtered ethereal solution, 33.2 g. (71.7 %) of an isomer mixture of 1,2-
diphenyl~ p-[2-(diisopropylamino)-ethoxy]-phenyl~-1-butene hydrochloride
are precipitated and isolated. The mixture i5 crystallized in the way des-
cribed in Example 3, and the base is liberated, affording 15.40 g. (36.0 %)
of /Z/-1,2-diphenyl-1-lp-[2-(diisopropylamino)-ethoxy]-phenyl~ butene;
m.p. 68-70 C.
