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Patent 1179359 Summary

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(12) Patent: (11) CA 1179359
(21) Application Number: 358369
(54) English Title: 1,1,2-TRIPHENYLPROPANE- AND PROPENE DERIVATIVES, A PROCESS FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE NEW COMPOUNDS
(54) French Title: DERIVES DE 1,1,2-TRIPHENYLPROPANE ET -PROPENE; METHODE DE PREPARATION, ET COMPOSITIONS PHARMACEUTIQUES QUI RENFERMENT CES NOUVEAUX PRODUITS
Status: Expired
Bibliographic Data
(52) Canadian Patent Classification (CPC):
  • 260/267.1
  • 260/543.2
  • 260/602.2
  • 260/370.4
  • 260/393.7
  • 260/590.9
(51) International Patent Classification (IPC):
  • C07D 295/08 (2006.01)
  • C07C 17/00 (2006.01)
  • C07C 17/14 (2006.01)
  • C07C 17/26 (2006.01)
  • C07C 17/354 (2006.01)
  • C07C 37/00 (2006.01)
  • C07C 37/055 (2006.01)
  • C07C 43/225 (2006.01)
  • C07D 295/092 (2006.01)
  • C07D 303/22 (2006.01)
(72) Inventors :
  • ABRAHAM, GIZELLA (Hungary)
  • HORVATH, TIBOR (Hungary)
  • TOLDY, LAJOS (Hungary)
  • BORVENDEG, JANOS (Hungary)
  • CSANYI, ENDRE (Hungary)
  • KISS, EVA (Hungary)
  • HERMANN, ILONA, NEE SZENTE (Hungary)
  • TORY, KALMAN (Hungary)
(73) Owners :
  • GYOGYSZERKUTATO INTEZET (Not Available)
(71) Applicants :
(74) Agent: FETHERSTONHAUGH & CO.
(74) Associate agent:
(45) Issued: 1984-12-11
(22) Filed Date: 1980-08-15
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
1455 Hungary 1979-08-15

Abstracts

English Abstract




ABSTRACT OF THE DISCLOSURE
The invention rotates to new 1,1,2-tri-
phenylprepane and -propene derivatives of the gen-
eral formual (I),

Image (I)
wherein
A and B each stand for hydrogen or they fore to-
gether a valence bond,
X and Y are identical or different and stand for
phenyl group or a phenyl group having a
halogen, hydroxy, methoxymethoxy, C1-6
alkoxy or benzyloxy substituent in the
para position,
R1 is a C1-6 alkyl, epoxyalkyl, azidoalkyl, methoxy-
methyl or benzyl group or a group of the
general formual (II),

Image (II)
wherein R2 and R3 each represent hydrogen or
a C1-6 alkyl, hydroxyalkyl or
haloalkyl group, or R2 and R3
form together with the adjacent



nitrogen atom an up in 8-mem-
bered heterocyclic group, an up
to 6-membered heterocyclic group
optionally containing further
hetero atom(s), which hetero-
cyclic groups optionally have a
lower alkyl or hydroxyalkyl sub-
stitutent, a guanidino group, an
?inoguanidino group or a nitro-
guanidino group,
with the proviso that if A and B form together a
valence bond and X and Y each stand for phenyl or X
is phenyl and Y is p-methoxyphenyl, R1 may not stand
for a dimethylaminoethyl, diethylaminoethyl, pyrroli-
dinoethyl, piperidinoethyl or morpholinoethyl group
in the (Z) isomers,
stereosiomers and isomeric mixtures thereof, further-
more to acid additon salts of the basic compounds
of the general formual (I).
The compounds of the general formula (I) can
be prepared so that
a) a compound of the general formula (III),

Image (III)



is reacted with an amino of the general formula
H2R3NH or with an allkali metal azide, or
b) a compound of the general formual (IV)

Image (IV)
is reacted with an alcohol derivative of the general
formula R1OM, and, if desired, the methoxymethyl or
benzyl protecting group is split off, or
c) a compound of the general formula (V),

Image (V)
is reacted with an R1-halido or an R1-sulfonate in the
presence of an acid binding agent, or
d) a propane derivative of the general
formula (I) in dehydrogenated.
In the above formulae A, B, X, Y and R1
are as defined above, Z is halogen or sulfonyloxy and
M represents an alkali metal atom.
The new compounds of the general formual (I)
act on the endoorine system. They exert oestrogenic
or antioestrogenic effects of varying strength, further-


more inhibit the growth of the mammary tumor induced
by 7, 12-dimethyl-benz(a)anthracene.


Claims

Note: Claims are shown in the official language in which they were submitted.



THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 1,1,2-triphenylpropane

or -propene derivative of the general formula (I),


Image (I)


wherein
A and B each stand for hydrogen or they form together a valence bond,
X and Y are identical or different and stand for a phenyl group or a
phenyl group having a halogen, hydroxy, methoxy-methoxy,
C1-6 alkoxy or benzyloxy substituent in the para position,
R1 is a C1-6 alkyl, a C1-6 epoxyalkyl, a C1-6 azidoalkyl, methoxy-
methyl or benzyl group or a group of the general formula
(II),

Image (II)


wherein R2 and R3 each stand for hydrogen or a C1-6 alkyl, a C1-6
hydroxyalkyl or a C1-6 haloalkyl group, or R2 and R3 form
together with the adjacent nitrogen atom an up to 8-
membered heterocyclic group, an up to 6-membered hetero-
cyclic group optionally containing further hetero atom(s),
which heterocyclic groups optionally have a lower alkyl or
hydroxyalkyl substituent, a guanidino group, an amino-
guanidino group or a nitroguanidino group,
with the proviso that,


- 69 -


A) when A and B form together a valence hond and X and Y each
stand for phenyl or X is phenyl and Y is p-methoxyphenyl, R1 may not
stand for a dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl,
piperidinoethyl or morpholinoethyl group in the case of the (Z)
isomers,
B) when A and B form together a valence bond and X and Y each
stand for phenyl, R1 may not stand for methyl or ethyl,
C) when A and B form together a valence bond and X and Y each
stand for phenyl, then in the case of the (Z) isomers R1 may not stand
for dimethylaminoethyl, diethylaminoethyl, morpholinoethyl or piper-
idinoethyl,
D) when A and B form together a valence bond, X stands for
phenyl and Y stands for p-methoxyphenyl, R1 may not stand for methyl
or pyrrolidinoethyl,
E) when A and B form together a valence bond, X stands for
p-methoxyphenyl, p-fluorophenyl or p-ethoxyphenyl, and Y stands for
phenyl, R1 may not stand for methyl,
F) when A and B form together a valence bond, X is phenyl and
Y is p-hydroxyphenyl, R1 may not stand for methyl,
G) when A and B form together a valence bond, and X and Y
each stand for p-methoxyphenyl, R1 may not stand for methyl,
or stereoisomers or isomeric mixtures thereof, or a pharmaceutically
acceptable acid addition salt of the basic compound having the
general formula (I),
which process comprises:
a) for preparing a compound of the general formula (I) in
which A and B are as defined above, X and Y are identical or different
and represent a phenyl group, a p-halophenyl group or a p-(C1-6


- 70 -



alkoxy)-phenyl group, R1 stands for azidoethyl group or a group of
the general formula (II), wherein R2 and R3 are as defined above,
reacting a phenoxyalkylhalide or -sulfonate of the general formula
(III),


Image (III)


wherein A and B are as defined above, X and Y are as defined in
point a) and Z stands for halogen or a sulfonyloxy group, with an
amine of the general formula R2R3NH, wherein R2 and R3 are as defined
above, or with an alkali metal azide, and, if desired, reducing the
resulting azido derivative, and, if desired, a resulting amino
derivative is converted into the respective guanidino, aminoguanidino
or nitro-guanidino derivative; or
b) for preparing a compound of the general formula (I) in
which A and B form together a valence bond, X and Y are identical or
different and represent an unsubstituted phenyl group or a phenyl
group which has a chloro, bromo, methoxymethoxy, C1-6 alkoxy or
benzyloxy substitutent in the para position, and R1 stands for a
group of the general formula (II), wherein R2 and R3 form together
with the adjacent nitrogen atom an up to 8-membered heterocyclic
group or an up to 6-membered heterocyclic group optionally contain-
ing further hetero atom(s), which heterocyclic groups optionally
have a lower alkyl or hydroxyalkyl substituent, dehydrogenating a
compound of the general formula (IV),


- 71 -


Image (IV)

wherein A and B stand for hydrogen and X and Y are as defined in
point b) above, and then reacting the dehydrogenated product with
an alcohol derivative of the general formula R1OM, wherein R1 is as
defined in point b) and M stands for an alkali metal atom; or
c) for preparing a compound of the general formula (I) in
which A and B are as defined above, X and Y are identical or different
and represent an unsubstituted phenyl group or a phenyl group having
a halogen or C1-6 alkoxy substituent in the para position and R1
stands for a C1-6 alkyl, epoxyalkyl, methoxymethyl or benzyl group
or represents a group of the general formula (II), wherein R2 and
R3 each stand for a C1-6 alkyl group or they form together with the
adjacent nitrogen atom an up to 8-membered heterocyclic group or an
up to 6-membered heterocyclic group optionally containing further
hetero atom(s), which heterocyclic groups optionally have a lower
alkyl substituent, reacting a compound of the general formula (V),

Image (V)

wherein A and B are as defined above and X and Y are as defined in
point c), with an R1-halide or an R1-sulfonate, wherein R1 is as
defined in point c) above, in the presence of an acid binding agent;
or
d) for preparing a compound of the general formula (I) in
which A and B form together a valence bond, X and/or Y stands for a

- 72 -


p-hydroxyphenyl group and R1 is a group of the general formula (II),
wherein R2 and R3 each represent hydrogen or a C1-6 alkyl group or
they form together with the adjacent nitrogen atom an up to 8-
membered heterocyclic group or an up to 6-membered heterocyclic
group optionally containing further hetero atom(s), which hetero-
cyclic groups optionally have a lower alkyl substituent, reacting
a compound of the general formula (IV), wherein A and B are as
defined in point d) and X and/or Y is a p-(methoxymethoxy)-phenyl
group or a benzyloxyphenyl group, with an alcohol derivative of
the general formula R1OM, wherein R1 is as defined in point d) and
M is an alkali metal atom, and then subjecting the methoxymethoxy
group or the benzyloxy group to an ether splitting reaction; or
e) for preparing a compound of the general formula (I) in
which A and B form together a valence bond, X and Y are identical
or different and stand for an unsubstituted pheny1 group or a pheny1
group which has a halo, methoxymethoxy, C1-6 alkoxy or benzyloxy
substituent in the para position and R1 represents a C1-6 alkyl,
epoxyalkyl, azidoethyl, methoxymethyl or benzyl group, dehydrogen-
ating a compound of the general formula (I), wherein A and B each
stand for hydrogen and X, Y and R1 are as defined in point e); or
f) for preparing a compound of the general formula (I) in
which R1 represents a group of the general formula (II) and in this
latter formula R2 and/or R3 stands for a C1-6 haloalkyl group,
halogenating a compound of the general formula (I), wherein R1 is a
group of the general formula (II) and in this latter formula R2
and/or R3 represents a C1-6 hydroxyalkyl group;
and, if desired, separating the individual stereoisomers
from a resulting isomeric mixture, and, if desired, converting a


- 73 -



basic compound of the general formula (I) into its pharmaceutically
acceptable acid addition salt or liberating a basic compound from
its acid addition salt.

2. A process for the preparation of a 1,1,2-triphenylpropane
or -propene derivative of the general formula (I),

Image (I)

wherein
A and B each stand for hydrogen or they form together a valence bond,
X and Y are identical or different and stand for a phenyl group or
p-hydroxyphenyl group,

R1 is an epoxyalkyl group with up to four carbon atoms, an

azidoethyl group or a group of the general formula (II),

Image (II)

wherein R2 and R3 each stand for hydrogen, a C1-4 alkyl group or a
C1-4 hydroxyalkyl group or they form together with the adjacent
nitrogen atom, a piperazino, pyrrolidino, piperidino or morpholino
group each optionally having a C1-4 alkyl substituent,
with the proviso that,
A) when A and B form togther a valence bond and X and Y each
stand for phenyl, R1 may not stand for a dimethylaminoethyl,
diethylaminoethyl, pyrrolidinoethyl, piperidinoethyl or morpholino-
ethyl group in the case of the (Z) isomers,
or stereoisomers or isomeric mixtures thereof, or a


- 74 -


pharmaceutically acceptable acid addition salt of the basic compound
having the general formula (I),
which process comprises:
a) for preparing a compound of the general formula (I) in
which A and B are as defined above, X and Y are a phenyl group, R1
stands for azidoethyl group or a group of the formula (II), reacting
a phenoxyalkylhalide or -sulfonate of the general formula (III),


Image (III)

wherein A and B are as defined above, X and Y are as defined in
point a) and Z stands for halogen or a sulfonyloxy group, with an
amine of the general formula R2R3NH, wherein R2 and R3 are as
defined above, or with an alkali metal azide, and, if desired,
reducing the resulting azido derivative,
b) for preparing a compound of the general formula (I) in
which A and B form together a valence bond, X and Y are a phenyl
group and R1 stands for a group of the general formula (II) wherein
R2 and R3 form together with the adjacent nitrogen atom a piper-
azino, pyrrolidino, piperidino or morpholino group each optionally
having a C1-4 alkyl substituent, dehydrogenating a compound of the
general formula (IV),


Image (IV)

wherein A and B stand for hydrogen and X and Y are as defined in
point b) above, and then reacting the dehydrogenated product with an
alcohol derivative of the general formula R1OM, wherein R1 is as


- 75 -



defined in point b) and M stands for an alkali metal atom; or
c) for preparing a compound of the general formula (I) in
which A and B are as defined above, X and Y are a phenyl group, R1
stands for an epoxyalkyl with up to 4 carbon atoms or represents a
group of the general formula (II), wherein R2 and R3 each stand for
a C1-6 alkyl group or they form together with the adjacent nitrogen
atom, a piperazino, pyrrolidino, piperidino or morpholino group
each optionally having a C1-4 alkyl substitutent,
reacting a compound of the general formula (V),

Image (V)

wherein A and B are as defined above and X and Y are as defined in
point c) with an R1-halide or an R1-sulfonate, wherein R1 is as
defined in point c) above, in the presence of an acid binding agent;
or
d) for preparing a compound of the general formula (I) in
which A and B form together a valence bond, X and/or Y stands for a
p-hydroxyphenyl group and R1 is a group of the general formula (II)
wherein R2 and R3 are as defined above,
reacting a compound of the general formula (IV), wherein
A and B are as defined in point d) and X and/or Y is a p-(methoxy-
methoxy) phenyl group or a benzyloxyphenyl group, with an alcohol
derivative of the general formula R1OM, wherein R1 is as defined in
point d) and M is an alkali metal atom, and then subjecting the
methoxymethoxy group or the benzyloxy group to an ether splitting
reaction; or


- 76 -



e) for preparing a compound of the general formula (I) in
which A and B form together a valence bond, X and Y are a phenyl
group and R1 represents an epoxyalkyl of up to 4
carbon atoms or an azidoethyl group,
dehydrogenating a compound of the general formula (I),
wherein A and B each stand for hydrogen and X, Y and R1 are as
defined in point e);
and, if desired, separating the individual isomers from a
resulting isomeric mixture, and, if desired, converting a basic
compound of the general formula (I) into its pharmaceutically
acceptable acid addition salt or liberating a basic compound from
its acid addition salt.


3. A process according to claim 1, wherein process variant
a), b), c), d) or f) is carried out employing starting materials in
which A and B form together a valence bond, or process variant
e) is carried out, whereby a compound of the general formula (I)
in which A and B form together a valence bond is prepared.


4. A process for the preparation of threo-1-[4-(2,3-epoxy-
propoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propane, which process
comprises; reacting threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-
hydroxyphenyl)-propane with 1,2-epoxy-3-chloropropane in the presence
of an acid binding agent.


5. A process for the preparation of (E)-1,2-diphenyl-3,3,3-
trifluoro-1-[4-(2-/4-methylpiperazino/-ethoxy)-phenyl]-propene or a
pharmaceutically acceptable acid addition salt thereof, which process
comprises; reacting (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-



- 77 -



3,3,3-trifluoro-propene with N-methylpiperazine, and, if desired,
converting the basic product into a pharmaceutically acceptable
acid addition salt thereof.


6. A process for the preparation of 1 [4-(2-dimethylamino-
ethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-
propene, or a pharmaceutically acceptable acid addition salt
thereof, which process comprises; splitting off the benzyl group
of 1-(4-benzyloxyphenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]-2-
phenyl-3,3,3-trifluoropropene or the methoxymethyl group of
1-(4-methoxymethoxyphenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]-2-
phenyl 3,3,3-trifluoropropene, and, if desired, converting the
basic product into a pharmaceutically acceptable acid addition salt
thereof.


7. A process for the preparation of (E)-1,2-diphenyl-3,3,3-
trifluoro-1-[4-(2-/2-hydroxyethylamino/-ethoxy)-phenyl]-propene or
a pharmaceutically acceptable acid addition salt thereof, which
process comprises; reacting (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-
diphenyl-3,3,3-trifluoropropene with 2-aminoethanol, and, if
desired, converting the basic product into a pharmaceutically
acceptable acid addition salt thereof.


8. A process for the preparation of (E)-1-[4-(2-azidoethoxy)-
phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, which process
comprises; reacting (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl
-3,3,3-trifluoropropene with an alkali metal azide.


- 78 -



9. A process for the preparation of 1-[4-(2-dimethylaminoethoxy)-
phenyl]-3,3,3-trifluoro-1,2-bis (4-hydroxyphenyl)-propene or a pharmaceutical-
ly acceptable acid addition salt thereof, which process comprises; splitting
off the methoxymethyl group of 1-[4-(2-dimethylaminoethoxy)-phenyl]-3,3,3-
trifluoro-1,2-bis(4-methoxymethoxyphenyl)-propene or the benzyl group of 1-
[4-(2-dimethylaminoethyl)-phenyl]-3,3,3-trifluoro-1,2-bis(4-benzyloxyphenyl)-
propene, and, if desired, coverting the basic product into a pharmaceutically
acceptable acid addition salt thereof.

10. A 1,1,2-triphenylpropane and -propene derivative of the general
formula (I)

Image (I)

wherein
A and B each stand for hydrogen or they form together a valence bond,
X and Y are identical or different and stand for phenyl group or a phenyl
group having a halogen, hydroxy, methoxymethoxy, C1-6 alkoxy or
benzyloxy substituent in the para position,
R1 is a C1-6 alkyl, Cl-C6 cpoxyalkyl, C1-C6 azidoalkyl, methoxymethyl or
benzyl group or a group of the general formual (II),


Image (II)

wherein R2 and R3 each represent hydrogen or a C1-6 alkyl, C1-C6 hydroxy-
alkyl or C1-C6 haloalkyl group, or R2 and R3 form together with

- 79 -



the adjacent nitrogen atom an up to 8-membered hetero-
cyclic group, an up to 6-membered heterocyclic group
optionally containing further hetero atom(s), which
heterocyclic groups optionally have a lower alkyl or
hydroxyalkyl substituent, a guanidino group, an amino-
guanidino group or a nitroguanidino group,
with the proviso that
A) when A and B form together a valence bond and X and Y
each stand for phenyl or X is phenyl and Y is p-methoxyphenyl, R1
may not stand for a dimethylaminoethyl, diethylaminoethyl,
pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the
case of the (Z) isomers,
B) when A and B form together a valence bond and X and Y
each stand for phenyl, R1 may not stand for methyl or ethyl,
C) when A and B form together a valence bond and X and Y
each stand for phenyl, then in the case of the (Z) isomers R1 may
not stand for dimethylaminoethyl, diethylaminoethyl, morpholino-
ethyl or piperidinoethyl,
D) when A and B form together a valence bond, X stands for
phenyl and Y stands for paramethoxyphenyl, R1 may not stand for
methyl or pyrrolidinoethyl,
E) when A and B form together a valence bond, X stands for
paramethoxyphenyl, parafluorophenyl or paraethoxyphenyl, and Y
stands for phenyl, R1 may not stand for methyl,
F) when A and B form together a valence bond, X is phenyl and
Y is parahydroxyphenyl, R1 may not stand for methyl,
G) when A and B form together a valence bond, and X and Y
each stand for paramethoxyphenyl, R1 may not stand for methyl,


- 80 -



or stereoisomers of isomeric mixtures thereof, or a pharmaceutically acceptable
acid addition salt of the basic compound having the, general formula (I),
whenever prepared or produced by the process of claim 1 or by an obvious
chemical equivalent thereof.


11. A compound of formula (I) as claimed in claim 10 in which A and B
form together a valence bond, whenever prepared or produced by the process
of claim 3 or by an obvious chemical equivalent thereof.


12. A compound of formula (I) as claimed in claim 10 in which A and B
form together a valence bond or each of them represents hydrogen, X and Y
are identical or different and stand for phenyl or p-hydroxyphenyl and R1
is an epoxylakyl with up to four carbon atoms, an azidoethyl group or a
group of the general formula (II),

Image (II)


wherin R2 and R3 each stand for hydrogen, a C1-4 alkyl group or a C1-4
hydroxyalkyl group or they form together with the adjacent nitrogen atom a
piperazino, pyrrolidino, piperidino or morpholino group each optionally
having a C1-4 alkyl substituent, with the proviso that,
A) when A and B form together a valence bond and X and Y each
stand for phenyl, R1 may not stand for a dimethylaminoethyl, diethylamino-
ethyl, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the case


- 81 -



of the (Z) isomers,
or stereoisomers or isomeric mixtures thereof, or a pharmaceutically
acceptable acid addition salt of the basic compound having the general
formula (I), whenever prepared or produced by the process of claim 2 or by an
obvious chemical equivalent thereof.

13. Threo-1-[4-(2,3-epoxypropoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-
propane, whenever prepared or produced by the process of claim 4 or by an
obvious chemical equivalent therof.


- 82 -



14. (E)-1,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-/4-methyl-
piperazino/-ethoxy)-phenyl]-propene or a pharmaceutically acceptable
acid addition salt thereof whenever prepared or produced by the
process of claim 5 or by an obvious chemical equivalent thereof.


15. 1-[4-(2-Dimethylaminoethoxy)-phenyl]-2-phenyl-3,3,3-
trifluoro-1-(4-hydroxyphenyl)-propene, or a pharmaceutically
acceptable acid addition salt thereof, whenever prepared or produced
by the process of claim 6 or by an obvious chemical equivalent
thereof.


16. (E)-1,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-/2-hydroxy-
ethylamino/-ethoxy)-phenyl] -propene, or a pharmaceutically accept-
able acid addition salt thereof, whenever prepared or produced by
the process of claim 7 or by an obvious chemical equivalent thereof.


17. (E)-1-[4-(2-Azidoethoxy)-phenyl]-1,2-diphenyl-3,3,3-
trifluoro-propene, whenever prepared or produced by the process of
claim 8 or by an obvious chemical equivalent thereof.


18. 1-[4-(2-Dimethylaminoethoxy)-phenyl]-3,3,3-trifluoro-1,2-
bis-(4-hydroxyphenyl)-propene or a pharmaceutically acceptable acid
addition salt thereof, whenever prepared or produced by the process
of claim 9 or by an obvious chemical equivalent thereof.


19. A process for the preparation of a 1,1,2-triphenylpropane

derivative of the formula (I-i),

Image (I-i)

- 83 -


wherein X and Y are identical or different and stand for a phenyl
group or a phenyl group having a fluorine atom, a chlorine
atom, hydroxy or methoxy substituent in the para position,
R1 is an epoxyalkyl with up to four carbon atoms, an azidoethyl, or
a group of the formula (II-i)

Image (II-i)

wherein R2 and R3 each stand for hydrogen, a C1-6 alkyl group or a
C2-4 hydroxyalkyl, or R2 and R3 form together with the
adjacent nitrogen atom a heterocyclic group selected from
heptamethyleneimino, piperazino, pyrrolidino, piperidino
or morpholino group, each heterocyclic group optionally
having methyl or hydroxyethyl substituent,
or a stereoisomer or an isomeric mixture thereof, or a pharmaceuti-
cally acceptable acid addition salt thereof, which process comprises:
a) for preparing a compound of the general formula (I-i) in
which X and Y are identical or different and stand for a phenyl
group or a phenyl group having a fluorine atom, a chlorine atom or
methoxy substituent in the para position, R1 stands for azidoethyl
group or a group of the general formula (II-i),
reacting a phenoxyethylbromide of the general formula
(III-i),

Image (III-i)

wherein X and Y are as defined in point a), with an amine
of the general formula R2R3NH, wherein R2 and R3 are as defined

- 84 -


above, or with an alkali metal azide, and, if desired, reducing the
resulting azido derivative, and, if desired, converting a resulting
amino derivative into the respective guanidino, aminoguanidino or
nitro-guanidino derivative; or
c) for preparing a compound of the general formula (I-i) in
which X and Y are identical or different and represent an unsub-
stituted phenyl group or a phenyl group having a fluorine, chlorine
or methoxy substituent in the para position and R1 stands for an
epoxyalkyl with up to 4 carbon atoms or a group of the formula
(II-i), wherein R2 and R3 each stand for a C1-6 alkyl group or they
form together with the adjacent nitrogen atom the heterocyclic group
as defined above, reacting a compound of the formula (V-i),

Image (V- i)

wherein X and Y are as defined in point c), with. an R1-
halide wherein R1 is as defined in point c) above in the presence of
an acid binding agent;
and if desired, separating the individual isomers from a
resulting isomeric mixture, and, if desired, liberating a basic
compound from its acid addition salt and, if desired, converting a
basic resulting compound into a pharmaceutically acceptable acid
addition salt.


20. A process for the preparation of a 1,1,2-triphenylpropene
derivative of the formula (I-ii),


Image (I-ii)

- 85 -


wherein X and Y are identical or different and stand for a phenyl
group unsubstituted or substituted by p-fluoro, p-chloro-
p-hydroxy or p-methoxy substituent, R1 is an epoxyalkyl
with up to four carbon atoms, an azidoethyl or a group of
the formula (II-ii),
Image (II-ii)
wherein R2 and R3 each stand for hydrogen, a C1-6 alkyl group or a
C2-4 hydroxyalkyl, or R2 and R3 form together with the
adjacent nitrogen atom a heterocyclic group selected from
heptamethyleneimino, piperazino, pyrrolidino, piperidino
or morpholino group, each heterocyclic group optionally
having methyl or hydroxyethyl substitutent,
with the proviso that,
A) when X and Y each stand for phenyl or X is phenyl and Y is
p- methoxyphenyl, R1 may not stand for a dimethylaminoethyl, diethyl-
amino, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in
the case of (Z) isomers ,
D) when X stands for phenyl and Y stand for p-methoxyphenyl
R1 may not stand for pyrrolidinoethyl,
or a stereoisomer or an isomeric mixture thereof, or a pharmaceuti-
cally acceptable acid addition salt thereof, which process comprises:
a) for preparing a compound of the general formula (I-ii) in
which X and Y are identical or different and stand for a phenyl
group unsubstituted or substituted by p-fluoro, p-chloro or p-
methoxy substitutent, R1 stands for azidoethyl group or a group of
the general formula (II-ii),

- 86 -


reacting a phenoxyethylbromide of the general formula
(III-ii),
Image (III-ii)
wherein X and Y are as defined in point a) with an amine
of the formula R2R3NH, wherein R2 and R3 are as defined above, or
with an alkali metal azide, and, if desired, reducing the resulting
azido derivative, and if desired, converting a resulting amino
derivative into the respective guanidino, aminoguanidino or nitro-
guanidino derivative; or
b) for preparing a compound of the general formula (I-ii) in
which X and Y are identical or different and represent a phenyl
group unsubstituted or substituted by p-chloro or p-methoxy sub-
stituent and R1 stands for the general formula (II-ii), wherein R2
and R3 form together with the adjacent nitrogen atom the hetero-
cyclic group as defined above, reacting a compound o e the general
formula (IV-ii),
Image (IV-ii)
wherein X and Y are as defined in point b) above, with an alcohol
derivative of the general formula R1OM, wherein R1 is as defined
in point h) and M stands for an alkali metal atom;
c) for preparing a compound of the general formula (I-ii) in
which X and Y are identical or different and represent a phenyl
group unsubstituted or substituted with p-fluoro, p-chloro or
p-methoxy substitutent and R1 stands for an epoxyalkyl with up to

- 87 -


four carbon atoms or a group of the formula (II-ii), wherein R2 and
R3 each stand for a C1-6 alkyl or they form together with the
adjacent nitrogen atom the heterocyclic groups as defined above,
reacting a compound of the general formula (V-ii),
Image (V-ii)
wherein X and Y are as defined in point c) with an R1-
halide wherein R1 is as defined in point c) above in the presence of
an acid binding agent; or
d) for preparing a compound of the general formula (I-ii) in
which X and Y stand for a p-hydroxyphenyl group and R1 is a group
of the general formula (II-ii), wherein R2 and R3 each represent
hydrogen or a C1-6 alkyl group or they form together with the
adjacent nitrogen atom the heterocyclic group as defined above,
reacting a compound of the general formula (IV-ii) wherein
X and/or Y is a p-(methoxymethoxy)-phenyl group or a benzyloxyphenyl
group with an alcohol derivative of the general formula R1OM wherein
R1 is as defined in point d) and M is an alkali metal atom, and
then splitting off the methoxy group or the benzyloxy
group of the condensation product; or
e) for preparing a compound of the general formula (I-ii)
in which X and Y are identical or different and stand for a phenyl
group unsubstituted or substituted with p-fluoro, p-chloro or p-
methoxy substitutent and R1 represents an epoxyalkyl with up to
four carbon atoms or azidoethyl, dehydrogenating a compound of the
formula

- 88 -


Image

wherein X, Y and R1 are as defined in point e);
and, if desired, separating the individual isomers from
a resulting isomeric mixture, and, if desired, liberating a basic
compound from its acid addition salt, and, if desired, converting
a basic compound to its pharmaceutically acceptable acid addition
salt.

- 89 -

Description

Note: Descriptions are shown in the official language in which they were submitted.


~7~33~
NEW L,L,2-TRIPE~NYLPROP~NE A~ -PROPENE ~ERIVATIVES,
A PROCESS FOR Tl~ PRE`PARATION r~REOF AND PFfARMA-
CE~TICAL COMPOSITIONS CONTAINING T~ NEW CO~POUNI~



The invention reLates to ne~ ~,1,2-t~i-
pherlylpropane and -propene deri~ati~e~ a process for
the preparation thereof and pharmace~ticaL conipositions
which contain the ~ew compounds,
It is l~nown that some triphen~LaLkane deri~a-
tive~ posses~ oestrogenic properties ~JO Grundy: Chem,
Rev, ~7~ 281 (L9~7); P.R, Ca~rter et aL.: J. Chem. Scc~
L ~ 0; N,P~ Buu-Hoi et aLO Chim, Thex~ L96~ 327;
W.J~ MiddLeton et aL,: J, Med~ Chem, L4, 1193 (L97L);
U,~, patent specification No~ 3,7L2,929~, AnaLogous
L~ derirative~ with a ba~ic substit~ent on the phenyL
xing posse~s primaxiLy antioes-tro~enic e~fects ~D.J.
ColLins et aL,: J, Med, Chem. L4, 9~2 (L97L)], The
two most impoxtant repxesentatives of these compounds
are L-C4-(2-diethyLaminoetho~y)-phenyL~-L,2-dipher~
-2-chloroethyLene (Clomlfen) and (Z)-1-~4-(2-dimetb~L-
amlnoethox~)-pherl~L~-L~2-dLphenyL-'L-~uterle (Tamo~i~en)
- ~oe F,P, PaLopoli et ~L, J, Med, Chem, 'LO, 84 (L966);
G.R, ~od~ord et al.: Natw~o 272, ~33 (L966), ~lthough
~)oth oompounds show antioestrogenlo (oestro~en-anta-

2~ ~onlzlng and sLL~ht oestrogen-agonlæin~) aotl~itLes,
the ~ormor oompound is appLied prlmaril~ to Lncl~loe
0~7LatLon CM. Murray et aL,: ~, Obstet, ~ynaeoJ Br.
3L292-62-PT


1~ 3~9
- La -

,~ .
~ommon~. 78~ L108 (L97L)~ and in the treatment o~
oLigospel~y ~J~F. Potts: J. Am. Med. Ass, 23L~ 907
(L97~)~, whereas ~he main ~ield of use o~ Tamoxifen
ls the tre-t=-nt o~ =a=mary tumors ~M.P. CaLe et al.:




:




:

:: : :: :; :




~ ...... . :: :
.~ ' ' , .

~ .

:

~L3L7~35~


Brit. J. Cancer 1971, 27 ~ . Both compounds have, however, the disadvantage
that upon prolonged treatment undesired side effects~ such as eye damages
LH.J. Silverman: Am. J. Optom. ~9, 335 (1972); L.M. Roch et al.: Arch.
Ophtalm. 77, 1~ (1967); M.J. Kaiser-Kupfer et al.: Cancer Treatment Rep. 62,
315 ~1978)7, liver damages LMartindale: The Extra Pharmacopoeia XXVII. 1392
(1977); The Pharmaceutical Press, LondonJ , and thrombosis LK. ~evassaari
et al.: Lancet, 9~6 (1978~ appear.
The invention aims at providing new compounds which are superior in
activity than the known ones, exert more specific effects and cause only
10minor undesired side effects.
The new compounds according to the invention exert various effects
on the endocrinous system, and greatly inhibit the growth of mammary tumors
induced experimentally by 7,12-dimethyl-benz~a)anthracene (DMBA).
The new 1,1,2-triphenylpropane and -propene derivatives according
to the invention correspond to the general formula ~I),




C~'3 - C - C - ~ - ORl ~I)
X Y


wherein
Emd n each stancl Eor hydrogen or they Eorm together a
valcllcc bond,
20X ancl Y are idcntical or diEEcrent and stand for phenyl group
or a phcnyl group having a halogen, hydroxy, methoxymethoxy~ Cl 6
alkoxy or benzyloxy substituent in the para position,
w

3~17~3~9

Rl is a Cl_6 alkyl, Cl_6 epoxyalkyl; Cl 6 azidoalkyl, methoxymethyl or
benzyl group or a group of the general formula (II),




-cH2-cH2-N (II)




wherein
R2 and R3 each represent hydrogen or a Cl 6 alkyl, Cl 6 hydroxylalkyl or
Cl 6 haloalkyl group, or R2 and R3 form together with the adjacent
nitrogen atom an up to 8-membered heterocyclic group, an up to 6-
membered heterocyclic group optionally containing further hetero
atom(s), which heterocyclic groups optionally have a lower alkyl or
hydroxyalkyl substituent, a guanidino groupJ an aminoguanidino
group or a nitroguanidino group,
with the proviso that
A) if A and B form together a valence bond and X and Y each stand
for phenyl or X is phenyl and Y is p-methoxyphenyl, Rl may not stand for a
dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl, piperidinoethyl or
morpholinoethyl group in the (Z) isomers,
B) if A and B form together a valence bond and X and Y each stand
for phenyl, Rl may not stand for methyl or ethyl,
C) if A ancl B orm together a valence bond and X and Y each stancl
2~ for phenyl, then in the case of the (Z) isomers Rl may not stand for dimethyl-
c~minoethyl, diethylaminocthyl, morpholinoethyl or piperidinoethyl,




.'~.

33~9
D) if A and B form together a valence bond, X stands for phenyl
and Y stands for paramethoxyphenyl, Rl may not stand for methyl or pyrrolid-
inoethyl,
E) if A and B form together a valence bond, X stands for paramethoxy-
phenyl, parafluorphenyl or paraethoxyphenyl, and Y stands for phenyl, Rl may
not stand for methyl,
F) if A and B form together a valence bond, X is phenyl and Y is
parahydroxyphenyl, Rl may not stand for methyl,
G) if A and B form together a valence bond, and X and Y each stand
for paramethoxyphenyl, Rl may not stand for methyl, or stereoisomers or
isomeric mixtures of the above compo~mds~ or pharmaceutically acceptable acid
addition salts of the basic compounds having the general formula (I), when
prepared by the process of the present invention which is described in detail
hereina~ter.
The term "alkyl group"~ used either alone or in combinations (such
as alkoxy, azidoalkyl, epoxylakyl, hydroxyalkyl or haloalkyl) refers to a
straight-chained or branched saturated aliphatic hydrocarbyl group of 1 to 6,
preferably 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec.-butyl~ etc., preferably methyl or ethyl group). The term
"halogen" embraces all the four halogens, i.e. fluorine, chlorine, bromine
and iodine. When R2 and R3 form together with the adjacent nitrogen atom an
optionally alkyl-substituted heterocyclic group, this group is preferably a
pyrrol:idino, piperidino, hcptlmethyleneimono, morpholino, piperaz:ino or
N-mcthylpiperazino group.
In a preEcrred subgroup oE the compounds having the gencral formula

~7~
~I) A and B form together a valence bond.
Those compounds of the general formula (I) are also preferred, in
which A and B each stand for hydrogen or they form together a valence bond,
X and Y are identical or different and stand for a phenyl or p-hydroxyphenyl
group, and ~1 represents an epoxyalkyl wi~h up to 4 carbon atoms, an a~idoethyl
group of a group of the general formula (II), wherein R2 and ~3 each stand
for hydrogen, a Cl 4 alkyl group or a Cl 4 hydroxyalkyl group or they form,
together with the adjacent nitrogen atom, a piperazino, pyrrolidino, peperidino
or morpholino group having optionally a Cl 4 alkyl substituent with a proviso

that,
A) when A and B form together a valence bond and X and Y each stand
for phenyl, Rl may not stand for a dimethylaminoethyl, diethylaminoethyl,
pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the case of the
(Z) isomers,
or stereoisomers or isomeric mixtures thereof, or a pharmaceutically
acceptable acid addition salt o~ the basic compound having the general formula
(I)-

Particularly preferred representatives of the compounds of thegeneral formula (I) are the following derivatives:
threo-1-L4-(2,3-epoxypropoxy)-pheny ~ -1,2-diphenyl-3,3,3-trifluoro-propane,
(E)-1,2-diphenyl-3,3,3-trifluoro-1 ~ -(2-/4-methylpiperazino/-ethoxy)-phenyl7 -
propene, 1- /4-(2-dimethylaminoethoxy)-phenyl 7 -2-phenyl-3,3,3-tri:Eluoro-l-
~-hydroxyphellyl)-propene, (~ 2-diphenyl-3,3,3-trifluoro-l- L4-(2-/2-
hy(lroxyethylamino/-c-tlloxy~-phenyl 7 -propene, (E.)-:L- ~ -(2-azicloethoxy)-
phcnyl 7 -1,2,-d.iphenyl-3,3,3-tri:eluoro-propene, 1- L4-(2-di.methylc~ino-ethoxy)-




-- 5 --

~17~35~

phenyl 7-3,3,3-trifluoro-1,2-bis-(~-hydroxyphenyl)-propene and pharmaceutical-
ly acceptable acid addition salts thereof.

The basic compounds of the general formula (I) form pharmaceutically
acceptable acid addition salts with mineral or organic acids, such as hydro-
chloric, hydrobromic, sulfuric, phosphoric, maleic, fumaric, lactic, methane-
sulfonic, p-toluenesulfonic, citric, etc. acids.
The compounds of the general formula (I) can be presented in the
form of various stereoisomers, such as (Z) and (E) isomers, threo and erythro
isomers. All of the stereolsomers and mixtures thereof are embraced by the
scope of the invention.
The invention relates further to a process for the preparation of
1,1,2-triphenylpropane and -propene derivatives of the general formula (I),
wherein A, B, X, Y and Rl are as defined above, stereoisomers and isomeric
mixtures thereof, and pharmaceutically acceptable acid addition salts of the
basic compounds having the general formula (I)~ These compounds are prepared
according to the invention as follows:
a) to prepare a compound of the general formula (I) in which A and
B are as defined above, X and Y are identical or different and represent a
phenyl group, a p-halophenyl group or a p-(Cl 6 alkoxy)-phenyl group, Rl
stands for azidoe~hyl group or a group of the general ormula (II), wherein
R2 and R3 are as defined above, a phenoxyalkylhalide or sulfonate of the
general formula (III),



~ y ~ - ~ C~12 ~ C~12 ~ Z (I[I)



whercin A and B are as defilled above, Y and X are as deflned in point a) and

Z stands eor halogen or a sulfonyloxy ~roup,


- 5a -

3~

is reacted with an amine of the general formula
R2R3N~I, wherein R2 and R3 are as defined above, or
with an aLkali metaL azide, and, if desired, the re-
suLting azido deri~ative is reduced, and, if desixed,
a resuLting amino deri~ative is con~erted into the
respecti~e guanidino~ aminoguanidino or nitroguanidino
deri~ati~e; or
b) to prepare a compound of the generaL
foImuLa (I) i. which A and B foxm to~ether a ~aLence
L0 bond, X and Y are identical or different and represent
an unsubstituted phenyl. group or a phen~l gl'OUp ~hioh
has a chLoro, bromo, metho~ymethoxy, CL 6 alko~ or
benzyLo~y sl1bstituent in the para position, and Rl
stands ~or.a group of the general fol~ula (II), wherein
1~ R2 arld R3 each repre~ent hydrogen or a Cl 6 aLk~L group,
or R2 arlcl R3 form togethQr with the ad~acent ni$rogen
atom an up to 8-membered he$erocycLic group or an up

to 6-membered heterocycLic group optionally ~ontai~ing
further hetero atom(s), whi.ch heterocrclic groups
optLonaLly ha~e a lowar aLkyl or hydro~yalkrL substi-
tuerlt, a oompound of the ~;eneral :rormuLa (IV),



~ :B



2~ X ~ ~ ~ F (IV)




wherein A and B ~tand fox b.ydrogen ancl X and Y are as

7 --



defined in point b) abo~e, is dehydro~enated and
then raacted with an aLcohoL deri~ative of the gen-
eral formuLa RLQM, wherein RL is as defi.ned in point
b) and M stands for an alkali metal atom; or
c) to prepare a compound of the ~eneral
formula ~I) in which A and B are as defined abo~e,
X and Y are identicaL or different and represent an
unsub~tituted phenyL group or a phenyl group having
a halo~en or CL 6 aLkoxy substit-uent in the para
LO position and Rl stand~ for a Cl 6 aLkyl, apox~aLkyL,
methoxymethyL or ben~yL group or represents a group
of the g~neraL formuLa (II), wherein R2 and R3 each
stand for a CL 6 alkyL group or they form togethar
with the adjaoent nitrogen. atom an up to 8-me~bered
1~ heterocycLic group or an up to 6-membered heterocycLic
group optionalLy containing further hetero atom(s),
which heterocyoLic groups optionalL~ have a lower
alkyl substituellt, a compound of the gen.eraL fonnula
('V~ ,




! I ~ OI-~ (V)


.~ Y




2~ wherein ~ and B are a~ defLned above and X and Y ar-e
as defined ln polnt c), ls reacted wlth an RL-haLlde


~ 1

35~

- 7a -



or an Rl-sulfonate, wherein Rl i~ as defined in
point c) abo~e, in the pre3ence of an acid binding
agent; or
d) to prepare a compound of the general
formuLa (I) in which A and B form tog~ether a ~aLence
bond~ X and/or Y 3tands for a p-hydroxyphenyL ~roup
and RL is a group of the general formuLa (II), where-
ln R2 and R3 each rep.resent hydrogen or a Cl 6 aLkyL
group or they form together with the adjaoent nitrogen
L0 atom an up to 8-membered heterocycLic group or an up
to 6-membered heterocycLic group optionalLy contai.ning
further hetero atom(s), which heterocycLic groups op-
tionaLLy ha~e a Lower alkyl substituent, a compound of
the genaral foxmula (IV), wherein A and B are as
l~ defined in point d) and X and/or Y i9 a p-(meth.ox~-
metho~y)-phenyL group or a benzyLoxyphenyL group, is
reacted with an aLcohoL deri~ati~e of the general
formuLa RLOM, wherein RL i~ as defîned in point d)
and M is an aLkaLi metal atom, and then the methoxy-

methoxy g.roup ox the benzyLo~y group 1s s~jected tonn ether spllttlne~ reactlon; or


~'7~35~


e~ to prepare a compound of the general formula ~I) in which A and
B form together a valence bond, X and Y are identical or different and stand
for an unsubstituted phenyl group or a phenyl group which has a halo, methoxy-
methoxy, Cl 6 alkoxy or benzyloxy substituent in the para position and Rl
represents a Cl 6 alkyl, epoxyalkyl, azidoethyl, methoxymethyl or benzyl group,
a compound of the general formula (I), wherein A and B each stand or hydrogen
and X, Y and Rl are as defined in point e), is dehydrogenated; or
f~ to prepare a compound of the general formula ~I~ in which Rl
represents a group of the general formula (II) and in this latter formula R2

and/or R3 stands for a Cl 6 haloalkyl group, a compound of the general formula
(I), wherein Rl is a group of the general formula (II) and in this latter
formula R2 and/or R3 represents a Cl 6 hydroxyalkyl group, is halogenated;
and, if desired, the individual stereoisomers are separated from a
resulting isomeric mixture, and, if desired, a basic compound of the general
formula (I) is converted into its pharmaceutically acceptable acid addition
salt or liberated from its acid addition salt.
Process variant a) of the invention is performed preferably so that
the starting substance of the general formula (III) is heated with an amine of
the general formula R2R3~-1 in an inert solvent or diluent (such as alcohol,

aqueous alcohol, acetone, etc.) in the presence of an acid binding agent (such
as potassium carbonate or an excess of the amine reactant), or is reacted with
an allcali metal azlde in dimethylEormamicle or preEerabLy in aqueous 2-methoxy-
cthanol. lE desired, a resulting azido clerivative can hc reduced in a manner
known per se e.g. with an alkali metal hydride or




'~.'~'

3~
g

with hydro~en in the presence of paLLadi.um-on-carbon
cataLyst.
In the ~tarting~ substances of thc general
formula (III) Z is preferably a haLogen atom (~luorine,
chLorine, bromine or iodine), an alkyLsuLfonyloxy group
(e g. methrlsuL`onylo~ group) or an aryLsuLfonyLoxy
group (e.g an optionaLLy substituted phen~LsuL~onyL~
oxy group, such as phenyLsuLfonyLoxy, p-toLuene~ul~onyL-
oxy or p-bromophenyLsuLfonylo~y group).
L0 Process variant b) o~ the in~ention -Ls par-
formed preferably so that a compound o~ the general
formuLa (IV), wherei.n A and B stand for hydrogen, is
reacted wl.th L to 3 moLar equi~aLents of 2,3-dLchloro-
-~6-dicyano~1,4-ben%oqllinone in an inert sol~ent
1~ (e.~. ben~ene or dioxane) at the boilin~ point of
the reaction rnixture, and the resuLting compound is
reacted with an aLcohol deri~ative of the g~eneral
foxmula RlOM in a bipoLar aprotic sol~ent (e g di.-
methyl aoetamide~ hexamethy'lphosphoric triamide, etc.)
ox pro~rab'L~ ln an excess o~ the aLcoho'L o~ the gen-
eral :~oI~rlula RLOH. Thl~ Latter reaction Ls per`ormed
pre:~erabLy at '100 lo '160 C.
.hooordln~ to proce~s varlant o) of the in~en-
tLon a pheno'l deri~ative o` the genera'l ~ormuLa ~V) i~
2~ reacted with an R~~haLide or an RL-suL`onate in a sol-
~ent or cliluent, such a~ benzene, aloohol, etc., in the
,i.~

~:17~3~
-- 10 --

presence of an acid bindingP agent, such as an aLkali
metaL hydroxide or an aLkaLî metaL carbonate. Accord-
ing to a preferred method the process is performed
with an aLkaLi metaL salt of the starting phenoL
deri~ati~e, which also qer~es as acid bindingP a~ent,
Prooess ~axiant d) of the invention is per-
foI~ed preferablr a~ described above for process
variant b)~ The resulting methoxymethoxy or benzyl-
oxy deri~ative is treated then with an acid or reduced
1~ to effect the spLittin~ of the ether group.
In process ~ariant e) of the invention a
compound of the generaL formula (I), wherein A and B
each ~tand for hydrogen, is deh~drogenatedt Dehydroge-
nation is performed preferabLy by reactingP the start~
L5 ingP 9ub9tance wi.th 2~3-dichloro-~6-dicyano-1~4-benzo-
quinone in an inert ~oL~ent (e,gP. ben~ene or dioxane)
at the boiLin~ point of the reaction mixture (see
Org~ Synth, ColL, Vol, ~, 428-431).
According to proce~s variant f) of the in~en-

tion a compound of the generaL f`ormuLa (.L), whereinR'L 1~ a ~roup of the gPene.raL f'orlnuLa (II) and l.n thi~
L~tter ~ormula R2 and/or I~3 stands f.`or hydroxyaLkyL,
:Ls reaoted with a haLogPenatin~ a~ent to obtaLn the
re~pectl~e deri~ati~e wh.e~rein R2 and/or E~3 i~ a halo-

2~ aLkyL ~roup, ~a'LogPenatlon .Ls per~formecl in a mannerknown per ge, utLLi~ing con~entionaL halogenating
agPents~ such as thionyL chLoricie, etc,

.~1

35i~3:
-- 11

The individual stereoisomers can be
separated from their mi~tures by methods ~nown per~
se, such as fractionaL crystallization~
The basic compounds of thc ~eneral foxmula
(I) oan be converted into their acid addition saLts
by reacting them with the appropr-late acid in an
inert soLvent Of the acid addition saLts those
formed with pha~naceuticaLly acceptabLe acids are
preferred The bases can be liberated from the re-

L0 spec-tire acid addition salts by treatment with a strong
base
The startin~ substances of the ~eneral
fo~nuLae (III), (I~) and (V) are, ~ith the exception
of (Z)-L,2-diphenyL-3,3,3-trifLuoro-L-(4-fLuorophenyL)-

1~ ~propene, tZ)-L,2-diphenyL-3,3~3-tri~Luoro-L-(4-hydroxy-

phenrL)-propene and (E)-2-phenyL-3,3,3-tri~Luoro-L-
-(4-hydrox~phen~L)-L-(4-methoxyphenrL)-propene, new
compound~. The preparation of the new startin~ substances
i9 described in detail in the exampLes
The endoorinolo~loal and tutllour-inhlb.Lto:ry
c~*ects of the new compounds aoeordirl~ to the lnven-
t;Lon aro clemon~trated by the ~olLowi.n~ tests J The oom-
pound~ tc~ted are llsted below:
L = throo-L-~4-(2,3-epoxypropoxy)-phenyL~ 2-diphenyl-

2~ -3,3,3-trl~Luoro-propane,
2 = 1-~4-(2,3-epoxypropoxy)-phenyL~-1,2-diphenyL-3~3,3-

~;,. -trifluoro-propene,

~7~3~

3 = ~E)-L~2-diphenyl-3~3~3-trifLuoro-l-c4-(2-/bis-/2
-hydroxyethyL)-amino/-ethoxy)-phenyL~-propene,
4 = (E)-L,2-diphenyl-3,3,3-trifluoro-L-[4-(2-f4-methyl-
piperazino/-ethoxy)-phenyL~-propene,
.~ = L-C4-(2-dimethylaminoethoxy)-phenyL~-2-phenyl-
-373,3-txifLuoro-1-(4-methoxyphenyl)-propene1
6 = 1-C4-(2-dimethylaminoethoxy)-phenyl~-2-Phenyl-
-3,3,3-trifLuoro-1-(4-hydroxyphenyL)-propene,
7 = 1,2-diphenyl-3,3,3-trifLuoro-L-C4-(2-/2-hydrox~-
LO ethylamino/-ethoxy)-phenyl~-propene,
8 = L-C4-~2-dimethylaminoethoxy)-phenyl~-l-phenyl-
-3,3,3-trifluoro-2-(4-hydro~yphenyL)-propene,
9 = (E)-L~2-diphenyl-3~3~3-trifluoro-2-[4-(2 pyrro-
lidinoethoxy)-phenyLJ-propene,
Lg 10 = (E~-1,2-di.phenyl-3,3,3-trifluoro-1-~4-(2-morpholino~
ethoxy)-phenyL~-pr~opene,
11 = (E)-l-C4-(2-diethyLaminoethoxy)-pheny7~ 2-di-
phenyl-3,3,3-trifluoro-propene,
12 = (E)-l-C4-(2-azidoethoxy)-phenylJ-1,2-diphenyL-
-3,3,3-trifluoro~propene,
13 - (E)-1,2-dipherlyl-3,373-trlfluoro-L-C4-(2-/bi~-
-~2-ohloreth~L)-amLrlo/-ethoxy)-phenyl~-propene7
'lL~ = 'l-C4-(2 dlmethr'lamLnoethoxy)-phenyl~-3,3,3-tri-

~luor-1,2-bl~-(4-hrdroxyphen~l)-propene hydro-
2g ohlorlde~
Lg = L-phenyl-2-(4-tnethoxyphenyl)-L-C4-(2-c11methyl-

amLnoethoxy)-phenyl~-3,3,3-trifluoro-propene,

7~S~
- L2a -



L6 = (E)-L,2-diphenyl-3,3,3-trifLuoro-1-[4~(2-~nitro-
~uanidino)-etho~y)-phenyL~-propens,
The antioestrogenic effect was detex~ined
by the method of M,J~K, Harper et aL, 1J~ Reprod,
Fert, 13, lOl (1967)~. 24 days oLd infantiLe female
rats were treat0d with daiLy dosages of ~ /ug/kg of
oestradioL for 3 days~ The test compound was aLso ad-
ministered once a day oraLLy for 3 da~s~ On the 4th
day the animaLs were sacrificed~ and their utex~s was
re~o~ed and weighed. The data characteristic of the
antioestro~enic aotivity (inhibition of the utero-
tropic effect of oestrac1ioL) of some compounds accorcl-
ing to the in~ention are listed in Table l,
The antioestrogenio acti~ity of some of the
compounds Listed in Table l reaches the acti~ity of
Clomifen or TamoxLfen, applied as reference substances,
Compound No, l produces~ howe~er, onL~ a sLi~ht inhibi-
tion when appLied Ln an oral dosage of 1 mg/kg, The
degree of inhibition ~tilL remains Low (39 %) when
the dosage is i~oreased to LO mg~


359

. .

o , ~ ~ 0 0 h
,1 r~ co ~ ~ r~ N K~ ,1 ~1 ~ ~ 4
~ ~ D Lr~ ~D
. .~

. ~.O ~ ~Lr~ ~0
u~ C~ ~~ l N~ t~
J~ P~ t~ ' OCt) C`~ i` O r-l ~
h ~ ~ ~ ~o ~ ~ Lr~ O Lr~ O
.
C>
q_l bO ~
~1 !~ ~ . 4-1
O 00 ~ 1 ~ -
1:1 bO . . . ~ Lq
1~ O ~ tl ~1 ~,1
o l~ o ~ ~ Lr~ o
~-1 ~1 . o. ~
C' O N~ 0 ~ ~1 0 C~ 0 ~ ~ q~ ~.
~ ~ ~ 0 ~l q ~lo l q ~w
~rJ J:~ bO ~ ~1
S~ ~ ~ ~ ~ h U~
O O Lr~ 1 0 ~1 O ~
. P~ t ¦ ~ N ~ O
~ N N ~J ~ N
O O Ll'~ ;l ~ L~ N Lt~ O~ C)~ ~I ~) ~
~) Lt~ ~I h

. l . 5
Lr~ 0 h ,~ ~

0 , ~ ~, . -- ho

O ~ N ~ ~ '!;J ~
.~ D~
.~ ~1 ~
h w ~
~ .~ ~



¦ h~ ~, ~ W ~ h¦
V ~ V El p;

~ 7~3355~
-14-




The oestrogenic (uterotropic) effect was determined
according to the method of R. J. Dorfman [Endocrinology 55, 65
(1954)]. 24 Days old female rats were treated with single daily
oral dosages of the test compounds. On the 4th day the animals
were sacrificed, and their uterus was removed and weighed. The
data characteristic of the oestrogenic (uterotropic) effects of
some of the compounds according to the invention are listed in
Table 2. Ethynyloestradiol, a highly effective oestrogenic
substance, and Clomifen and Tamoxifen, two known antioestrogenic
agents, were also tested and their activity data are also pre-
sented.
The compounds listed in Table 2 possess generally weak
oestrogenic properties, or, in the dosage range of 0.1 to 1.0
mg/kg, their activity is somewhat lower than that of Tamoxifen.
The dosage-activity curve oE Compound No. 1 is, however, some-
what steeper than those of the other compounds. Thus, in the
lower dosage range (0.01 to 3.0 mg/kg) applied, the oestrogenic
effect of Compound No. 1 is even weaker than the weak agonistic
effects of the antioestrogenic agents, whereas the maximum
increase in uterine weight attainable at higher dose ranges
(10 mg/kg) wi.th Compound No. 1 is higher than that attalnable
by -the antloestrogenic agents.


- o
o o cl~
o ~ ~
C~t ,l r~
~ ;t CO ~1
CO "`
~ ~ ~ o ~ ~o oo
~ t-i +l +l +~ +l +l +~
~ +1 ~1 ~ O ~ C~ ~ O O
O C~
O ~C~ O
oc~ o r~
S.l ~1_I d r~
c~ ~r~ r~
~ CO . ~ . o
~ o +~ ol ~1 01 +1 ,~1 ool O~
a) ~ ~ o r~~o ~ oo~
r~
~,~ o~ ~ ~ ~ .
o _l
r~ oo ~ r~
~ ~ ~ o ~
~ ~o ~o C~
,~ ~ +l+l +~ +l +l +l +1, +l
O+ I ~ ~ ~ C~ C~! O C~ O
d .co .
o ~ ~ ~ o ~ ~ r~~ ~ r~ ~
~o o o ~ o o c~o C7~ r~ ~!
t~ t~ ~ ,~ 1 ~0
C) ~ rl
~ ~:5 ~ ~
q~ ~ ~ O ~O -I ~O 0~ ~ ~ ~Q
D X ~ ~ cr~
+l +l +l +l +l +l +l +l rl O
o~ ~1 o ~ l O~ 0~ 0 o c~ ,Q
S~ ~ 0!:) ~O C~ ~n Ctl,1 ~ CU ~t 60
~ o~ cr r~ o~ o~ ~o o~ r~ o ~,
O 6D ~1 ~-1C~ O
c~l ~ ~ ~ ~ r~ ~ ~o o ~ r~ o o
_l ~ r~ o ` ` ~i
.Q o ~ +l +l ~1 +1 +1 -~1 +1 +1 +1
_ ~ ~o c~ ~ oo co oo ~o o O ~
6D ~ ~ . . O ~q
o o ~ ~u r~ ~ o o~ ~ ~ oo c
,~ ~ ~ ~ ~ O~OD 00 r~ u~ ~
r~ r~ o
o r~ o ~ ~o ~ ~
O . . . . . . . 6D ~D
sl ~ ~ o ~t In

+l +l +l +l +l ~1 +1 d
o C~ In ~o ~ In
o ~ . .
r~ r~ o ~ o~ a~
o o~ r~ In co ~ oo r~
,1
~0 ~X) C'l O t~
c~l r~ t c~ t r~ r~
O ~ . .
In ~ t ~ ~ t a) a~
d + 1~ + 1 ~1 + 1 ~ 1 Q. ,d
o o ~ +1 o c~l In ~o o~ a
~ ~~ ~ ~n ~ ,~ ~o~o ~ h ~
d ,~ In ~ oo ~o ~ r~ oo o
.,1 ~O ~O ~O t~
,U~ do
~n ~ ~ n In ~ n
~1 +1 ~ 1 +1 ~ 1 ~ a
c~ In ~n ~n c~ In ~ ~ c~
~n t ~ t In t 1~ In u~ ~
o d
d ..
_l ~ q, a) u~
~ ~ h t~ , ~1
o ~ s~
Q. ~ p~ ~ o ~ ~ ~ GO ~
~ ~q ~ ~g ~ o .1
o a) ~ a) ~ _l
v ~ ¢l O 1~ v

~:~'7
-- 16

The stimulating effect exerted on the secre-
tion of Luteinizlng hormone (LH) was determined as
foLLow3: 24 days oLd infantile female rats were treated
subcutaneously with the compounds to be tested on two
consecuti~e days, Two hours after the second treatment
the animals were bled and the luteinizing hoxtnone (LE)
Le~el of the plasma was determined b~ raclioimmune
assay, When administared in subcutaneous dosages of
L mg/kg, the oompounds tested pro~oke a considerabLe
inorea~e in the LE 'le~0L of the pLasma. The re~ults
are sutmmari~ed in Table 3,



TabLe 3
LE-le~el increasing effect on infantLLe femaLe rats



Compound testedPercentage change of the
LE Level in relation to
the controls
__
Tamoxif 3 n LL7

L 96

3 L3L~
1~. 1.06


7 39

9 ~3
_ . _ _ . . . . . _ _ . ~ _
2~ Remarks: The tests were per~o~ed on groups o~ 4 or
anima'Ls,
Dosage: 2xl mg ~ g s,c,

~. ~,t~ ,s~
- ~7 -



The effects of the new compounds exerted on
hormone-dependent twnours were tested b~ the method of
P. GriswoLd et aL. CCancer Research 26, 2L69 (L966)~
on mammary cancer induced by 7,L2-dimethyl-benz(a)~
anthracene (DMBA). The treatment was s-tarted when the
weight of the twnor reached about ~00 mg, and the
animaLs were trea-ted for 3 months with oraL dosages
o~` 20 m~/kg of the active a~ent, administered three
times a ~eek. The size of the tumors was measured as
L0 descrihed by the abo~e authors as well as accordin~
to the method of V.C. Jordan et aL. CEurcp, J. Cancer
L2, 419 (L976)~, with 3 caLiper gauge. The ~olume of
the twnor was determined 'by the method of ~.riswoLd~
The anirnaLs were kept under ob~ervation for 2 addi-

L~ tionaL months af-ter the termination of the treatment
period, and the tumors were measured in this latter
period as weLl.
A relati~e effectivity index was lntroduced
to characterize the activities of the compounds tested~
'rO oaLou~ate the relatLve effeotLvit~ index the nwnber
o~ an;Ltnals showinr; a permarlent or transitory oure or
relrl:L9~iorl o~ varLou~ d~lratLorl~ was determlnod and
soored aooorclLn~ to the fo'Llowing ta'ble:
pornlF1,rlentLy oured L0 points
2~ temporariLy oured 8 poLnts
dura'b'le rem-Ls~ion 6 points
sho.rt remission or unohanged state 4 points

- L7a -



The ohanges in average tumor number appear-
ing during the treatment period were evaLuated acoord-
ing to the folLowing scale:
no increase in tumor count in any of the animaLs 8 points
the a~erage number of tumors inoreases twofoLd 6 points
higher inorease in the a~erage nurnber of tumors O points
The soore numbers deterrnined for -the indi-
~iduaL animaLs by the abo~e two scaLes were added 7 and
the resuLt was expressed in percents reLated to the
LO scOr~ number which oorresponds to the ma~imum ac-
ti~ity (permanent cure). This percentage ~a'lue is the
reLati~e effectivit~ index.
The resuLts of the test are listed in Table
47 where the figures in brackcts ha~e the folLowing
L~ meanings:




., /

3~9

~l) pormanently cured; ~2) temporarilg Cured; (3) durable
remission; (4) shor~ remission; (5) unchanged sta~a~
Table 4
~fect on tlle marr~ary cance $_Dc5g__~ogyg~g_gy_

Compound Activity Relative
~ested (l) (2) (33 (4) (5) index
~_ ~ ~
Untreated.
controls - - - 25/25 0
Tamoxi~en 2/5 1/5 - l/5 l/5 7
l 4/5 1~5 _ _ _ 96
3 l/5 l/5 - 3/5 - 65
4 _ _ 3/~ 1/4 -- 60
6- 2/5 1/5 l/5 - l/5 78
7 2/5 l/5 l/5 ~ l/5 78
l~ ~j5 ~ 5 9
11 l/5 - 3/5 - l/5 72
12 2/5 2/5 l/5 - - 85
13 l/5 l/5 l/5 2~5 ~ 67
2/5 - 2/5 - l/5 7
16 _ l/L~ 3/4 - - 73

The invention relake~ ~urkher ~o pharmaceutical composi-
bion~ which conbain as actlve agent o~e or more compound90f
bhe ~enaral ~ormula (I) in the form o~ single isomers or
mi~tures o~ i30m~r~, or .acid addibion sal~ o~ the basic
compou~d~ oP the general ~'orrnula (I) to~ether with con~entio~al
inert~ solid or liqui.d phaxmaceu~ical carriers. q'hese phar-
maceutic~l compo~itions can be applied both in the human
therap,y and ~or veterina~,; purposes to in~luence bhe endocrine
~y~tem~ Some o~ the compound~ o~ ~he genaral :~'ormula (I) can

3~

- L9 -



aLso b0 applied in the treatment of t~nors, since the~
inhibit the growth of tumors induced experimentaLLy by
DMBA to a great extent. The pharmaceuticaL compositions
can be presented preferabLy in the form of oraLLy ad-
minister-abLe preparations (such as tabLets~ capsuLes,
powder mixtures, soLutions, suspensîons~ emulsions,
elixirs, etc ) or as compositions for paren.texaL ad-
ministration (e g. injectable solutions or suspensions)
These compositions may con-tain con~entionaL inert,
soLid or liquid carriers (such as starch, lactose,
magnesium stearate, siLicon dio~ido, ma~nesiwrl carbon-
ate, polyvinyLpyrroLidone, water, etc )~ The active
a~ent contents of the compositions ~aries generaLLy
between 0.0~ and 98 %. The pha~naceutical compositions
L~ ma~ aLso contain con~entional pharmaceutical. additi~es
or au~iLLar~ agents, such as emuLsifyin~, dispe.rsing,
wetting, or disintegrating agents, b~fers, etc.
The pha~rlaceuticaL compositions can be pre-
pared by methods commonLy applied in the pharmaceuticaL
inclu9t~y
The claLLy dosage of the co1npouncls acco.rdi~Æ
to the l~ent1on depend~ on varLous faotors, such as
the a~e and genexaL hea'lth oonclit~ons of the patient,
se~erLty of the disorc1er, actLvity of the inclividua'L
2~ oompound~ eto. The daiLy oral do9ages va.ry gene.raLly
withLn about O OL to L() mg/.kg 'body we~ght
The abo~e clata are, howe~er, onLy of informative


ix

~l'7~
- L9a -

charaoter, sinoe hi~her or Lower dosa~es oan aLso be
appLied, if neccssar~,




~:




:

:
:, :

~l~'7~3S~
-- 20 --

The invention is elucidated in detail by the aid o~
the following non-limiti~g ~l~ample~J
~a~
~ _ o- and threo-1,2-d~p~,y3~,~ ,~
5 trifluoro~ L(?-mo:~linoethoxy~-phe~1
A mixture o~ 1.20 g (2~67 mmoles) o~ erythro~
(2-bromoethoxy)-phenyl7-1, 2~diphe~yl-3,3,3-tri~luoro-propane
and 4~80 g of morpholine is hea~ed to boili~gl ~hen cooled,
diluted with 50 ml of ether and washed with water u~bil
neu~r~ he e~heral solution is dried, evaporate~ to dryn~ss~
~nd the residue i~ crystallized ~rom hexane. 1002 ~ (8~.6
o~ ery~hro-1,2-diphenyl~3,~,3-trifluoro~ 4-(2-morpholino-
etho~y)-phen~_7-propane ar~ obtained~ m.p.: 112~115Ca
~aly~
calculated for C27H28~3N02:
C: 71.19 ~, ~: 6.20 %, ~: 12.51 %, ~: 3.08 %;
~ou~d: C: 71.07 %, ~: 6.37 %, ~: 12.71 %, ~: 2.97 %.
A mix~ure of 3.60 g (8 mmoles) of threo~ 2-bromo-
ethoxy)-phen~-1,2-diphen~ 3,3-trifluoro-propana and
20 14 g of morpholine is heated to boili~g, and ~herea~t~r one
proceed~ as described aboveO The resulti~g product is
or;~tallized from he~ane ~o ob~ain 2085 g (78"3 %) o~ threo-
1~2-dlph9nyl-3,3 ,3-~ri:eluoro~ (2-morpholinoethoxy)-
phenyl7-propane; m ~.p.: 88-91C .
h~ly~ls:
aalcul~od :Eo~ a27H28F3N02:
a: 71019 %, H: 6.20 %, F: 12051 %, N: 3~08 %;
found: a: 71.24 ~/1 H: 6.44 %, F: 12.45 %, N: 3.03 ~0.
~he startin~ substenc~s, erythro and threo~ L(2-

bromoe thoxy) -phen~l~r-1 ,2-diphenyl-3, 3,3-trifluoro-propane,

-- 21 --

are prepared a~ follow~
A solution of 456 g ( 1~17 moles) of benzyl-triphenyl-
phospho~iumchloride ~.~ibtig: Chem. Ber. 87~ 1318 (1954~,7
in 1500 ml of dry ethanol is add~d to a solutio~ of 27 g
(1.17 g.~atom~) of sodium i~. 500 ml of dry etha~ol at 0-~C.
~he re~ulting mixture i~ combined wibh 3 ~olution OI 204 g
(1.17 moles) oî 2,2 ,2-tri~luoroacstophenon~ in 100 ml o~ dry
ethanol 7 and the mixbura is allowed to ~and ovarnight~. ~he
~olutio~ i~ svapora~ad, the re~idue i~ admixed with 800 ml
of petroleum ethar, filtered, and the îilter cake iY wa~hed.
~he Iiltr~be is evaporated~ and bhe residue i~ di3billed i~
D rc7p~
~, V'8CUO. 268 g (92.5 %) of 1,2-diphallyl-3,3,3-tri~luoro~
are obtained; bop~ 107-109C/0.2 mm Hg9 m.p.: 58-61Co
Analy~is: .
calculated ~or C15HllF3:
C: 72.57 %, H: 4.47 ~0, F: 22.96 %7
found: C: 72.49 %~ H: 4.23 ~0, ~: 23.20 %.
268 g ( 1.08 mole ~) o~ tha above producb are ~ydro-
genated at 20C for 6-8 hour~ in 4000 ml of acetic acid, i~
the pre~ence of 20 g of a lO~o palladium-on-carbo~ cataly~
The ~olution i~ evaporatad and the residue i~ distilled in
v~cuoO 252 g (93.3 %) of 1,2-diphanyl-3,3,3-briPluoro-propana
- are ob~ained; b.,p.: 94--96C/0.1 mm Hg, nD = 1.5100.
Analy~ ls:
¢~lcul~ted Por C15H13~3s
C: 71.98 %, ~I: 5.26 %, ~: 22.75 %;
Pound: a: 72.12 %, H: 5,L~. %~ F: 22.50 %0
5 g (0.02 moles) of benzo~l peroxide are added to
a solution of' 250 g (1 mole) of the sbove produc~ in 2500 ~il
o~ carbon betrachlorid~, and then a solution of 176 g (1.1

3S~
_ 22 -

mole~) oP bromi~e in 500 ml of carbo~ ~etrachloride i~ add~d
to ths mi~ture at 50C within 30 mi~utes~ The re3ulti~g mi~-
ture i~ boiled Yor 2 hours9 then cooled, washed with ~odium
thio~ul~ate solution, sodium hydrocarbonata solution and
then with water, dried and evapora~edO ~he residus i~
crystallized ~rom 1260 ml oP ethanol to obtai~ 140 g ~42.6 %~
o~ erythro-1-bromo-1~2-diphsnyl-3,3,3-trifluoro propane;
m.p.: 1~64-165OC
An~ly~
calcula~ed ~or al5H12Br~3:
C: 54.73 %~ ~: 3767 ~09 ~r: 24~28 %9F~ 17,32 %~
fou~d: C: 54.97 %, ~: 3.93 %~ Br: 230~8 ~17.36 %.
~he mother liquor is evaporated to about o~e~third
of its origin~l volume~ 130 g (3905 %) of ~hreo-1-bromo-1,2-
diphenyl-3,3~3-tri~luoro propane separate; m.p.: 91 94C.
Analysis:
calculated ~or C15H12Br~3:
a: 54.73 Y0, H: 3.67 ~09 Br: 24.28 %, F: 17.32 %;
îo~d: C: 54.86 %, H: 3082 %, BI~: 24.01 %, ~: 17.27 %.
~he N~R spectra of the compou~ds confirm th~
assigned ~tructure~.
270 g (0.82 moles) oî an erythro thr~o i~omeric
mixbure obbained as described ~bove flre dissolv~d :Ln 2500 oiL
of anisole, 110 g (0.83 moles) oP anhydrous alumi~ium trl-
~5 ohloride are addod to the stirred solution at 6C~ a~d the
mixture ~s allowed to 3tand ab room temperature over~lghb.
~'he reaction mixture is poured onto a mixture of 4 kg of
crushed ice and 600 ml of 36~o aqueous hydrochloric acid a~d
extractod with 3 litres of chloroform. The organic solutio~
is wash~d with aqu~ous sodium hydrocarbonate solution and


-- 23 --
~h~n with water, d:riad and evaporaked. The dry rs~idue i~
cry~tsllized ~rom 750 ml of isoprop~nol, and the rq~ulti~g
crude product (~62 g3 55 ~o~, m.p.: 121-126C3 is cr~tallized
~g~in ïrom 1500 ml of i80prOpa~101. 109 g (37 ~0) oî bhreo
1,2-diphsn~1-3,3,3-brifluoro-1~ methoxyphe~yl)-propane are
obtained; m.p.: 129-131C.
A~ si ~:
calculated ~or C22H19F30:
C: 74~14 ~, H: 5.37 %, F: 16~00 æ;
~ou~d: C: 74.08 %, ~ 5.47 %9 F: 15.75 %
Spqotr~l daba: ~ CH 35~ 30259 2995, 2950, 2925
2900, 2830
~C=C 1~05~ 1580, 150~
~ Ar 8Q~ ~ 7~6, 758, 702
~CH(Ar)2 ~ 4-60 (d) a L~
8CH(GF3) - 4-23 (m)~ lH
~O~H3 = 3~60 ~), lH
~Ar = 6.7-703 ~m), 14H
~hc ~obher liquor obtained in the fir~t cry~talliza~
20 tion ~ep i3 evaporated bo dryne~s, the residue i~ admixad
wibh 300 ml oP hexane and ~ilbered. 'rhe.re~ulbi~@s crude
l~roduct ~96 g, 27 S~o, m.p.: 89-101C) is cry~balïi~d a~;ain
from 9~0 ml oî i~opropanol ~o obtai~ 4-1.4 g (14 %) o~ erg~ro-
1,2 diph~yl-3,3,3-triPluoro~ matho~yph~ prop~no~
m.p. s 108-111C.
A~aly~is:
¢alculabed.~Or a22Hl9~l3o:
a: 74014 a/O~ H: 5.37 %1 F: 16.00 %;
fou~d: C: 74"23 %9 H: 5 ,18 //a~ F: 16.17 %.

l793~9
~p~ctral d~ta: ~)C:~[ 399 3060, 3025~ 3010, 2960
29L~0, 2915, 28L~O
')C=C 1658, ~612 9 1590, 1513 7 ~500
t Ar 808 9 790, 762, 708, 702
CH ( Ar) 2
CH~C1?3) = 4-23 (m) ~ 1~
~OCH3 - ~ .60 ( 8~, 3H
C Ar - 6 44-~7 " 6 ( m), l~H
100 g (0~,28 mOle9) of t~reo-1,2~-diph~nyl-3"3 j3-~ri-
10 ~luoro~ m~ho~yphe~ propana are heated with ~00 g o~
pyridina h~drochloride for 3 hour~ at ~!00-220~Co ~he mixtur0
i~ cooledl, diluted with 700 ~nl of chloroîorm, w~shed with
w~ter ur~til n~utral, dried and evaporat~d4 ~he rs~idue i3
cry~tallized ~rom a 1:2 mi~ture of Ghloroform a~d hexane to
obt~in 85.7 g (90 %) o~ bhreo~ ?-diphenyl-3?3~3-tri~luoro-
hydroxyphenyl)-propane; m.p.: 1?3- 125C.
Ana l;y ~
calculatsd ~or C2~ ?P30:
G: 73~67 ~o~ H: 5.01 ~0, F: 16.65 ~;
found: a: 73.56 %, H: 4.92 ~0, F: 16.?8 ~,~0~
40 g (0.11 mole 8) o~ erythro-1,2-diphenyl-3,3,3~tri;
Pluoro~ mothoxyphenyl)-propane are reac~ed with 120 g
o~ pyxidi~e hydrochloride ~8 d~cribed aboveO ~he ra,sul~ing
erythxo-1,2-diphenyl-3,3,3-~rifluoro~ 4-hydroxyph~Dyl)w
~5 prop~ne i~ ory~talliz~d ~rom a 1:2 mixtur~ oP chloro~orm and
hex~ne to obt~n 32~,5 g ( 84, 5 ~0) o~ the product; m.p.s 114-117C,,.
A~ lya~ 5:
calculated ~or C211I17~;3:
C: 73.67 ~0, H: 5.01 %, E`: 16.65 %;
~ou~d: C: 73.52 'Y0, H: 4.97 %, ~`: 16.71 ,0.
~ a~l~

59
- ~5 --
A mixture of 85.6 g (0.25 mole~) o~ thr~o-1,2-di-
ph~nyl-3,3,3-trifluoro-1-(4-hydro~yphenyl)-propane, 400 ml
of 1,2-dibromoethane and 18.5 g (0.33 mole~) o~ powdered
potas~ium hydroxid~ is boiled undar ~tirring. ~he reac~io~
mixture is dilut~d with 1.5 litres of dichloromethane9
washed with 10% aqueou~ hydrochloric acid and wabar, dried,
and the solvent and the excess o~ 1,2-dibromoethane are
di~tilled off i~ vacuo. The re~idue i~ crystallized ~rom
be~zene to obbain 97.7 g (87 %) OI bhreo-l-L4~ bromoeth
oxy)-pheny ~ -1,2-diph0nyl-3,3~3-trifluoro-propana; m.p.:
144 lsla.
Analysi3:
calculabed îor c23~I20Br~l3,o:
C: 61.48 %9 H: 4049 %, Br: 17.,78 %, ~: lZ.68 ~0;
15found: C: 61.55 u~O, ~: 4.57 %, Br: 17063 %, ~: 12~71 %0
30 g (8706 mmoles) o~ er~hro-1~2-diph~yl-~3~3-tri-
~luoro-1-(4-hydroxyphenyl)~propan~ are reacted wlth 1,2-dl-
bromoethane a~ described above. Th~ resulting ~rythro-l-
~(2-bromoethQxy)-phe~y~-1 92-diphenyl-3 ,3,3-tri~luoro- -
propane is crysballlz~d from benzene bo obtai~ 2709 g (71 %)
of ~hG product; m.p.: 130-133C.
~na l~
calculabcd for C23~20Br~30:
C: 61.48 %, ~I: 4~49 %, ~r: 17078 %, F: 12.68 %;
~5 ~ou~d: C: 61.60 %1 H~ 4~63 %, Br: 17060 %, ~: 12.77 %l
~a~ .
Prepar~tion o~ threo~ di~h~nlh=~ L~L____-

A mix~ure of 6074 g (15 mmoles) of threo-1-/4-~2-
bromoethox~)~ph~nyl7-1,2~dipheny1-3,3,3-tri~luoxo-propane,

35~3
- 26 --

prepared as da~cribed in ~`xample 19 9015 g ( 150 mmole~ o~
2-aminoethanol and 15 ml o:~ 2 m~ thoxyebhanol i~ boiled for
005 hour~. The reac~ion mixbure i5 coolad9 dilutad wi~h
,200 ml of chloroform) wa~hsd wibh water, dri~d and evapora~ed~
5 The residua i9 cry~tallized from a 1:1 mixture o~ b~nzena
and hexane to obtairl ~.32 g (67 %~ o~ khe aimed compoundg,
m.p.: 120-122C.
Ana lysis;
c~l c ula t ed î or C25H26~ ~;N2
10C: 69.go %, H: 6.10 ~ F: 1~.27 ç~0, N: 3.26 %;
found: C: 69.71 Yo9 H: 6015 ~13.17 %~ N: 3035 %0
~2a~
~ ~ ~ri~luoro-

~~ ~
~ ~
8.98 g (20 mmoles) of erybh~o 1~ 2-bromos~hoxy)-
pheny ~-1,2-diphen~1-3, ~,3-tri~luoro-propa~e, prepaxed a~
described in :Example 1, are dis~olved in 42 g (400 mmoles)
of diethanolamin~, a~d ~he so~ution 19 hea~d at lOV-120C
20 ~or 0.5 hour~0 ~he reacbion mixture is proces~sd a~
de~¢ribed i~ ~xample 2, alld bhe re~idue i~ cry~tallized :erom
a 1:2 mixtur~ oï ~n i~opropanol ~olu~ion o~ hydrochloric
aoid and ~bh~r. 5~,98 g (58~7 %) oî bho almed compou~d ara
obbained; map.: l90-1g5c~
25An~ly~is i
c~c~llated ~~ a27H31Cl?3N~S ,
C: 63.59 %, ~: 6013 %, Ols 6.95 %, F: 11.18 %,
N: 2~75 %;
~ou~d: C: 63,~1 4~o~ H: 6029 ~%~ Cl: 7008 %, F: 10.98 %;
N: 2"80~.

9~3
- 27 -



Ex~ e 4
_
Preparation of erythro-L,2-diphenyL-393,3-
~trifLuoro-l-C4-(2-/bi~;(2-chloroethyL)-
-amino/-ethoxy)-phenyl~-propane hydxo-
_ ~ _ _ _ _
~ chLoride
_
A mixture of 2.o4 ~ (4 ~moLes) o~ cxythro-
-L,2-diphenyl-3,3,3-trifLuoro-L-~4-(2-/bis(2-hydroxy-
ethyl)-amLno/-ethoxy)-phenyL~-propane-hydr-ochloxide,
prepared as described in Example 3, 10 ml of chloro~
L0 form and 3 ml (40 mmoLes) o~ thionyL chloride 1s boiLed
for 2 ho~lrs. The e~ce~s of thionyL chloride is e~ap-
orated in ~aouo, and the residue 1s cxy~talli~ed from
a L:2 mixture of methanol and ether~ l.16 g (~3 ~0)
o~ th~ aimed compound are obtained; m p.: L40-l43 C.
L~ AnaLys i9:
calculated~for C27~I29c L3F3N
C: 59 30%~ 34%, Cl: L9.4~%, F: Lo.42%, N: 2.~6~o;
found: C ~9~ L6%~ 3%, Cl 19 32%~ F: 10. 60%~ N: 2 . 62%.




PreparatLon o~ ex~thx-o~l
. ~
-phenyL~-'1,2-clLphony'L-3,3,3-trl~luoro~pxop _
A solutlon o~ 3.2S ~ (~0 t;mloles) o~ sodium

a~lde Ln Ll InL of water 1~ addecl to a ~oLution of '1l.2

2S (2.S mtnole~) o:~ erythro-'L~ ~(2-bromoethoxy)~phenyL~-1,2-
-dLphenyl-3,3,3-tri~Luox-o-pxopane, prepared as descrL~ed

Ln Examp'1e L~ Ln l'L2 ml of 2-methoxyetb.atloL, and the

33S~


mixture is boil.ecl ~'or one hour. The reaction mi~ture
ls e~aporated to dryness, 30 ml of toluene is added
to the residue, and the rrlixture is evaporated again
to remove the Last traces of 2-metho~ethanoL The
soLid resjdue is triturated w-lth ~ate-, fiLtered of~
and washed with ~ater, The crude product is recrys-
taLLi~Ged twice from ethanoL. 7~83 g (76 %) of the
aimed compound are o'btained; m. pO 144-L48 C
AnaLysis:
L0 calcuLated for C23~2oF3N30
C: 67~L4%~ H: 4.90'~, F: L3.8~ %~ N: L0.21 %;
~'ound: C 67.3~o~ H ~ %? F: 13.94 %, N: Lo.o6 %.




L~ ~
-phor~l]-1~2-dLpllenyL-3,3L3-____Luoro-propane
~.L~ g (12.~ mtnoLe~) o.~ erythro-L-C4-~2-
-a~ldoetho~y)-phenylJ 1,2-diphenyl-3,3,3-trifluoro-
-propane, prepared as described :Ln 'E~a~pLe ~, are
hydrogenated ~`o.r cLbout one hou.r in a rrli.xture of L00 ml
of rnethlnol and l~o ml o:~ te~.r~ahyclrofuran, ln the pre-
sono~ o~ 0, 6 ~ of a ~~0 pa'llad~ n-on-ca~ibon oatal~t~
The solutlon L9 e~aporated and tho re~Lclu-3 is oryq
taL'LLæed :~.rom hoxane. 3 86 ~ (80.2 ~0) o:~ the desirecl
2~ oompouncl ax-e o'btal.ned; m.p~: L2~-L27 C.

~:~'7~3~
- 29 _



Analysis:
calculated for C23H22F3NO:
C: 7L 67 ~0, E: ~ 7~ %, F: 14~80 ~0, N: 3 63 %;
found: C: 7L.87 %, H: ~.7L ~0, F: L4.80 ~0, N: 3.~4 ~0.



Example 7
_eparation of _ -L-~4-(2-~zidoethoxy)-
-phenyl~-L,2-diph0nyL-3,3,3-trifLuoro--
-propene
._ _
LO 9.83 g (22 mmoLes) of ~E)-L-C4-~2-bromoethoxy~
phenyL~-L,2-diphenyL-3,3,3-tri~Luoro-propene are dis-
soLved in 100 ml of 2~ethoxyethanoL, a soLution of
2D86 g ~44 mmoLes) of sodium azide in LQ ml of water
i9 added, and the mixture is boiled for one hour~ The
L~ reaction mixture i~ processed as described in Example
~, and the product i~ recrystaLLized twice from
ethanoL. 7 40 g (82 ~o) of the aimed compound a~e
obtained, rn.p : 73 -7~ C.
AnaLysis:
0 caLouLated for a23El8F3N30:
a 67 47 %~ ~: 4 43 ~%, F: L3.92 ~u, 'N: 10~27 %
~ound: a 67,61 %, :EI: L~ %, F: L3.77 ~o~ N: LO.LL %
The startLng ~ub3tance, ('E)~ 4-(2-bromo-

ethoxy)-p~enyl~-L,2-d-LphenyL-3,3,3-tri~'luoro-p.ropene,~ l~ prepared a9 fol'lows:


4~ 4 g (0.2 moLes) of 2,3-dichLoro-~,6-di-
cyano-1,4-'benzoql1Lnone CD. 'WaLl~r et alA: ~. Org Chem.


1 ~';'~3S~
- 30 -



30, 3240 (L96~)~ axe added to a soLution of 44 7 g
(0~1 moles) of threo-1-~4-(2-bromoethox~)-phenyl~-1,2-
-diphenyl-3,3,3~trifluoro-propane, pxepared as descxibed
in ExampLe L, in 22~ mL of dxy benzene~ and the mix-
ture is cooLed and the separated 2,3-dichloro-~6-
-dicyano-1,4-hydr-oquinone are fiLtexed off~. The fil-
txate is evaporated to dryness, the residue is ad-
mixed with 100 ml of chloroform, and the separated
2,3-d:Lchloro-~,6-dicyano-1~4~benzoquinone i9 fi~tered
L0 o~f Tho filtrate is diLuted with 400 ml of chloro-
fo~m, ~ashed with a L0 % aqueous sodium hydrocarbon-
ate solution and then w.ith water, dried and e~apor-
ated. The residue is crystaLLiæed from 220 mL of
ethanol to obtain 34 4 ~ (77 %) of a crude product
L~ melting at lL0-lL8 C This crude product, which is
a 4:1 mi~ture of the E and Z isomers, is rocrystaLliæe~
from 200 ~1 of ethanol~ 29.~ g (66 %) of the E isomer
are obtained; m, p,: 118-120 C
AnaLysis:
oa'lcuLatecl *or C23H~8BrF30:
C: 61.67 %~ H: 4~o6 %7 BX': 'L7,87 %~ F: L2 74 %;
Founcl: ~: 61,80 %, El: 4~L~ %~ Br: 17.~9 (70, F: 12~90 %.
Spoot.ra'L data: ~C~I 3060, 3020~ 2920~ 2900, 28~0

~C=a 1~90~ 'L49
2~ ~r 81~, 822, 7~8, 70


~OCH2 = 4 08 (t)y 2H
dBXa~I2= 3.46 (t)s 2H


Ar - 6 4-7 4 ~m), L4H

35~

3L -



The mother liquor obtained abo~e is evap-
orated, and th0 residue is recrystaLlized se~eraL
times from ethanoL, 2,L4 g (4,8 ~) of (Z)-L-~4-(2-
-bromoethoxy)-phenyL~-L,2-diphenyl-3,3~3-trifLuoro-
-propene are obtained; m.p.: L3~-'138 C,
SpectraL data: ~CII 3080~ 3060, 303~, 293~ 2870


~C C L6Lo, L5L0
~Al~ 832~ 770, 760, 7L~
~OCH2 4,28 (t), 2H
~BrC~I2 = 3~9 (t), 2H
3Ar = 6,8-7~4 (tn), 14H

~e~ ~
Preparation of (E)~ 4-(2-aminoetho~y)-

L~ _phenyl~-1,2-cliphen~L-3,3,3-trifluoro-
-propene
7~40 g (18 mmoLes) of (E)-L-~4-(2-azido-
ethoxy)-phenyl~-L,2-cdiphenyL-3,3,3-trifLuoro-propane,
preparod ~ d~sori'bed in Examp1e 7~ are cllssolvod in
'L00 ml o~ mothano'L, 0,70 g o~ a ~% pa'Llacliulll-or1-oar'bon
oata'lyst are adcl~cl, ,ancl the tllixture Ls hydrogenatecd
~or about one hour, Tho oataL~st is fiLterecl off, the
soLut,Lon 1~ e~aporated, and the resicl1le L~ or~staLLLzed
from hexane~ 3,63 g (~2,3 %) o~ the aimed compound are
2~ obtalned; m,p~: 7L -76 C,

3~
- 32 -



Analysis:
calcuLated ~or C23H20F3N0:
C: 72 0~ %, E: ~26 %, F: L4 87 %, N: 3.6~ ~;
found: C; 72.36 ~0, ~: ~.30 %, F: 14.88 %, N: 3.~2 ~/0.



ExampLe 9
_
Preparation of (E)-1,2-diphonyL-3,3,3-tri-

~luoro-L-C4-(2-morpholinoethoxy)-phenyL~-
-prop0ne
A mixture of 3.34 g (7 ~ mmoles) of (E)-
-L-[4-(2-bromoethoxy)-phenyLJ-L,2-diphenyl-3,3,3-
-tri~luoro-propene, p.repared as described in ExampLe 7,
and L3 ~ of morp~oline is boiled for one hour The
reaction mixture is proce~sed as described in ExampLe
1~ 1, and the crude product is cr~staLlized from hexane.
2 80 g (82 4 %) of the aimed compound are obtained;
m.p. 84-89 C.
AnaLysis:
oalculated for C27E26F3N02:
C: 71 ~L %, :E.[: ~ 78 %, F: 12.~7 %1 N: 3~09 ~0;
founcl: C: 71.80 %~ :EI: ~.98 'lo~ F: 12.70 %, N: 3.28 ~0.



~X~

-




PreparatLon of (E)-1,2-dlphen~1-3,3~3-trl-
. . , . _ _
2~ :~L~oro-L C4-(2 /4-.lTIethylpLperazlno/-ethox~)-



L~;o g of :N~meth~lpiperaæine are added to a



: '.

-- 33 --



sol~tion of 4.47 g (lO mmoLes) of (E)-L-~4-(2-bromo-
ethoxy)-phenyL]-L,2-dlphenrL-3,3,3-trifLuoro-propene,
prepared as described in ExampLe 7, in 80 mL of dry
ethanoL, and -the mixture is boiLed for 6 hours, The
5 reaction mixture is evaporated to dryness, and then
one proceeds as described in ExampLe L. The product
is crystaLLlzed from hexane, 3,45 g (7~ %) oP the
aimed compound are obtained; m.p.: 94-97 C,
AnaLysis:
10 calcuLated Por C28H29F3N 0:
C: 72,08 yO, EI: 6.27 %, F: L2.22 ~0, N: 6,oo a~O;
found: C: 72.27 %, H: 6,32 %, F: L2,28 ~0, N: 5,77 %.



ExampLe lL
L~ Preparation of (E)-L72-diphenyL-3,3?3-



-piperazino/-ethoxy)-phenyL~-propene
1~ mixture of L,79 ~ (4 mmoles) of (E)-l-
-~4-(2-bromoethoxy)-phenyl~-L72-diphenyL-3,3,3-tri
20 Pluoro-propene, preparecl as de~cribed in ExampLe 7,
and Lo.4 ~ of L~(2-hrdroxyHthy'1)-plpera~slt~e ;ls heated
for ol~o hour. Th(3 mixture L~ proce~secl EIS deqcribed
ln Example 'I, and the product i4 crystclllLæed Prom
hexlne~ l.3~ (68 %) of the al~ned compour~cl ar~e ob-

2~ taLned; rn~p,: 79-8L C.



i.~

7~33S9
3~

AnaLysis:
calcuLated for C29H3LF3N202:
C: 70.L~ %, H: 6.29 %, F: 11,48 %, N: ~,6Lf %;
found: C: 70.L~ %, H: ~.6~ ~0, F: LL,36 %, N: ~,48 %.



ExampLe L2
Preparation of (E)-L,2 diphenyl-3,3,3-tr~i~
fLuoro~ 4-(2-/2-hydroxyethylamino/-ethoxy)-

6,71 g (1~ mmoles) of (E)-L-C4-(2-bromo-
etho~y)-phenyL~-1,2-diphonyl-393,3-trifluoro-propene,
prepared as described in E:~ampLe 7, are dls~oL~ed in a
mixture of ).1~ g of 2-amino-athanol and 1~ ml of
2-me-thoxyetharloL. The solution is boiLed ~or 30
1~ minutes~ and then the mixture is process~d as described
in Example 2, The product is crystalliæecl from a l:L
mi~ture o:f e-thyl acetate and hexane, ~29 g (83 %) of
the aimed compound are obtained9 m,p,: 96-98 C,
Analys i9:
20 oaLculated f`or C2~1~I24F3N02:
a: 70.24 %~ ,66 %~ F: 13,33 %~ N: 3~28 ~o;
:found: (~: 70,1~2 %, ~it: ~.80 %, F: L3.39 ~o, N: 3,23 ~o,



Ex:ulp'L~ L3
_.
2~ æh~ 3,3~3-
-tri:~Luoro-L- r 4 f 2-/bLs~2-hydroxye-thyL)-

yl~~propen~



!~;.

3S~
-- 3~ --

A soLution of 7,L~ ~ (L6 mmoLes) of (E)-
-l-C4-(2-bromoethoxy)-phenyl]-1,2-cliphenyL-3,3,3-tri-
fLuoro-propene, prepared as de~cribed in ExampLe 7,
in L6.8 ~ of diethanoLamine is heated at L20-L40 C
for 0.~ hours, and then one proceods as described in
Example 2, The pxoduct is crysta.Llized from a L:l
mixture of ethyl acetate and hexane, ~,66 g (7~ %) of
the desired compound are obtained; m.p~: LL3,5-LL6 C~
Analysis:
L0 caLcuLated for C27H28F3N03:
C: 68.78 ~0, H: ~,~9 %, F: L2,09 %;
found: C; 68,7~ %, H: ~,78 %, F: L2.L3 ~.



.ExampLe L4
L~
fLuoro-L-C4-(2-/bis (2-chLoroethyL)-amino/-
-ethoxy)-pheny'L~-propene
3,6 mL (~0 mmoLes) of thionyl chloride are
added to a solutlon of 2,36 g (~ mmoles) of (E)-1,2-
-diphen-yL-3,3,3-trLfluoro-l-C4-(2-/bis~2-hydro~yethyL)-
-am:Lno/-ethoxy)-pheny'l~ properle, prepared as desorLbed
lt.~ E~alrlp'le 13, ln 12 mL o~ ohLox~ofo~sl, anq the mL~ture
1~ boLled for 2 hour~.. The exoess of thLonyl chLoride

ls e~aporated Ln vaouo 7 and the req-Ldue is crystaLLized
2~ :~.r~om hexane. L,90 g (74~7 %) of the desi.red oompound
are obtained; m,p~ 74-76 ~,



"

63~S~
- 36 -



AnaLysis:
caLcuLated for C27H2~C12F3NO:
C: 63~.79%, H: ~,L~%, CL: L3,9~%, F: LL,2L~oJ N: 2,7~o;
found: C: 64,o3%, H: ~.03~0, CL: 14.00~o~ F 10.93%, N: 2,7~olo,




Preparation of L-C4-(2-az-idoethoxy)-phenyL~-
-L-phenyl-3,3,3-trifLuoro-2-(4-fLuorophenyL)-
_ opene
lL.63 g (2~ mmoles) of L-~4-(2-bromoethoxy~-
-phenyl~-L-phenyL-3 t 3,3-trifluoro-2-( 4-f luorophenyl)-
-propene are con~erted in-to the a~ido deri~ati~e as
describ~d in E~ample ~. The product is cryqtaLL-.ized
~roln ethanoL -to obtain 8,~4 g (80 %) of the aimed com-
L~ pound; m.p,: 62-64 C.
AnaLysis:
caLculated for C23HL~F4N3:
~ : 64.63 %, H: 4,oL %, F: L7,78 %, N: 9.83 %;
found: C: 64,71 %~ H: 4.13 ~ F: L7..74 %, N: 9.63 %,
2() L-C4-(2-Bromoethox-y)-pherlyL~-:L-pheny:L-3,3,3-
-tx~l~'Luoro-2-(4-~'Luorophenyl)-propene, appLLecl a~
~tlrtln~5 gub9tanoe~ i3 preparod by the method of
Examp'les '1 and 7 as ~oLLow~:
L~ ~-Fl~lo.ro-2, 2, 2-trlfLuoroacetophQnone ~F,E.
2~ Elerkes et aL.: J, O.rg, Chelll, 32~ L31L-18 (1967)~ is

reaoted with benzyl-triphenyL-phosphoniuln ohloride in
the presence o~ arl ethanol soLution of ~odium ethoxide,
L-PhenyL-3,3,3-tri~luor~o-2-(4-fLuorophen~L)-propene is
~1 ` !

~ ~7~33~9

- 37 -



obtained with a yield of 9L %; b.p~ L10-LL4 C/0.2 mm H~,
m.p,: 43-4~ C.
Analysis:
caLcuLated for CL~HloF4:
C: 67J67 %, E: 3.79 %, F: 28,~4 %;
found: C: 67~83 %, H: 3.90 %, F: 28.33 ~0.
This compound is h~drogenated in the pre-
sence of a paLladium-on-oarbon cataL~st to obtain L-
-phenyL-3,3,3-trifLuoro-2-(4-fLuorophenyl)-propane
L0 with a yieLd of' 9L.7 %; b~p~: 100-L04 C/0.2 mm H~;
nD = 1~4980A
Analysis:
calculated fo~ Cl~H12~4
0: 67.16 %, H: 4.~L %, F: 28.33 %;
1~ found: C: 67.30 %, ~: 4.68 ~0, F: 28.L8 %.
The above product is brominated in caxbon
tetraohlor-Lde, and the brominated compound Ls crys-tal-
Lized from ethanoL, l-Bromo-l-phenyl-3,3,3-trif`Luoro-
-2-(4-fluorophenyL)-propene i~ obtained wlth a ~ieLd

f` 48.2 %; m,p,: L44-146 C,
~ naLy~Ls:
oa'lou'lat~d ~or a ~ BrFI:

~ : ~1.90 %~ FL: 3.19 %~ Br: 23.02 %, F: 21.89 ~0;
~o~mcl: a: ~L.70 ~, ~: 3JL8 %~ Br: 23,0(; ~0, F: 22.03 %.
2~ The br~omlnated compound is reaoted wLth anl301e


ln the pre3ence of aLumLnium trlohloride. The resu'Ltln~
'L-phenyl-3~3~3-trLfLuc)ro-2-(4-fLuorophenyl)-l-(4-methox-sr

1~7~35~
- 38 -



phenyl)-propane (mixture of isomers) is crystaLLized
from isopropanoL Yield: 79.8 /0, m. p.: 1~2-167 C~
Analysis-
caLcuLated for C22HL8F40:
C: 70~8 ~0, H: 4.8~ ~0, F: 20.30 %;
found: C: 70.80 %, E: 4.78 alO, F: 20.40 %.
The above compound is heated with p~ridine
hydrochloride, and the resulting l-phenyl-3,3,3-tri-
Pluoro-2-(4-fluorophenyl)~ 4-h~droxyphe~yL)-prOpane
is reacted directly, without puri~ication, with L,2-
-dibromoethane in the presence oP potassi~m hydroxide
under heating. The resulting L-~4-~-bromoethoxy)-
-phanyL~-L-phenyL-3,3,3-trifluoro-2-(4-fluorophenyl)-
propane is crystaLLi~ed .~rom isopropanoL; L~ to 20 ml
1~ of isopropanol are applied Por 1 g of the crude product.
The Pirst Praction, which is a mixture oP isomers, melts
at 'L70-175 C.
Analysis:
caLculated ~or C23HLgBrF40:
a: ~9.LL %, H: 4.Lo %, Br: 17 10 %~ F: L6 26 ~0;
-~ound: C: ~8.88 alO~ .a: 4.21 %, Br: 16 96 %, F: L6.~o %0.
The mother lLquor is evapo.rated to clryness~

and tho solld Ls reorystaLlLzed Prom benzene ~ Inl oP

'ben~ene are appLied for 1 g oP the solid. The result-

2~ in~ qecond Praotion, whioh Ls a mixture of Lsomers,
me'l-ts at 100-110 C.


. ~




.

7~3
-- 39 --

Analysis:
calcuLated for C23HlgBrF40
C: ~9~LL ~0, II: 4.Lo %, Br: L7.L0 %, F: L6026 ~0;
found: C: ~8.96 %, H 4.07 %9 Br- L7.0~ %, F: L6~32 %.
The abo~e two fractions are combined and
hoiled with 2,3-dichlo~o-~,6 dicyano-L,4-benzoquinone
for 2~ hours as described in ExampLe 7~ The product
is crrystaLLized from ethanoL. l-C4-(2-Bromoethoxy)-
-phen-yL~-l-phenyl-3~3~3-t~ifLuoro-2 (4-fLuorophenyl)-
L0 -pxopene is obtained with a yieLd of 66.~ %; m.p.:
Ll~-lL8 C.
AnaLysis:
caLcuLated for C23~IL7BrrF40
C: ~9.37 %, H: 3J68 %, Br: L7.L7 %, F: L6,33 ~0;
L~ found: C ~9.48 %, H: 3.87 %, Br: L7.L9 %, F: L6.~L %.



E ~
Prepar~ation of L-C4-(2-aminoethoxy)-phenyL~-

-L-phenyL-3,3,3-tri~'luoro-2-(4-fLuorophenyL)=

-prope~e
~ soLutlt~n of 8.~l~ B (20 nmlo'Los) o* L-~
-(2-azlcloetho~ phonyL ¦-L-pheny'L-3~3~3-tri:l~luoro-2-(L~-
-fLuorophenyL)-propent-~9 prepart-~cl a~ desorLbed in Example
L~, Ln 170 ml o* methano'L i~ hydro~enated ~or a`bout one
2~ hour in the preserloe of 0.9 g o* a ~ % palladi~ orl-
-oarhorl oatalyst~ The solution is e~aporatecl and the
product L3 orys~aLLiæed ~rom hexane. 4~51 g (~6~4 %)

.~

~:~'7~
39a -

of the title compound are obtainecl; m.p,: 83-89 C.
Ana ly9 is:
calculated for C23HLgF4N0:
C: 68.82 %, H: 4.77 ~0, F: L8.93 %, N: 3.49 %;
found: C: 68.93 ~0, H: 4.g9 %, F: L8.83 ~, N: 3.33 %.

~1~ .
Preparation o~ L~phenyl-3,3,3-tri~L-uoro-2-
-(4-fLuorophenyL)-L ~4-(2-morpholinoethoxy)-
L0 -phenyL~-propene
3.2~ g (7 mmoles) of 1-[4-(2-br~moethoxy)-
-phenyl~-L-phenyl-3,3,3-trifLuoro-2-(4-fluorophenyl)-
-propene~ prepared as described in Example 1~, are
reacted ~ith morphoLine as described in Example 1.
L5 The product i9 crystaLli~ed frotn hexane~ 2.~ ~ (75~7 ~0)
of th~ aimcd compound are obtained; m~p~: 67-69 C.
Analysis:
calculated for C27E2~F4N02:
C: 68~78 %, H: ~3~ %, F: L6~L2 %, N: 2,97 ~0;
~ound: C: 68.62 %, EI: ~.94 %, F: L6.40 %, N: 3.L4 %~

'~.~
Prcparatlon o~ 2-phenyL-3,3,3-trL~lu~ro-
-L-(4-~LuorophenyL)-l-C4-(2-tnorphoLlnoethoxy)-
2~ -phe~yl]-propene
..,_
3.2~ g (7 mmoLe3) of L-C4-(2-bl~omoethoxy)-
-phenyL ¦-2-phenyl.-3,3,3-trifLI:loro-L-(4-:ELuorophenyl)-
i,~;'

~7~35~

- 39b -



-propene are reacted with morphoLine as descxibed
in Example L The product is crystallized from hexane.
3.03 g (92 %) of the aimed compound are obtained;
m~p : 9~-96 C.
AnaLrsis:
caLcuLated for C27~I2~F4N02
C: 68.78 %, H: ~3~ a~o~ F: 16.L2 ~0, N: 2~97 %;
found: C: 68,96 %~ H: ~ 83 alO~ F: L~.98 alO~ N: 3~00 %.
L-C4-(2-Bromoethoxr)-phenyL~-2-phenrL-3, 3 ~ 3-

-trifluoro-1-(4-fluoxophenrl)-propene, applLed as
startin~ substance~ is prepared accordin~ to the
method of E~ample 1 as foLLows:
2~2~2-1`ri.Eluoroacetophenone is reacted ~ith
-triphenyl-(4-fLuoroben~rl)-phosphonium chLoride CR.A~
1~ Jon0s: Australian J. Chern. 18, 903-6 (196~)~ in ethanol
in the p.res~nce oE sodium ethoxicle. 2-Phenyl-3~3~3-
-trifluoro 1-(4-fLuorophenyL)-propene is obtained
with a yield o~ 90 %; b,p.: 10~-L07 C/0.2 mm Hg,
m~p, 3~-41 C.
~na'l.~sLs:
oa:Lou'lateCl for CL~HL0Fl~:
C~: 67,67 a~O~ :Ll: 3.79 %~ F: 28,~4 %;
:Eou~.d: ~: 67~8 a~O~ ~: 3.9~ %~ F: 28.~0 ~o,
The abo~e procluct Ls h~drog--~natecl ~-Lth a
2~ paLLacl;il:lm-on-carb~n oataLyst to obtain 2-phenyL-3~3~3-
-trLfL-uoro-L-(L~-fLuorophen~L)-p.ropene with a yieLd o:E


9~ %; b~p,: 9~-100 a/o. 3 mm Hg,

,~./.. .'

3S~
-- 39c --



AnaLysis:
calcuLatod for CL,,~EL2F4:
C: 67~L6 %, EI: 4.~L %, F: 28.33 %;
found: C: 67~22 %, H: 4J73 %, F: 28.40 %,
,,~ The obta1ned product is brominated in carbon
tetrachLoride, and the resuLtin~ L-hrorno-2-phen~1-
3~3,3-trif1uoro~ (L~-~luorophenyL) propane is cry-
staLLized from ethanoL. 3.,~ rnL of ethanoL is appLiecl
for one ~ of the soLid. The obtained first fractiorl,
L0 which is a mixture o~ isomers, rneLts at L43-L4~ C.
AnaL~sis:
caLcuLated for CL,~ILlBrFL~:
C: ~L,90 %, H: 3,L9 ~o, Br: 23.02 %, F: 2L~89 ~0;
fol:lnd: C: ~L.9L %, E: 3.L3 %7 Br: 22"92 ~0~ F: 22.o6 %0
L~ The mother Liquor is e~aporated to a'bowt one-
-third of' its originaL ~oLuma, The obtained seconcl frac~
tion, a mixture of -Lsomer~s, meLts at 69-76 C.
AnaL~rsis:
oaLo~lated for CL~E1LBr~F4
20C: ,~'L.90 %~ 'fC: 3.1~) %, Br: 23.02 %~ F: 2L,89 %;
~o~-Lnd: C: ~L.74 %, EC: 3.33 %7 Br: 23108 %7 F: 22.02 j~.
The tota'L rie'Ld amoLlnts to 76 %.
The above fraotLons are oom'binecl ancl reaotecl
hr;Ltt,l arl:LsoLe Ln the presence of a1LLm;LrlLLlrn txich'Loricle,
2~ '[`he restlLt-,Lng 2-pheny'1-3~3~3-trif'luoro-L-(4-:~Luoro-

phenyL) L-(LI-rnethoxyphenyl)-propane is crrstaLLized
frorn ethanoL. 4 mg o~ ethanoL are appLLecl for L g of

35i~
- 39d -

the solid, The ~irst fraction, a mi~ture of isomers~
meLts at L20-L27 C,
Ana Ly9 is:
calcuLated for C22~IL8F40:
C: 70,S8 %, H: 4,8~ %, F: 20,30 %;
fo-und: C: 70,81 %, H: S,OL %, F: 20.3~ %.
The mother liquor is concentrated to about
one-si~th of its originaL ~oL~e, The resuLting second
~raction, a mixture o~ isomers, meLts at 84-9~ C.
AnaL~sis:
calculated for C22HL8F40:
C: 70,~8 %~ H 4,8~ %, F: 20.30 %;
found: C: 70~72 %, H: 4,92 %, F: 20,L8 ~,
The totaL yieLd amounts to 78.8 %,
LS The above fractions (mi~tures of isomers)
are combined and heated with p~ridine hydrochLoride,
The rasuLting crude ~-phen~L-3,3,3-tri~Luoro-1-(4~
-fLuorophenyL)-L-(4-hydroxy-




'`,`"''`~

~7~3

phenyl)-propane i~ reacted directlyg withQut puri~ication~
with 1,2-dibromoethane in the presence of potassium hydro~lde.
~he resulti~g 1- ~ (2-bromoethoxy)-phe~y~-2-phe~yl-393t3-~ri-
~luoro~ fluorophenyl)-propane is cry~allized ~rom etharLol.
5 4 ml of e~ha~ol are applied for 1 g o~ tha ~olid,. ~he ~ir~'G
~r~ction,, a mixture o~ isomers, mel~s at 119-123C~,
~ nal~sis ~
c~lculated for C23HlgBrF40:
C: 59~11 %9 H: 4010 æ, Br: 17010 %, F: 16.26 %;
~ourld: C: 59~30 %, H: 4016 y~, :Br: 17.03 ~9 F: 16.26 5~.
~ he mo~her liquor i~ evaporated to aboll~ one-hal~
o~ its origi~l volume. The obtained second ~rac~ion~ a mi~-
~ure o~ i~omer~, melts at 7~74C.
~ alysi~:
15 calcul~ted for C23HlgBrF~,~:
C: 59.11 %, H: 4.10 %, Br: 17010 %, F: 16,.26 %;
~ou~d: C: 59D27 ~ H~ 4.,30 %~ Br: 17.13 %, F~ 16.3~ ~.
~ he above ~ractions (mixtures of isom~rs) are com-
blned and reacted with 2,3-dichloro-5,6 dicyano-1,4-bsnzo;-
20 quinorLe in be~e~e under bolli~g, as de~cribed in E~ample 7.The reaction ~i~ture is proca~ed as de~cribad in ~ample 79
~d th~ product i~ cry~tallizod ~rom i~opropanol~ (2-
bromoetho~y3~phan~ ~-2 phonyl-3,3,3-briPluoro-1-(4-fluoro-
phenyl)-prop~ne 1~ ob~ained wibh a yi~l~ o~ 58.4 %9 m.p.:
1~2~14~~.
A~ly~is:
c~lcul~ d ~~ a23~17Br~4
c: 59037 ~/o~ H: 3.68 %, Br: 17u17 '~0, F: 16~33 %;
founds ~: 59.20 %, ~: 3.90 Y~" Br: 17.36 %, F: 16.20 %D

.. eJ~, ~

'7~S~


Pr~parabion~o.f~
=~b~3yL=~hlb~= ~ ro~
-39 g ~t~7 g~-atanS) ~ sodium are dis301ved i~
7.12 g (35 mmole~) of 2-dimethylamino~ethanol~ 3015 ~ ~805
mmole~) of 1 pheDyI 3j3,3 brifluoro-].-(4~1uorophe~yl3-2~
me~ho~yphe~ propen~ are added to th.e solution9 and the mix-.
tur~ i8 heated at 150~155C ~or one hour. The rea¢bio~ mixture
i~ cooled, diluted with 200 ml o~ ~bher) wa9hed wibh wa~er
until n~utral, dried and e~aporat~d~, The resi~ue is di~olYed
in 30 ml oî ho:~:a~e3 bhs solution i9 ~iltered~ and bhe filtrate
i3 evaporated. 3039 g (90 70) of l~ dimebhyl~mino-ebhoxy~
phe~ phenyl-3,3,3-tri~luoro-2~ methoxyphe~yl)-propene
ara obb~ d as ~ resinou~ ~ub~bance; bhe produ¢t i~ ~ 3:4
mixture oî bhe (~) and (E3 i~omer~
~naly~
calculaSed for C26H2 ~ 3~0~:
C: 70073 ~0, H: 5.94 %, F: 12091 %, ~: 3017 %;
~o~d~ C: 70~65 %, H: 6.07 %, F: 13.05 %, N: 3.26 %.
l~Pho~yl-3,3,3-triPluoro-1~(4-~luorophe~J.)-2~(L~
methoxyph0nyl)-propa~e~ applied a~ sbarti~g substan~e, i~ prs-
p~red a¢cordinæ ~o the method of ~xampl~ 1 a~ ~ollow~:
4~-Mebhoxy-2~2,2-bri~luoro~cebophenone ~ ~, ~uch~s
J. Or~. Chom. 22~ 99~_99L~ ~195'7L7 i9 rea¢t~d wibh triph0nyl-
25 (4~fluorob~nz~ pho~phonium chloride (~e~ ampl~ :L8) in~abha~ol in th~ pr~nce o~ ~odlum othoxida. 3,3,3-~ri~luoro-
~ luorophenyl)-2-~4-methox~p~en~ prop~n~ i~ ob~flined
wlbh a yl~ld o~ 87 ~0; b~p,: 138-142C/005 mm ~gO
An~ly~
calcLllat~d Por ~16~

~:~'7
- ~2 -

C: 64.86 %~ ~: 4.08 ~0, ~: 25~65 %9
found: C: 65~03 ~0, H: 4.27 %, ~: 25.40 %.
~ho above compound is hydr~ge~ated i~ the prese~ce
o~ a palladium-on-carbo~ cataly~t to obtain 373,3-tri~luoro~
1-(4~1uorophe~yl3-2-~4-m~bhoxyphen~ propa~e wlth a yiald
of 93 ~0; b.p.: 134~136C/0.4 mm Hg, ~ - 1.5070.
A~aly~is:
calculated ~or C16~14F40:
Cs 64.43 %, H: 4073 ~/0, F: 25048 ,~;
found: C: 54~60 %, H: 4085 %, F: 25.~5 %0
~he ~bove compound i~ bromin~bed in carbo~ tatra-
chloride, and th~ producb i~ cry~tallized from h~xane. l-Bromo-
3,3,3~tri~1uoro-1~(4~Pluorophenyl)-2-(4-me~hoxyphe~yl)-propan3
(mixture o~ i~omers) i~ obtain~d with a yiald o~ 49 %;
mOp- 7~-94a.
Anal~si~:
calculatod Por C16Hl~BrF40:
C: 50~95 ~ .L~7 %~ Br: 21.19 Y0, F: 20~15 %;
found: C: 50.82 %, H: 3060 %~ Br: 21.11 %9 F: 20030 ~.
~he ~bove aompound is reacted w~th b~n~ene in ~he
pre~e~ce o~ alumi~ium trichloride~ a~d the re~ul~ing l-ph~nyl-
3,3,3-~bri~luoro-1-(4-Pluorophe~yl)-2~(4-mebhoxyphe~yl)-
propane 1~ cry~tallized Prom i~oprop~olO 5 ml oP isopropanol
are applied Por 1 g of the solid~ ~he Pir~t .~raat~t a
mixture oP i~omers, melt~ ab 126--145C.
Anal~si~:
~lculat~d ~or ~22H18~4
C: 70.58 %, H: 4~85 ~0, F: 20.~0 70;
~ound: C~ 70~77 %, H: 4.67 %~ F: 20.45 ~70.
~h~ mother liquor i~ evaporated to one-Pifth oP it5

3~

original volume. Th~ re~ultin~ s~3cond f`raction~ a mi~ture of
isomer~, m~lts a ~ 102-110C .
Analysis:
calculated for C22~Ilg~40:
C: 70.5~ Yo7 H: 4.85 570~ ~: 20330 %;
îound: C: 70.65 ~07 H: 4080 ~0~ F: 20~51 %.
~ he abov~ two fra ctions are combined and r~aoted
wikh 2,3-dichloro-5,6-dicyano~ benzoqulnona as de~cribed
in Example 7 ~or 120 hours under boili:ng. ~he product i~
10 crg~tallized from i~opropa~olO l-Phe~ ,3,3-triîluoro~
~luorophe~l)~2-(4-methoxyph~ prope~s is obtailled with a
yield o~ 62 %; m.p.: 113-120CD
~n~l~si~:
~alcula~ed for C22~ LO
C: 70c,96 ,~0, fI: 4033 5'0, F: 20041 %~
fou~d: G~ .17 %, H: 4~48 %, F: 20.70 %,,
ample 2Q


0046 g (OrO2 g.-a~oms) o~ sodium are di~olved
405 g ~50 mmoles) of 2-dimethylamino-ethanol,, ~o72 g (10 mmole~
o~ ~phe~1-~,3,~-trifluoro-1-(4-~luoroph~ 4-metho~y-
phonyl)~prope~e are added to ~he ~olubio~, bh~ mlxture ia hoat-
~d a~ 150-155C ~or one hour, and the~ p;roce~ed a~ de~cribed
1~ ~xample 19. 3.95 g ~890~ %) o~ (2 di~th;ylamino-ebh-
ox~ ph~n;y~ pherurl-3, ~93-tri~luoro~1~ metho~rphengl) -
propene ~xe obtai~ed ~ a re~i~ou~ ~u~s~ e; ~ha produc~ i.B
a 9:1 mixSure o~ the (Z) a~d (æ) i~omer90
An~ l~si~:
~0 ¢alculabed ~or C26H26F3N0

3S9


C: 70.73 ~, H: 5094 %, F: 12.91 %, N: ~.17 %;
found: C: 70.50 %, H: 6~11 %~ ~: 12.73 %, N: 2.91 %.
2-Phenyl 3,373-triîluoro-l-(~fluorophenyl~ bh-
o~yphen~ propane, applied as starting sub~tance, i8 preparsd
5 as ~ollows:
2-Phe~ 3,393-tri~luoro 1~ fluorophsnyl)~ meth-
oxyphe~yl)-propane, prepared a~ described in EXample 18, i~
reac~d wi~h 273-dichloro-5~6-dicyano~1,4-benzoquinona under
boiling for 8 hour~ as described in EXample 7. ~he reacbion
mixture i~ proce~sed, and the product i~ crysballizad from
ethanolO 2 Phenyl 3,3, 3-tri~l uoro-l- ( 4-~luorophenyl ) -1~ ( 4~m~ th~
oxyphenyl~-propene ls ob~ained with ~ ~ield of 51 %; m.p.:
52-56C.
~aly~
calculated ~or C22H16F40:
C: 70096 ~0, H: 4.33 ~, F: 20.41 %;
îound: a: 71.22 ~0, H: 4~51 %, F: 20~54 %0
E:~
Prepara ~orl of 1-/~ ( 2-dime thYlamino-e~ho~y]=~Z
20 l-~he~yl 3, 3, 3-~ri~luoro-2~ b;sTdro~h~nyl~-pr~opene h;ydro-
chl
0076 g ~1062 mmoles) of 1~ (2-dimeth~lamlno-etho~
phe~ ph~ 3, ~, 3-triîluoro -2-~r~ ( me thoxy-m3 ~ho:l~y) -phen~
prope~e ~re di~olved in 8 ml of a 1i'o metiha~ollo hydrochloric
25 ac~d. ~h~ ~olubio~ i~ hea~0d for 0c5 hour, ~he~ evapora~ed,
a~d the product i~ cry~t~llized from i~opropanol" 0.56 ~; (7~ %)
o~ thfl aimed compound i9 obtained; m.p~: 196-220C,.
Anal~si3:
calcula ted ~or a2s~25clF3~o2:
C: fi4~7~i~o~ H: 5.~%9 Cl: 7~64%, F: 12.29%,, N: 3.02%;

~'7~359
-- 1~5 --

fou~d: C: 64.51%, H: 5.31%, Cl: 7.4~0, ~: 12.51~ N: 2.~4%~
~ 2- ~athylamino-ethoxy)-pheny ~ -1 phe~yl-3,393-
tri~luoro-2-~,~ ( me thoxy-ms thoxy) -pheny~7-propene, applied
starting substance, is preparsd as follows:
~ mixture of 18072 g (50 mmoles) of l-phanyl~393,3~
tri~luoro-l (4-fluorophenyl)-2~(4-methoxyphenyl)-propa~e5 pre-
pared as described in ~'xample 19, a~d 56 g of pyridine hydro
chlorid~, ls h~ated at 200a for 3 hours, and then processed
as describsd in Exampla 1. ~he resulting crude l~pheDyl- .
3,3,~-tri~luoro-1-(4-fluorophe~yl)-2-(4-hydroxyphenyl)-propa~e
then
i9 dissolv~d in 70 ml o~ benzene,/6.44 g ~80 mm~le~) o~
ch}orom~th~Tlether and 6 g (300 mmoles) oî powd~ered sodium
hydroxide are addsd, and the mixture i~ boiled ~ar one hour~
~he :reaction mixture i8 diluted with 100 ml o~ benzene, washcd
1$ until nsutral with a 20% aqueou~ ammo~ium chloride solution,
dried and aYaporatad~ The rssidue is cry~tallized ~rom iso-
propanol. 12.54 g (62 %) o~ 1-phen~ 3,3-trifluoro-1-(4-
~luorophe~yl)-2- ~ (methoxy-methoxy)-phen~ ~ -propa~e are ob-
tained; m.p.: 96.5-99C~
Analg~is:
calculated for C23H20FLI.02
C: 68.31 %, ~,.99 %, ~: 18.79 ~0; .
~ou~d: C: 68.45 %, EI:5.07 %, ~: 18.73 %.
12~13 ~ (30 mmole~3 of the abovo compound are boilad
wlth 13.62 ~ l60 mmole~) of 2, 3-dichloro--5,6 dicya~o-1,4--
benzoquinone in be~ze~e fox 120 hour~ ~he reaction mixture
i8 proce~ed ~ de~cribed in ~'xample 7, and the producb i~
~ tallized ~rom isopropanol. 3.38 ~ (28 %) of l-phenyl
3,3,3~trifluoro~} (4-~luorophenyl)--2-~4-(methoxy-metho~y)-
~ p~n~
3~ ph~ny ~ -~r~p~ are obtained; m.p.: 85~88C.

11 7~35;9
- ~6 -

Analysi~:oalcul~ted ~or C23H18~42
C: 68.65 %, H: 4.51 c~O, ~: 18~89 %;
~ound: a: 68,78 ~ 4.65 %~ ~: 18.81 %0
0.09 g (0~004g_a~s)0~ sodium are di~solved i~ 0089 g
(10 mmoles) o~ 2-dimeth~lamino-ethanol. 0.80 g (2 mmole~) o~
the above compou~d are added~ and the mixture is rea¢ted a~
des¢ribed in Example 19. 0.76 g (80.6 %) of 1-~(2-dimebh~
ami~o-stho~y)-phe~y ~ _l-phs~l 3,3,3-trifluoro 2~ tmebho~;
msbhoxy)-phsny ~ ~propene i9 obtai~d a~ a rssinou~ sub-
~ance, whiah ca~ be utilized in the subsequan~ s~sp withou~
puriî~ cation.
xamPle 22


2.06 g (4.56 mm91a~ of 1~ benæ~lox~phen;yl)~
( 2-dima th;srla mino-e thoxy) -pheny~7-2-phe~1-3, 3 9 3-~riIl uoro-
propene are di~olvad in 45 ml oP acetic acid an~ hydroge~at-
ea i~ the px~senc0 of 0~,5 g o~ a lO~o palladium-on~-carbon
20 cataly~ he ~olution i~ evapora~ed and the residue i~
c~y~tallizsd ~rom e~her. 0~77 g (39,5 ~) o~ ~he al~ed com-
pound is obtained; m.p.: 149-155C~,
A~lysi~:
c~lcul~b~d for C25~24~3~ 2
25a: 70024 %, H: 5.66 ~0, F: 13.33 æ, N: ~.28 %;
~ounds a: 69.92 %, H: 6.1Z o~O~ ~: 13,.28 V/o, N: 3~38 yO~
1- ~ 4-B~z~loxy-phe nyl) ~ ( 2-di ms bhylflmino-~ tho~;sr) -
E~hen~;~7 2-phsrl;yl-3,3,3-~ri~luoro-propen~, appli~d as starti~s
~ub~tanoe, is prepar~d es follows:
2-I'henyl-~,3,3-tri~luoro~ 4~1uorophenyl)-1-(4-mebh-

~ t7
- ~7 -

oxyph~nyl)-propa~e, prepaxed as described in ~ample 189 i~
reacted with pyridine h~ydrochioride as describeà i~ ~a~npla 1~
and th~ r~sulting 2~ phenyl-3~3~ rifluoro-1-(L~fluorophen;srl)-
1-~4~hydroxyphenyl)-propane is reacted wlth benzyl chlorida
in ethanol solu~io~:L, in the presence of sodium hydrvxide.
The product i9 cx~Tst~llized from ethanol. 1~ e~zyloxy-
phenyl)-2-phenyl-373,3-tri~luoro-1-(4-fluorophenyl)-propa~e
i~ obtained with z yield. o~ 64 ',~; m.p.: 104-125C.
An~ly~is:
calcula~ed for C28H~2F40:
C: 74.65 %, H: 4~92 ~" F~ 16,87 ~;
found: C: 74~,82 %, H: 4.68 5~, F: 16.92 ~. .
~his compound is rsacted with 2~3-dichloro~5,6-di-
cyano~l,4 benzoqui~one ~or 6 hours a~ described i~ ~xample 7~
The obtained product is cry~allized from athanol. 1-(4-Be~z~l-
~rop~
1~ oxypheDyl)-2-phenyl-333,~-trifluoro-l-t4--fluorophenyl)~e
i~ obt~ined wi~h a yield o~ 24.5 %; m.pO~ 114C.
Analy~
c~lculated for C28H20F40:
C: 74O99 %, H: 4.50 %, F: 16.94 %;
~ound: C: 75.17 %, H: 4.81 %, F: 16.91 %.
Th~ oompound is reacted wi~h a ~olu~ion o~ 2-di-
~th~l~mL~o~eth~ol snd sodium e~ describ~d in ~:ample 19.
q~he re~ulti~ ~bonzyloxyphe~rl) l~ (2-dimqthylamir~o-
ethox~)_phe~y ~ ~2~phenyl-3,3,3-brifluoro- ~ c~n be appliod
in the subsequ~n~ stop without purificationO
~` m~
Pr~paret;ion e~ threo-1,2-diEh~n~ luoro-
~ (methox~-m~th ~
2 g (50 mmole~) of sodium h;ydroxide and 4 g (50 mmolea)

~'7~3S9

of chlorome~yl ether are added to a ~olutio~ o~ 10~26 g
~0 mmole~) of ~hreo-192-diphenyl-3"3"3-triIluoro~ ydro~-
phenyl)~propane, prepared as de3cribed in ~ample 1~ in 40 ml
o~ benzene, and the mixtur~ i~ boiled ~or one hour. The reac~
5 tion mixture i~ diluted wi~h 100 ml o~ benzene9 ws~hsd wi~h
a 20~o squeou~ ammo~ium chloride solution, dried alld ev~porat~
ed. ~he residue iq crystallized from isoprop~ol., 7~.45 g
(64.2 ,%JI of the almed compound are o~ai~ed; m.pO: 100-103C.
A~ly~
calcul~ted for C23H21~32
C~ 71049 %;, H: 5.43 ~0, F: 14.75 ~;
~oulld: C: 71.72 ~0, H: 5~71 ~ 14691 %
:~;xample 24


0"48 g ( 12 mmole ~) oî sod~um hydroxide and 9 .2 g
( 100 mmole~) o~ 1 ,2-epoxy-3~ohloropropane are added ~o a
solut~o~ o~ 3.42 ~ (10 mmole~) of threo-1,2-diphsn~ 3,3,3~
tr~luoro-1-(4--hydroxyphe~ propar:le 7 prepared a~ d~scribed
20 in Bxample ls in 40 ml o~ ethanol, ~nd the mi~ture i~ boiled
~or o~e hour. ~h~ reactlon mixtAr~ is evaporated, ~-bubanol
~ gain
i~ uddad to the residue, and th~ mix~ura i~/~vaporated.
'rhe re~idue i~ dilul;ad
wibh 30 ml of dichlorom~thane, w~hed wl'Gh wab~r, dri~d und
25 e~porab~d. 'r'he re~idue ~ ¢ry~tallized ~rom metha~ol, 2~85 g
~71.6 %) o~ the aim~d compound are obt~i~ed; m.p.: 113-116C.
Analy~
c~lculabad ~or C2L~H21~302
a: 72~5 %, ~I: 5~31 "~o~ 14~31 ~o;
~0 fou~d: a: 72.26 %, H: 5014 %, ~ 1LI~.LI.7 0~O.

- 49 -



ExampLe 2~
__
Prep~ration o~ erythro~ 4-(2,3-epoxy-
propoxy)-phenyL~ 1,2-diphenyL-3,3,3-trif1uoro-
-propane
4.28 ~ (12~ mmoles) of e.r~thro-1,2-diphen~L-

3,3,3 trifLuoro-1-(4-hydroxyphenyL)-propane~ prepared
as described in E~ampLe L, are reacted with 'L,2-epoxy-
-3-chLoropropane in the presence of sodiwm h~droxide
a~ described in E~ampLe 240 The product is recrysta1-
Lized twice from methanoL. 2~18 ~ (44 ~) of the aimed
compound ar0 obtained; m~p : lL5-118 C.
Analysis:
caLculated for C24H2LF302:
C: 72.35 ~0, lI: 5.31 %, F: 14~31 %;
L5 found: C: 72.L8 %7 H: ~r46 ~, F: L4.37 %.



E~ample 26
Preparati.on of (E~-l.-r4-(2,3-epo:~ypr~'l::
-phen~'LJ -L 7 2~diphenyl-3,3,3-tri~Luoro propen~
0.29 g (L2 mmoles) of sodiwm hyclr-Lde are
addecl to a soLut10n of 3~40 ~ (:L0 mmo:Les) o~ (.E)-
-1,2-d:iphen~'L-3,3~3-trl.~:Luoro-L-(L~-hydro~yphen~L)-
-propene in 30 m'L o:~ cl.ry 'benzene, ancl t'he mLxt-u.re i~

~1;1.rrecl fo.r 0.5 hour-s. Theroa:~ter '1.39 ~ ('1.~ nmloLes)


2~ of 'L,2-epoxy-3-oh'Loropropano a.r0 1ntroduc0d~ ancl the
Illi~ ture ,i9 heatecl:~or ~ hours. The .reaotLon mLxtu.re
1.~ cli'Luted with 70 mL of benzene, washed with water,
d~led, e~aporated~ ancl the resldue is crystaLLized

- 49a -

~om ~ethanoL. 2.46 ~ (62 %) of -the airned compound
are obtained; m~.p~: 73 a ~~70 c
AnaL~sis:
caLculated for C2L~HLgF30
C: 72.72 %~ H: 4~83 %~ F: L4938
found: C: 72.89 ~0, ~: 4.88 %, F: L4~6L %~

~L7~3~3
-- 50 --

t~)-1,2 Dipheny~ 3~3-trifluoro-l-(4-hydroxyphenyl~-
pxopene, applied as startin~ sub~tance9 i8 prepared a~ follows:
2~2 g (55 mmoles) of sodium hydro~ide and 6c9 g (55
mmole~) o~ b~nzyl chloride are added ~o a ~olutiorl o~ 15.4 g
(45 mmole~) of 1 92-diphenyl-393,3-~xifluoro~ ydroxyphenyl)-
proparle, prepared as described in :Example 1~ 75 ml of e~hanol~
snd ~he re~ulting mixture i~ boiled for one hour. The reaction
mixture i~ diluted with 300 ml OI wa~er, neutralized with ~n
1 n aqueous solu~ion o~ hydrochloric acid, and extracted with
200 ml of chloroform. The or~;anic phase is wa~hed with w~ter,
dried and evaporatad. ~he residue i~ crystelliæed ~rom ethanol.
17 g (86.6 ~) oî ~he produc~ are obtained; m,p.: 94-118C.
Analysi~:
calcul~ted ~or a28H23F30:
C: 77.76 G~o~ H: 5.~6 %, ~: 13.18 %;
~ou~d~ C: 77.95 %, H: 5.44 %, ~: 13.42 ~0
~ mixturs of 16.42 g (38 mmole~) o~ the above produot~
17.25 g ~76 mmole~) o~ 2,~-dichloro-5~6-dicya~o-1,4~benzoquino
and 80 ml of be~ze~e i8 boiled ~or 2 hour~ and th~n it i8
prcces~ea ~9 de~cribed in ~xample 70 ~ho p~oduct i~ cry~ ed
~rom ethanol. 6.21 g (38 %) o~ (E3~ 4-benzyloxyphenyl)-1,2-di-
phcnyl-3,3,3-tri~luoro-prop~ ar~ obtai~ed; m.p.: 128-129C~
Analy~
~lc~l~b~d ~or C2~H21~3: .
~5 ~: 78013 %, H: ~o92 ~, ~?: 13.24 %;
~ound: C: 78.34 %, H: 5~10 C~o~ F: 13.2~ %.
~ h~ NMR 3pectrum of the product co~firms the structurev
6.02 g (14 mmoles) of` the above product ~re hydrogenat-
ed in a 1:1 m ~ure o~ methanol and tetrahydrofuran in the
pre~ence o~ e 57v p~lladium-on~c~l~bon c~t~lyst. The solution i3

~:~'7~s~a


e~aporated and the residue is crystaLLized from a
L:2 mixture of chLoroform and hexane~ 3,~0 g (73.~ 3~0)
o~ (E) L,2-diphenyL-3,3,3~trifLuoro-L-(4-hydrox~rphenyL)-
-propene are o'btained ; m, p,: LL3-L20 C~
Ana Lys i s:
caLcula-ted for C2lHL~;F30:
C: ~L~,Ll 9~o~ EI: 4,1~4 %, F: 16,7~ alO;
found: C: 74, L7 %~ EI: 4. 8~ ~0~ F: 16. ~3 ~.



10ExampLe 27
Preparatio7l of 1-~4-(2~3-cpoxypropo~)-
~=~
- ( 4-chLorophenyL ) -propane

0.8 ,g (20 mmoles) of sodiurn h~rdro~ide and

L~ 14~.8 ~ (160 mmoLe~) of 1,2-epoxy-3-chLoropropane are
added to a soLu-tion of` 6,o3 ~ (L6 mmoLes) of l-phenyl-


-3 ~ 3, 3 -t rif luoro -1- ( 4 -hydroxyphenyL ) -2 - ( 4-chLorophenyl ) -

-propane in 60 ml o~ me thanoL. The mi~ture is 'boiled

for 2 hours and then processed as descri~ed in Example
2a 2~, The product ,is cr~rstaLlL~;ed froln metharlol. 4.44 g

(6l! %) o~ tho a,imed compound are obta,LrLecl j m~ p.:

LL~ 'Ll.~l~ (`~
Ana Lys ,Ls:
ocllou'Lat(3d l~or C2L~H20ClF302:
2~ C: 66,~i9 '~ E: 4,,66 %7 CL: 8.'L9 %~ F: 13.17 %
fol;lnd: C: 66,71 %~ EI: ~,0~ %, Cl: 8.3~ %, F: 13~29 %,
l-Phen~ 'L-3 ~ 3 1 3 -t r~Lf luoro ~ L- ( 4-h~droYyphenyL ) -

1~ 7~35~3i
- ~La -



-2-(4-chlorophenyL)-propane, appLied as startin~ su~-
stanee~ is prepared by the method of ExampLe L as
follows:
4'-ChLoro~2~2~2-trifluoroacetophenone CR.
~uohs~ J. Or~. Chem. 22, 993-994 (L9~7)~ is reacted
wlth bonzyL-trlphenyL-phosphonium chlorid~ in th~
presenee of an ethanoLie soLuticn of sodium etho~ide~
The produot is crystaLLized from hcxane~ L-Phen~L-
-3,3,3-trifLuoro-2-(4-ehLorophen~L)-propene is ob-


10 tain0d
.




:




, . ~ . . . .
'

s~
~ ~2

with ~ yield o~ 68 %; mOpO 63-66C.
Ana ly~i s:
calcula~ed for C15HloClF3:
CJ 63~73 %9 ~Ia 3.57 ~v~ Cl: 12a54 %9 F: ~Oal6 %~
found: C: 63.91 %, H: 3081 %~ Cl: 12~37 %9 ~: 20~0~ ~
~ he above product is hydrogenated in acetie acid ~n
~he pre~ance oP a l~o palladium-on-carbon ca~alysb bo obtain
l-phonyl~3,3,3~tri~1uoro-2-~4-chlorophenyl~-propane wlth a
yield o~ 86 %; b~p.: 118-120C/0.4 mm Hg~ ~ - 1.5230.
Analysi~:
~alculabed for al5H12al~3:
C: 63.2~ ~o~ H: 4025 %~ Cl: 12~45 v~O, ~: 20~02 %~
~ou~d: C: 6~51 %~ H: 4.40 %t Cl: 12~38 ~o~ ~ 19~93 %~
The above product i9 bromi~ated in carbon ~etrachlorid~
~nd the bromine d~i~abive is cry~tallized from hexane~ l-Bromo-
l-phonyl 3,3,3-~rifluoro~2-t~-chlorophenyl)-propana i9 obbainod
wibh a yi~ld o~ 45~3 %; m.p.: 143-146a.
Analysis:
calculated ~or C15~1 ~rClF3:
C: 49.55~0, H: 3.05V~9 Br: 21~98%~ Cl: 9~75%~ F: 1506a~o~
Pound: C: 49~68%~ ~: 7015~o~ Br: 22.0~%, Cl: 9.71%, ~: 15.53%.
~h~ ~bove product i~ reacted with ani~ole in the
pro~nc~ of aluminium brichloridc~ and ~he re~ultlng l-phanyl-
713,~bri~1uoro-2-(4-chloroph~nyl)-1-(4-methoxyphenyl)~-propa~e
i~ crys~lllzed Prom isopropanol. Yiold: 66 ~O; m.p.: 164-171C.
Ana~y~
c~lculated ~or C2~H18Clli~0~
a~ ~7.61 %, ~ .64 ~0, al; 9.07 %~ F: 14~58 %;
~ound: ~: 67075 %~ H: L~70 %9 Cl: 9.01 ~0, ~ 4~45 %.
,30 The abovo produc~ i9 reacted with pyridi~ hydxochlor-

'79;~559

ide to obtain 1 phell~yl-3,3~3-trifluoro-1-(4-h~Tdro}~yphenyl)-2-
(4-chlorophanyl)-propane~ which is utilized in the ~ubsequont
step without purific~tion.
Exam~l~ 28
Preparstion of thr~o- ~Q=~3~-
P~h~ 7-l ~2~d~phe nyl~3,3,~-trifluoro-~ropane h~drochloride
A mixture o~ 6.84 g (20 mmoles) of threo-1,2-diph~
3,3,3-trifluoro-1-(~hydroxyphenyl)-propane, prepar~d a~
d~scribed in Example 1, 0.6 g (24 mmoles) of ~odium hydride
and 60 ml of dry xylene is stirred for 0.5 hours, 7,2 ml o~ a
4.16 molar xylen~ ~olution of 2-dimethylaminoethyl chloride
(= 30 mmol~s) are i~troduced, and the reaction mi~ture is heabed
for 2 hoursO ~rhe mixture is evapora~ed, the re~iduo is admixod
with 10 ml oî a 9.36% methanolic hydrochloric acid, and tho
15 solve~lt i9 evaporated. The residue is crystalli~ed îrom iso-
proPanol. 5076 g (64 ~0) of the ai~ed compound are obtai~ed;
mOp- 229~231C.
Ana ly9i S:
calcula ~d fol C~25H27ClF3~0:
C: 66.74%, H: 6~05%, Cl: 7~88%~ F: 12.677~" N: 3.11%;
found: C: 66~47~o~ H: 6~03~/ot Cl: 7.96~ F: 12.86Yo, ~: 3.00~h.


~2~morpholinoethox;~ ~phe~yl7-pro~an~
301~2 ~ ~10 mmoles) o~ threo-1,2-dipheng1-3,3,3wtri-
fluoro~l~(4-hgdroxyphorlyl)-propane, prepared as d~cribed in
Ex~mple 19 ere reacted in xylene with ~odium hydride a~d then
wit;h 2-chloroethyl-morpholine as de~cribed in ~xamplo 28. The
product is cr~stalliYod f`rom hoxan~ 12 g (6~.5 ~0) o~ the de-
sired compoun~ ar~ obt;ained; m.p.: 87-89C.
~53~

3~3
_ 51~ _

Analysi~:
calculat~d ~or C27H28~ ~ 2
C: 71019 %, H: 6.20 %, F: 12.51 %, N: 3.08 %,
foundo C: 71.41 %, H: 6.48 %, Fo 12035 ~0~ N: 3.01 %.
~E~
Pr~aratio~ o~
e
2v72 g (8 mmoles) o~ 1,2-diphe~ 3,3~-tri~luorQ-
1-(4-hydrox~phenyl)-propen0, prepared as describ~d i~ Ex~mple
26D are reacted in xylene with ~odium hydride and ~h~ wlth
2-chloroe~hyl-pyrrolidine as described in Example 26. The
produ~t is cr~ballized ~rom haxane. 2015 g (61,4 %j o~ the de-
sired compound aro obtai~ed, mOp. 84.5-86C9
A~aly~
cal~ul~ted Por ~27H26~3~-
C: 74012 %, H: 5.99 ~, F: 13.03 ~0, ~: 3020 ~
~ou~d: C~o 74.40 %, E: 6.11 %~ F: 13.15 %, N: 3.15 %.
xa~le
PreParation of 1~ 2-dim~th
20 .~ L~ 9~c~
0.46 ~; (0,02 g_a~m~ of sodium axe dis~olved 1~ 3.56 ~;
(40 mmoloa) of 2-dimethylamino-etha~ol, 4.02 g (10 mmola~) of
1~(4-~luoroph~ 3,3,~-trifluoro~1,2-bi~-~4 methox;~rpho~
prop~ re add~d~ and th~ mixture is hesbed at 170C ~or o~e
hour. ~he roacbio~ mi~ture i~ coolod, diluted wibh 200 ml o~
~bh~r, wash~d with water until neutral~ dried and then ev~p_
orat~d. Th~ re~idu~ i~ recry~alliz~d from 45 ml of hexa~
3.43 ~ ~ 73 %) of the aimed compound ar~ obtained; m OpO:
77 79C.

~L793~i~
Analysis:
calculated ~or C27H28F3N~: .
C: 68.92 %, EI: 5078 %, F- 12~11 %, N: 2098 %9
found: C: 68~97 %~ H: 5085 ~o~ F: 12.10 ~v, ~: 2~99 %.
1-(4-Fluoropherlyl)-3,3,3~ tri~luoro-1,2-bis (4--m~thox~-
phenyl)-prop~n~, applied as ~tarting substa~ce, i9 prepared
as follows:
20 g (0.15 moles) of anhydrous aluminium trichloriae
are 2dded ~o a solution of 56.6 g (0.15 mol~s) of l-bromo~
3,3,3-trifluoro-1-(4-~luorophenyl)-2-(4-methoxyphenyl)-propan~,
prepared as described in f~xample 19, i~ 570 ml OI anisol at
6C under stirxing~ The reaG~ion mi~ture i~ allowed to s~a~d
a~ room tempera~ure ov~r~ight, ~hen it is pour~d into a mi~ture
o~ 600 g of crush~d ic~ and 100 ml o~ a 36~ aqueous hydro_
chloric acid, and the r~sulting mixturo is extracbsd with
500 ml o~ chloro~orm. ~he organic solutio~ is washed with
aqueous ~odium hydrocarbon~te solu~ion and w~ter, dried~ and
the solvant is evapora~ed. ~he dry residua i~ crystalliz~d Prom
2~0 ml of isopropanol to obtain 34.6 g (57 C~o) 0~ 1-(4-fluoro-
ph~nyl)-3 9 3,3-trifluoro-1,2-bis (4-methoxyphenyl)-propans;
m.p.: 132-135C.
~na ly~
calculab~d ~or C23H20F~02.
C: 6a.31 %, II: 4099 %, h`: 18~79 %,
25fou~d: ~: 68045 ~0, EI: 5.14 ~0, F: 18.63 ~.
13.62 g (60 mmol~) of 2,3~dichloro-5,6-dlcyano-1,4-
benzoquinor~e ar~ ~dded ~o a ~oluliion of 12013 g (30 mmol~) O.r
the ~bove product in 60 ml o~ dry benzene, and the mixture
is ~irr~d ~nd boiled for 16 hours. ~`her~after one proceeds ~s
3~ d~scrib~d in ~3xaLnpl~ 7. 'rhe crude produc t is c~ystallized

9 3

- 56 ~

~rom 40 ml o~ isopropa~ol to ob~ai~ B~75 g ~72.5 %) o~ 1-(4-
fluorophenyl)-3,~13-tri~luoro 1,2-bi (4-methoxyphanyl~-prop~e~
.p.: 75-77C.
A~alysi~:
calculated for C23~18F4o2-
a: 68.65 ~o~ H~ 4.51 %9. F: 18~89 %~
found: a: 69.07 %, H: 4~57 %5 F: 19~03 %.
xample 32

~ tr~luoro-1,2-bis (~ droxy~h~ propen~
10 ml o~ a 970 m~tha~olic hydrochloric acid ~rs adaad ~o
a solu~ion o~ 4~0 g (7~47 mmole3) o~ (2-dime~hylamino-
athoxy)-pheny_7~3,3,3-trifluoro-}~2-bisOt4-methoxym~thoxy-
phenyl3-propa~e i~ 40 ml o~ matha~o~, ~nd the mixture is boiled
for ona hour. ~h~ solu~io~ is evapo~a~ed to dr~nasj, a~d the
ra idus is crystallized from ethanol. 2.67 g (74.4 %) o~ th~ de-
~red.compound are obtalned; m.pu: 256-262C.
Analysis:
calculated Xor C25H25C1~ ~ 3
C: 6Z,57%~ H: 5.25~o~ Cl: 7.39%7 F~ 885o~ N: 2.,92%~
found: C: 62.61~, H: 5.52%, Cl: 7.62%, ~: 11.69~ 2.81%.
~ (2-Dimethylamlno-ethoxy)-phenyl7-3,3,3-trifluoro-
1,2-bi~ methoxyme~hoxy-ph~nyl)-propene, applied ~ ~tarting
~ub~ta~ce~ i3 prepared a~ ~ollow~:
A mixture o~ 18.72 ~ ~46 mmole~) o.f 1-~4~Pluoroph~yl)-
3,3,3-trlfluoro-1,2-bis-(4-methoxyphanyl)_propane, prepared
d~eribed in Example ~1, and '76 ~ of pyridine hydrochloride i~
h~at~d fl~ 200-210C ~or 3 hour~. 'rhe mixture i9 cooled, dilu~ed
with 200 ml of chloro~orm and washed with water until neutralO
'~ ~rhe ~ nn ia dried and evaporated. ~h~ resulting 17~7 g

~tjJ~335~

-- ~7 --

of 1-(4-fLuorophenyL)-3,3,3-trifLuoxo-L,2-bis-(4-
-h~droxyphen~L)-pxopane are dissol~ed as ~uch,
withou-t purif~cation, in 200 mL of benzeneq LL.L
(L38 mmoLes) of chLorometh~l ether and 10 ~ (27~
mmoLes) of powdered sodium hydroxide are added to
the soLution, and the mlæture is boiled for one
hour, The mixture is diluted with LQ0 ~L of benzene,
washed with a 20 % aqueous ammonium chLoride soLution
untiL neutraL, dried and evaporated, The xesidue is
crystalLized from isopropanoL, L~,63 g (73 ~0~ o~
1-(4-fluorophenyL)-3,3,3-tr~ifluoro-1,2-bis-(4-tnethox~-
metho~y-pheny1)-propane are obtained: m,p,: 106~107 C~
AnaLysis:
caLcuLat~d ~or C2~EI24~4o4:
L~ C: 64,6~ %~ EI: ~,21 %0, F: L6~36 %;
found: C: 64.60 %, H: ~,~2 %~ F: 16,47 %,
~ ,86 ~ (26 mmoLes) of 2~3-dlchLoro-~,6-di-
cyano-1~4-benzoquinone al~ added to a soLution of
6~o g (L2,9 ~mnoles) o~ 1-(4-~luoropherlyl)-3,3,3-tri-

~Luoro-L~2-bis-(4-metho~ymethoxy-p~1enyl)-propane ln
30 m'L o~ clx~ bonzone~ The mLxture Ls bo;LLecl ~or 28
ho~lr~ and then proce~secl as closcriberl ;Ln ExampLe 7
The produot ls cxystaLLLz~cl frorn LsopropanoL~ 4ll~2 g~

(71~ %) 0:~ th~ aLmecl compouncl ax~ obtaLnecl~
2~ rn,p,: 73-74 a ,


.~

S9


AnaLysis:
caLcuLated for C2~I22F404:
C: 64,93 %, H: 4~0 %, F: L6,43 ~;
found: C: 64.67 %, ~I: 4.98 %, F: L6.49 %.
3~0 g (6,~ mmoLes) o~ -the abo~e product
are addecl to a soLution of 0,3~ g (O.OL~ atoms)
oP sod-Lum in 2,67 g (30 mmoles) of dimethyLamino~
-ethanol. and the mixtuxe is treated as dcscribed in
Example 19~ 3.97 g (LOO ~) of 1-C4-(2-dimethy1amino-
LO -ethoxy)-pherlyl~-37373~trifLuoro-L~2-bîs~4-moth
~ethoxy)-phenyL propene ax^e ohtained as a resinous
substance, This product is utili~ed in the subsequent
step without purification.



1~ Example 33
Preparation of 2-pher~1-3,3,3-trit`Luoro-1-

. _ . . . _
-(4-hydroxy-phenyL)-L-C4-(2-morpho1inoethoxy)-

~phsnyL~-propene

'10 mL ot' 9 % methano'Llc hydroohLorLc ac,Lcl

are aclded to a soLutLon o~ 3~08 ~ rmnoLes) o~ 2-
~pheny'1-,'3~3,3-trl:fLuoro-L-~4-~2-moxphoLLnoethoxy)-
-ph~n~L~-L-(L~ ethox~rtletho~y-phonyl~-properle .~rl L~o ml
o~ rrlethanoL~ ancl tho mLxtuxe Ls boLLed ~ox one hour,
The soLution is renclerecl aLkaLine with L,~ mL o~ a

2~ LO n ~odi~n hydroxide soLution and then evaporated~

The reslduo L9 dLssoLved in 400 mL of ether~ -the soL-

utLon is washed with water untiL neutral, dried and



~.~'7~33~

,~9

e~aporated. The residue is cr-ystalLized from acetone.
2.23 g (73.6 %) of the airned compound are obtained;
m.p.~ 7 C
Analysis
calcuLated for C27H26F3N03:
C: 69.o7 %, H: S.~8 %, F: L2~14 %, N: 2.98 ~;
Eound: C: 69.37 %, H: ~ 82 %~ F: l2.04 %, N: 2~87 %~
2-Phenyl-3~3~3-trifLuoro-L-(4-methoxy-
me-thoxy-phenyL)-L-~4-(2-morphoLinoetho~cy)-pher~yl~-

LO -pxopene, appLied as starting substance, is pre-
pared as fo7Lows:
9.6 g (L20 mmoles) of chLoromethyL ether
and 8.4 g ~210 mmoLes) of powdered sodium h-ydroxide
are added to a so'Lution of 27 7 ~ (76 mmoles) of 2-

1~ -phenyL-3~3~3-trifLuoro-L-(4-fluorophenyl)-L-~4-
-h~droxyphenyL)-propane ln LOQ ml of benzene pre-
pared as described in ExampLe 22, and the mixture is
boiLed for one hour. The reaotion mixture is di7uted
with L~O rnL of benzene, washed with a 20 % aclueous
20 amrnonlum ohloride soLution ~mtiL ne-utraL, dried and
evaporated. The resLdue i9 d LssoL~ed in benser/le and
pa~secl th:rou~h a ohromato~raphlc coLwTnn ~l'l'lecl with
6~o ~g of sLLLca ge'l~ The first eLuate fractions are
oorrlbirlecl and e~aporatecl to o'btain 20.66 ~ (66 6 ~)
2~ oE 2-phony'L-3,3,3-trL~Luoro-'1-(4-~Luoropher~
-mothoxyrnethoxy-phenyL)-propane 9 which is appLied
ln the subsequent step without purification.


3~9

_ 60 --



22.7 g (100 mmoLes) o~ 2,3-dichLoro-~,6-
-clicyano-1.~4-benzocluinone are adcled to a solution of
L9.70 ~ (48.7 mmoLes) o:E the abo~e product in LOO rnL
o:~ dry benzene~ The mixture is boiled :~or 17 hours
and then processed as described in Example 7 The
produot is crystaLLized :~rom isopropanol. 7120 ~ (36.7 %)
of 2-phen~L-3~3~3-trifLuoro-L-~4-fLIlorophenyl)-l-
-(4~methoxymethoxy-phenyL)-propene are obtained;
m~p.: 66~68 C.
LO AnaLysis:
caLcuLated :~or C23~IL8F4Q2
C: 68.6~ %, H: L~ ~L ~0, F: L8.89 q'o;
found: C: 68..~0 ~90, ~ .73 ~, F: L9.OL %.
0,28 g (Q.012 ~.-atoms) o:E sodlum are
L~ dissol~ed in 4,72 g (36 mrnoles) o:E (2-hydroxyethyL)-
-morphoLine, 2,40 ~ (6 rnmcLes) o:~ the abo~e product
are adcled, and -the mi:2cture is heated at L~O C for
one hour The mixture is cooled, diLutecl with LOO mL
OI ethor, wa~hed wi-th water untiL neutral and driedO
20 3,08 g (100 %) o:f 2-phenyL-3~3~3-trL:~Luoro~L-(4 rne-thoxy-

~nethoxy-p~lerly'l)-'l.-Cl~-(2-tnorpho'lLnoethoxy)-phenyL~-
-propone a.re obtained as a resinou.s substanoe Thls
produot i9 utlLlz;od Ln the subsequent step wlthout
pur-l:f`lcat1on.
2~

7~3S~

- 6L -



ExampLe 34
Preparation of 2-phenyL-3,3,3-trifluor~-




-ethoxy?-phenyL~-propene hydroohLoride
L.~ ml of 9 % methanoLic hydrochLoric
aGid are added -to a soLution of L ~0 g (3.28 mmoLes)
of 2-phenyL-3,3~3--trifLuoro-L-CL~-(2-methyLaminoethoxsr)
-phenyl~-L-(4-metho~Lymethoxy-phen-yL)-propene in L~
mL of methanoL, and the mixture is boiLed for one
L0 hour~. The soLution is e~aporated to dr~ness, and the
residue is crystaLlized from isopropanoL L. o6 g
(7L.5 %) of tke aimed compound are obtained; m.p
213-2L8 C.
AnaLysis:
L~ calcuLated for C24EI23CLF3N02:
C: 64 07%~ H: ~ 1~%, CL: 7.88%, F: L2.67%, N: 3.LL%;
found: C: 64.74%, H: ~.~3%, CL: 8.0L%, F: L2.4~%~ N: 3.03~0.
2-Phen~1-3~3,3-trifluoro-L~C4-(2 methylamino-

ethox~)-phenyL~-L-(4-met;hoxymethoxy-phenyl)-propene~
20 appLLed as startLng~ substanoe, is preparod as foLlows:
0.28 g (0.012 g~-atoms) of soclL~ml are clLs-
soLvod ln 2.70 g~ (36 mrnoLes) of N-methyLamLrlo-ethanol,
2~36 g (~.86 mmoles) of 2-phenyL-3~3~3-tri~`Luoro-1-(4-



-fl.uorophen~r'l)-L-(4-rnetho~c$rmetho~-phens~'l.)-ps~opene9
2~ preparecl as descrLbed in E~annpLe 33, are aclded~ ancl
the mixtuxe Ls heated at L50 C for one hourO The
mLxture i~ oooLed9 dLLuted with L00 mL of ether,


`'~'~ '

5~

~ 62 _



washecl with water untiL neutraL, dried and e~aporated
The residue is crystaLLi~ed fro~ hexane L.94 ~ (72~4 %)
of 2-phenyL-3,3,3-txifLuoro-L~4~(2-me-thyLa~inoethox~)-
-phenyl]-L-(4-methoxymethoxy-phenyL)-propene are ob-
tained; m.p : 87-90 C.
Analysis:
calculated for C26E26F3N0 :
C: 69.2~ %, H: ~ 73 %, F: L2.46 %, N: 3 o6 %;
found: C: 70.08 %, H: ~.6~ %, F: L2066 %~ ~: 3.L6 %.



Example 3~
Preparation of (E)-L,2-diphen~1-3,3,3-tri-
fLuoro-L-~4-(2-heptamethyLenei~ino-ethoxy)-


.. .. .. _ _ . _ _ ,, , , _
-phenyl~ propene
_
2 32 ~ (20 mmoLes) of heptamethyleneimine
are added to a solution of 4 47 ~ (L0 mmoLes) of
(E~ 4-(2-bromoe-thoxy)-phenyl~-L,2-dLphenyl-3,3,3-
-trifluoxo-propene, preparecl as clescxibed in E~ampLe
7~ in 30 ml of ethanoL, ancl the ~ixture ls boiLed for
~ hours. The reaotion mixture ls e~aporatecl-to dry-
ncss rhoxeaPtex one proceecls as desoribed in ExanlpLe
L~ ancl orystalLizes tho procluct from he~ane. 3~22

(67 ~,) o~ tho closirecl oompo~lncl are obtaLned~

m.~.: 73-77 C~
AnaLysis:
calcuLated for C30~I32F3N0:
a: 7~L3 ~0, H: 6~73 %, F: LL 88 %, N: 2 92 %
found: C: 7~.1L %~ H: 6~7~ %~ F: LL.88 ~ N: 2 98 %


3~
-- 63 --



I?xampLe 36
P~eparation of (E)-L-~4-(2-diethylaminoethox~)-
-phenrl~-L,2-diphenyl-3,3,3-trifluoxo
-propene picrate
5,37 g (12 mmoles) of (E)-L-~4-(2-bromoethoxy)-
~phenyL~-1,2-diphenyl-3,3,3-trifLuoro-propene, pre-
pared as described in Example 7, are boiled with 8.8
g of diethyLa7nine for ~ hours,. The reaction mi~ture
is diluted with ~Q ml of benzene, washed with water
10 untiL ne-utxaL, dried and e~aporated, The residue is
dissolved in 20 mL of 95 % e-thanol, and a soLution of
3,22 ~ (14 mmoles) of picric acid in 32 mL of 9~ %
ethanol is added, The sepaxated crystals are fiLtered
off, washed with ethanol and ether. 6,46 g (80.4 %)
L~ of the aimed compound are obtained; ttl.p9: L3L-13~ C,
Ana LrS is:
caLcuLated for C33H3LF3N48
C ~9,28 %, H: 4~ 67 %~ F: 8,~2 %, N: 8,40 ~;
folmd: C: ~9,~ %~ ~I: 4,78 %, F: 8,73 %, N: 8,3
XO
~E~
Prepar?tLon o~ ~-L-~4-(~ditnethyLamitlo-

thox~ ph_nyLLL,2-diphen~ tx,Lfltloro-

-prop~3ne suLfate
2~ Q,03 mL (0.~ mtnoLes) o 98 % sulfuric acid
axe addecl to a soLution of 0,20~ g (0.~ mmoLes) of

(E)-'L-~4-(2-dimeth~latninoethox~)-phenyL~-1,2-diphen~l-

~;

~17~g3~9
- 64 -



-3~3~3-trifluoro-propene in 1 J ~ ml of isopropanoL
The iseparatecl crystals are fiLtered of`f~ washed
with ether, and the cr~de product is recrystaLLized
~rom isopropanol. 0.22 g (84.6 %) of the aimed com-
pound are obtained; m.p.: L~0-1~3 C.
Analysis:
calcuLa-ted for C2~I26F3No~S
C: ~8~93%, ~ .14%, F: ll.l9~o~ N: 2 7~%~ S: ~29 ~'Q
found: C: ~9.07%~ H: 5 30%~ F: 11l29%, N: 2.70%~ S: 6.46 %
L0 (E)-L-C4-(2-DimethyLaminoethoxy)-phenyL~-
-L,2-diphenyl-3,3,3-trifluoro-propene, appLied as
starting substanc0 Ls prepared as follows:
10 mL o~ a 40 % aqueous solution of climethyl_
atnine are added to a solution of ~.37 ~ (12 mmoles)
1~ of` (E)-L-C4-(2~bromoethoxy)-phenyl~-1,2-dlphenyl-3,3,3-
-tri~luoro-propene~ prepared as described in ExampLe
7~ in L0 ml o~ ethanol. The mixture is a'Llowed to
s-tand ~or 3-4 days 7 then evaporated, the residue is
di'Lut~cl with ~0 ml of benzene, the resulting so'Lution
20 ls washQd with wator until neutraL, driecl ancl e~apor-

atecl, 'rho ro~ld~le Ls ory~ta'llized ~rotn hexane. 4. 26 g
(86.2 %) o~ (E)-'l-~LI-(2-climethy'Latninoethoxy)~phenyL~-
-'L,2-dLpheny'1-3,3,3-trLf`lLloro-propeno are obtaLned;

In p-: 90-9L C
Ana'Ly~is:
oalouLated for C2~Ft24F3~0
C: 72.98 %~ H: ~.88 qO, F: 13.8~ %~ N: 3 40 %;



!;~. found: C: 72.80 ~, H: ~.~1 %, F: 14.0L qO, N: 3~3 %.

3~;~
- 6

Example 38

Preparation of (E)-1,2-dipheny~1-3,3,3-tri-
.. ~
fLuoro-l-C4-~2-/4-(2-h~d~o~eth~L)-piperazino/-
-ethoxy)-phen~L3-propene mes~Late
~ _
A solution of 0 2 g (2 mmoles) of rne-thane-
suLfonic acld in 2 ml of isopxopanol is added to a
solution of Or ~SO g (L rrlmole) of (E)-L,2-diphenyl-


-3,3~3-trifluoro-1-C4-(2-/4-(2-h~rdroxye-th~rL)-pipera~ino/-
-etho}~y)-phenyl~-propene, prepared as desclibed in

L0 ExampLe lL, in L mL of isopropanoL. The separated
crystals are I iltered off and washed with ether .

0 ~8 g (96.7 %0) of the a-imed compound are obtained;

m.p.: 203-209 C.

AnaLysis:

1~ calculated for C31H39F3N208S2
c: ~4~o6%, H: ~.7L~o~ F: 8.28%, N: 4.07%, S: 9.31%;
found: a: ~3.71%, H: ~.90%, F: 8.42%, N: 3 81%, S: 9.03%.

ExatrlpLe 39

ProparatLon o~ -(2-aminoethoxy)-

-phe~yl~-1,2-dlphen~rL-3~3~3-trifLIloro-propene
tosyl.ate
. .,_ .. _. _ .
1~ ~oltttLon ol~ 0~20 g (L rnrnole) o~ p~toLuene~
suL~orlLo acid -ln 1 ml of Lsopx-opanoL Ls added to a sol-


2~ utlon of 0.30 ~ (0~8 mr~oLes) of (E)-1-~4-(2-arninoethox$r)-

~pherlyL J -L,2-dLphenyL-3,3,3-txlfluoro-propene, prepaxed
as desorLb~d in ExarnpLe 8, in 0.~ rnL of Lsopxopanol. The

, .

3~
- 66



separated crystaLs are filtered off and ~ashed with
et;her. 0.37 ~ (84 ~0) o:f the aimecl compound are ob-
tained; m.p : L62-L63 C.
Analysis:
calculated for C30~I28F3N4S
C: 64.8~ 7~0~ :H: $.08~ F: Lo.26~o7 N: 2.$2~o~ S: S.77%;
found: C: 64 98 %, H: S.3%, F: 10.S3%, N: 2 23%, S: S g3%-




ExampLe 40
___
L0 Preparation of (E)-L,2-diphenyl-3,3~3-tri-
__
fLuoro-L-~4-(2-/2-hydroxyethylamino/-ethoxy)-

-phenyl~-propene citrate
_
A solution of 0.13 ~ (o.6 mmoles) o:f` citric
acid hydrate in 0.8 ml of acetone is added to a so~-
1~ ution of 0.2L ~ (O.S mmoLes) of (E)-1~2-diphenyL-
-3,3,3-trlfLuoro-l-C4-(2-/2-hydroxyethyLamino/-ethoxy)-
-phenyL~-propene, prepared as descrlbed in ExampLe L2
in 0.2 mL of acetone The mixture is cooled, the
separ-ated crystals are fiLterecl off ancl washecl wLth
2() aoetone~ 0~18 6 (S8 '~o) of the aimod colnpourld is ob-
~tQirl~cl ; In~ p~: 127-129 C.
~n~LYsls
oaloulated for C3~E32F3 N09:


C: 60.09 'J~o~ ~:[: S,21 %~ F: 9.20 ~o~ N: 2.26 %
2~ fOund: C 60.L8 %9 H S.13 ~o~ F 9~24 %9 N: 2,37 %


- 67 -



EæampLe 4L
.. . ... ....
Preparation of (E)-1,2-diphenyL-3,3,3-tri-
fluoro-L-~ (2-hex~lamino-ethox~)-phenyL~-
-propene tosyLate

.
2 23 g (~ mmoLes) of (E)-L-C4-(2-bromoethoxy)-
-phenyl~-L,2-diphen-yL-3,3,3-trifLuoro-propene, prepared
as described in ExampLe 7, are clissoL~ed in a mixture
of ~.0 g (~0 mmoLes) of n-he~yLamine and LO mL of 2-
-methoxyethanoL. The mixture is boiLed for 30 minut~s,
LO then e~aporated~ and the residue is passed through
a chromatographic coLumn fiLled with ~0 g of siLica
geL. The coLumn is eLuted with ben~ene The fraotions
which are chromatographicaLLy uniform are combined
and e~aporated, the residue is dissoL~ed in ~ mL of
L~ isopropanoL, and a soLution of L.20 g (6 mmoLes) of
p-toLuenesuLfonic acid in 6 mL of isopropanoL is added,
The separated crystaLs are fiLtered off and washed
wi-th e-ther. 2~L4 g (9L.8 %) ~ the aimed compound are
obtained; m p.: L~l-L~3 a ,
AnaL-y~ls:
oa'lc~l'latod ~or a36Etl F3NOIS:
C: 67.58%, EI: 6.30'~o, F: 8.9L%, N': 2.L9%, S ~.OL%;
fo-und: C: 67.6L%~ H: 6.~ oS F: 9.08%~ N: 2 39alu, S: ~.L~%.




2~ ExampLe 42
.
Pre~aration of ~I~-L,2-dipheny'L-3~3~3-tri-
fLuoro-L-C4-(2-/3-hyclroxy-propylalnino~-
et'hox~ -pheny ~ ropene
:.

'7~S9
- 67a -



2,23 g (5 mmoLes) of (E)~ 4-(2-bromoethoxy)-
-phen~lJ-L,2-diphen~rL-3,3,3~trifLuoro-propene~ prepared
as descri'bed in ExampLe 7, are dissol~ed in a mix-ture
of 3.80 g of 1-amino-3-propanol and 10 mL of 2-methoxy-
ethanoL, The rnixtu~e is boiLed for 30 minutes anc3 then
processed as descri'bed in Example 2. The mixture is
cr5tstallized frotrl a 1:1 mixture of ethyL acetate and
hexane, 1,77 g (80.'5 %~ of the aimed compound are ob-


tained, m~p.: 97-99 C,

L0 Anal~sis:
ca,lculated for C26H26F3N02:
C 70.73 %, H: ~.94 %, F: 12.91 %, N: 3.17 %;
~ound: C: 70.7L %, H. ~,94 %, F: L2.83 ~0, N: 3,.23 %.



L~ Example 43
Preparation oE (E)-1,2~diphenyL-3,3~3-tri-
fLuoro-1-~4-(2-nitroguarlidino-ethoxy)-phenyL~-
-propene

A soLutLon o~ 3,83 g (L0 mmoLes) o~ (E)-l-
20 _r.L~ (2-amLnoethoxy)-phen~L~-'1,2-diphen~L-3,3,3-trL-

r Luoxo-propcn~ pxcparocl as cle~;cxLbecl Ln Examp'Le 8~
ancl 'L.22 ~ (9 mmolcs) o~ 2-methy'l-1-nitro-2-Lsothiourea

~L,. Fish'b~ln et al.: J, Arn. (~hom. Soc. 76, 1877 ('19~4)~
in 2~ rnl o:~ ethanol is 'boLLocl ~or one hour. The xeactLon
25 mLxture is evaporated ancl the residue is crystalLlzed
~rom methanoL, 2.78 g (66 ~) o:~ the aimed compound aro
o'btained; m.p.: 112-'LL6 C (decomposition).


~'79~35
- 67~ -



Analysis:
caLcuLatod ~or C2~ 2 LF3N43
C: 6L.27 %, 'H: 4,~0 '~0, F: 12.L2 ~0, N: LL.9L %;
found: C: 6L.2L %, H: 4,80 %, F: L2.27 %, N: LL.62 %.



Example 44
Prep_ration of ~Z)-L,2-dLpheny_3,3,3-t~i-
fLuoro-L-~4-(2-/2-hydroxyethyLamino/-0thoxy)-
-phen-yl~-propene fumarat,e

L0 0.~9 ~ (L.L7 mrnoLes) of (Z)-L-C4-(2-bromo~
etho~ phenyL ~-L, 2-diphen~L-3 ~ 3 ~ 3 -t~i:~Luoro-propetle,
propared as described in ExampLe 7, are dissoLved in
a mixture of L.34 g o~ 2-arninoethanoL and L~ mL of
2-metho~yethanoL, The soLution is bo,LLed for 30 minutes
L~ and then processed as described in ExampLe 2, The
crude product is crystaL1ized from a 1:3 mi~turre o~
ethyL acetate and hexane, 013~ ~ (70 %) of the base
~orm of the -ti-tLe compound are o~tained, m~p,: 8L-83 C,,
Thc ~rec 'base ;is dLssoL~ecl in L.~ rlll of ethcLrloL~ ~nd
20 an othanoL soLutlon o~ O,L2 g ('L mmoLe) o~ ~um,arLc
aolcl ls adcled,, The ~cparatecl crystaLs are ~lLtored o~E
ancl washecl w1th ethe~, 0,28 g~ (62,2 '~0) o~ the clesLrccl
oompollnd ar~-3 o'btalnecl; Itl, p.: L68-L72 C.

AnaLys1s:
2~ caLcul.~Lted ~o.~ C29ll28F3No6:

~ : 6l~,o8 %; II: ~, L9 %, F: 'LO,1~9 %, N: 2.~8 %;
fownd: C 6l~140 '~0~ H: ~,32 ~0, F: Lo,6~ %~ N: 2,8~ %,
.~

35~
- 67c -



ExampLe 4
Pr~parati ~



0.8Q g (20 mmoLes) of powdered sodium hydroxid'e
and 6.8 g (40 mmoLes) of n~propyl iodide are added to
soLution of 3t42 g (L0 mmoles) cf threo-1,2-diphen-yL-
-3~3~3-trifLuoro--1-(4-hydrox-yphen-yL)-propane~ prepared
as described in ExampLe L~ in 3~ mL of d~y benzene,
and the mixture is boiLed for 4 hours. The mi~ture is
L0 diLuted with ~0 mL of benzene~ washed with water untiL
neutraL, dried a.d e~aporated The residue i.s ory~taL-
lizecl ~rom isopropanoL~ 3 32 g (8~ 0) o~ the aimed
compound are obtained; m.p.: 77-80 C
AnaLysis:
1~ caLcuLated ~o~ C24~I23F30
C 74,98 %, H: 6.o3 %, F: '14.83 ~0,
~ownd: C: 7~,0L ~o, H: 6~20 ~0~ F: L4.9~ ~o.



Exam~Le 46
Pre~ar.atlon o:~ threo-1-~4-(/(31L~-e ~ ~
~y-phenyL]-L,2 -cllphony'L-3 ? 373~
-trL~`luoro-propane
A mlxture O:r 3~1~2 g~ ( L0 InrnoLes) o:f threo-
- 1 7 2-cllphe~yL-3,3,3-trLfLuoro-'L-(4-hydroxypheny'L)-


2~ -propane, prepared as de~orl'bed ln ~x~mpLe 1, and L7
mL o~ M,-cllepoxybutane ls heate d at LQ0 C ~o.r 0,~
hours. The reaction mixture is e~aporated~ t~e .resi.due
ls d.iLuted with 300 mL o~ ethe.r, washed wi.th water,


~. .

~ ~'7~

- 67d -



dried and e~aporated, The residue is crystalLized from
isopropanol. The obtained subst~nce, ~eighing 3~22 g
(7~2 %; m.p.: L2L~L26 C)~ is subjected to ch~omato~
graph~ in a 3:2 mlxtur0 of hexane and acetone, and the
chromatographicaLly uniform produot is cr~staLLized
from isopropanoL. L.90 g (44.4 ~o) of the desired com-
pound are obtalned; m.p.: 130-L33 C,




'~``'',

33S~39


Analysis:
calculated for C25H23F303:
C: 70.08 %, H: 5.41 %, F: 13.30 ~;
found: C: 70.30 %, H: 5.74 %, F: 13.09 %.
Example 47
Preparation of Pharmaceuti.cal compositions
a) Tablets
Tablets for oral administration, each containing lO mg of
the active agent, are prepared in a manner known per se.. The
composition of one tablet is as follows:
(E)-1,2-Diphenyl-3,3,3-trifluoro-1-~4-(2-/2-hydroxyethylamino/-
ethoxy)-phenyl] -propene (calculated as free base) lO.0 mg
Maize starch 4g.6 mg
I,actose lO9.0 mg
Polyvinylpyrrolidone 5.4 mg
Magnesium stearate l.0 mg
Colloidal silicon dioxide 5.0 mg
Average weight: 180.0 mg
b) CapsuIes
Hard gelatine capsules, each containing lO mg of the
active agent, a:re prepared in a ~manner known per se. The composition
of one capsule is as follows:
threo-1-~4-(2~3-Epoxypropoxy)-pheny~ -1,2-diphenyl~3,3,3-trifluoro~
propane lO.0 mg
Maize starch 84.0 mg
Magnesium stearate l.0 mg
Colloidal si:Licon dioxide 5.0 mg




68 -

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Administrative Status

Title Date
Forecasted Issue Date 1984-12-11
(22) Filed 1980-08-15
(45) Issued 1984-12-11
Expired 2001-12-11

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1980-08-15
Owners on Record

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Current Owners on Record
GYOGYSZERKUTATO INTEZET
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Drawings 1993-12-21 1 14
Claims 1993-12-21 21 782
Abstract 1993-12-21 4 90
Cover Page 1993-12-21 1 26
Description 1993-12-21 84 3,118