Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3633
~ he present invention i~ co~cerned with new basically
substituted phenol ethers of the formula I
1 ~ . 3
H / R
OC~ - c;~- CH2 - N
R2
in which ~1 and R1 are ident~cal or different and represent
hty~rogen, an alkyl or alkoxy r~dical contain~ng 1 - 4 carbon
atoms, the allyl group, a halogen atom or the nitro group,
R2 represents an acryl~c acid radical or acrylic acid nitrile
radical ha~ing respectively the ~ormulae
R R R R6
- C = C - ~ - oR7 and - C = C - C~l
in which R5 represents 4ydro~en, a C1 - C5-alk~l radical,
an aryl or aryl-lower alkyl radical which is unsubst tuted
or substituted by lower alkyl or al~ox~, R6 represents hydro-
ge~ or an alk~l radical contai~ing 1 - 8 carbon atoms, and
R represents hydrogen, a lower alk~l rad~ cal or an aryl-
lo~-er alkyl radical,
R~ a~d R4 together with the nitrogen atom represent a hetero-
cyclic ring containing 5 - 7 members optionally substituted
b~ C1 - C4-alkyl, in which ri~g a carbon atom may be replaccd
by an oxyge~ atom, sulphur atom or a further nitrogen atom,
and the latter may be qubstituted by an alkyl, alkoxy, ox-
alkyl, ac~l or carbalkoxy residue i~ each case containing
1 to 5 carbon a~oms, a pyridyl radical or a phenyl radical, t
which may itself be substituted one or more times b~ the
.
3633
hydroxyl group, halogen or an alkyl or alkoxy radical
containing 1 to 4 carbon atoms, or
R3 represents hydrogen and ~4 represents a straight-chained
or branched ~1k~l or o~alXyl radical containing 1 - 8 carbon
atoms, a straight-chained or branched unsaturated aliphatic
h~drocarbon radical containing 2 to 6 carbon atoms, a c~clo-
aliphatic hydrocarbon radical containing 3 to 6 carbon atoms
or a phen~l-alkylene or phenyl-alkylidene radical of the
formula
~(CH2~n
R9
in which n is a number from 1 to 3, and R and R9 are iden-
tic~1 or differe~t and represent hydrogen, an alkoxy radical
containing 1 to 3 c æbon atoms or the benzyloxy radical,
or R8 and R9 together represent a bismeth~lene-dio~ radical,
and also physiologically tolerable acid addition salts thereof.
~he invention includes both the racemic mixtures and the
individual opticall~ active isomers of the formula I.
The present invention is also concerned with a process
for the production of compounds of the formula I, which is
characterised in that
(a) a compound Or the formula II
R1 '
~ OCH2 - CY. - CH2 II
! '
633
in which ~1, R1 and R2 have the meanings gi~en for formula I,
is reacted with an amine of the fo~mula III
HN III
~4
in which R3 and R4 have the meaning~ glven for formula I,
or
(b) a c~mp~u~a o~ the ~ormula I~
OCH2 - CH - CH2X IV
R2 OH
in which ~1, R~1 and R2 have the ~eani~gs ~i~en for formula
I, and x represents a halogen atom, the sulphuric acid
r~dic~l or a sulphonic acid radical~ is reacted with a~
amine of the general formula III, or
(c) a compound of the formula V
R1
R ~ - CH2 - CIH - CH2 ~H2
R2 OH
in which R1, R1 and R2 ha~e the meanings ~i~en for formula
I, is reacted with a compound of the formula ~I
4 VI
in which R4 has the meaning given for formula I and ~ has
the meaning given for formula IV, or
(d) a phenol of the formula VII
,:
,, ' '' , ' ' ,:
'', ~ ' ,' '
~OH VII.
: ' :
in which R1, ~1 ~nd R2 have the me~i~gs given for formula
I, is reacted with a ~ompound of the formula VIII
/
- GH2 - ~ - C~2 VIII
O~I \ *
in which R3 and R4 have the meanings given for formula I
and X has the me~ning given for formula IV, in the presence
of an acid-binding agent, or
(e) a compound of the formula V or I~
OCH2 - C0 - C~2 - N~2 IX
R
in which R1, R1 and R2 have the meanings given for formula
I, is reacted with a suitable ketone and the condensation
~roduct is reduced, or
(f) a compound of the formula X
1 '
R~ OCR2 - CO - CH2 ~lRR4
~2
,
~ 33
in which R1, Rl , R2 ana R4 have the meanings given for
formula I, is reduced, or.
(g) a compound of the formula ~1
` 1 .R1
~ ~ CH2 ~ CN XI
R2 \ /
in which R1, R1 , ~2 and R4 have the meaning~ given for
formula I and Z represents a carbo~yl group or a methylene
group optionally substituted b~ a phen~l group o~ one or
two lower alk~l radicals, is h~drolysea, or
(h) in a compound of the formula XII
1 ' '
R1~ - C~2 - f~' ~ C~2 ~ N - R3 XII
OR10 R11
R2
in which R1, R1 , R2 and R3 have the meanin~s given for
formula I, ~10 represe~ts ~drogen, a lower ac~l radical
or the be~zyl radical, and R11 represents hyaroge~ or the
be~zyl radical, but R10 and R11 cannot both simultaneously
represent hydro~en,
the be~zyl groups are split off by catal~tic hydrogenation
in the presence o~ ~ noble metal ~nd/or the acyl group
is h~drol~sed,
. ~ . .
~ 3 ~
a~d the compounds obtained in accordance with methods (a)
to (h) are optionally converted into physiolog~cally tolerable
acid addition ~alts.
Among the substituents mentioned the following are
- 5 preferred:
~or R4 (when R3 - H): alkyl, alko~y or oxalkyl radicals
conta~ning 1 - 5 carbon atoms, especiall~ branched radicals
such a the isopropyl or tert.-butyl radical, also non-
branched unsaturated aliphatic hydrocarbons containing 2 - 4
~9 carbon atoms, especially the allyl ~adical, c~cloaliphat$c
hydrocarbon radicals containing 4 or 5 carbon atoms, espec-
ially the cyclopentyl radical, and also dialkoxyphenyl-
ethylidene radicals, especially the 5',4'-dimethoxyphenyl-
ethylidene radical or the 1-methyl-2-3',4'-dimethoxyphen~l-
' 1~ ethylidene radical.
~Jhen R3 and R4 together with the nitrog~n atom form
a heterocyclic ring, there are preferred as ring systems
those containing 5 or 6 members, ~or exa~ple, pyrrolidine,
piperidine and morpholine, which may be substituted once or
twice by a lower alkyl radi¢al or substituted by the pyridyl
radical. Especially pre~erred is the piperazine ring,
which may be substituted at the second nitrogen atom b~ an
alkyl, alkoxy, oxalk~l or acyl group containing 1 - 4 carbon
atoms, by a carbal~oxy group containing 1 - 5 carbon atoms,
~5 by a pyridyl radical or by an optionally substituted phenyl
radical.
For R5: hydrogen, an unbranched alkyl radical containing l - 4
carbon atoms, especially the methyl, ethyl radical,
and the phenyl radical,
For R6: hydrogen, an alkyl radical containing 1 - 4 carbon atcms,
,
.: -
. .
- .... .
. . -
~i8633
For R7: an alkyl radical containing 1 to 4 carbon atoms,
especially the methyl, ethyl and tert.-butyl radical,
and also the benzyl radical.
For Rl and Rl : hydrogen, alkyl or alkoxy radicals containing
1 - 3 carbon atoms, fluorine, chlorine and also the
nitro group.
As amine~ of the formula III there come into consider-
ation for the reac~Dns according to methods (a) and (b):
1. Primary amines, such, for e~ample, as: ~ethyla~ne,
ethylamine, isopropyl~mine, isobutylamiDe, sec.-butylamine,
tert.-butylamine, 1-methylpropylamine, 2-aminoethanol,
2-metho~y-ethylamine~ 1-methyl-3-h~droxy-propylamine,
~llylamine, 3-dimethylP~ino-propyl~mine, phenylethylamine,
3-~henyl-propyl~mine, 1-phenyl-ethylamine, 1-methyl-2-
15 phenyl-ethyl~mine, 1-methyl-2-(4-metho~y)~pkenylethyl~ine,
1-methyl-2-(3,4-dimethoxy)-phenylethylamine, 3,4-dimethoxy-
phenylethylamine, 3-methoxy-4 ethox~-phenylethylamine,
3-methoxy-4-hydroxy-phenylethylamlne, 3-methoxy-4-benzyl-
ox~phe~ylethylamine, 3-benzyloxy-4-methoxy-phenylethyl-
amine, 3~4-methylenedioxy-phenylethylamine, 2,5-dimethoxy-
phènylethylamine, 2,4-dimethoxyphenylethylamine, 2,3-
dimethoxyphenylethylamine., 3,4,5-trimethoxy-phenylethyl-
amine, 2-~tho~henylethylamine, 3~methoxyphenylethyl-
amine, 4-methoxyphenylethylamine, 3,4-dimethoxyphenyl-
methylami~e, 2-h~dro~y-2-phenyl-ethylamine~ 1-methyl-2-
hydroxy-2-phenylethylamine, 3,4-dimethylphenyleth~lamine,
4-chlorophenylethylamine, 3,4-dichlorophenylethylamine,
4-h;ydroxyphenylethylamine, heptaminol, cyclopropylamine,
cyclopentylamine, cyclohexylamine, 2-adamantylamine.
~G ~he use of isopropyl~m~ne and tert.-butylamine and also
~a
. . ~ ~ . .. ... , . .~ - . .. . ...
.
` 1SL~8633
homoveratrylamine, has been found especially advantageous.
2. 5 - 6 Membered c~clic secondary amines such, for example, as:
Phenylpiperazine, N-2'-methylphenylpiperaz~ne, ~-3'-methyl-
phenylpiperazine, ~-4'-methylph~nylp~perazine, ~-2'-methcxy-
phen~lpiperazine, ~-~'-methoxyphenylpiperazine, N 4'-methoxy-
phenylpiperazine, ~-2'-chlorophenylpiperazine, N-~'-chloro-
phenylpiperazine, ~-4'-chlorophenylpiperazine, N-2'-p~ridyl-
piperazine, N-3'-pyridylpiperazine, N 'I'-pyridylpiperazine,
N-2'-hydroxyphenylpiperazine, N-3'-hydroxyphenylpiperazi~e,
O ~-4'-h~droxyphenylpiperazine, N-oxyethylpiperazine, N-methyl-
piper~zine, N-ethylpiperazine, N-carbQmetho2ypiperazi~e,
N-carbethoxypiperazine, N-carbo-(2-h~droxy-2-methyl)-propoxy-
piperazine, 2-methylpiperazine, 2,6-dimethylpiperazine,
2,6-dimeth~lpiperidine, 3-~-pyridylpiperidine, piperidine,
~5 mor holine and also p~rrolidine.
~he introduction of the amine radical according to
method (a) is carried out by reaction of the two compone~ts,
optionally in the presence of organic solvents such as
alcohols, for example, methanol, ethanol, isopropanol,
aromatic solvents such as benzene, toluene or ethers such
as dioYane, tetrahydrofurane or carboxylic acid amides,
especially dimethylformamide. In a preferred modification
the two components dissolved in alcohol may be reacted with
one another at a raised temperature. ~s reaction temperatures
there come into consideration temperatures from room temper-
ature up to the boiling point of the solvent.
~he glycidyl ethers of the formula II used as starting
materials in method (a) can be obtained in accordance with
our co-pendinq Patent Application Serlal No.
. .: , .; :
3633
In the method described under (b) the a-haloge~
hydroxy-propyl ethers of the formula IV are used as starting
materiàls. I stead of the halogen atom, preferably chlori~e
or bromine, in the ~-positio~ there may be used the corres-
ponding esters of sulphuric ~cid or esters of sulphonic acids.
~he starting substances can also be obuained by splitting
the epoxide of the formula II with a hydrohalic acid, sulphur-
ic acid or sulphonic acid. ~he reaction with an amine of
the formula III is carr~ed out in the presence or absence of
o sultable organlc solvents, such as alcohols, ~or e~ample,
methanol, ethanol, isopropanol, aromatic solvents such as
benzene, toluene, or ethers such as dioxane, tetrahydrofurane,
or carbox~lic acid amides, especially dimethylfor~amide.
~he reaction may be carried out at temperatures between room
1~ te~p~r2~ure ~nd the boiling point of the ol~ent, and is
preferably c2rried out at a raised temperature. ~or bind- -~
ing the liberated acid, for ex~mple halogen hydride, the
operation may be carried out in the presence of acid-binding
agents, for example, tert.-amines, such as triethylamine,
pyridine or alkali or alkali~e earth metal hydroxides,
carbonates or bicarbonates. ~he amine used can advantage-
ously be used for the reaction in e~ces~, for example, in
twioe the molar quantity.
~or the m~thod described under (c) there is used 'he
pheno~y-2-hydroxy-1-aminoprop~ne derivative of the formula V.
The latter ~ay also be present in the form of a salt.
~he reaction with a reactive ester of the formula VI is
carried out under the reaction conditions mentioned in
method (b). ~he amine of the formula V used as starting
~.' 10
~.: ,~,
3633
material can be obtained, for example, by reactin~ the
epoxide of the formula II with ammonia. It can also be
obtained from the halogen compound IV with ammonia.
~he preparation of the products of the process is also
effected in accordance with the method described under (d),
in which the above-mentioned phenol of the formula VII is
used. ~he phenol may also be used in the form of its
alkali metal salts, such as the sodium or potassium salt.
As reaction components of the formula VIII there are used
~-halogeno-2-h~droxy-3-al~ylam~nopropanes. It is al~o
possible to start from sulphuric or ~ulphonic acid esters
of the 1,2-dihydroxy-~-al~ylaminopropanes. ~he reaction
is advantageously carried ou~ in the presence of an acid-
binding agent, such as an alk~limetal hydro~de. In an a ~ line
medium the 1-halogeno-2-hydroxy-3-alkylaminopropane used
can change intermediately into the corresponding 1,2-epoxy-
propane, which reacts with the phenol. ~he reaction may
be carried out in the presence or absence of solvents such,
for example, as alcohols, for eYample, methanol, ethanol,
isopropanol, aro~atic solvents such a3 benzene or toluene,
or ethers such as dioxane, tetrah~drofurane, or carboxylic
acid am~des, especiall~ dimeth~lformamide, at normal tem-
perature or a raised temperature up to the boiling point of
the solvent used. ~he compounds of the formula VIII used
as starting materials are obtainable, Por example, b~ the
reaction of an a~ine of the formula III with epichlorh~drin
at low temperatures.
In the method described under (e) the amine of the
formula v is hydrogenated with a ketone appropriate for the
meaning of R4 in the presence of catalytically activated
,, .- ;.. .. , . .; -; , :
. . . . . . - .. . . .
... ..
1~8633
h~drogen. As ketones th-ere may be mentioned, for example,
acetone, methyl ethyl ketone, cyclopropanone and cyclohexanone.
~s catalysts there are used, for example, Raney nickel,
platinum or palladium. Generally, the operation i8 carried
out in the presence of an inert solvent such as methanol,
ethanol or isopropanol. It is also poss~ble first to
condense the amine of the formula ITI with the abo~e mentioned
ketone and ~hen to reduce as above the Schiff'~ base so
obtained, optionally without isolating it. ~he reduction
the aæomethine may also be carried out in the usual manner
with sodium boranate, lithium alanate or other complex metal
hydrides, and also with aluminium amalgam.
By the method (e) there are obtai~e~ only those compounds
of the formula I in wnich the radical R,l is connected to the
~i~ nitrogen atom by a secondary carbon atom.
The mathod described under (e) c~n also be carried out
by using the ~minoketone of the formula I~. The reaction
is carried out in the same manner as in the case of the
aminopropanol of the formula V, since in the reduction,
either in one reaction stage or after preparinga~d optionally
isolating the azomethine, the keto group is simultaneously
reduced with the azomethine double bond. ~he preparation
of the aminoketone used as starting materi~l may be carried
out, for example, by mild oxidation of the aminopropanol
of the formula V.
The method described under (f), namely the reduction of
aminoketones of the formula X can also be carried out by
catalytic hydrogenation in the manner already described for
method (e). The reduction of the keto group can also be
carried out with lighium alanate or other complex metal
12
.
.. : : .. . ~: :
~. .~ . ~ :, .
6;~3
hydrides or by the Meerwein-Ponndorf method with aluminium
isopropylate. The preparation of the ketones of the formula
X can be carried out, for example, by reacting appropriate
l-halogen-2-oxo-3-~phenoxy)-propanes with an amine of the
formula III.
A further modification of the process of the invention
is the hydrolysis of an oxazolidone or oxazolidine of the
formula XI by method (g). Such oxazolidones can be obtained,
for example, by reacting the corresponding l-amino-2-hydroxy-
3-tphenoxy)-propanes with a reactive derivative of carbonic
acid, such as diethyl carbonate, chlorocarbonic acid methyl
ester or phosgene, or by reacting a 5-hydroxymethyl-oxazoli-
done-(2) optionally appropriately substituted in the 3-position and in
the form of a hydrohalic acid-, sulphuric acid- or sulphonic
acid ester with an appropriate alkyl phenolate. Suitable
oxazolidines can be prepared, for example, by reacting the
corresponding l-amino-2-hydroxy-3-phenoxy-propanes of the
formula V with aldehydes or ketones. Oxazolidones or
oxazolidines not substituted at the nitrogen atom may be
alkylated with compounds of the formula VI as described
undex method (c). The hydrolysis of these oxazolidone
derivatives or oxazolidine derivatives may be carried out
in an acid or alkaline medium, for example, by means of
dilute hydrochloric acid, dilute sulphuric acid, dilute
sodium hydroxide solution or dilute potassium hydroxide
solution. It is of advantage to apply heat in order to
accelerate the hydrolysis. The hydrolysis may also be
carried out in water-soluble solvents, for example, lower
alcohols. The products of the process can also be
30;~i; obtained from compounds of the formula XII, in which the
,, ~,
.~,
-: ~ . ` . : "
~ ':
,, ~ ~: ,
- ~ .
3633
h~drox~l and/or the secondary amino group is protected by
the radical R10 or R11 respectively, by splitting off the~e
protecting groups. As protecting groups there come into
consideration acyl radicals or the benzyl radical. ~he
splittin~ off of the benzyl radical is carried out by cata-
lytic hydrogenation in the presence of noble metals, such
as palladium or platinum. If acyl-compounds are used,
the acyl radical preferably being a lower aliphatic acyl
radicæl, such as the acetyl or propion~l radical, the split-
ting is carried out hydrolytically either in an acid or
alkal~ne aqueous medium. The preparation of the corres-
ponding benzyl- or acyl-compounds of the formula XII may be
carried out by one of the methods described above, the
correspo~ding acylated or benzylated startin~ ma~erials
being use~. ~Jhen starting materials of the for~ula XII
ar~ to be prepPred, in which R2 represe~ts an acyl radical,
there may be acylated, for exa~ple, the compound of the
formula III, a~d then the corre~ponding acyl-compounds are
reacted by method (b) to form compounds of the formula ~II.
~his applies correspondingly for compounds in which R10
represents a benzyl radic~l, the corresponding hydroxy-
compounds being benzylated, instead of acylated. If it
is desired to start from compound~ of the formula ~II, in
which R11 represents a be~zyl radical, there can be used
in accordance with method~ (a), (b), (c), (f) or (d),
instead of the primary amines, the correspo~ding ~-benzyl-
compounds. When a~ acyl radical and ~ benzyl radical
a~e in juxtaposition as R10 and R11, these groups can be
split off in succession in the manner described.
It may sometimes be of advantage ~n methods (a), (b),
i~ 14
, . ~
-' , ~ `. ~ . '., ~"
..
, -:- ,
, - ; ,,, . - , ~ .:
633
(d) or (h) to combine the preparation of the starting
compounds directly with the furtber reaction, that is to
5ay~ not to isol~te the starting materials separately.
The product~ of the process may be obtained in the
form of the base or in the form of salts thereof, and
when nece~sary they are purified by the usual method~,
for example, by recr~stallisation or optio~ally conversio~
into the free base and subsequent treatment with a suitable
acid. The products of the process may, if desired, be
converted into salts of phy~iologically tolerated or~anic
or inorganic acids.
As organic acids there may be mentioned, for example,
acetic acid, malonic acid, propionic acid, lactic acid,
succinic acid, tartaric acid, maleic acid; Lumaric acid,
citric acid, malic acid, benzoic acid, salicylic acid,
oxyethane sulphonic acid, aceturic acid, ethylene diamine
tetracetic acid, embonic acid and also synthetic resins
containing acid ~roups.
As inorganic acids there come into co~sideration, for
example, hydrohalic acids such as h~drochloric acid or
hydrobromic acid, sulphuric acid, phosphoric acid and
amido-sulphonic acid.
~he optically active isomers of the racemic basically
substituted phenol ethers of the formula I can be obtained
by splitting the latter into their components with optically
acti~e acids.
As acids there come into consideration for the prepara-
tion of optically acti~e salts in accordance with the
invention, for example, (+)- and (-)-tartaric acid, (+)-
~ and (-)-dibenzoyl-tartaric acid, (+)- and (-)-ditoluyl-
r
8fi33
tartaric acid, (+)- and (-)-mandelic acid, (f)- and (-)-
camphoric acid, (f)-camphor-~-sulphonic acid, (+)--bromo-
camphor-x-sulphonic acid and N-(para-nitrobenzovl)-(+~-
glutamic acid. ~he preparation of the optically active
salt~ may be carried out in water or a~ueous or anhydrous
org~nic solvents. The use of alcohols or esters of
organic carboxylic acids has been found advantageous.
For the prep~ration of optically active compounds the
racemate of the base is reac~ed in a solvent, preferably in
molar proportions, with a~ optically active acid, and the
optically active salt of the compound of the formula I is
isolated. In certai~ cases i~ is also possible to use
only one half of an equivalent of the optically active
acid in order to remove o~e of the optically active antipodes
from the racemate, and also quantities of optically active
acid in excess may be used.
Depending on the nature of the optically active
acid the desired ~ntipodes can be obtained either directly
or from the mother liquor of the first crystallizate.
Subse~uentl~, the opticall~ active base may be liberated
from the salt in the usual manner~ and this optically active
base oan be converted into a salt of one of the physiolog-
ically tolerable organic or inorganic acids mentioned above.
~he compoun~s of the formula I and physiolo~ically
tolerable acid addition salts thereof have been found in
animal tests o~ dogs to have valuable therapeutic, especially
~-adrenol~tic, ~1-adrenolytic, and/or blood pressure-lowering
and/or anti-arrhythm~c~ properties, and can therefore be
used, for e~ample, for the treatment or prophylaxis of
disorders of the coronary ~essels, for the treatment of
~ 16
,.
~i3633
cardiac arrhythmia and for the treatment of high blood
pressure in human medicine.
Special emphasis may be given to the follow~ng:
A therapeutically fa~ourable split between ~1- and ~2-
receptor blocking action, the ~2-receptors not being blocked,
is exhibited by compou~ds o~ the formula I in which R4, when
R3 = E, represen~s a phen~l-alkylene radical. For example,
the product according to Example 15 ~hibits a substantiall~
stronger ~l-sy~pathicolytic (in the absence o. ~2-symp~thico-
0 lytic) action than do the known 1-[(3,4-dimethoxypheneth~l)-
amino-~-aryloxy-2-propanols such, for example, as 1-t(3,4-
dimetho~henethyl)-amino-3-(meta-tolyloxy)-2-p~opanol
hydrochloride (M.L. ~oefle et. al., J. Med. Chem. 18 (1975),
148).
'~ The products of the process may be administered in
the form of free bases or salts ~hereof orall~ in the form
of ~ablets or dragees, optionally mixed with the usual pharm-
aceutical carrier subst~nces and/or st~bilizers or parenter-
ally in the form o~ solutions in ampoules. As carrier
substances for tablets there come into consideration, for
example, lactose, starche , tragacanth a~d/or magnesium
stearate.
For in~ection purposes there comes into consideration
a dosage of about 2 - 20 mg, and for peroral dosage between
about 6 and 150 mg. A single tablet or a dragee may
contain about 5 to 50 mg of active substance.
A therapeutic similarly desired long-lasting significant
lowering of the blood pressure with only little or no
~- receptor blocking is exhibited by compounds of the
formula I, in which R3 together with R4 and the N-atom
17
..
. .
- ~
. . . .
633
re.present a hetexocycle, such as the unsubstituted or
substituted at the second M-atom piperazino, piperidino
or morpholino radical.
Compounds of the formula I, in ~which R3 = H and R4
represents a branched aliphatic or cycloaliphatic hydrocar-
bon radical, are distinguished by a generally very strong
blocking of the ~-receptors.
~he following Examples illustrate the in~ention.
~i 1 8
. . .
. . --- ,.
. - . ,
,, .... ~ ... . ...
~ 3
ExamPle 1
[D,T]-3-~2-(3-tert -but~lamino-2-hydroxy-~ropoxy)-phenyl]-
crotonic acid nitrile hydrochloride.
7.0 Grams of [D,~]-3-~2-~2,3-oxido-propoxy)-phenyl~-cro-
tonic ao~d nitrile are heated under re~lux at the boil in
a mixture of 80 ml of ethanol (98% strength) and 15 ml of
tert.-butylamine for 1 1/4 hours. Concentrating to dry-
ness in acuo is then carried out and e~aporation with
toluene in ~acuo is carried out several times. ~he oily
distillation residue (free base) is dissolved in 50 ml of
ethanol, and the mix~ure is adjusted to a pH-value of 4 by
the dropwise addition of concentrated hydrochloric acid
and then evaporated to dryness in vacuo. . By e~aporation
in vacuo with ~oluene several times the distillation residue
is dried, and then recrystallised f-o~ a s~all amoun~ of
eth~nol and ether and again from ethanol.
~here were obtained 7~1 grams of ~D,~]-3-t2-~3-tert.-
butyl~mino-2-hydroxypropoxy)-phenyl]-crotonic acid nitrile
hydrochloride melting at 155-156C.
Example 1 a.
2-(~-tert;.-butylamino-2-h~dro~y-propoxy)-4-fluoro-
~en~l]-crotonic acid nitrile h~drochloride.
14.0 Grams of ~D,~]-3-~2-(2,3-oxido-propoxy)-4-fluoro-
phenyl]-crotonic acid nitrile in 50 ml of ethanol and 100 ml
of tert.-butylamine are heated on a stesm bath under reflux
for 2 hours. ~y working up as described in Example 1
8.6 grams of ~D,~-3-~2-(3-tert.-butylsmi~o-2-hydroxy-prop-
oxy)-4-fluorophenyl]-crotonic acid nitrile hydrochloride
melting at 158-159C. were obtained.
- 19
. . ~ ...... , ; ;: : : .
.. ~ , ,
- ~
3633
Example 1 b
tD,L]-3-~2-(3-3~,4~-Dimethoxy-pheneth~l-ami~o-2-hydroxy-
~ropoxy)-4-fluoro-phen~l~-crotonic acid nitrile hydrochloride
14.0 Grams of tD~-3-[2-(2,3-oxido-propo~y)-4-fluoro-
phenyl~-crotonic acid nitrile i~ 15 ml of ethanol are heated
with 20.0 grams of homoveratryl~mine for 2 hours on a steam
bath ~nder reflux, working up is carried out as desGribed
in Example 6, and the hydrochloride is recrystallised ~rom
isopropanol/ether.
Yield: 11.4 grams of [D,L~-3-~2-(3-3*,4~-dimethoxy-phenethyl-
~minG-2-hydroxy-propoxy)-4-fluorophenyl~-crotonic Pcid nitrile
hydrochloride melting at 153 - 155C~
Example 1 c
~D,~-3-~2-(~-~*t4~-D~methox~-~hen~t~ ino-2-h~lro~-
propoxy)-5-1uorophenyl]-crotonic acid nitrile hydrochloride
12~0 Grams of tD,L]-3-~2-(2,3-oxido-propoxy)-5-Lluoro-
phe~yl]-crotonic acid nitrile in 15 ml o~ etkanol are react-
ed with 12.0 grams o~ homoveratrylamine ln ~he mann~r des-
cribed in Example 16 e. The 10.6 grams of ~ree base melting
at 105-107C. f~r~t obtained are con~erted i~ the usual
manner (analogous to Example 1) into 8.8 gram~ of ~D,L]-3-
~2-(3-3*,4*-dimethoxy-pheneth~l-ami~o-2-hydro-~y-propoxy)-
5-fluoro-phenyl~-crotonic acid nitrile hydrochloride melting
at 145-147C.
: 25 . Example 1 d
[D,L]-3-[2(3-tert.-butylamino-2-hydroxy-propoxy)-5-fluoro-
: phenyl]-crotonic acid nitrile hydrochloride.
12.0 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-5-fluoro-
phenyl]-crotonic acid nitrile hydrochloride in 50 ml of
ethanol are heated at the boil under reflux for 2 hours with
.
~,~ 20
:: -: ~ . i - :
- .: ~ . :
.. . . -. .. .
~ 63~
too ml of tert.-butylamine. Working up is carried out
in the usual manner (Example 1). ~he crude hydrochloride
is recr~stallised from isopropanol/ether and again from
isopropanol.
Yield: 9.7 grams of [D,~]-3-t2-(~-tert.-butylamino-2-
hydroxypropoxy)-5-~luorophenyl~-crotonic acid ni~rile
hydrochloride meltins at 134 - 135C.
Exam~le 2
~D~-3-[2-(3-Morpholino-2-h~droxy-propoxy)-phen~l]-crotonic
acid nitrile h~drochloride.
15 Grams of [D.,L]-3-[2-(.2,~-oxido-propo~y)-phenyl]-
crotonic acid nitrile in a mixture of 90 ml of ethanol and
6.1 gram~ of morpholine are heated at the boil under reflux
for 2 1/4 hours. Working up is then carried out as des-
cribed in ~xample 1, and ~he product is converted into the
hydrochloride.
There were obtained 12.9 grams of [D,L]-3-[2-(3-morpho-
lino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile h~dro-
chloride melting at 184.5 - 18~C.
Example 3
tD,L]-3-t2-(3-N-Phenyl-piperazino-2-hydroxy-~ropoxy)-phenyl~-
crotonic acid nitrile hydrochloride.
15 Grams o~ tD,~ 2-(2,3-Oxido-propoxy)-phenyl]-
crotonic acid nitrile in 90 ml of ethanol and 11.4 grams of
~-phenylpiperazine are boiled under re~lux for 1 1/2 hours.
Working up and conversion into the hydrochloride are then
carrled out as described in Example 1.
~here were obtained 14.0 grams of tD,~-3-t2-(3-~-
phenyl-piperazino-2-hydroxy-propoxy)-phenyl~-crotonic acid
.~trile h~drochlor~de melting at 177-178C.
...~ 21
. . .
~ 3
Example 4
~D,~]-3-[2-t3-Isopro~ylamino-2-hydrox;r-propo ~)-pheayl~-cro-
tonic acid nitrile hydrochloride.
27 Grams of [D,L~-3-[2-(2,3-oxido-propoxy)-phenyl]-cro-
tonic acid nitrile in a mixture of 270 ml of ethanol and 60 ml
of isopropylamine are boiled under reflux for one hour.
Working -~p and conversion into the hydrochloride are then
carried out as described in Example 1.
~here were obtai~ed 21~5 grams of tD,L~-3-C2-(3-iso-
.propylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile
hydrochloride melting at 145 - 146C.
Example 5
CD,~]-3-~2-(3-2~,6~-Dimethylpiperidino-2-hydroxy-propox~
henyl]-crotonic acid nitrile hydrochloride.
15 Grams of [D,~-3-[2-(2,3-oxido-propo~y)-phenyl]-
crotonic acid nitrile in a mixture of 90 ml of ethanol and
8.0 gr~ms of 2,6-dimetkylpiperidine are boiled under reflux
for 13 hours, and working up and conversion i~to the hydro-
chloride are carried out as described in Example 1.
~here were obtained 12.4 grams of [D,~-3-t2-(~-2*,6~-
dimethylpiperidino-2-hydroxy-propoxy)-phenyl]-crotonic acid
nitrile hydrochloride melting at 157 - 158C.
Example 6~ -
CD ,~] -3-~2-(3-3*,4*-dimethoxyphenethylamino-2-hydro~y-
~ oxy)-Phenyl]-crotonic acid nitrile hydrochloride.
19 Grams of [D,~]-3-t2-(2,3-Oxido-propoxy)-phenyl]-
crotonic acid ni~rile in a mixture of 100 ml of ethanol and
~ 12.7 grams of homoveratrylamine are boiled under reflu~ for
; 5 hours. Worki~g up and conver~ion into the hydrochloride
are then carried out as described in Example 1.
;` ~ 22
~ . ,~ .. - - . -
:, - ~ . , - :, - .
. ,, . ,, . ,.. , ~ :
., - . .... . . .
., ; .
3~3
There were obtained 10.8 grams of [D,L]-3-[2-(3-3*,4*-
dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic
acid nitrile hydrochloride melting at 164 - 156C.
The free base is isolated from the mother liquor in the
5 usual manner (rendering al~aline, extracting with toluene,
concentrating to dryness in vacuo) and there were obtained
by recrystallisation from toluene/diisopropyl ether 1.2 grams
thereof melting at 88 to 89C.
Example 6 a
[D,L]-3-[2-(3-3*,4*-Dimethoxy-phenethyl-amino-2-hydroxy-
propoxy)-4-methoxy-phenyl]-crotonic acid nitrile hydrochloride
7.0 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-4-methoxy-
phenyl]-crotonic acid nitrile in a mixture of 7.0 grams of
homoveratrylamine and 7.0 ml of ethanol are heated on a
steam bath (while refluxing) for one hour. The reaction
mixture is cautiously adjusted with concentrated hydrochloric
acid to a pH-value of 3.5, stirred into 1 1 of water and
extracted three times with toluene/ethyl acetate. The
aqueous phase is then adjusted to a pH-value of 8 to 8.5
with sodium hydrogen carbonate and is again extracted with
toluene. The basic extracts are dried, rotated and the
crude base is converted into the hydrochloride in the manner
described in Example 1.
There were obtained 9.4 grams of [D,L]-3-[2-(3-3*,4*-
dimethoxy-phenethylamino-2-hydroxy-propoxy)-4-methoxy-phenyl]-
crotonic acid nitrile hydxochloride melting at 169 - 170 C.
~xample 7
[D,L]-3-[2-(3-N-[2*]-Pyridino-piperazino-2-hydroxy-propoxy)-
phenyl]-crotonic acid nitrile trihydrochloride
7 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-
23
-
.: , .
l~g8633
crotonic acid nitrile in a mixture of 70 ml of ethanol and
6 grams of N-(2-pyridino)-piperazine are boiled under reflux
for 3 hours. Working up and conversion into the trihydro-
chloride is then carried out as described in Example 1.
5.1 Grams of [D,L]-3-[2-(3-N-[2*]-pyridino-piperazino-
]-hydroxy-propoxy)-phenyl]-crotonic acid nitrile trihydro-
chlorid~ melting at 121C are obtained.
Example 8
[D,L]-3-[2-(3-N-[4-Acetylphenyl]-piperazino-2-hydroxy-propoxy)-
phenyl]-crotonic acid nitrile dihydrochloride
7 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile in a solution of 6.8 grams of N-(4-
piperazino)-acetophenone in 70 ml of ethanol are boiled under
reflux for 3 hours. Evaporation to dryness in vacuo is then
carried out. The oily distillation residue crystallises
after a few hours. Trituration with a small amount of ether
and filtering off with suction are then carried out. The
filter residue was dissolved in exactly the sufficient
quantity of chloroform, and a saturated solution of hydro-
chloric acid/chloroform is added in portions, while stirring,
until the reaction is acid. After a short time the dihydro-
chloride separates from the clear solution.
By filtering off with suction, washing with a small
amount of chloroform/acetone and drying there are obtained
9 grams of [D,L]-3-[2-(3-N-[4-acetylphenyl]-piperazino-2-
hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochlor-
ide melting at 151C.
^ Example 9
[D,L]-3-[2-(3-N[2-Methoxyphenyl]-piperazino-2-hydroxy-
30 ~ propoxy)-phenyl]-crotonic acid nitrile dihydrochloride
:: -. : : , : . : - -
:: :
6 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile in a solution of 5.5 grams of N-(2-
methoxy-phenyl)-piperazine in 60 ml of ethanol are boiled
under reflux for 3 hours. Concentration to dryness in
vacuo is then carried out, the residue is dissolved in
chloroform and the solution is rendered acid with hydro-
chloric acid/chloroform. Rotation to dryness in vacuo
is then carried out, and crystallisation is brought about
by trituration with a small amount of ether. By filtering
off with suction and drying there are obtained 10.5 grams
of [D,L]-3-[2-(3-N-[2-methoxyphenyl]-piperazino-2-hydroxy-
propoxy)-phenyl]-crotonic acid nitrile dihydrochloride
melting at 171°C.
Example 10
[D,L]-3-[2-(3-N-[2-Methylphenyl]-piperazino-2-hydroxy-
propoxy)-phenyl]-crotonic acid nitrile dihydrochloride,
7 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile in a mixture of 6.5 grams of N-(ortho-
tolyl)-piperazine and 70 ml of ethanol are reacted and worked
up as described in Example 9.
There are obtained 10 grams of [D,L]-3-[2-(3-N-[2-
methylphenyl]-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic
acid nitrile dihydrochloride melting at 138°C.
Example 11
[D,L]-3-[2-(3-N-[Methylpiperazino]-2-hydroxy-propoxy)-phenyl]-
crotonic acid nitrile dihydrochloride,
7 Grams of [D,L]3-2-[2-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile are reacted with 3 grams of N-methyl-
piperazine in 60 ml of absolute ethanol and worked up, as
described in Example 9. The crude dihydrochloride is
dissolved in 50 ml of water and filtered over 3 grams of
active carbon. The filtrate is concentrated to dryness
~8633
finally under a high vacuum. ~he resulting fo~m is tritur-
ated with ether, filtered off with suction and dried.
~here are obtained 4~9 grams of strongly hygroscopic
[D,L~-3-C2-(3-N-[methylpiperazino~-2-hydroæy-propoxy)-
phenyl~-crotonic acid nitrile dihydrochloride.
~he compound exhibits in the IR characterist~c bands
at 2203, ~599, 1435, 1235 and 745 cm 1.
Exam~le 12
- [D.L~-3-[2-(~-N-~2-$Iydroxyethyl~-piperazino-2-hsrdro~-proP
oxy)-vhenyl~-crotonic acid nitrile dihydrochloride.
7 Grams of [D,L~-3-~2-(2,3-Oxido-propoxy)-phenyl~-
crotonic acid nitrile are reacted with 4.7 grams o~ ~-(2-
hydroxyethyl)-piperazine in 70 ml of absolute ethanol
are reacted and wor~ed up, as described in Example 9.
~here are obtained 8.5 grams of [D,L]-3-~2-(3-N-
[2-hydroxyethyl]-piperazino-2-hydrox~-propox~)-phenyl~-
crotonic acid nitrile dihydrochloride melting at 146C.
Example 12 a
~D.L~-3-[4- -tert.-Butylamino-2-hydroxy-propox~ henyl~-
crotonic acid nitrile hydrochloride.
6.0 Grams of [D,~-3-[4-(2,3-Oxido-propoxy)-phenyl~-
crotonic acid nitrile in 40 ml of ethanol are reacted with
i 40 ml of tert.-butylamine and worked up, as described in
Example 1.
Yield: 6.0 grams of [D,L~-3-[4-(3-tert.-butylamino-2-
hydroxypropoxy)-phenyl]-crotonic acid nitrile hyarochloride
` melting at 186-187C.
26
,
1~8633
~xample 12 b
[D,L~-3-~2-Methoxy~ (3-teru.-3u~ylamino-2-h~dro~-propoxy)-
phenyl~-crotonic acid nitrile hydrochloride.
3.4 Grams o~ [D,~]-3-[2-Metho~-4-(2,3-oxido-propoxy)-
phenyl~-croto~ic acid ~itrile are boiled under reflux for
2 1/2 hours with 20 ml of ethahol and 40 ml of tert.-butyl~m-
ine and worked up as described i~ E~ample 1.
Yield: 4.0 Grams of [~,L1-3-[2-Metho~y-4-(3-tert.-butylamino-
2-hydroxy-propoxy)-phe~yl~-cro~onic acid nitrile h~drochlor-
ide melting at ~45-146C.
Example t2 c
-
[D,L~-3-[2-(3-tert.-Butylamino-2-h;~dro~;Y-propo~y)-4-methox~-
phenJl~-croto~ic acid ni~rile h~drochloride.
5.0 Grams of tD,L]-3-[2-(2,3-oxido-propoxy)-4-methoyy-
phe~yl]-crotonic acid nitrile dissolved in 20 ml of eth~nol ~ ^
are, after the addition o~ 50 ml of tert butylamine5 heated
at the boil under reflux ror 3 hours, and the~ wor~ing up
is carried out as described in Example 1.
Yield: 4,3 grams of ~D,L]-3-[2-(3-tert.-bu~la~ino-2-hydrox~-
propoxy)-4-methoYy-phenyl~-crotonic acid ~itrile hydrochlor-
ide melting at 144 - 145C.
Exam~le 1~
[D?L]-3-[4-(3-N-Pken~lpiperazino-2-h;s~d-ox;~-proQox~ hen~l]-
- crotonic acid nitrile h~drochloride
10.75 Grams of [D,~-3-~4-(2,3-oxido-propox~)-phenyl]-
crotonic acid nitrile in a solution of 8.1 ~rams of ~hen~l-
piperazine in 60 ml of ethanol are boiled under re~lux for
3 hours. ~he reaction mixture is the~ cooled with ice
and, after standing for a short time, the crystals that
27
- ;. , - ., -
,. ~ ,. : - .
., .
633
separate are filtered off with suction and recrystallised
from a small ~mount of ethanol.
12.9 Grams of the free base melting at 133 - 134C. are
obtained. ~he base is dissolvsd at room temperature in ju~t
the sufficient quantity of acetone, and then concentrated
h~drochloric acid is added dropwise, while stirring, u2til
the pH-value is 4.5. After a short time the hydrochloride
; precipitates. It is filtered off with suction and dried.
There are obtained 13.9 ~ra~s of crude hydrcchloride meltin~
at 158 - 160C.
By recrystallisation once from a large amount of ethanol
13.3 grams of [D,~-3-~4-(3-N-phenylpiperazino-2-hydroxy-
propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting
at 160-161C, are obtained.
Exam~le 14
- [D,L]-3-[4-(3-Morpholino-2-hydroxy-propoxy)-phenyl]-crotonic
;"
acid nitrile h~drochloride
15.0 GramQ of tD~]-3-[4-(2~3-oxido-propoxy)-phenyl]
crotonic acid nitrile in a solution of 6.1 grams of morpholine
.~.
~ 20 in 100 ml of ethanol are heated at 80C. for 4 1/2 hours.
. .,
~he mixture i5 allowed to stand for a further 12 hours at
;- room temperature. ~he mi~ure is then concentrated to dry-
ness in vacuo and evaporated three times with toluene.
~he distillation residue is dissolved in a small amount of
toluene, and caused to cryatallise by the addition of
diisopropyl ester. ~y filtering off with suction and drying,
~; 18.0 grams of the free base melting at 79-80C. æ e obtained.
,:
Conversion into the hydrochloride is then carried out
` as de~cribed in Example 1.
3o There are obtained 16.4 grams of [D,~]-3-t4-(3-
28
.
~, : . . :
- -- : ~ : -
,.. , , . , . ~ -, ..
- - : : : , .. .
,- - . . ..
~8633
morpholino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitriie
h~drochloride melting at 121 - 122C.
Example 15
~D,L]-3-t4-(~-2~,6*-Dimethylpiperidino-2-hydroxy-proPox~)-
S _he~yl]-crotonic acid nitrile h~drochloride.
15 Gra~s of ~D,L]-3-[4-(2,3-oxido-propoxy)-~henyl]-
crotonic acid nitrile in a solution Or 8.0 grams of 2,6-
dimethylpiperidine i~ 100 ml of ethanol are boiled under
reflux for 6 1/2 hou~s. The mixture is the~ evaporated
to dryness in acuo, and the dist_llation residue is dissol~-
ed i~ 80 ml of tolue~e. After the additio~ o~ 300 ml o~
water, the mixture is adju6ted to a pH-value of 4 with
concentrated hydrochloric acid with good agitation.
~o the aqueous phase are added 80 ml of fresh tolue~e and
the p~-value is adjusted to 10 by agitation with sodium
hydroxide solution. Extraction is carried out twice
with 50 ml of toluene each time, a~d the combined organic
; extracts are washed with water, dried over sodium sulphate
and concentrated to dryness i~ vacuo. By trituration with
diisopropyl ether, filtering off the resulting cr~stals
with 6uction and dr~ing there are obtained 15.0 grams of
~ the free base melting at 97 - 98C.
; ~rom the latter there are obtained in a manner described
in Example 1 14.5 grams of ~D,L]-3-t4-(3-2~,6~-dimethyl-
piperidi~o-2-hydroxy-propoxy)-phenyl~-crotonic acid nitrile
hydrochloride melting at 168 - 169C.
Example 16
[D~]-3-[~3-3~,4~-Dimetho~gPhenethylamino-2-hg~rox~-
~roPox~)-phen~l~-crotonic cid nitrile h~drochloride.
17.5 gr~ms of [D,L]-3-[4-(2~3-oxido-propoxy)-phenyl]-
.
: :
- , .. ~ :
~8633
crotonic acid nitrile in a solution of 15.0 grams of homo-
veratrylamine in 100 ml o ethanol are heated at the boil
under reflux for 5 hours. After the usual working up
(see ~xample 1) the free crude base is recr~stallised from
ethanol/diisopropyl ether and again from ethanol.
~here are obtained 15.1 grams of free base melting
at 141.5-142C. From the latter there are obtained in a
manner analogous to that i~ Example 1 13.6 grams of [D,L]-
3-[4-(3-3~,4~-dimethoxyphenethylamino-2-ny~roxy-propoxy)-
phenyl]-crotonic acid ~itrile hydrochloride melting at
148-149 C.
Example 16 a
~D,L~-~-[2-Methoxy-4-(3,3~,4~-dimeth_xy-pheneth~l-amino-2-
hydrox~-pro~ox~)-phenyl~-crotonic acid nitrile hydrochloride
6.7 Grams of [D,L]-3-[2-Methoxy-4-(2,3-oxido-propoxy)-
phenyl]-crotonic acid nitrile in 7 ml of e~hanol are boiled
under reflux for one hour with 7.0 grams of homoveratrylamine
and reacted as described in Example 16.
Yield: 6.6 grams of ~D,L]-3-~2-methoxy-4-(3-3~,4~-dimethoxy-
phenethyl-amino-2-hydroxy-propoxy)-phenyl]-croto~ic acid
nitrile hydrochloride melting at 131 - 132C.
~xample 16 b
[~,L]-3-~3-Chloro-4-(~-3~,4~-dimethoxy-pheneth~l-amino-2-
hydrox~-propoxy)-phenyl]-crotonic acid nitrile h~drochloride
5.0 Grams of tD,L~-3-~3-Chloro-4-(2,3-oxido-propoxy)-
phenyl]-crotonic acid nitrile are boiled u~der reflux with
15 ml of ethanol and 5 grams of homoveratrylamine for 4 hours.
50 Grams of ethanol are then added, and the mixture is
adjusted to a pH-value of 3.5 with concentrated hydrochloric
3o acid t and the r~action mixture is poured into 5 litres of
: . : : . : . : , ~ ,
:: . .
. ~
3633
water. After extraction o the neutral fraction with
ethyl acetate/toluene ~2 : 1), the aqueous phase is rendered
we~kly alkaline with sodiu~ hydrogen carbonate. Extraction ~ -
is carr ed out w th toluene/ethyl ac~tate (2 : 1) and the
organic phase is dried and rotated. By crystallisation
with toluene/diisopropyl ether there are obt~ined 5.1 ~rams
of free base me1ting at 117 - 1t9C. ~he latter is convert-
ed into the h~drochloride as described n Example 1.
Yield: 4.7 grams of [D,L]-3-~3-chloro-4-(3-3~4~-dimetho~y-
phenethyl-amino-2-hydroxy-propoy.y)-phen~l]-crotonic acid
nitrile hydrochloride melting at 146 - 148C.
Example 16 c
[D,~]-3-t3-Chloro 4-(3-tert.-butylamino-2-hydroxy-~ropox~)-
-crotonic acid nitrile hydrochloride.
4.5 Grams oI [D,L]-3-[3-chloro-4-(2,3-oxido-propoxy)-
phenyl]-crotonic acid nitrile in 15 ml of ethanol ~e
reacted for 3 hours, as described in Example 6 a, with 50 ml
of tert.-butylamine, and wor~ed up in the manner described
in Example 1.
Yield: 6.0 grams o~ [D,~]-3-~3-chloro-4-(3-tert.-but~lamino-
2-h~droxy-propoxy)-phenyl]-crotonic acid nitrib hydrochlcride
melting at 188 - 189C.
Example 16 d
~ ~]-3-[3-~luoro-4-(3-tert.-butylamino-2-hydro~r-proPoxy~-
- phen~l]-crotonic acid nitrile hydrochloride
5.0 Grams of ~D,~]-3-[3-fluoro-4-(2,3-oxido-propox~)-
phenyl]-crotonic acid nitrile in 15 ml of etha~ol ~re
boiled under reflux for 3 1/2 hours with 50 ml of tert.-
butylamine ~nd worked up as described in Example 1.
Yield: 6.9 Grams of [D,~-3-[3-~luoro-4-(3-tert.-butyl~mino-
31
: . . .. . .
' ' ' ;': , ~'; ' ~ '' , :
11~8633
- 2-hydroxy-propox~)-phenyl]-crotonic acid nitrile h~drochloride
melting at 190-191C.
Example 16 e
[~?~]-3-[Z-Fluoro-4-(3-3*,4*~dimethoxy-Phenethgl-amino-2-
hydroxy-propox~)-phenyl]-crotonic acid nitrile hydrochloride
10 Grams of ~D,L~-3-[3-fluoro-4-(2,3-oxido-pr~pox~)-phenyl]
-crotonic acid nitrile in 20 ml of ethanol a~d ~0.0 grams of
homoveratrylamine are heated under reflux on a steam bath
; for 3 1/2 hours. Working up is then carried out as in
Example 16 b. 7.9 Grams of the free base so obtained
melting at 111 - 112C. are converted as described in Example
1 into 7.3 grams of ~D,~]-3-[3-fluoro-4-(3-3*,4~-di~ethoxy-
phenethyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid
~itrile hydrochloride melting at 163 - 164C.
Example 16 f
tD,L]-3-[3-methoxy-4-(3-3~4~-dimethoxy-phenethyl-amino-2-
~` hydrox~-Propox~)-phen~l]-crotonic acid nitrile hydrochloride.
i 9.8 Grams of [D,L]-3-~3-methoxy-4-(2,3-oxido-propoxy)-
phe~yl]-crotonic acid nitrile are heated for 2 hours on a
steam bath under reflux.
~he mixture is then diluted with about 50 ml of ethanol,
ad~usted to a pH-value of 1 with concentrated hydrochloric
acid, and the reaction mixture is poured into 5 litres of
water. The neutral constituents are extracted with toluene/
ethyl acetate. The aqueous phase is rendered weakly basic
with sodium hydrogen carbonate, extracted with toluene and
the basic extracts are dried by rotation, and recrystallised
from toluene/ether and then from ethanol.
~ Yield: 7.6 gram~ of free base melting at 115 - 116C. It is
3o con~erted in the usual manner (see Example 1) into the hydro-
chloride, and the latter is recrystallised from ethanol/ether
32
- . i, . ...
. :
- . .
. ~ , ... :, .... .
t : .
:` . :.'' . `. '~.' ... . ':
~ ~38~33
and ethanol.
Yield: 6.4 gr~ms of LD9~-3-~3-mathoxy-4-(3-3~,4~-dimethoxy-
phenathyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid
nitrile hydrochloriae melting at 110 - 112C.
Example 16
[D,~]-3-[3-Metho~-4-(3-tert.-but~lamino-2-h~droxy-pro~oxy)-
ph~nyl]-crotonic acid nitrile h~drochloride~
7.0 Grams of [D,L3-3-[3-methoxy-4-(2,3-oxido-propox~)-
phenyl~-crotonic scid nitrile in a mixture of 28 ml o~ ethanol
and 70 ml of tert.-butylamine are heated at the boil under
reflux for one hour. Workins up is then carried out as
described in Exam-ple 1.
Yield: 7.1 ~rams of [D~]-3-~3-methox~-4-(3-tert.-butyl~min
2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile h~drochloride
melting at 157 - 158C.
Example 17
",
[D,L3-3-[4-(3-N-2~-pyridyl-piPerazino-2-h~droxy-~ropo~
.,
phe~ -crotonic acid nitrile dihydrochloride.
10.75 Grams of tD,~-3-~4-t2,3-oxido-propoxy)-phenyl]-cro-
tonic acid nitrile in a solution of 8.2 grams of pyridyl-pip-
erazine in 60 ml of ethanol are boiled under reflux for 3
hours. ~he mixture is then cooled with ice, and the pre-
cipltated cr~6tals are collected and dried. ~he resulting
17.1 grams of free base melting at 131 - 132C. are converted
in the usual manner into 15.1 grams of [D,~]-3-[4-(3-~-2~-
pyridyl-piperazino-2-hydroxy-propoxy)-phenyl3-crotonic acid
nitrile dihydrochloride melting at 259-260C.
Example 18
~D,L~-3-[4-(3-~-4~-Acetyl-phenyl-piperazino-2-h~droxy-~roPox~)
~henyl3-crotonic acid nitrile hydrochloride.
10.75 Grams of [D,~]-3-[4-(2,3-oxido-propoxy)-phenyl~-
33
. . , ~' -' ' ., '
~-, . : - .
.
;33
crotonic acid nitrile are boiled under reflux in a solution
of 10.2 grams of para-piperazinoacetophenone for 4 hours.
The base, obtained by cooling, crystallising, filtering off
with suction and drying (20.1 grams, melting at 160-- 161C.)
is adjusted in 100 ml of absolute ethanol and 30 ml of dimethyl-
formamide with concentrated hydrochloric acid to a pH-value of
5. The hydrochloride that crystallises out is collected
and recrystallised hot from ethanol/water.
There are obtained 17.7 grams of [D,L]-3-[4-(3-N-4*-
acetyl-phenyl-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic
acid nitrile hydrochloride melting at 221 - 222C.
Example 19
[D,L]-3-[4-(3-N-2*-Methoxy-phenylpiperazino-2-hYdroxy-propoxy)-
phenyl]-crotonic acid nitrlle hydrochloride
10.75 Grams of [D,L]-3-[4-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile are boiled under reflux for 5 hours
in a solution of 10.3 grams of N-(2-methoxyphenyl)-piperazine
dihydrochloride in a mixture of 14.0 ml of triethylamine
and 60 ml of ethanol. Concentration to dryness is then
carried out ln vacuo, and the crude base is caused to cryst-
allise by the addition of ethanol. By filtering off with
suction, subsequently washing with ethanol and water there
are obtained, after drying, 15.0 grams of free base melting
at 102 - 103C. It is then converted in the usual manner
(see Example 1) into the hydrochloride. By recrystallisa-
tion twice from ethanol there are obtained 13.3 grams of
[D,L]-3-[4-(3-N-2*-methoxy-phenylpiperazino-2-hydroxy-
propoxy)-phenyl]-crotonic acid nitrile hydrochloride
melting at 198-199C.
~ 34
,~....
.~, ::: . .. ;.
~ 3 3
E~ample 20
[D,~]-3-[4-(3~N-?~-Methyl-phenyl-piperazino-2-hyaroxy-
propoy~)-phenyl3-crotonic acid nitrils hydrochloride~
10.95 Grams of [D,L]-3-[4-(2,3-oxido-propoY.~)-phenyl]- -
crotonic acid nitrile are boiled under reflux for 3 hours
in a solution of 8.8 grams of ortho-tolyl-piperazine.
After cooling, 15.5 g~ams of the free base crystallise out,
melting at 104 - 105C. It is converted into the hydro-
chloride as described in Example 1. 3y fi~lly recrystall-
ising twice from ethanol there are obtained 10.0 grams o
tD,L]-3-[4-(3-N-2~-methylphenyl-piperazino-2-h~droxy-propoxy)-
phenyl]-crotonic acid nitrile hydrochloride melting at 233-
234C.
Exam~le 21
tD,~]-3-[4-(3-~-3~-Methyl-phenyl-piPerazino-2-hydroYy-Propox~
phenyl]-crotonic acid nitrile hydrochloride-
10.75 Grams of [D,L]-3-[4-(2,3-oxido-propoxy)-phenyl~-
crotonic acid nitrile are reacted as described in Example 19
with 8.8 grams of meta-tolyl-piperazine.
By working up in the same manner there are obtained from
16.4 grams of the free base melting at 108 - 109C., 14.6
grams of [D,L]-3-~4-(3-~-3~-methyl-phenyl-piperazin~-2-hydroxy-
propoxy)-phen~l]-crotonic acid nitrile hydrochloride
meltin~ at 151 - 152C.
ExamPle 22
[D,~-3-[4-(3-N-Methyl-piperazi o-?-hydroxy-propoxy)-pkenyl]-
croto~ic acid nitrile dih~drochloride,
10.75 Grams of [D,L]-3-[4-(2,3-oxido-propoxy-phenyl]-
croto~ic acid nitrile are reacted as described in Ex~mple 19
3o with 5.0 grams of N-methylpiperazine in 60 ml of ethanol,
- . . ~ : ';
33
and, as described i~ Example 1, worked up and converted into
the dihydrochloride.
There are obtained 11.8 grams of [D,~]-3-[4-(3-N-methyl-
piperasino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile
dihydrochloride meltin~ at 217 - 218~.
Example 23
[D,L]-3-[4-(3-N-2*-oxyethyl-piperazino-2-hydroxy-propo
~en~l]-crotonic acid nitrile dihydrochloride~
5.0 Gr~s of [D,~]-3-[4-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile are boiled under reflux for 2 hours
in a solution of 3.5 grams of hy~roxyethyl-piperazine in
50 ml of ethanol. After evaporation to drynes~ in vacuo,
crystallisation frsm toluene is carried out. The result-
in~ 5.7 grams of ~ree base melting at 101 - 102C. are
converted as described in Example 1 into 6.7 grams of
~D,~]-3-[4-(3-N-2~-oxyethyl-piperazino-2-hydroxy-propox~)-
phenyl]-crotonic acid nitrile dihydrochloride mslting at 204
- 205C.
[D~ 3-[4-(3-7~5~-Dimethyl-5~-h~droxy-hexylamino-2-hydroxy-
~roPox~ henyl]-crotonic acid nitrile oxalate.
8.5 Grams of [D,~]-3-[4-(2,3-oxido-propoxy) -phenyl~-
crotonic acid nitrile are boiled under reflux for 2 hours in
a solution of 1.6 grams of sodium hydroxide and 7.2 grams
f heptaminol hydrochloride in 50 ml of ethanol. ~he mix-
ture is then concentrated in ~acuo, the distillation residue
is taken up in 85 ml of water and adausted to a pH-value o~
7 with hydrochloric acid. Washing with toluene and ethyl
acetate is carried out twice each time, and the aqueous
~o phase i9 rendered alkaline at a pE-value of 10 with sodium
36
-.
: . .
: ' '':'' :"' ,, : . ' : ` .
- - :, ' ` :
: ~~ . . , ' .,
633
hydrox~de solution. Extraction with ethyl acetate/toluene
(1:1) is then carried out, the organic extracts are dried
and evaporated to dryness in vacuo. ~he crude base is take~ r
up in ethanol, and the mixture is adjusted to a pH-value o~
4 with a concentrated solution of oxalic acid in ethanol.
3y filtering off with suction and drying there are obtained
7 ? grams of [D,~]-3-[4-(3-7~,5~-dimethyl-5~-hydroxy-hexyl-
amino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile
melting at 155C.
~xam~le 25
[D,L]-3-[2-(3-tert.-butylamino-2-h~dro~y-propoxy)-phenyl]-
acrylic acid nitrile hydrochloride.
7.0 Grams of [D,~]-3-[2-(2,3-oxido-propoxy)-phenyl]-
acrylic acid nitrile in a solution of 15 ml o~ tert.-butylam-
i~e in 80 ml of absolute ethanol are boiled under reflux
for one hour. In the manner described in Example 1,
working up and conversion into the hydrochloride are carried
; out. ~here are obtained 5.3 grams of ~D,L]-3-[2-(3-tert.-
; butylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid nitrile
hydrochloride melting at 155C.
Example 26
[D,~]-3-t2-(3-tert.-butylamino-2-hydrox~-propoxy)-~henyl]-
acrylic acid tert.-butyl ester hydrochloride.
30.0 Grams of [~,~]-3-[2-(2,3-oxido-propoxy)-phenyl]-
acrylic acid tert.-butyl ester are boiled under reflux for
3 hours in a mixture of 30 ml of tert.-butyl~mine and 150 ml
of ethanol. After working up in the usual manner (see
Exampla 1), the crude hydrochloride is dissolved in water,
the aqueous solutiou is extracted twice with toluene, and
a concentrated aqueous solution of sodium chloride is then
added to the a~ueous pha~e. In this way the [D~]-3-
37
633
[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-acr~lic
acid tert.-butylester hydrochloride crystallises out.
The product is filtered off with suction, dried in vacuo,
~ and again recr~stallised twice from isopropanol. ~here are
- 5 obtained 13.8 grams of [D,L]-3-[2-(3-tert-butylamino-2-
hydroxy-propoxy)-phenyl]-ac~ylic acid tert.-buty~ ester
hydrochloride melting at 186 - 187C.
xamPle 27
[D,h]-3-[2-(3-3~,4~-Dimethox~-pheneth~lamino-2-hydrox~-
~ro~ox~-phenyl]-acrylic acid tert.-but~l ester hydrochlor~de
30.0 Grams of CD,L~-3-C2-(2,3-oxido-propoxy)-phen~l]-
acrylic acid tert.-butyl ester are heated at the boil under
reflux for 2 hours in a solution of 20.0 gram3 of homovera-
trylamine in 60 ml of ethanol. After wor~ing up in th e
usual manner (see Example 1) 15.9 grams of tD,L)-3-t2-(3-
3~,4~-dimethoxy-phenethylamino-2-hydroxy-propoxy)-phenyl]-
acr~lic acid tert.-butyl ester hydrochloride melti~g at
167 - 168C. are obtained.
Example 28
; 20 tD~L2~3-[2-(3-N-2~-oxyet~l-piperazino-2-hydrox~-propoxy)-
_henyl]-acrylic acid tert.-but~l ester dihydrochlorlde.
11.0 Gram~ of [D,L]-3-[2-(2,3-oxidopropoxy)-phenyl]-
acrylic acid tert.-butyl ester are boiled u~der reflux for
2 hours in a mixture of 55 grams of ~-hydroxyethyl-piperazine
and 60 ml of ethanol. Working up is then carried out
as in Example 14, but in this case the pH-value is 3 instead
of 4. 5.4 Grams of CD,L]-3-[2-(3-~-2~-oxyethyl-piperazino-
2-hydroxy-propoxy)-phenyl~-acrylic acid tert.-butylester
dihydrochloride melting at 168C. (with decomposition~ are
obtained.
38
.. . .. . ...
.
,: ~, -
33
xample 29
tD,L~-3-t2-(3-~-phen~lpi~erazino-2-hydrox~ ~ropo~)-phen~l]-
acr~lic acid tert.-but~l ester hy~rochloride.
11.0 Grams of tD~-3-[2-(2,3-oxidoPropoxY)-phenyl]-
acr~lic acid tert.-butyl ester are boiled under reflux for
one hour in a ~ixture of 6.5 grams of phenylpiperazine and
50 ml of ethanol, and working up is carried out as described
in E~ample 1. In this case the h-~drochloride is finally
recrystallised twice from ethanol. 6.2 Grams o~ [D,L]-
3-[2-(3-~;-phenylpiperazino-2-hydroxy-propoxy)-phen~l]-ac~ylic
acid tert.-butyl ester hydrochloride melting at 200 - 201C.
(with decomposition) are obtained.
Example 30
[D~T ~ -3-[4-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl~-
acr~lic acid tert.-butyl ester hydrochloride.
15.0 Grams of [D,L]-3-[4-(2,3-oxidopropoxy)-phen~l]-
acr~lic acid tert.-butyl ester are boiled under reflux for
2 hours in a mixture o~ 25 ml of tert.-butylamine and 100 ml
of ethanol (98% strength). The mixture is then concentrated
to dr~-ness in vacuo, the distillation residue is evaporated
twice with to;uene (in vacuo) and finally caused to crystal-
lise with diisopropyl ether. 16.7 grams of free base
melting at 107 - 108C. are obtained. ~rom the l~tter
there are obtzined as described in ~xample 28 12.3 grams
of [D,~]-3-[4-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-
acrylic scid tert.-butylester hydrochloride melting at 192
- 193C. (with decomposition).
Exa_ple 31
[D,L~-3-[4-(3-3*,4*-Dimethox~phenethylamino-2-hydrox~-
~roPo~y~enyl]-acrylic acid tert.-butyl ester h~drochloride,
39
, : ~
~8~
15.0 Gra s of [D,L~-3-t4-(2,3-oxidopropoxy)-phenyl]-acryl-
ic acid tert.-bu~yl ester a-e boiled under reflux for 8 hours
in a solution of 10.5 grams of homoveratryl~mine. Working
Up i9 carried out in the usual manner, and the crude hydro-
chloride is dissolved in 6 litres of water, ~xtracted several
times with ~oluene and the aqueous phase is adjusted to a
p~-value of 9 wi~h sodium hydroxide solution. ~he mixture
is then e~tracted with toluene and eth~l acatate. ~he com-
bined organic extracts are e~aporated to dryness in vacuo,
and crystallisation is caused with diisopropyl ether.
6.95 Grams of free base are obtained melting at 100 - 101C.
From the latter are obtained as described in Example 1
7.4 grams of [D,L]-3-t4-(3-3~,4~-dimethoxyphenethyla~ino-
2-hydroxy-propo~y)-phenyl]-Gcrylic acid tert.-butyl esver
hydrochloride melting at 176 - 177C., which W2S finally
recrystallised twice from ethanol.
Example 32
[D.L3-3-Phen~1-3-[2-(3-ter'.-butylami~o-2-hydroxy-~ropo~)-
~ 3-acrylic acid nitrile hydrochloride,
5.4 Grams of ~D,L~-3-phen~1-3-~2-(2,3-oxidopropox~)-
phe~yl]-acrylic acid ~itrile are boiled under reflux for 2
hours i~ a mix-ture of 15 ml of tert.-butylamine. ~ha mix-
ture is then eva~orated to dryness in vacuo, and e~aporated
twice with toluene in ~acuo. ~he distilla~ion residue is
caused to crystallise by digestion with toluene/petroleum
ether. 6.4 Grams of free base melting at 92 - 93C. are
obtained. From the latter are obtained as described i~
Example 1,5.5 ~ra~s of [D,L]-3-phenyl-3-[2-(3-tert.-butyl-
amino~2-hydrox~-propoxy)-phenyl]-acrylic acid nitrile
hydrochloride melting at 171 - 172C.
; ,,,
~ ~ 40
, - . .
, : , -. . ; ~ : ~
~8633
:ExamPle 33
[D,I,]-3-Phe~ 3-r.? (~ s4~-Dimetho~y~he~eth;ylamino-2-nydrox;
propox~)-phen~l]-acrv~lic acid nitrile semi-oxalate~
5.4 Grams of [D,~]-3-phenyl-3-[2-(2,3-oxidopropoxy)-
phenyl~-acrylic acid nit~ile are boiled under re~lux for 3
hours in a solution of 3~7 grams of homoveratrylamine i~
50 ml of ethanol. Wor~ing up is then carried out as des-
cribed in Example 30. ~he oily free base is then converted
as described in Ex~mple 23 into the oxalate, but in this
case it is adjusted to a p~-value of 6.5 by the addition of
oxalic acid. The crude semi-oxalate is again recrystallised
twice from ethanol, and 4.1 gramæ of tD,L]-3-phenyl~3-[2-
(3-3#,4~-dimethoxyphenethylamino-2-hydrox~-propo~y)-phen~l]-
acrylic acid nitrile semioxalate melting at 172-173C. are
obtained.
Example 34
[D,L]-~-Phenyl-3-~2-(3-N-phenylpiPerazino-2-hydroxy-propo~)-
phenyl]-acr~lic acid nitrile hydrochloride,
6.0 grams of tD,L] 3-phenyl-3-[2-(2,3-o~idopropoxy)-
phenyl]-acrylic acid nitrile are boiled under reflux for 2
hours in a solution of 3.5 grams of phenyl-piperazine in
50 ml of ethanol. ~hen, as described in E~ample 1, working
up and converaion into the hydrochloride are carried out.
For further purification the procedure is as described i~
Example 30. ~he free base was purified by crystallisation
with toluene/dii~opropyl ether~ 4.1 Grams melting at
102 - 103C. are obtained. ~he free base is again as
described in Example 1 converted into the hydrochloride.
~here are obtained 4.4 grams having the double melting point
85C./184C.
41
, . ~ .
.:
. .
~ 3 ~
[D ~]-3-Phenyl-j~[4-(3-tert_-butylamino-?-hydroxy-~
phen~l]-acr~]ic acid nitrile_n~ochloride
10.0 Grams of [D~L]-~-phenyl-3-[4-~2,~-oxido-~propoxy)-
phenyl~-acrylic acid nitrile are heated at the boil under
reflux for 2 hours in a ~lixture of 20 ml of tert.-butylamine
a~d 50 ml of ethanol. ~hen, as described in ~xample 1,
working up and conversion into the hydrochloride are carried
out, he crude hydrochloride ~as finally recrystallised
again twice from e~hanol. 4.6 Grams of [D~-3~phenyl-3--
L4-(~-tert.~butylamino-2-hydroxy-propoxy)-phenyl~-ac~lic acid
nitrile hydrochloride melting at ~33 - 234C. ale obt~ined.
~he ethanolic mother liquor from the second recr~stallisat~on
is concentrated to dr~ness ~n ~acuo, and con~erted into the
free base in a manner a~alogous to that in Exa2ple 30~
After crystallisation of the crude base by trit~ration with
diisopropyl ether 1~1 grams of the free base melti~g at
112 - 114C. are obtained.
~xample 36
~D~I.]-3-Phenyl-3-[4-(3-3 ,4~-Dimethox~heneth~lamino-2
~rox~-propoxy)-phenyl]-acxylic acid nitrile oxalate.
10.0 Grams of [D,~]-3-phenyl-3-[4-(2,3-oxido-propoxy)-
phen~l]-acrylic acid nitrile are boiled under ~e~lux for 2
hours in a mixture of 6.5 ml of homoveratrylamine and 50 ml
of ethano'. Working up is then carried out as described
in Example 30. ~he oily free base is then converted into
the oxalate as described in Example 23. 4.9 Gr~ms of
[D,L]-3-phen~ [4-(7-3~,4~-dimethoxy-phenethylamino-2-
hydrogy-p~opox~)-phe~yl] acrylic aci d nitri le oxal ate
melt~ng at 124 - 125C. are obtai~ed.
- . .. -.
;, :: ,. . :. . ;
,. . :~:,. :
6~3
~Z
CD~ 3- Phenyl-~-[4-~3-N-phen~lpipera
~henyl]-acr~lic acid nitrile_d h drocnloride.
10.0 Grams of [D,~1-3-phenyl-3-[4-(2,3-o~ido-propoxy)-
phenyl]-acrylic acid nitrile are boiled under reflux for 2
hours in a solution of 5.9 grams of phenyl-piperazine in
50 ml of ethanol. ~y working up in a manner analogous to
that in Example 1 6.8 grams o~ [D,~-3-phenyl-3~4-(3-N-
phenylpiperazino-2-hydrox~-propoxy)-phenyl~-acrylic acid
nitrile dihydrochloride melting at 189-190C. are obtained.
xample 38
[D~L]-3-Phen~1-3-~4-(3-~-~2-h~droxyeth~l]-piperazi~o-2-
h~drox~-~ropoxy)-phenyl~-acrylic acid nitrile dip~drochloride
In a man~er analogous to that in Example 36, 10.0 grams
f [D,L]-3-phen~1-3-[4-(2,3-oxido-propoxy)-phenyl]-acr~lic
acid ni~rile are r~acted with 4.7 grams of ~-hydroxyethyl-
piperazine in 50 ml of ethanol a~d worked up. 9.8 Grams
of tD,L]-3-phenyl-3-[4-(3-N-[2-hydroxyethyl]-piperazino-2-
hydroxy-propoxy)-phenyl~-acr71ic acid nitrile dihydrochloride
melting at 164 - 165C. are obtained.
[D,L]-3-[4-(3-3~,4~-Dimethoxyphenethylamino-2-h~drox~-prop-
ox~)-phenyl]-acrylic acid methyl ester h drochloride.
6 Grams of [D,L]-3-[4-(2,3-oxido-propoxy)-phe~yl]-
~5 ~cr~lic acid methyl ester are boiled under reflux for 2 1J2
hours in a solution o~ 4.7 grams of homo~eratryl~mine in
60 ml of absolute ethanol, and then working up is carried
out as described in Example 1. 6.2 Grams o~ [D,L]-3-[4-
(3-3~,4~-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-
acrylic acid methyl ester h~drochloride melting at 162C.
are obtained.
43
,, ,, . " ~ ,
. ~ - , ..
: ~ ' ;
33
[D?L~-3- [4-(3-1 ~ 5-Dimeth~rl-5-hydro~ -hex~lamino-2-h~drox,~7 -
5.~ ~rams of ED,L]-3-[4-(2,3-oxido-propox~)-phenyl]-acryl-
ic acid met~yl ester are boiled under refll~ for 4 hours in
a solution of 4~6 grams of 6-amino-2-methyl-2-heptanol hydro-
chloride (heptaminol h~droehloride) a~d 1.02 grams of sodium
hydroxide in 70 ml of absolute ethanol. Wor~ing up is ~hen
carried out a~ described in Example 1. Ether is used ~or
recrystailisation of the free base and for recr~stallisation
of the hydrochloride. 1.2 Grams of [D~L]-3-~4-(3- [1,5-
dimethyl-5~hydro~y]-hexyla~ino-2-h~droxy-propo~y)-phenyl]-
acrylic acid methyl ester h~drochloride melting at 110C.
are obtained.
~xample 40 a
[D~L]-3-[4-(3-N-2~-methoxv~hen~l-E~ azino-2-h~drox~-pr?~oxy)-
~henyl]-crotonic acid meth~l ester.
15.0 Grams of [D,L~-3-~4~(2,3-oxido-propoxy)-phenyl]-
croto~ic acîd methyl est~r are heated for ono hour on a ste~m
bath in 50 ml of ethanol and 10 gram~ of 2-metho~y-phen~l-
piperazine. Worki.ng up is the~ carried out as described in
Example 1. 6.2 Grams of [D,LJ-3-[4-(3-~-2~-methox~phenyl-
piperazino-2-hydroxy-propox~)-phen~l]-crotonic acid meth~l
ester melting at 183 - 184C. are obtained.
Example_41
[D~L~-3-[4-(3-N-2~-Methoxyphen~l-pi~erazino-2-hyaroxy-propoæ~)-
phen~l]-acrylic acid methyl ester dihydrochlorid~.
4.5 Grams of [D,L]-3-[4-(2,~-oxido-propoxy)-phenyl~-
acrylic acid methyl ester are boiled under reflux for 3 hGurs
in a solution of 4.0 6rams of N-(2-metho~y-phenyl)-pi~erazine
44
.:,: - ,.., ~ :
- : :: : , ~ :- :
, ~ , .
~ 6 3 ~
in 60 ml O.L absolute eth~nol. By the usual working up
(see E~ample 39j 6.05 grams of [D,L~-3-[4-(3-N-2~-methoxy-
phenyl-piperazlno-2-hydroxy-propoxy)~phenyl]-acrylic acid
methyl ester dihydrochloride melting at 204C. are obtained.
Example 42
~3~L]-3- [?-(3-3~,4~-Dimetho}~-phenethylamino-2-hydro~y-prop ~)
~enyl]-acrylic acid eth~l ester _ ~drochloride.
10.0 Grams o~ [D,L~-3-~2-(2,3-oxido-propo~y)-phenyl]-
acr~lic acid eth~l ester are boiled under reflux for 4 hours
in a solution of 7.3 grams of homoveratrylamine in 60 ml of
ethanol. The mixture is then concentrated to dryness ~n
vacuo. B~ digestion with hexane the oily distillation
residue is caused to cr~stallise. After ~iltering of~ snd
drying 9.8 grams Or free base melting at 80 - 82C. are ob-
tained. From the lattsr is prepared as described in E~ample
1 the hyd~ochloride, which is once a~ain recrystallised from
ethanol/water and finally from isopropanol. 8.1 Grams of
tD,L]-3-2-(3-3~,4~-dimethoxy-phenethylamino-2-hydroxy-propoxy)-
phenyl]-acrylic acid ethyl ester hydrochloride melting at
161 - 162~C. are obtain~d.
Example 43
[D,L~-3-t2-(~-N-phenylpiperazino-2-h~droxy-propox ~-Phenyl]
acr~lic hcid ethyl ester hydrochloride.
10.0 Grams of [D,L]-~-~2-(2,3-oxido-propoxy)-phenyl]-acry-
lic acid ethyl ester are voiled for 4 1~2 hours in a solution
of 6.54 grams of N-phenyl-piperazine in 60 ml of ethanol.
l'hen, as described in ~xample 1, working up a~d con~ersion
into the hydrochloride are carried out. ~he hydrochloride
once
so obtained is finally recrystallised agai~yfrom isopropanol
and then lrom ethanol/water. 10.2 Grams of [D,L]-3-[2-
- . : , , . ~ :
- ~ , . . .
633
(3-~-phen;s~lpiperazi.no-2-h~dro~xy-propoxy)-,phenyl~-ac~ylic
obt~ined.
acid ethyl ester hydrochloride melti~ at 185 - 187G. ~re /
E~ampl~ 44
[D,L]-3-[2-(3-tert.-bu~yl~ino-2-hydrox~-prouox~)-phenyl~-
acr~lic acid eth~l ester h~drochloride.
10.0 Grams of [D~I,]-3-[2-(2.3-oxido-propo2y)-phenyl]-
ac~ylic acid eth~i ester are boiled for 5 1/2 hours in a
mixture of 4 25 ml of tert.-butylamine and 60 ml of ethanol.
'~hen, as described in Example 1, working up is carried out
and the crude h~drochloride obtained, which is precipitated
in the usual manner from ethanol/h~drochloric acid and i5
then evaporated with toluene, is recrystallised from ethanoi/di-
isopropyl ether. As described in Example 30, the hydrochlor-
ide is then purified again via the free base. I~ this case
suspensio~ of the hydrochloride in about 100 ml o~ water b~
the addition o~ sodium nydroxide solution is sufficient.
B~ recr~stallisation from isopropanol 5.8 grams of [D,L]-
3-t2-(3-tert.-butylamino-2-hydro~y-propoxy)-phenyl~-acrylic
asid ethyl ester hydrochloride melti~g at 133 - 134C are
obtained.
[D,~] 3-~4-(3-tert.-but~lamino-2-h~drox~-~ropo~ phenyl~-3-
eth~l-acrylic acid nitrile hydrochloride.
10.0 Grams of [D,L~-3-[4-(2,3-oxido-propoxy)-phen~l]-
3-ethyl-acrylic acid nitrile are boiled under reflux for 2
hours in a mixture of 15 ml of tert.-butyl~mine and 50 ml of
etha~ol. Working up is then carried out as describad in
~xample 1. The crude free base first obtained is recryst-
allised from toluene/hexane. '~he 7.0 ~rams so obtained
- melting at 73 - 75C. are converted as described in ~xample 1
into the hydrochloride. 3.4 Grams of [D~L~-3-[4
4~
.:. : - ....... :. . :
: ::,, . :: - :
- :. .. :, ::: . ~ ::. :
:
~863~
tert.-but~lamino-2-hydroxy-propoxy)-phenyl~-3-ethyi-acrylic
acid nitrile hyd~ochloride melting at 170 ~ 171Co are
obtained.
Example 46
[D~L]~3-[4-~3-3~,4~-Dimetho~-phenethylam ~o-2-hydroxy-prop~
oxy)-phenyl]-3-eth~l-acr~lic acid nitrile hydrochloride.
15.0 Grams of [D 9 ~] -~ -[4-(2,3-oxido-propoxy)-phenyl]-
3-ethyl-acrylic acid nitrile are boiled for 2 hours in a
solution of 12.0 grams of homoveratrylamine in 100 ml of
ethanol~ and wor~ing up i~ carried ou~ as dsscr bed in
Example 30. ~here are obtained first 10.3 grams of the
free base melting at 103 - 104C. ~rom the latter are ob-
tained as described in ~xample 1,7.5 grams of [D,L]-3-[4-
(3-3~,4~-dimethoxy-phenethylamino-2-hydroxy-propoxy)-phenyl]-
3-etnyl-acrylic acid nitrile hydrochloride melting at 120 -
121C.
Example 47
[D,L~-3-[4~ N-Phenyl-piperazino-2-hydroxy-Propoxy)-p~enyll-
; 3-ethyl-acrylic acid ~itrile dihydrochloride.
10.0 Grams of [D,~]-3-[4-(2,3-oxido-propoxy)-phen~
3-ethyl-acrylic acid nitrile are boiled u~der reflux for
2 hours in a solution of 11.0 grams of phe~ylpiperazine
in 50 ml of ethanol. ~he reaction mixture is then cooled
to 5~C., and the free base crystallises out. 8.2 Grams of
the free base melting at 110 - 115C. are obtained, from
which there are obtained, as described in Example 1 by means
of 4.19 ml of 10 N-hydrochloric acid, 8.1 grams of ~D,~]-3-
[4-(3-N-phenyl-piperazino-2-hydroxy-propoxy)-phenyl]-3-
ethyl-acrylic acid nitrile dihydrochloride melti~g at 202 -
~0 204oc
863~
Examnle 48
[D~l~-3-[4~t3-N-~2-~I;Ydrox~eth~l~-niperazino-2-hydr
~e~yl~-3~eth l-acrylic_acid nitrile dihydrochloriae.
10.0 Grams of [D,L~-3-~4-(2,3-oxido-propoxy)-phenyl]-
3-ethyl acrylic acid nitrile in a solution of 6.0 grams of
N-hydroæyethyl-pipe-azine are, as in Example 45 or 30
(2.0 litres of water) reacted and wor~ed up. ~here are
obtained first 6.4 grams of ~he lree base melting at 80 -
81C. and therefrom by mea~s o~ 3.57 ml o~ 10N-hydrochloric
acid, 7.2 grams of ~D,~]-3-[4-(3-N-[2-hydroxyethyll-piperazino-
2-hydroxy-propoxy)-phenyl]-3-ethyl-acrylic acid nitrile
dihydrochloride melting at 181 - 182C.
_xamPle 49
[D,L~-3-~2-(3~ 4*-Dimethoxy-phenethylamino-2-h~droxy-propoxy)
he~yl~-3-ethyl-acrylic acid methyl ester hydrochloride.
8 Grams of [D,L]-3-[2-(2,3-oYidopropoY~)-pheny~]-3-
ethyl-acrylic acid meth~l ester h~d-ochloride are boiled under
reflux for 3 hours in a solution of 5.7 grams of homo-reratryl-
amine in 80 ml of absolute ethanol. Working up is then
carried out as described in Example 45. 4.3 Gr~ms of ~D,L~-
3-[2-(3-3~,4~-dimethoxy-pheneth~lamino-2-hydro~y-Propoxy)-
phenyl~-3-ethyl-acrylic acid methyl ester hydrochloride are
ob~ained ~he free base shows characte~is~ic ~R-bands ~t
2920, 171~ 1630, 1585, 1505, 1437, 1225, 1145, 1015, 793
and 748 cm 1
Exam~le 50
[D~]-3-[2-(3-~J-2~-MethoY~y-phen~yl-pi~erazino-2-h2~dro~-
proPoxy)-~henyl~-3-et~yl-acrylic acid meth~ ester_dih~ro-
chloride.
8 Gr~ms of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-3-
~ 48
~: : : :: :: : : ::
633
e~nyl-acrylic ac~d methyl esver are reacted, as ~escribed
~n Example 41, with a solution of 6.8 ~rams o~ ~-(2-methoxy-
phenyl)-piperaæine in 80 ml of absolute ethanol, and worked
up, 4.4 G ~ms of ~D,L]-3-[2-(3-~ 2~-methoxy-~hen71-piper-
azino-2-'nydroxy-propox~ phenyl~-~-e'hyl-acrylic acid me~hy~
es~er dihyd~ochloride melting at 120 - 122C. ~re cbtained.
Ex~le 51
[D,~]-3-[2-(3-~ert.-Bu~lami~o-2-hydroxy-propQx~)-phenyl]-
crotonic acid ethyl ester h~drochloride~
10.5 Grans of [D,~]-3-[2-(2,3-oxjdo-~ropo~y)~pheny']-
crotonic acid ethyl ester are st~re~ for 16 hours at 20 -
25C. in a mixture of 20 ml of tert.-butylamine and 50 ml of
ethano~. Working up is then carried out as described ~n
E~ample 1. ~he hydrochloride s in this case rec~stallisea
from isopropa~ol/ether twice. 5.4 Grams o~ [D,L3-3-[2-(~-
tert.-butylamino-2-h~droxy--propoxy)-phenyl~-crotonic aci~
ethyl ester hydrochloride melting at 118 - 119C. are obtained.
Exa~ple_52
[D,~-3-~2-(3-3~,4~Dimetho~ Pheneth~lamino-2-hydrox~-
pro~oxy)-phenyl~-crotonic acid ethyl ester oxalate.
12 0 Grams of [D,~]-3-[2-(2,3-oxido~propoxy)-phen~
crotonic acid eth~l ester are stirred fvr 16 hours at 20 to
25C. in ~ solutio~ of 7.2 grams of homove-atrylamine in
100 ml of ethanol, and then worki~g up is ca~ried out as
described in E~.ample 24. 4.5 Grams of [D,~3-3-~2-(3-~,4~-
dimethoxy-phenethylamino-2-hyd~ox~-propoxy)-phe~yl]-croto~ic
acid ethyl ester oxalate melting at 115 - 117C. (with
decompositio~) are obt~ined.
Example 53
[D,L]-3-[2-(3-N-2*-Methoxy-phenylpiperazino-2-hydroxy-propoxy)-
phenyl]-crotonic acid ethyl ester dihydrochloride.
}
~ 49
.
,. : ~ ;~ . .~ , ,.
.
.. ~ . . ,. . - . ...
~. . - . , .
.
~8633
7.9 Grams of tD~L]-3-[2-(2.3-oxido-propoxy)-phen~
crotonic acid eth~l ester ~re stirred at room temperatnre
for 48 hours in a solution of 5.8 grams of N-2-methoxy-phenyl-
piperazine in 10C ml of ethanol. ~hen workin~ up to the
crude base is then carried out as described in Example 1.
It is dissolved in a small amount of ethyl acetate and
chromatographed over a column of 240 grams of silica gel
(Silica gel 60, Merck). ~inally elution with ethyl acetate
yielded 4.4 grams of purified base i~ the form o~ an oil.
~; 10 It is then converted in the usual manner (see Example 1) into
2.9 grams o~ ~D,L~-3-~2-(3-N-2~-methox~-phen~lpiperazino-
2-hydroxy-propo~y)-phenyl]-crotonic acid ethyl ester dihydro-
chloride melting at 134 - 136C.
; Exam~le 54
[D~L~-3-t3-(3-tert.-b~t~lamino-2-h~droxy-propox~-phen~l]-
acrylic acid nitrile h~drochloride.
15 Grams of [D,L]-3-t3-(3-(2,3-oxido-propoxy)-phenyl]-
acrylic acid nitrile are boiled under reflu~ for ons hour in
a mixture of 40 ml of tert.-butylamine and 200 ml of ethanol.
By the usual working up, 8.3 graLs of stron~ly h~groscopic
[D,~-3-~3-(3-tert.-butylam$no-2-hydroxy-propox7)-phenyl]-
acr~lic acid nitrile hydrochloride are obtained. ~he free
base exhibits characteristic IR bands at 3300, 2950, 2208,
1608 (shoulder), 1590 (shoulder), 1570, 14?3, 1435, 1372
and 743 cm 1.
Example 55
[D~L~-3-[3-(3-N-2~-Methoxy-phen~ iperazino-2-hydroxy-
ro~ox~-phen~l~-acrylic acid nitrile dinydrochloride.
12.0 Grams of ~D,L]-3-~3-(2,3-oxido-propcxy)-phenyl]-
l~j,
- .~
8633
acrylic acid nitrile are boiled under xeflux for one hour
in a solution of 11.5 grams of N-2-methoxy-phenylpiperazine
in 50 ml of ethanol. ~hen working up is carried out in a
manner analogous to that in Example 31 (but in this case
4 litres of water, soda solution, instead Or NaCl). ~he
crude free base is oily and is con~erted as described in
Example 1 into 15.7 grams of [D,L]-3-[3-(3-N-2~-methoxy-
phenyl-piperazino-2-hydroxy-propox~)-phenyl]-acrylic acid
nitrile dihydrochloride melting at 210C. (with decompositio~).
gxamPle 56
[D.~]-3-~3-(3-N-[2-~ydroxyeth~l]-piperaæino-2-hydrox~-
~opoxy)-phenyl]-acrylic acid nitrile dihydrochloride.
12.0 Grams of [D,L]-3-[3-(2,3-oxido-propoxy)-phenyl]-
acrylic acid nitrile are, as de3cribed in Example 55,
reacted with 20.0 grams of ~-2-hydroxy-ethylpiperazine in
50 ml of ethanol and worked up. 13.5 Grams of [D,~-3-
[3-(3-~-[2-hydroxyethyl]-piperazino-2-hydroxy-propoxy)-
phenyl]-acrylic acid nitrile dihydrochloride melting at
180 - 182C. are obtained.
Example_57
~D,L]-3-~3-(3-3~,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-
phenyl?-acr~lic acid nitrile hydrochloride.
12.0 Grams of [D,L]-3-~3-2,3-oxido-propoxy)-phenyl~-
acrylic acid nitrile are reacted as in Example 55 with 20.0
grams of N-2-hydroxyethyl-piperazine in 50 ml of ethanol,
and worked up to 13.5 grams of [D,L]-3-[3-(3-3~,4~-
dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl~-acrylic
acid nitrile hydrochloride melting at 180 - 182C.
.. . . .. . . .. . .. . . . . . . .
,,, , ,, . ,, ,:
- ,: :: ,, . , ;,
., : . ,, :,, . . , . : : ~ ,>, ..
. , - .. : .. " ,.: ::: -: ..
. ~. .. , . : ,- , . , ~- ..
., , :. .: . . - - . , :.
, :.- ; . , . ~ :,
:. - : . , ~
11~8633
Example 58
~D,L]-3-[3-(3-tert.-but~lamino-2-hydroAyy propox~)-phenyl]-
crotonic acid nitrile h~drochloride.
15 Grams OA~ [D,lA]-3-[3-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile are, as described in Example 55,
reacted with 40 ml of tert.-butylamine in 200 ml of ethanol
and worked up. 13.8 Grams of [D~L]-3~[3-(3-tert.-butylamino-
2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride
are obtained having characteristic IR-bands at 3320, 2960,
2205, 1668, 1570, 1473, 1430, 1370, and 772 cm 1.
ExamPle 59
~D,Ll-3-[3-(3-3~,4*-Dimethoxy-pheneth~lamino-2-h~droxy-propoxy)~
phenyl]-acrylic acid ethyl ester hydrochloride.
6.0 Grams of [D,L]-3-[3-(2,3-oxido-propoxy)-phenyl]-
acrylic acid ethyl ester are stirred for 16 hours at room
temperature in a solution of 3.6 grams of homoveratrylamine
in 30 ml of ethanol, and then worked up to the crude base
as described in Example 24. ~he latter is reacted as described
in Example 1 to yield 3.6 grams of [D,L]-3-[3-(3-3~,4~-
dimethoxy-phenethylamino-2-hydroxy-propoxy)-phenyl~-acrylic
acid ethyl ester melting at 128 - 129C.
Example 60
[D,~-3-[3-(3-N-2~-Methoxg~henyl-piperazino-2-hydrox~-propoxy)-
phenyl]-acr~lic acid eth~l ester dih~drochloride.
6.0 Grams of [D,~]-3-[3-(2,3-oxido-propoxy)-phenyl~-
acrylic acid ethyl ester are stirred for 48 hours at room
temperature in a solution of 3.9 grams of N-2-methoxy-phenyl-
piperazine. By working up in a manner analogous to that
in Example 1 3.4 grams of [D,L]-3-~3-(3-N-2~-methoxyphenyl-
piperazino-2-hydroxy-propoxy)-phenyl]-ac~ylic acid ethyl
ester dihydrochloride melting at 164 - 165C. are obtained.
52
.
86~
xample 61
~D~-3-[3-(3-N-[2-Eydrox~eth;yl~-piperazino-2~h;~droxy-~ropoxy)
~hen~ acr~lic acid ethyl ester dih~drochloride.
12.0 Grams of [D,L~-3-[3-(2,3-o2ido-propoxy)-phenyl]-
acrylic acid ethyl ester are stirred for 48 hours at 20 to
24C. in a solution of N-2-hydroxyethyl-piperazine in 60 ml
of ethanol. By working up in a manner analogous to that in
Example 59 9.3 grams of [D,L]-3-[3-(3-~-~2-h~dro~yethyl]-
piperaz no-2-hydroxy-propox~)-phenyl]-acrylic acid eth~l ester
dihydrochloride melting at 189 - 190C. are obtained.
ExamPle 62
~D,L]-3-[Phenyl-3-[4-(3~-2~-metho~Yyphenyl-piperazino-2-
h~droxy-propoxy)-phenyl]-acrylic acid methyl ester dihydro-
chloride.
:
15.0 Grams of [D,L]-2-phenyl-3-[4-(2,3-oxido-propoxy)-
- phenyl]-acrylic acid methyl ester are stirred for 16 hours
at 20 to 24C. in a solution of 9.3 grams of N-2-methoxy-
phenyl-piperazine in 150 ml of methanol. Working up to the
free base is carried out as desoribed in Example 31.
~he purif~ed base obtained as an oil is converted into the
hydrochloride as described in Example 1. By recrystall-
isation from methanol/ether and finally from methanol
13.8 grams of [D,L]-2-phenyl-3-[4-(3-~J-2~-methoxyphe~yl-
piperazino-2-hydroxy-propoxy)-phenyl]-acrylic acid meth~l
ester dih~drochloride meltin~ at 168 - 170C. (with decom-
position) are obtained.
Example 63
[D,L]-3-Phen~1-3-[4-(3-N-[2-hyd~ox~ethyl~-~iperazino-2-
h~droxy-propo~y)-phen~l]-acrylic acid meth 1 ester dihydro-
chloride.
15.0 Grams of [D,L]-2-phe~yl-3-[4-(2,3-oxido-propoxy~-
53
, .. .
~;
. ~ .
.. .: .. : : ~ :
, : :
...
i33
phenyl]-acrylic ~cid methyl ester are reacted as described
in ~xample 62 with 6.3 grams of N-2-hydro} yethyl-piperazine
in 150 ml of methanol and l"orked up. 16.4 grams of [D,L~--2-
phenyl-3-[4-(3-N-[2-hydroxyethyl~-piperazino-2-hydrox;y-
propo}~)-phenyl]-acrylic acid methyl ester dihydrochloride
melti~g at 218 - 220C. are obtained.
~{ample 64
tD,L]-3-Phenyl-3-~4-~-3*~4~-Dimetho}ypheneth;~lamino-2-
hydroxy-propoxy)-phenyl~-acrylic acid methyl est_r.
15 Grams of tD,I.]-2-phenyl-3-[4-(2,3~oxido-propoxy)-
phenyl]-acrylic acid methyl ester are stirred at room temper-
ature for 24 hours in a solution of 8.22 grams of homovera-
trylamine. ~he crude hydrochloride obtained in a manner
analoE;ous to that in l~xample 1, this time by adjusting the
pH value to 6, is recrystallised first from isopropanol/di-
isopropyl ether and finally from toluene/met hylen e chloride.
4.1 Grams of CD,I.]-2-phenyl-3-~4-(3-3*,4~-dimethoxyphenethyl-
amino-2-hydroxy-propoxy)-phenyl]-acrylic acid methyl ester
melting at 145 - 147C. are obtained.
Example 67
[D,L]-3-[3-(3-3~,4~-Dimethoxyphenethylamino-2-hydroxy-
~ropoxy?-~hen;~l]-crotonic acid nitrile hydrochloride.
15 Grams of [D,L]-3-[3-(2,3-oxido-propoxy)-phenyl]-
crotonic acid nitrile are boiled under reflux for 2 1/2 ho~rs
in a solution of 12.62 grams of homoveratrylamine in 150 ml
of ethanol, and worked up as described in Example 31. ~he
oily free base so purified is finally converted, as described
in Example 1, into 6.5 grams of pure [D,lj]-3-~3-(3-3~,4*-
dimethox;yphenethylamino-2-hydrox;y-propoxy)-phenyl]-crotonic
acid nitrile hydrochloride melting at 135 - 138C.
54
-: .~ : .,
, . . .
, ,.,, ,
633
ExamPle 66
[D,~-3-~3-(3-N-2~-Methox~phen~l-piperazino-2-~ydroxy-pro~oxy~
phenyl]-crotonie acid nitrile h~drochloride.
15 Grams of ~D,L]-3 [3-(2,3-oxido-propox~)-phenyl]-
crotonic acid nit~i le are boiled under reflux for 1 1/2 hours
in a solution of 3.9 grams of ~-2-methoxy-phenylpiperazine
; in 150 ml of ethanol. By working up in a manner analogou~
to that in Example 1 17.1 grams of [D,L]-3-[3-(3-N-2~-
methoxyphenyl-piperazino-2-hydrox~-propox~)-phenyl]-crotonic
acid nitrile hydrochloride melting at 160 - 162C. are
obtained.
Example 67
[-]- and [+]-3-[4-(3-3~,4~-Dimethoxy~he~eth!Ylamino-2-hydrox~-
propoxy)-phenyl]-crotonic acid nitrile h~drochloride.
A solution of 50 grams of ~D,1]-3-~4-(3-3~,4~-dimethox~-
phenethyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid
ni~rile in 200 ~l of ethanol is mixed with a solution of
19.2 grams of D-(-)-mandelic acid in 150 ml cf ethanol~
After standing for a short time, the crystals that separate
are filtered o~f with suction. By washing with a small
amount of ethanol and drying in vacuo there are isolated
32.8 grams of [-]-3-~4-(3-3~,4~-dimethox7phenethylamino-2-
hydro~y-propo~y)-phenyl~-crotonic acid nitrile-D-9-)-
mandelate melting at 114 - 116C. which is sparingl~ soluble
in ethanol, ~ ~ ]3 = -35.4~ (c = 0.6, methanol). By recryst-
allisation from 200 ml of hot ethanol 28.9 grams of the
pure mandelate are obtained melti~g at 118 - 119C. and
having a rotation value of [~]D = -38.2 ~c = 0.6, methanol),
yield 83. 50~G .
~o a rapidl~ stirred mix~ure of 23 grams of the above
- ,, :.
.. . . , :, : . -, . - . :: :.
. , :. . - ~, : . . ,-
: . . . . , . , , . . .,: . ..
- . - . : .. .- ..... . ..
.. - ,, : : .: . . ... ~ ~. .
-,
63~
laevo-rotatory mandelate, 230 ml of water a~d 100 ml of
chloroform is added dropwise, while cooling with ice, a
mixture of 3.15 ml of concentrated aqueous ammonia solution
and ~0 ml of water. ~he organic phase is separated,
~Jashed ~ith some water, and, after being dried over sodium
sulphate, is concentrated to dryness in vacuo.
~`rom the resulting ~ 3-[4-(3-3~,4~-dimethoxyphenethyl-
amino-2-hydro~y-propoxy)-phe~yl]-crotonic acid nitrile is
obtained the h~drochloride described in Example 1, which,
after recrystallisation from ethanol/ether, melts at 166
- 167C. and has a rotation value of [a~D = -12.8 (c = 0.5 .
methanol), final yield 17.5 grams (96%).
By evaporation of the ethanolic mother liquor~ of the
abo~e racema~e splitting there is obtained the t+]-3-[4-t3-
3*,4~-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-
crotonic acid nitrile-D-(-)-mandelate, which is very readily
soluble in ethanol. ~rom the latter the [+]-3-[4-(3-
3~,4~-dimethoxyphenethylamino-2-hydroxy-propox~)-phenyl]-
crotonic acid nitrile can be prepared as described above.
3y recrystallisation from toluene/petroleum ether 25.4 grams
of the nitrile melting at 132 - 135C. are obtained. ~he
latter, as in the case of the (-)-antipodes already described,
is converted into the dextro-rotatory hydrochloride.
By recrystallisation from ethsnol/ether there are obtained
25.5 grams (930/G) of not quite optically pure [+]-3-[4-
(3-3~,4~-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl-
crotonic acid nitrile hydrochloride melting at 162 - 164C.
having a rotational value of aD = +9~7O (c = 0.6, methanol).
56
. .
.. ; , .
