Note: Descriptions are shown in the official language in which they were submitted.
3839
RAN 4~60/91
The present invention relates to stilbene derivatives.
More particularly, the invention is concerned with stilbe~ne
derivatives, a process for the manufacture thereof and
pharmaceutical preparations containing same. The invention
is also concerned with intermediates occurring in said
process.
The ~tilbene derivatives provided by the pr~sent
invention arP compounds of the general formula
, wherein n st&nds for 1 or 2 and, when n
stands for 1, Rl and R2 represent hydrogen,
lower alkoxy or halogen, or, when n stands
for 2, Rl represents hydrogen, lower alkoxy
or halogen and R2 represents hydrogen~ R3,
lS R4, RS &nd R6 represent hydrogen or lower
alkyl; R7 represents hydrogen, me~hyl or
ethyl; R8 and R9 represent hydrogen, lower
alkyl or halogen; and R10 represents a
Grn/27.11.78
~.~.Z383g
-- 2 ~
group of the foxmula -(CH~CRl9) Rll i h
m stands for zero or 1 and Rll represents a
group of the formula
R12 o
- ~ -R or - I - R15
or the 2-oxazolinyl group, or, when m stands
for l,also represents hydrogen; R12
represents hydrogen or lower alkyl; R13
represents hydrogen, low~r alkyl or a group
of the formula N(R17 R18) or -oR14; R14
represents hydrogen, lower alkyl or alkanoyl;
RlS represents hydrogen, lower alkyl or a
group of the formula -OR or -(CH2)pN(R17,
R18); R16 represents hydrogen, lower alkyl,
hydroxy-(lower alkyl), aryl, substituted
aryl, aralkyl or aralkyl substituted in the
aryl portion; R17 and R18 represent
hydrogen or lower alkyl or R17 and R
tGgether with the nitrogen atom to which
they are attached represent a heterocyclic
gr_up; Rl9 represents hydrogen or lower
alkyl and p stands for zero, 1, 2 or 3; as
well as ketals of compounds of formula I in
which Rll represents a group of the formula
-C(O)R and R represents hydrogen or
lower alXyl,
and salts of compounds or formula I.
23839
- 3 -
As used in this Specificatlon, the ter~ "lower" means
that the groups qualified thereby contain up to 6 carbon
atoms.
Alkyl and alkoxy groups can be straight-chain or
branched-chain, examples of alXyl gro~ps being the methyl,
ethyl, isopropyl and 2-methylpropyl groups and examples of
alkoxy groups being the methoxy, ethoxy and isopropoxy
groups. Alkanoyl groups are derived, for example, from
acetic acid, propionic acid or pivalic acid, or also from a
higher carboxylic acid containing up to 20 ca~bon atoms
(e.g. from palmitic acid or stearic acid). me ~henyl
group is a preferred aryl group. Examples of substituted
aryl groups are hydroxy-, nitro- and halo-phenyl groups.
The benzyl group is a preferred aralkyl group. Examples of
heterocyclic groups denoted by -N(Rl7,R18) are 5-membered or
6-membered nitrogen-containing hetarocyclic rings which may
contain an oxygen or sulphur atom or a further nitrogen
atom (e.g. the piperidino, piperazino, morpholino, thia-
morpholino and pyrrolidino groups). Examples of ketals
are di(lower alkyl) ketals and lower alkylene ketals. The
oxazolinyl group can be substituted by one or two lower
alkyl groups. Of the halogen atoms, chlorine and bromine
are preferred.
A preferred class of compounds of formula I herein-
before comprises those in which, when n stanas or l, Rl andR2 represent hydrogen, lower alkoxy or halogen, or, when n
~.2383~
-- 4 --
stands for 2, R represents hydrogen, lower alkaxy or
halogen and R2 represents hydrogen; R3, R4, R5 and R6
represent hydrogen or lower alkyl; R7 represents hydrogen,
methyl or ethyl; R8 and R9 represent hydrogen, lower alk~l
or halogen; and R10 represents hydroxymethyl, alkoxymethyl,
alkanoyloxymethyl, carboxyl, alXoxycarbonyl, formyl,
alkylenedio~ymethy-l, alkanoyl, carbamoyl, mono(lower alkyl)-
carbamoyl, di(lower alkyl)carbamoyl, N-heterocyclylcarbonyl
or 2-oxazolinyl. Furthermore, compounds of formula I in
which n stands for 2 are preferred, as are compounds of
formula I in which Rl, R , R5, R , R8 and R9 represent
hydrogen and R3, R and R7 represent methyl. A furthex
preferred class of compounds of formula I comprises those
in which R10 represents a group of the formula -(CH=C~)mRll,
especially when m stands for zero and, moreover, when R
represents lower alkoxycarbonyl, lower alkylcarbamoyl,
lower alkoxymethyl or lower alkanoyloxymethyl.
According to the process provided by the present
invention, the stilbene derivatives aforesaid (i.e. the
compounds of formula I and their salts) are manufactured by
reacting a compound of the general formula
A
~R5,R ~ Rl (II)
R 2
with a compound of the general formula
~L~.2383~
R8
,X~Rl o -^
a~9 (III)
rein Rl, R2, R3, R4 R5 R6 R8 R9 lo
and n have the signi~icance given earlier,
and either ~ represents a triarylphosphonium-
alkyl group of the formula ~-CH-P[Q]3 ~ Y ~ ,
in which R represents a hydrogen atom or the
methyl or ethyl group, Q represents an aryl
group a~d Y represents the anion o~ an
organic or inorganic acid, and B represents
the formyl group; or A represents the
formyl, acetyl or propionyl group and B
represents a dialkoxyphosphinylalkyl group
of the formula R-CH-P[Z]2, in which R has
the significance given earlier and Z
represents a lower alkoxy group;
to give a compound of formula I and, if desired, functlonally
modifying the group R10.
The aryl groups denoted by Q in the aforementioned
triarylphosphoniumalkyl groups include all generally known
aryl groups, but especially mononuclear aryl groups such as
phenyl, lower alkyl-substituted phenyl or lower alkoxy
-substituted phenyl (e.g. tolyl, xylyl, mesityl and p
-methoxyphenyl). Of the inorganic acid anions denoted by Y
~.23~39
-- 6 --
the chloride, bromide and hydrosulphate ions are preferred
and of the organic acid anions the tosyloxy ion is preferred.
The alkoxy groups denoted by Z in the aforementioned
dialkylphosphinylalkyl groups are preferably lower alkoxy
s groups (i.e. alkoxy groups containing 1-6 carbon atoms such
as the methoxy and ethoxy groups).
The starting materials of formula II, insofar as their
preparation is not known or described hereinafter, can be
prepared according tc known methods or in an analogous
manner to the methods described hereinafter.
Compounds of formula II in which A represents a
formyl, acetyl or propionyl group and Rl and R represent
hydrogen ~oxo compounds of formula II] can ~e prepared, for
example, by subjecting an indane derivative, which is
substituted in the cyclopentene ring corresponding to the
desired compound of formula I, or a tetrahydronaphthalene
derivative, which substi~uted in the cyclohexene ring cor-
responding to the desired compound of formula I, to an
acylation. This acylation can be carried out, for example,
in the presence of a Lewis acid.
Suitable acylating agents are formaldehyde/hydro-
chloric acid, acetyl halides (e.g. acetyl chloride) and
propionyl halides (e.g. propionyl chloride). me preferred
Lewis acids are the aluminium halides such as aluminium
7 ~3.~3~339
~richloride. The acylation is conveniently carried out in
a solvent, such as nitrobenzene or a chlorinated hydrocarbon
such as methylene chlorlde. The acylation is preferably
carried out at a temperature of from 0C to about ~5C.
i A resulting oxo compound of formula II in which Rl and
R2 each represent a hydrogen atom is reacted in accordance
with the present invention with a phosphonate of formula III
in -~hich B represents a dialkoxyphosphinylalkyl group to
give a compound of formula I in which Rl and R2 each
represent a hydrogen atom.
The phosphonium salts of formula II in which A rep-
resents a l-(triarylphosphonium)-(methyl or ethyl or propyl)
group required for the reaction with an aldehyde of formula
III in which B represents an oxo group can be prepared, for
example, as follows:
A~ aforementioned oxo compound of formula II in which
Rl and R2 represent hydrogen is reduced to give a cor-
responding alcohol at about 0C to about +5C using a
complex metal hydride (e.g. sodium borohydride in an alkanol
or lithium aluminium hydride in an ether, tetrahydrofuran or
dioxan). The resulting alcohol is subsequently halogenated
in the presence of an amine base (e.g. pyridine) using a
customary halogenating agent (e.g. phosphorus oxychloride or
phosphorus tribromide~. The halide obtained is then
reacted with a triarylphosphine in a solvent, preferably
i~ Z3839
triphenylphosphine in toluene or xylene, to give a deslred
phosphon~um salt of formula II.
Oxo compounds and phosphonium salts of formula II in
which Rl and R2 represent alkoxy or halogen can be prepared,
for example, by converting a corresponding phenol in a
manner known per se into a corresponding alkoxy-substituted
derivative of formula II by treatment with an alkylating
agent (e.g. a lower alkyl halide or a lower alkanol in the
presence of an acid agent).
The aforementioned phenols can be obtained, for
example, as follows:
An oxo compound of formula II in which Rl and R2
represent hydrogen is nitrated by treatment with a mixture
of concentrated nitric acid and concentrated sulphuric acid.
The nitro group which is preferentially introduced in the
ortho-position to the formyl, acetyl or propionyl group is
catalytically reduced in a manner known per se (e.g. with
the aid of Raney-nickel) to the amino group which is
replaced by the hydroxy group via the diazonium salt in a
known manner.
If the diazonium salt prepared from the amine is
.reated in the warm with a copper (I) halide, then there i~
obtained the corresponding halo derivative of the oxo com-
pound of formula II. By treating said halo derivative with
~.Z38~39
g
nitric acid it is possible to introduce, in the meta-
-position to the formyl, acetyl or propionyl group, a nitro
group which likewise can be replaced in the manner
previously described by the hydroxy group or a halogen atom~
By converting the hydroxy group into an alkoxy gxoup there
can be obtained, if desired, ketones of formula II which
carry similar or mixed substitution.
A halogen atom present on the aromatic nucleus can be
removed, i desired, by reduction in a manner known per se.
The compounds of formula III in which B represents the
formyl group can be prepared from phenyl derivatives which
are nitro-substituted in the l-position in the manner des-
cribed in Chem. Berichten 102 (1969), pages 2502-2507.
They can also be prepared by reducing a corresponding p-
-carboxy substituted phenyl derivative. The reduction of
the carboxyl group to the formyl group can be carried out,
for example, with dlisobutylaluminium hydride.
The compounds of formula III in which B represents a
dialkoxyphosphinylmethyl group can ke prepared from the
aforementioned compounds of ormula III in which B rep-
resents the formyl group by converting the formyl group
using a metal hydride (e.g. sodium borohydride) into the
hydroxymethyl group, halogenating the hydroxymethyl group
using a customary halogenating agent (e.g. phosphorus tri-
chloride) and reacting the resulting halomethyl group with a
38~!3
-- 10 --
trialkylphosphite, especially triethylphosphite, to give adesired phosphonate of formula III.
A compound of formula III in whlch B represents the
formyl group or a dialkoxyphosphinylmethyl group can be
prepared by halogenating a corresponding phenyl derivati~e
which is methyl-substituted in the l-position and either
reacting the resulting halomethyl derivative with a tri-
alkylphosphite or hydrolysing said halomethyl derivative to
the hydroxymethyl derivative and oxidising the latter by
treatment with an oxidising agent (e.g. manganese dioxide).
The reaction of a compound of formula II with a com-
pound of formula III in accordance with the process provided
by the present invention can be carried out according to the
known methods of the Wittig reaction or the Horner reaction.
There are preferably used as the starting ma~erials those
compounds of formula III in which R10 represents a group
which is not reactive towards phosphoranes such as, in
particular, the formyl group.
The functional modification of a group R10, also in
accordance with the process provided by the present inven-
tion, can comprise, for example, the conversion of the
carboxyl group into a salt, an ester, an amide, an oxaline
derivative or into the hydroxymethyl group which can sub-
sequently be etherified or esterified. Another functional
C 25 modification comprises the saponification of a carboxylic
383~
acid ester or the reduction thereof to the hydroxymethyl
group. The hydrox~methyl group can also be oxidised to the
formyl group. Compounds of formula I which contain a
formyl group can be converted, e.g. by means of a Wittig
reaction, into compounds of formula I in which R10 rep-
resents a group of the formula -(CH=CR19)mRl1 in which m
stands for 1, R19 represents hydrogen or alkyl and R
reDresents alkoxymethyl, alkanoyloxymethyl, carboxyl,
alkoxycarbonyl, or alkyl. All of ~hese
functional modifications can be carried out according to
methods known pex se.
In the case of the Wittig reaction, the starting
materials are reacted with one another in the presence of an
acid binding agent, for example, in the presence of a strong
base such as butyl lithium, sodium hydride or the sodium
salt of dimethyl sulphoxide, but preferably in the presence
of an ethylene oxide which is optionally substituted by
lower alkyl such as 1,2-butylene oxide, if desired in a
solvent (e.g. an ether, such as diethyl ether or tetra-
hydrofuran or an aromatic hydrocarbon such as ben~ene) at atemperature between room temperature and the boiling point
of the reaction mixture.
In the case of the Horner reaction, the starting
materials are reacted with one another in the presence of a
base and, preferably, in the presence of an inert organic
~, solvent; for example, in the presence of sodium hydride in
~,
~L~.Z3839
- 12 -
benzene, toluene, dimethylformamide, tetrahydro~uran, dloxan
or 1,2-dimethoxyalkane or in the presence of a sodium
alcoholate in an alkanol le.g. sodium methylate in methanol)
at a temperature between 0C and the boiling point of the
S reaction mixture.
It has been found to be convenient in certain cases to
carry out the aforementioned reactions in situ, i.e. to
react ~he starting materials with one anothel~ without
isolating the phosphonium salt or phosphonate in question
from the medium in which it is prepared.
A carboxylic acid of formula I can be converted in a
manner known per se (e.g. by treatment with thionyl
chloride, prefera~ly in pyridine, or phosphorus trichloride
in toluene) into an acid chloride which can be converted by
l; reaction with an alcohol into an ester or by reaction with
an amine into a corresponding amide. Amides can be con-
verted into amines in a manner known per se; for example,
by reduction with complex metal hydrides such as lithium
aluminium hydride.
A carboxylic acid ester of formula I can be hydrolysed
in a manner known per se (e.g. by treatment with alkali,
especially by treatment with aqueous-alcoholic sodium
hydroxide or potassium hydroxide) at a temperature between
room temperature and the boiling point of the mixture and
the resulting carboxylic acid can then be amidated via an
- 13 - ~.Z 383g
acid halide as described eaxlier. Alternatively, a
carboxylic acid ester of formula I can be directly amidated
as described hereinafter.
A carboxylic acid ester of formula I can be converted
directly into a corresponding amide, for example by treat-
ment with lithium amide. The ester is advantageously
treated with lithium amide at room temperature.
A carboxylic acid of formula I can be converted into
an oxa~oline derivative of formula I via a halide by
reaction with 2-aminoethanol or 2-amino-2-methyl-1-propanol
and subsequent cyclisation.
A carboxylic acid or carboxylic acid ester of formula
- I can be reduced in a manner known per se to give a cor-
responding alcohol of formula I. The reduction is advan-
tageously carried out using a metal hydride or alkyl metalhydride in an inert solvent. Especially suitable hydrides
are the mixed metal hydrides such as lithium aluminium
hydride or bls~methoxy-ethylenoxy]-sodium aluminium hydride.
Suitable solvents are, inter alia, ether, tetrahydrofuran or
dioxan when lithium aluminium hydride is used and ether,
hexane, benzene or taluene when diisobutylaluminium hydride
or bis~methoxy-ethylenoxy]-sodium aluminium hydride is used.
An alcohol of formula I can be etherified with an
alkyl halide (e.g. methyl iodide), for example, in the
:,
- 14 ~ 3~ 39
presence of a base, preferably sodium hydride, in an organic
solvent such as dioxan, tetrahydrofuran, 1,2-dimethoxyethane
or dimethylformamide, or in the presence of an alkali metal
alcoholate in an alkanol, at a temperature between 0C and
room temperature.
An alcohol of formula I can be esterified by treatment
with an alkanoyl halide or anhydride, conveniently ln the
presence of a base ~e.g. pyridine or triethylamine) at a
t mperature range between room temperature and the boiling
point of the mixture.
A carboxylic acid of formula I forms salts with bases,
especially with alkali metal hydroxides and preferably with
sodium hydroxide or potassium hydroxide.
The compounds of formula I occur predominantly in the
trans form. Cis isomers which may be obtained can be
separated or isomerised to the trans isomers in a mannex
known per se where desired.
The stilbene derivatives provided by the present
invention are pharmacodynamically valuable. They can be
used for the topical and systemic therapy of benign and
malignant neoplasms and of premalignant lesions as well as
for the systemic and topical prophylaxis of the said
conditions.
~ . -
- 15 _ 1~.23l 33~
The present stilbene derivatlves are also suitable ror
the topical and systematic therapy of acne, psoriasis and
other dermatoses accompanied by an intensified or patho-
logically altered cornification, as well as of in~lammatory
and allergic dermatological conditions. They can moraover
be used for the control of mucous membrane diseases
associated with inflammatory or degenerative or metaplastic
changes.
Compared with known retinoids, the stilbene deriv-
atives provided by this invention are characterised in thatthey are active in extraordinarily slight amounts.
The tumour-inhibiting activity of the present stilbene
derivatives is significant. In the papilloma test in mic~,
tumours induced with dimethylbenzanthracene and croton oil
regress. In the case of the intraperitoneal administration
of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)propenyl]-benzoic acid ethyl ester, the diameter
of the papilloma decreases in the course of 2 weeks by 75
at a dosage of 0.2 mg/kg/week, by 56~ at a dosage of 0.1
mg/kg/week and by 48~ at a dosage of O.OS mg/kg/week. In
the case of oral administration of p-~(E)-2-(5,6,7,8-tetra-
hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid
ethyl ester to mice, the diameter of the induced tumours
decreases in the course of 2 weeks (5 individual doses/week)
~y 63~ at a dosase of 0.4 mg(S x 0.08 mg)/Xg/week, by 48% at
a dosage of 0.2 mg (5 x 0.04 mg)/kg/week and by 37% at a
dosage of 0.05 mg (5 x 0.01 mg)/kg/week.
- 16 - ~ 383~
The stilbene derivatives provided by this invention
can also be used for the oral treatment of rheumatic ill-
nesses, especially those of an in1ammatory or degenerative
kind whlch attac~ the joints, muscles, tendons and other
parts of the motor apparatus. Examples of such illnesses
are rheumatic arthritis, Bechterew's spondyl-
arthritis ankylopcetica and psoriatic arthropathy.
For the treatment of these illnesses, the presPnt
stiIbene derivatives are administered orally, the dosage in
the case of adults conveniently being about 0.01-1 mg/kg
body weight per day, preferably 0.05-0.5 mg/~g/day. A
possible over-dosage can manifest itself in the form of a
vit-A hypervitaminosis which can readily be recognised from
its symptoms (scaling of the skin, hair loss).
The dosage can be administered as a single dosage or
in several sub-divided dosages.
The stilbene derivatives provided by the present
invention can therefore be used as medicaments, or example
in the form of pharmaceutical preparations which contain
them in association with a carrier material.
The pharmaceutical preparations suitable for systemic
.administration can be produced, for example, by adding a
compound of formula I or a salt thereof as the active
ingredient to non-toxic, inert, solid or liquid carriers
which are conventionally-used in such preparations.
- 17 - ~ Z 3~ 3g
The pharmaceutical preparations can be administered
enterally, parenterally or topically. Suitable preparations
for enteral ad~inistration are, for example, tablets,
capsules, dragées, syrups, suspensions, solutions and sup-
positories. Sultable preparations for parenteral admln-
istration are infusion or injection solutions.
~ he dosages in which the present stilbene derivatives
are administered can vary according to the particular dosage
form and mode of administration as well as according to the
requirements of the patient,
The stilbene derivatives of this invention can be
administered in amounts of ca 0.01 mg to ca 5 mg daily in
one or more dosages. ~ preferred form of administratlon
comprises capsules containing ca 0~1 mg to ca l.0 mg of
active ingredient.
The pharmaceutical preparations can contain inert as
well as pharmacodynamically active addltives. Tablets or
granulates, for example, can contain binding agents,
filling agents, carrier substances or diluents. Liquid
preparations can take the form of, for example, sterile
solutions which are miscible with water. Capsules can
contain, in addition to the active ingredient, a filling
agent or thic.~ening agent. Furthermore, flavour-improving
additives, substances normally used as preservatives,
stabilisers, wetting agents and emulsifying agents as well
~.Z3~39
- 18 -
as salts for varying the osmotic pressure, buffers and other
additives may also be present in the pharmaceutical
preparations.
The aforementioned carrier substances and diluents can
be organic or inorganic in natuxe; for example, water,
gelatin, lactose, starch, magnesium stearate, talc, gum
arabic, polyalkyleneglycols and the like. A prerequisite
is that all adjuvants used in the production of the pharma-
ceutical preparations are non-toxic.
For topical administration, the pharmaceutical
preparations are conveniently provided in the orm of oint-
ments, tinctures, creams, solutions, lotions, sprays,
suspensions and the like. Ointments, creams and solutions
are preferred. These pharmaceutical preparations for
topical administration can be produced by mixing the present
stilbene derivatives with non-toxic! inert, solid or liquid
carriers which are customary per se in such preparations
and which are suitable for topical administration.
For topical administration there ara suitably used ca
0.001~ to ca 0.3~, preferably 0.02% to 0.1%, solutions, as
well as ca 0.002% to ca 0.5%, preferably ca 0. 02~, to ca
0.1~, ointments or creams.
The pharmaceutical preparations may contain an anti-
oxidant (e.g. tocopherol, N-methyl-~-tocopheramine,
butylated hydroxyanisole or butylated hydroxyto-luene).
383~
-- 19 --
The following Examples illustrate the process provided
by the present invention:
Example 1
300 ml of butylene oxide are added to 30.5 g of ~1-
~(1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium
bromide and 8 g of 4~ethoxycarbonylbenzaldehyde and the
mixture is ~hen stirred at 65C for 12 hours in an inert gas
atmosphere. The resulting clear solution is cooled,
introduced into ca 500 ml of ice/water and extracted twice
with hexane. The organic extract is extracted three tim~s
with methanol/water, dried over sodium sulphate and concen-
treated under reduced pressure. m e residue is puri~ied
by adsorption on silica gel using hexane/ether (19:1) or
the elution. The p-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)-
lS -propenyl]-benzoic acid ethyl ester obtained from the eluate
melts at 70-71C after recrystallisation from ether/hexane.
The ~1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]-~ri-
phenylphosphonium bromide used as the starting material can
be prepared, for example, as follows:
87.8 g of acetyl chloride are dissolved in 240 ml of
nitrobenzene. 149.2 g of aluminium chloride are introduced
portionwise into the solution. The mixture is cooled down
to 0-5C and then treated dropwise while cooling well with
a solution of 195.0 g of 1,1,3,3-tetramethyl-indane in 360
~J.23839
- 20 -
ml of nitrobenzene. The temperature should no~ rise above
5C. The mixture is stirred at 0C for 15 hours, then
introduced into 3 litres of ice/water and extracted with
ether. The ether extract is washed twice with a 2-N sodlum
hydroxide solution and twice with a saturated sodium
chloride solution, dried over sodium sulphate and concen-
trated, firstly in a water-jet vacuum and then in a high
vacuum to remove the nitrobenzene. The residual oily
~1,1,3,3-tetramethyl-5-indanyl)-methyl ketone boils at lQ0-
-103C/0.5 Torr.
2.6~ g of lithium aluminium hydride are treated with
40 ml of absolute ether. While cooling to 0-5C there are
added dropwise within 30 min~tes 26 g of lrl,3,3-tetra-
methyl-5-indanyl methyl ketone. After a further 30
minutes, the mixture is cautiously treated dropwise with 25
ml of a saturated sodium sulphate solution. The solution
is filtered. The filtrate is washed once with a l-N sodium
hydroxide solution and twice with a saturated sodium
chloride solution, dried over sodium sulphate and concen-
trated under reduced pressure to remove the solvent. Theresidual oily a-1,1,3,3-pentamethyl-5-indane-methanol, which
is uniform according to thin-layer chromatography [flow
agent: hexane/ether (80:20)], is immediately processed as
follows:
24.0 g of ~-l,1,3,3-pentamethyl-5-indane-methanol are
dissolved in 20 ml of absolute ether and 100 ml of absolute
hexane. After the addition of 2 drops of pyridine, the
l~.Z3839
- 21 -
solution is treated dropwise over a period of 30 minutes
with 16.2 g of phosphorus tribromide dis501ved in 80 ml of
absolute hexane. After stirring at 0-5C for a further
hour, the product is introduced into ice/water and
exhaustively extracted wlth ether~ The ether extract is
washed twice with a saturated sodium bicarbonate solution
and twice with a sodium chloride solution, dried over sodium
sulphate and evaporated under reduced pressure to remove the
solvent. The residual ~ily 5~ bromoethyl)-1,1,3,3-
-tetramethyl-indane, which is uniform according to thin-
layer chromatography ~flow agent: hexane/ether (95:5)~, is
immediately processed as follows:
26.3 g of triphenylphosphine are dissolved in 120 ml
of xylene. The solution is treated with 30.9 g of 5~
-bromoethyl)-1,1,3,3-tetramethyl-indane dissolved in 60 ml
of xylene. The mixture is warmed to 100C while stirring
and left at this temperature for 12 hours. The thick-oily
1-(1,1,3,3-tetramethyl-5-indanyl)ethyl-triphenylphosphonium
bromide which thereby separates out and which crystallises
after seeding melts a~ 151-156C after recryst~llisation
~rom methylene chloride/toluene (crystals contain 0.3
equivalents of toluene).
Example 2
2.4 g of 1,1,3,3-tetramethyl-5-indanyl methyl ketone
and 3.4 g of 4-[(diethoxyphosphinyl)methyl]-benzoic acid
- 2~ 3~39
ethyl ester are dissolved in 7 ml of dimethylformamide,
The solution is treated dropwlse under ~rgon at room tem-
perature ~hile stirring with a sodium ethanolate solutlon
(prepared from 0.33 g of sodium and 7 ml of ethanol) and
; subsequently stirred at 70C for 18 hours. The mixture is
subsequently introduced into ice/water and extracted with
ether. The ether extract is washed with a saturated sodium
chloride solution, dried over sodium sulphate and evaporated
under reduced pressure. The residual p- L (E)-2-~l,1,3,3-
tetramethyl-5-indanyl)propenyl]-benzoic acid ethyl ester, a
brown oil, is puriried by adsorption on silica gel using
hexane/ether (9:1) for the elution. Tne ester melts at
70-71C after recrystallisation from hexane/ether~
Example 3
In a manner analogous to that described in Example l,
from ~1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl-
-benzaldehyde there can be obtained p~c~E)-2-~s~6~7~8-
-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic
acid ethyl ester or melting point 90-91C.
The [l-~5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)ethyl]-triphenYlphosphonium bromide used as the
starting material can be prepared in a manner analogous to
that des~ribed in Example l, rrom 5,6,7,8-tetrahyd~o-5,5,8,
8-tetramethyl-naphthalene via (i,6,7,8-tetrahydro-5,5,8,8-
-tetramethyl-2-naph-thyl)methyl Xetone, 5,6,7,8-tetrahydra- ~ -
- 23 _ ~.2383~
-a-5,5,8,8-pentamethyl-2-naphthalene-methanol and 2-(bromo-
ethyl3-5,6,7,8~tetrahydro-5,5,8,8-tetramethyl-naphthalene.
Example 4
In a manner analogous to that described in Example 1,
from tl-(3-methoxy-5~6~7~8-tetrahydro-s/5~8~8-tetrameth
-2-naphthyl)ethyll~triphenylphosphonium bromide and 4-
-ethoxycarbsnyl-benzaldehyde there can be obtained p`~(E)-
-2-~3-methoxy-5,6,7 r 8-tetrahydro-5,5,8,8-tetramethyl-2-
-~aphthyl)propenyl]-ben~oic acid ethyl ester of melting
point 97-98C.
The ~1-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)ethyl]-triphenylphosphonium bromide used
as the starting material can be prepared in a manner
analogous to that described in Example 1, rrom 3-methoxy-
-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene via
(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)methyl ketone, 3-methoxy-5,6,7,8-tetrahydro-S,S,
8,8-tetramethyl-2-naphthalene-methanol and 2-(1-bromoethyl~-
-3-methoxy-5,6,7,8-tetrahydro-S,5,8,8-tetramethyl-naphtha-
lene~
Example S
In a manner analogous to that described in Example 1,
from [1-(5,6,7,8-tetrahydro-5,i,8,8-tetramethyl-2-naphthyl)-
.
~3.Z3~339
- 24 -
ethyl]-triphenylphosphonium bromide and 3-methyl-4-ethoxy-
carbonyl-benzaldehyde there can be obtained p-~(E)-2-(5,6,7,
8-tetrahydro-5,5,8,8~tetramethyl-2-naphthyl)propenyl]-2-
-methyl-benzoic acid ethyl ester as a colourless oil which is
S uniform according to thin-layer chromatography, (Rf = 0.6;
hexane/15~ ether).
The aforementioned 3-methyl-4-ethoxycarbonyl-benz-
aldehyde can be prepared from 4-nitro-3-methyl-benzoic acid
in a manner analogous to that described for the preparation
of 2-methyl-4-ethoxycar~onyl-benzaldehyde by Huneck et al in
Chem. Ber. 102, 2502-2507 (1969).
Example 6
In a manner analogous to that described in Example l r
from [l-(1,1,2,3,3-pentamethyl-5-indanyl)ethyl]-triphenyl-
phosphonium bromlde and 4-ethoxycarbonyl~benzaldehyde there
can be obtained p-~(E)-2-(1,1,2,3,3-pentamethyl-5-indanyl)-
propenyl]-benzoic acid ethyl ester of melting point 79-
-80C.
Example 7
In a manner analogous to that described in Example l~
from [1-(7-methoxy-1,1,3,3-tetramethyl-5-indanyl)ethyl]-
-triphenylphosphonium bromide and 4-ethoxycarbonyl-benz-
aldehyde there can be obtained p-[(E)-2-(7-methoxy-1,1,3,3-
~.Z383~
- 25 -
-tetramethyl-5-indanyl)-propenyl]-ben~oic acid ethyl ester
of melting point 72-73C.
The [1-~7-methoxy-1,1,3,3-tetramethyl-5-indanyl)-
ethyl]-triphenylphosphonium bromlde used as the starting
material can be prepared, for example, as follows:
84.3 g of (1,1,3,3-tetramethyl-5-indanyl) methyl
ketone (prepared as descri~ed in Example 1) are dissolved in
160 ml of concentrated sulphuric acid and the solution is
cooled down to -20C. At this temperature there is added
during 10 minutes the nitrating acid prepared from 40 ml of
concentrate,d nitric acid and 80 ml of concentrated sulphuric
acid. After completion of the addition, the thick paste is
immediately poured on to ice and extracted twice with ether~
The ether extract is washed with a sodium bicarbonate
solution and a sodium chloride solution, dried over sodium
sulphate and freed from solvent under reduced pressuxe.
The separated (6-nitro-1,1,3,3-~etramethyl-5-indanyl) methyl
ketone melts at 111-112C after recrystallisation from
ether/hexane.
75.8 g of (6-nitro-1,1,3,3-tetramethyl-5-indanyl)
methyl ketone are dissolved in 1500 ml of methanol and the
solution is hydrogenated at 45C for 48 hours under nitrogen
with the aid of 20 g of Raney-nickel. 15 litres of
hydrogen are taken up. The solution is then filtered
through Speedex and the solvent is removed under reduced
3~3~
- 26 -
pressure. The separated (6-amino-1,1,3,3-tetramethyl-5-
-indanyl) methyl ketone melts at 161-162C after recrystal-
lisation from ether/hexane.
113.1 g of (6-amino-1,1,3,3-tetramethyl-5-indany~
S methyl ketone are suspended in 2260 ml of 20% hydrochloric
acid and the suspension is cooled down to 0-5C. The cold
mixture is treated dropwise within 10 minutes with a solution
of 33.9 g of sodium nitrite in 115 ml of water and the
resulting solution is stirred for 30 minutes. The cold
solution is subsequently introduced dropwise over a period
of 2 hours while stirring into a solution of 243.2 g of
copper (I) chloride in 250 ml of water and 250 ml of concen-
trated hydrochloric acid, which is warmed to 40-45C. The
mixture is then cooled down, introduced into ice-water and
lS extracted three times with methylene chloride. The organic
extract is washed with a sodium chloride solution, dried
over sodium sulphate and freed from solvent under reduced
pressure. The residue is purified by adsorption on silica
gel using hexane/acetone (19:1) for the elution. The (6-
-chloro-1,1,3,3-tetramethyl-S-indanyl) methyl ketone
obtained from the eluate melts at 69-71C after recrystal-
lisation from hexane/ether.
In an analogous manner, from (6-chloro-1,1,3,3-tetra-
methyl-5-indanyl) methyl ketone there can be obtained (6-
-chloro-7-nitro-1,1,3,3-tetramethyl-S-indanyl) methyl ketone
of melting point 119-120C, and from (6-chloro-7-nitro-
~ ~`.23~33~
- 27 -
-1,1,3,3-tetramethyl-5-indanyl) methyl ketone there can be
obtalned (6-chloro-7-amino-1,1,3,3-tetramethyl-5-indanyl)
methyl ketone of melting point 116-117C.
21.1 g of (6-chloro-7-amino-1,1,3,3-tetramethyl-5-
-indanyl) methyl ketone are introduced into 48 ml o concen-
trated sulphuric acid and, after the warming to S0C, the
mixture is treated slowly with 140 ml of distilled water,
After cooling down to 0-5C, there is introduced dropwise
into the mixture over a period of 45 minutes a solution of
5.5 g of sodium nitrite in 20 ml of water. The resulting
cold mixture is lntroduced dropwise while stirring over a
period of 2 hours into a solution, held at 70C, of 60 ml of
water and 60 ml of concentrated sulphuric acid. The
mixture is cooled, then introduced into ice-water and
extracted three times with ether. The organic phase is
washed with a sodium chloride solution, dried over sodium
sulphate and freed from solvent under reduced pressure.
The residue is purified by adsorption on silica gel using
hexane/ether (19:1) ror the elution. The t6-chloro-7-
-hydroxy-l,1,3,3-tetramethyl-5-indanyl) methyl ketone
obtained from the eLuate melts at 78-80C ater recrystal-
lisation from hexane/ether~
4.4 g of (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5-
-indanyl) methyl ketone are dissolved in 10 ml of dimethyl-
formamide. The solution is treated first with 1.1 g ofpotassium hydroxide (dissolved in 1.2 ml of water) and then
~.Z3l33g
- 28 -
with 5.5 ml of methyl iodide and the resulting mixture is
subsequently stirred at room temperature for 3 hours. The
mixture is introduced into ice-water and extracted twice
with ether. The organic extract is washed several times
with a sodium chloride solutlon, dried over sodium sulphate
and freed from solvent under reduced pressure. The
separated (6-chloro-7-methoxy-1,1,3,3-tetramethyl-5-indanyl)
methyl ketone meLts at 59-60C after recrystallisation.
25 g of (6-chloro-7-methoxy-1,1,3,3~te~ramethyl-5-
-indanyl) methyl ketone are dissolved in ca 200 ml of
methanol and, after the addition of 10 g of triethylamine
and 2.5 g o~ 5~ palladium/carbon catalyst, the mixture is
- hydrogenated at room temperature. 1 mol equivalent of
hydrogen is taken up over a period of 5 hours. The
solution is filtered over Speedex. The filtrate is
evaporated. The residue is dissolved in water/ether and
extracted several times with ether. The organic extract
is washed with sodium chloride solution, dried over sodium
sulphate and freed from solvent under reduced pressure.
The separated (7-methoxy-1,1,3,3-tetramethyl-5-indanyl)
methyl ketone melts at 76-77C a~ter recrystallisation from
hexane.
In a manner analogous to that described in Example 1,
.rom (7-methoxy-1,1,3,3-tetramethyl-5-1ndanyl) methyl ketone
via 7-methoxy-~-1,1,3,3-pentamethyl-5-ir.dane-methanol and
5-(1-bromoethyl)-7-methoxy-1,1,3,3-tetramethyl-indane there
~.Z3839
- 29 -
can be obtained [1-(7-methoxy-1,1,3,3-tetramethyl-S-indanyl)-
ethyl]-triphenylphosphonium bromide of melting point 209-
-210C.
Example 8
In a manner analogous to that described in Example 1,
from [(1,1,3,3-tetramethyl-5-indanyl)methyl]-triphenyl-
phosphonium chloride and 4-ethoxycarbonyl-benzaldehyde there
can be obtained p-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)-
vinyl]-bengoic acid ethyl ester of melting point 151-152C.
The ~(1,1,3,3-tetramethyl-5-indanyl)methyl~-triphenyl-
phosphonium chloride used as the starting material can be
prepared, for example, as follows:
34.2 g of 1,1,3,3-tetramethyl-indane, lS0 ml of
glacial acetic acid, 300 ml of concentrated hydrochloric
acid and 77 ml of formaldehyde solution (35~) are warmèd to
75-78C while stirring for 2 hours. A further 7.7 ml o~
35~ formaldehyde solution are then àdded dropwise within 10
minutes. The mixture is held at the same temperature for
lS hours, then cooled down, introduced into ca 1 litre of
ice-water and exhaustively extracted with toluene. The
organic phase is washed neutral with water, dried over
sodium sulphate and evaporated under reduced pressure. The
resulting crude product, a reddish cil, is distilled over a
Vigreux column The pure 5-chloromethyl-1,1,3,3-tetra-
methyl-indane boils at 1~3-146C/l9 mmHs.
1~.23~39
- 30 -
In a manner analogous to that described in Example 1,
from 5-chloromethyl 1,1,3,3-tetram~thyl-lndane and trl-
phenylphosphine t~ere can be obtained ~1-(1,1,3,3-tetra-
methyl-5-indanyl)m~thyl]-trlphenylphosphonium chlorlde.
S Example ~
In a manner analogous to that described in Example 1,
from ~1-(1,1,3,3-tetramethyl-S-indanyl)ethyl~-triphenyl-
phosphonium bromide and 4-acetyl-benzaldehyde there can be
obtained 4'-E(E)-2-(1,1,3,3-tetramethyl-5-indanyl)propenyl~-
-acetophenone of meltinq point 130-131C.
Example 10
49 g of p-~(E)-2-(5,6,7,8-tetrahydro-S,5,8~8-tetra-
methyl-2-naphthyl)propenyl]-benzoic acid ethyl ester
(prepared as descri~ed in Example 3) are dissolved in 500 ml
of ethanol at 45C and the resulting solution is treated
dropwise while stirring with a solution of 20 g of potassium
hydroxide in S0 ml of water. The mixture is stirred at
55C for 18 hours, then cooled, introduced into ice/water,
acidified to pH 2 with 3-N sulphuric acid and extracted
twice with methylene chloride. The methylene chloride
extract is washed with a saturated sodium chloride solution,
dried over anhydrous sodium sulphate and concentrated under
reduced pressure. me residual p-~(E)-2-(5,6,7,8~tetra-
hydro-5,5,8,$-tetramethyl-2-naphthyl)propenyl]-benzoic acid
~-~.Z~839
- 31 -
melts at 247-248C after recrystallisation from methylene
chloride/hexane.
Example ll
Into a suspension of 7.0 g of p-[(E)-2-(5,6,7,8-tetra-
hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid
(prepared as described in Example lO) in 40 ml of absolute
ether are introduced dropwise, a~ter addition of 1.8 ml of
pyridine, while stirring at 0-5C 3.5 ml of thionyl
chloride. ALter the addition of 5 drops of N,N-dimethyl-
formamide, the solution is warmed to room temperature,stirred for 18 hours and then decanted off. The clear
yellow solution of the acid chloride is introduced dropwise
u~der argon into a solution of 3 ml of ethylamine in 20 ml
of absolute ether. The mixture is stirred at room
temperature for Z hours, then introduced into a saturated
sodium chloride solution and extracted twice with ether.
The ether extract is washed with a saturated sodium chloride
solution, dried over anhydrous sodium sulphate and evapor-
ated under reduced pressure. The residual p ~(E)-2-(5,6,7,
8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-
-benzoic acid monoethylamide melts at 177-178.5C after
recrystallisation from methylene chloride/hexane.
Exam~le 12
:
11.3 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzoic acid ethyl es-ter
- 32 - ~ 3839
(prepared as described in Example 3) dissolved in 20 ml of
absolute ether and 20 ml of absolute tetrahydrofuran are
introduced dropwise at 0-5C into a suspension of 1.33 g of
lithium aluminium hydride in 20 ml of absolute ether. The
solution is stirred at room temperature for 12 hours under
an inert gas, then treate,d dropwise at 0-5C ~ith 5 ml of a
saturated sodium sulphate solution and filtered over Speedex.
The filtrate i5 diluted with ether and washed once with a
saturated sodium bicarbonate solution and twice with a
saturated sodium chloride solution, dried over sodium
sulphate and concentrated under reduced pressure. The
separated p-[(E~-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthyl)propenyl]-benzyl alcohol melts at 123-124C
after recrystallisation from methanol/ether.
Example 13
5.8 ml of acetyl chloride are introduced dropwise at
ca 5C while stirring into a suspension o~ 6.6 g of p-~(E)-
-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
propenyl]-benzyl alcohol (prepared as described in Example
12) in 10 ml of ether and 10 ml of pyridineO The mixture
is stirred at room temperature for 3 hours, then introduced
into ca 100 ml of ice/water and extracted three times with
ether. The ether extract is washed once with l-N hydro-
chloric acid and three times with a saturated sodium
chloride solution, dried over sodium sulphate and concen-
trated under reduced pressure. The separated p-[(E)-2-
31~39
- 33 -
-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)pro-
penyl]-benzyl acetate melts at 100-101C after recrystal-
lisation from ether.
Example 14
s S.0 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzyl alcohol (prepared as
described in Example 12) dissolved in 25 ml of dimethyl-
formamide are introduced into a solution of 0.4 g of sodium
hydride in 10 ml of dimethylformamide. After stirring at
room temperature for 1 hour, the mixture is treated with 4.8
g of methyl iodide and the resulting mixture is stirred for
a further 2 hours. The solution is then introduced into ca
200 ml of ice/water and extracted three times with ether.
The ether extract is washed three times with a saturated
sodium chloride solution, dried over sodium sulphate and
concentrated under reduced pressure. The separated p-[(E)-
-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
propenyl]-benzyl methyl ether melts at 55-56C after
recrystaLlisation from ether.
Example 15
3.48 g of p-~(E)-2-(5,6,7,8-tetrahydro~5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzoic acid (prepared as
described in Example 10) are suspended in 12 ml of toluene.
After the addition of 3.57 g of thionyl chloride, the
3~33~
suspension is stirred at 50C for 12 hours and then
evaporated to dryness under reduced pressure. The residue
is dissolved in 6 ml of methylene chloride. The solution
is introduced dropwise at 0C into a solution o~ 2.3 g of
2-amino-2-methyl-1-propanol in 6 ml of methylene chlorlde.
The white suspension is stirred at room temperature for 2.5
hours, diluted with ethyl acetate, washed three times with
water, dried over sodium sulphate and concentrated under
reduced pressure. The white crystalline residue is sus-
pended in 20 ml of ether and treated dropwise at 0C with6 g of t~ionyl chloride. The white suspension is stirred
at room temperature for 30 minutes and then treated
cautiously with a saturated sodium carbonate solution until
the pH value amounts to ca 9. The now clear solution is
diluted with ether. The ether phase is washed three times
with a saturated sodium chloride solution, dried over sodium
sulphate and evaporated under reduced pressure. The
residual 2-_ p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-phenyl 7-4,~-dimethyl-2-
-oxazoline melts at 115-116C after recrystallisation from
ether.
Example 16
In a manner analogous to that described in Example 1,
from [l-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
propyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl-
-benzaldehyde there can be obtained p-[(E)-2-(5,6,7,8-tetra-
~3.23~339
- 35 -
hydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butenyl]-benzoic
acid ethyl ester of melting point 82-83C.
The ~1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)propyl]-triphenylphosphonium bromlde used as the
starting material can be obtained in a manner analogous to
that described in Example 1 from 5,6,7,8-tetrahydro-5,5,8,8-
-tetramethyl-naphthalene and propionic acid chloride.
Exam~le 17
In a manner analogous to that described in Example 11,
from p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)propenyl]~benzoic acid and diethylamine there can
be obtained p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzoic acid diethylamide of
melting point 111-112C.
Example 18
In a manner analogous to that described in Example 11,
from p-~(E)-2-~5,6,7,8-tetrahydro-5,5,8,8-te~ramethyl-2-
-naphthyl)propenyl]-benzoic acid and morpholine there can be
obtained p-~(E)-2-~5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)propenyl]-benzoic acid morpholide of melting
point 143-144C.
~.Z3~3~
- 36 -
Example 19
In a manner analogous to that described in Exampl~ 11,
from p-~(E)-2-~5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-~-
-naphthyl)propenyl]-benzoic acid and isopropanol there can
S be obtained ~-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra~
methyl-2-naphthy})propenyl]-benzoic acid isopropyl ester of
melting poin. 119-120C.
. Example ~Q
6.7 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzyl alcohol (prepared as
described in Example 12) dissolved in 100 ml of absolute
ether are added dropwise within 10 minutes to a stirred
suspension, cooled to 0-SC, of manganese dioxide in 100 ml
of absolute ether. The mixture is stirred at room tem-
perature overnight and then filtered ~hrough*Celite. mefiltrate is concentrated to dryness on a rotary evaporator.
*trade mark
~L~.23~39
- 37 -
The yellowish oil crystallises. Recrystallisation from
ether yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzaldehyde in the form o~
colourless crystals of melting point 140-141C.
Examole 21
In a manner analogous to that described in Example 1,
from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
ethyl]-triphenylphosphonium ~romide and 4 acetyl-benz-
aldehyde there can be obtained ~ (E)-2-(5,6,7,8-tetra-
hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-acetophenone
of melting point 148-149C.
Example 22
3.0 g of 4'-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-acetophenone (prepared as des-
cribed in Example 22) dissolved in 40 ml of ben~ene are
treated with a catalytic amount of p-toluenesulphonic acid
and 0.6 g of ethyleneglycol and warmed in a Dean-Stark
apparatus, the water formed being concurrently separated
off. After heating under reflux for 2 days, the mixture is
cooled down, introduced into ice/saturated sodium bicar
bonate solution and exhaustively extracted with ether. The
ether extract is washed twice with a saturated sodium
chloride solution, dried over sodium sulphate and evaporated
_ under reduced pressure to remove the solvent. The oily
~.2~3~
- 38 -
residue ls purified by adsorption on silica gel using
hexane/ether (9:1) for the elution. The 2-methyl-2-L p-
-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tet_amethyl-2-naphthyl)-
propenyl]-phenyl 7-1, 3-dioxolane obtained from the eluate
melts at 122-123C after recrystallisation from ether.
Example 23
1.0 g of sodium borohydride is cautiously added
portionwise at 0-5C to 10.4 g of 4'-~(E~-2-(5,6,7,8-tetra-
hydro-5,5,8,8-tetramethyl-2-naphthyl)~ropenyl]-acetophenone
(prepared as described in Example 21) dissolved in 100 ml
of absolute methanol. The solution is stirred at 0C for
1 hour and at room temperature for 2 hours, then introduced
into ice/water and exhaustively extracted with ether. The
ether solution is washed twice with a saturated sodium
chloride solution, dried over sodium sulphate and concen-
trated under reduced pressure. The separated a-methyl-p-
-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
propenyl~-benzyl alcohol melts at 121-123C after crystal-
lisatlon from ethe~,
Example 24
In a manner analogous to that described in Example 14,
from -methyl-p-[~E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzyl alcohol there can be
obtained 1,2,3,4-tetrahydro-6-[(E)-p~ methoxyethyl)-a~
~.Z3~39
- 3g -
-methyl-styryl]-1,1,4,4-tetramethylnaphthalene of meltlng
point 88-89C
Example 25
In a manner analogous to that described ln Example 13,
; from a-methyl-p-[~E)~2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-b~nzyl alcohol there can be
obtained -methyl-p-t(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-
-tetramethyl-2-naphthyl)propenyl]-benzyl acetate of melting
point 85-86C.
Example 26
In a manner analogous to that described in Example 1,
from tl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
ethyl]-triphenylphosphonium bromide and 4-methyl-benz-
aldehyde there can be obtained 6-~(E)-p,a-dimethylstyryl]-
-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of
melting point 84-85C.
Example 27
In a manner analogous to that described in Example 1,
from tl-(5,6,7,8~tetrahydro-5,5,8,8~tetramethyl-2-naphthyl)~
ethyl]-triphenylphosphonium bromide and 4-isopropyl-benz-
aldehyde there can be obtained 6-[(E)-p- sopropyl-a-methyl-
styryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of
melting point 86-87C.
~.Z3B39
- 40 -
Example 28
In a manner analogous to that described in Example 1,
from tl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-~aphthyl)-
ethyl]-triphenylphosphonium bromide and 2,4-dimethyl-benz-
aldehyde there can be obtained 6-[(E)-a,2,4-trimethylstyryl]-
-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of
melting point 54-56C.
Example 29
In a manner analogous to that described in Example 1,
but preerably with a longer reaction time, from methyl~
-triphenylphosphonium bromide and p-~(E)-2-(5,6,~,8-tetra-
hydro-5,5,8,8-tetramethyl 2-naphthyl)propenyl~-benzaldehyde
(prepared as described in Example 20) there can be obtained
1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-~(E)--methyl-p-
-vinylstyryl]naphthalene of melting point 94-95C.
Example 30
In a manner analogous to that described in Example 1,
but preferably with a longer reaction time, from ethyl-
-triphenylphosphonium bromide and p-[(E)-2-~5,6,7,8-tetxa-
hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzaldehvde
(prepaxed as described in ~xample 20~ there can be obtained
1,2,3,4-tetrahydro-1,1,4,4 tetramethyl-6-~(E)- methyl-p-
-allylstyryl]naphthalene of melting point 64-66C.
S ~.
~.~.23839
- 41 -
Example 31
2 g of p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]-benzaldehyde (prepared as des-
cribed in Example 20) and 1.4 g of diethylphosphonoacetic
acid ethyl ester are dissolved in 5 ml of dimethylformamide.
A sodium alcoholate solution (prepared using 6.16 g of
sodium in 3 ml of absolute alcohol~ is added thereto at room
temperature while stirring.` After stirring at room
temperature for 18 hours, the mixture is poured into ice-
-cold l-N hydrochloric acid and exhaustively extracted with
ether. The ether phases are washed with saturated sodium
bicarbonate solution and sodium chloride solutlon and, after
drying over anhydrous sodium sulphate, are concentrated
under reduced pressure. The residue is purified by
adsorption on silica gel using hexane~ether (19:1) for the
elution. The (E)-p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-
-tetramethyl-2-naphthyl)propenyl]-cinnamic acid ethyl ester
obtained from the eluate melts at 126-127C after
recrystallisation from hexane/ether.
Example 32
In a manner analogous to that described in Example 11,
from p-~(E)-2 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)propenyl]-benzoic acid and benzyl alcohol there
can be obtained p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
~t ~_. methyl-2-naphthyl)propenyl]-benzoic a~id benzyl ester of
melting point-113-114C.
-
3~33~3
- 42 -
In a manner analogous to that described in Example 11,
from p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)propenyl]-ben20ic acid and 4-nitro-benzyl alcohol
there can be obtained 4-nitrobenzyl p-~(E)-2-(5,6,7,8-tetra-
hydro-5,5,8,8-tetramethyl-2-naphthyl~propenyl]-benzoate of
meltlng point 183-184C.
Example 34
In a manner analogous to that described in Example 11,
from p-~tE)-2-(s~6~7~8-tetrahydro-5~5~8~8-tetramethyl-2-
-naphthyl)propenyl]-benzoic acid and ethyleneglycol there
can be obtained 2-hydroxyethyl p-~(E)-2-(5,6,7,8-tetra-
hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-ben~oate of
meltin~ point 138-139C.
Example 35
60 ml of a 20% solution of dibutylaluminium h.ydride in
hexane are added dropwise at room temperature under an inert
gas atmosphere and while stirring to a solution of 14.1 g of
p-~(E)-2-(5~6/7~8-tetrahydro-s~5~8~8-tetramethyl-2-naphthyl!
propenyl]-(E)-cinnamic acid ethyl ester (prepared as des-
cribed in Ex~mple 31) in 70 ml of absolute hexane and the
mixture is stirred overnight. The solution is then treated
dropwise at 0-5C with iO ml of methanol and filtered over
~, ....
l~.Z~
- ~3 -
Speedex. The filtrate is diluted with ether, washed once
with a saturated sodium bicarbonate solution and twlce with
a saturated sodium chloride solution, dried over sodium
sulphate and concentrated under reduced pressure. The
separated 3~P- r ~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]phenyl 7- ~E)-2-propen-1-ol melts
at 109-110C after recry~tallisation from hexane.
Example 36
In a manner analogous to that described in Example 13,
from 3~P~ r [(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthyl)propenyl~phenyl 7- (E)~2-propen-1-ol there can
be obtained 3-P-L [(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)propenyl]phenyl 7 2-propen-1-yl acetate
of melting point 109-110C.
Example 37
In a manner analogous to that described in Example 14,
from 3-p / ~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthyl)propenyl]phenyl 7- (E)-2-propen-1-ol there can be
obtained 3-p-/ ~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl~propenyl]phenyl 7 2-propen-l-yl methyl
ether of melting point 88-90C.
The following Examples illustrate pharmaceutical
preparations pro~ided by the invention:
- 44 _ 1~.2 ~83g
Exam~le A
Capsules for oral administration can contain the fol-
lowing ingredlents:
Per capsule
p-~(E)-2-(5,6,7,8~Tetrahydro-
-5,5,8,8-tetramethyl-2-naphthyl)-
propenyl]-benzoic acid ethyl ester 0.1 mg
- Wax mixture 50.5 mg
Vegetable oil 98.9 mg
Trisodium salt of ethylenediamine-
tetraacetic acid 0~5 mg
Example B
An ointment can have the fol~owing composition:
p-[(E)-2-(5,6,7,8-Tetrahydro-
-5,5,8,8-tetramethyl-2-naphthy7)-
propenyl]-benzoic acid ethyl ester 0.01 g
Cetyl alcohol 2.t g
Lanolin 6.0 g
Vaseline 15.0 g
Distilled water q.s. ad 100.0 g
