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Патент USA US2404588

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Patented July 23, 1946 7
Henry Martin and Franz Hii?igcr, Basel, Switzer
land, assignors to J. R. Geigy A. G., Basel,
Switzerland, a Swiss ?rm
N0 Drawing.’ Application June 2, 1944,"Serial No. ,
538,542. In Switzerland December 16, 1942 ' - -
4 Claims. (01. zed-469)
. 1
corresponding products. described in the litera
I The present application is a continuation-111-;
part of our copending application Ser. No.‘ 506,-‘
760, ?ledVOctober 18,1943.
Therapeutically valuable compounds selected"
hitherto. It has now been found that the basic
not limited, by the following examples, the parts
being by weight, unless otherwise stated.
from the series of the cycloalkyl-monocarboxylic
acids or of their homologues and substitution
products respectively have not become known
The present invention may be illustrated, but
Example _1
20.8 parts ofv 1-phenylrcyclopenty1-bcarbox
ylic acid chloride, obtained from the acid (of.
esters of cycloalkyl-l-carboxylic acids arylated
in l-position possess very valuable therapeutical 10 Am. Soc. 1934, 56, 715) by meansof thionylvchloe
ride, are dissolved in 250 parts by volume of ab
solute ether, ' then,‘ while stirring and“ ‘cooling
In order to prepare the esters, for instance re
active derivatives of- the l-aryl-cycloalkyl-l
with a, mixture of common salt and ice a solution
'nitrogen‘atom or also reactive esters of the amino
2 hours at room temperature. i‘ Now, the whole is
of 12 parts of- diethyl amino‘ ethanol. in_50 parts
carboxylic acids, i. e. their halides, esters or an
hydrides, are allowed to interact in the presence 15 by volume .of absolute ether is allowed’ to drop
thereintdfthe temperature being maintained be
or absence of condensation agents with amino
low 0°'C., whereupon stirring is continued during
alcohols which are tertiarily substituted at» the
twice "shakenJout with water and once ‘with di
alcohols in question are allowed to react, if nec
essary in the presence of acid binding agents, 20 luted hydrochloric acid, the combined aqueous
. with the aforementioned acids or' salts thereof re-" ~ solutions are made alkaline with a potassium
carbonate solution andshaken out with ether.
spectively; jAmong the‘ l-aryL-cycLoaIkyl-Lcar
The ethereal solution is washed with water, dried
boxylic acids "there may be'understood the cor
over potassium carbonateland the solvent is dis
responding unsubstituted and substituted com
pounds of the benzene series. As essential sub 25 tilled oif. The base boils ‘at: a‘pressureof 0.07.
stituents may. be mentioned: alkyl groups, while
If, instead of diethylaminoethanol, l-dimeth
especially esters with hydrogen halide acids, with
ylamino-B-propanol is used, a compound with
aryl sulfonic acids and the like may be used as
reactive esters of amino alcohols. Moreover, it 30
is'also possible to'jc'onyert l-aryl-cycloalkyl-l
carboxylic acid into the halogen alkyl esters and
to cause the same to interact with secondary
amines. The production of the halogen alkyl es
ters is preferably carried out by causing alkylene
halogen hydrines to react with l-aryl-cycloal 35
kyl-l-carboxylic acids or their halides, esters or
anhydrides in the presence or absence of con
very similar properties is obtained. -
~ Q
‘If, instead of the l-phenyl-cyclopentyl-l-can
boxylic acid chloride, the chlorides of the corre
sponding carboxylic acids methylated in the
phenylnucleus are used, one obtains the ‘follow
ing esters:
1- (2 ’ - methylphenyl) -cyclopentyl- 1 -carboxylic
acid-diethylaminoethanol-ester B. P.0.o5 mm; 119°
120° C. and'therefrom the hydrochloride of the
melting point of 173°~174° _C.,
densation agents or by causing alkylene halogen
,1- (3' 1 methylphenyl) _-cyclopentyl-l-carboxylic
hydrines Or alkylene dihalides to react with salts 40 acid-diethylaminoethanol-ester B. P.o.0a m‘... 117°
of these acids and replacing by halogen the hy
119° C. and therefrom the hydrochloride melting
droxy groups which possibly may be present in
at 148°-149° C. and
the obtained, compounds.
1- (4'- methylphenyl) -cyclopenty1- l-carboxylic
By addition of alkyl halides, alkylene " halides,
aryl sulfonic, acid esters, dialkylsulfates, aralkyl
halides and so on the quaternary compounds of
the above esters are obtained in the usual man
ner. If,‘ for the conversion of the cycloalkyl
carboxylic acid halogen .hydrineesters, tertiary
acid-diethylaminoethanol-ester B. P.'o.o3 mm. 113°45
115° C. and therefrom thehydrochloride melting
1679-168‘‘ 6.
Emmplez I
-1 ,.
20.4 parts of l-phenyl-cyclohexyl-l-carboxylic
amines like trimethyl amine or triethylamine are 50 acid (Am. Soc. 1934, 56, 715) are heatedv for 24
hours to boiling,’ while stirring, with_14' parts of
used, the quaternary ‘ammonium compounds are
The l-aryl-cycloalkylelécarboxylic acidsare
> H ’
mostly known; the compounds‘ not known'hith
l9-chloroethyl-diethyla'miriev and 20 parts ‘of po
tassium carbonate in 250 parts by volumeoffdry
‘acetic ester.‘
After cooling'the potassium'chlo
erto‘ can be produced‘in the same manneryas the 55 ride is ?ltered ‘o? by suction, the residue washed
with acetic ester and the combined acetic ester
solutions are extracted by means of diluted hy-.
' drochloric acid.
over potassium carbonate and the solvent is
distilled off.
The 1-plrenyl-cyclopentyl-l-carboxylic acid
y-dimethylaminopropanol ester boils at 0.25 mm.
The acid solution thus obtained
is ?rst shaken outwith ether, then the base is
made freeby means of potassium carbonate solu 5 pressure at 125°-127° C. Therefrom may be ob
tained the hydrochloride melting at 147°-148° C.
tion and taken up in ethér. After having dried
'7 In the same manner the following esters can
the ethereal solution the solvent is distilled 01f.
, be. produced from the corresponding acid
The residue boils at l36°-138° C. and a pressure
of 70.12 mm.
By introducing hydrochloric'sacid '
gas into an ethereal solution of the base the hy-‘
.10 .
1 -; v(2"-methylplhenyl) -cyclopentyl-l-carboxylic
‘ acid-'y-dimethylaminopropanol ester, B. P.c.oa mm.
drochloride melting at 162° C. is obtained (when '
, recrystallised from absolute alcohol-l-acetic ..
'119°._-l21°.C_., and therefrom the hydrochloride
~me1ting .at1..l35°.-,136°' C.,
However, if the methyl or ethyl ester respec- -' » ' » 51- '(3'-methylphenyl) -cyclopentyl-l-carboxylic
ester) .
‘ester, B. P.c.09
1'17j-’-’l20° C, and therefrom the hydrochloride
' vacid
is boiled
with distillation
with diethyl
of amino
or ethanol
there I melting at 135°-_136° C.
respectively, the formation of the diethylamino
~' 1~‘- '(4’-methylphenyl) -cyclopentyl-l-carboxylic
tively of the 1-phenyl-cyclohexyl-l-carboxylic;
ethanol ester of the acid.
Erample 3
acid-y-dimethylaminopropanol ester, B..P.o.o4 mm.
. 20 109°-110° C., and therefromv the hydrochloride
melting at 186°-187°- C., and
23.7 parts or 1-(3’;4'-dimethylphenyl) -cyc1o
boxylic' acid-y-dimethylaminopropanol ester,
pentyl-‘l-‘carboxylic acid chloride are interacted
according to Example 1 with 12 parts of diethyl
amino ethanol; The base so-obtained boils at
13. P.0.15 mm; l36°-,137° C. and therefrom the hy
25 drochloride of the melting point of 156°-158° C. _
. 0.05 mm. pressure at 126°-128° C. 'When work
‘ Example 6
ing in the same manner, but'using 23.7 parts of
19.4 parts ‘of l-phenyl-cyclobutyl-lécarboxylic 7
1"— (4' - methylphenyl)-cyclohexyl-l-carboxylic
acid chloride are caused to interact with 12 parts
acid chloride and '12 parts ‘of diethyl amino
of diethylaminoethanol in the manner indicated
ethanol,‘ a base having the boiling point of: 30 in
Example 5. Ongworking up yl-phenyl-cyclo
1389-140” C. at 0.08 mm. pressure is obtained.
butyl-l-carboxylic acid diethylaminoethanol es
The‘base made according to Example 1 from
terboiling at 108°-110° C. at-0.1 mm. pressure is
obtained and therefrom the hydrochloride melt
23.7 parts of l~phenyl~2z5edimethyl-cyclopentyl
lr-ca'rboxylic acid chloride and 12 parts of di
' ethyl amino ethanol boils at l28°-130° C. atla'
pressure of 0.06 mm.
In thecsame mannerihomologues or the nu-_
clear-substituted 1 :- phenylcyclobutyl-l-carbox
Very similar compounds'are obtained when di
ethyl amino ethanol is replaced by 1-dimethyl
ing at l51°-152° C.
ylic acid esters respectively may be prepared; thus
7 i may be enumerated the derivatives of the 1-(,2,’
40 methylphenyl) -cyclobutyl-1-carboxylic acid, of
the 1- (3_'-methylpheny1) -.cyclobutyl-1-carboxylic
acid, ‘of the 1v-(4'-methylphenyl) -cyclobutyl-1
' Example 4
46 parts .. of al-phenyl-cyclohexyl-l-carboxylic
carboxylic acid, etc.
: 7'
acid chloride are causedto react with 17 parts
Example 7 7
of ethylene chlorohydrine in the presence of 45
pyridine, then, after, completion of the inter
l8 parts. of l-phenylécyclopro'pylél-carboxylic
action, the reaction mixture is shaken with ether
acid chloride are caused to react according .to the
and water, the ethereal solution dried, the sol-v
indications of Example 5 with 12 parts of diethyl
vent evaporated and the residue fractionated in
vacuo. '_ The 1 - phenyl-cyclohexyl-l-carboxylic 50
acid-p-chloroethyl ester boils at 110°-115°
aminoethanol. After working upione, obtains
l-phenyl-cyclopropyl;1-carboxylic acid diethyl
V aminoethanol ester of the'boiling point ‘at 0.05
0.02 mm. pressure. 27 parts of this compound
‘mm. pressure of f105°—107° C.‘ and‘ therefrom‘ the
are caused to react in the heat with 14 parts of
hydrochloride melting at 133°,—134° C’.
' c ' V
piperidine, then, after completionof the reac __ ' vIii‘ the same ma'n'nerthe' homologues‘or nu
tion, the mixture is shaken with ether and water' l'm clear-substituted jl-phenylcyclopropylQl-c'arbox+
and, after the evaporation of the solvent from
the ethereal solution, the l-phenyl-cyclohexyl-‘lw
carboxylic acid piperidine ethyl ester is obtained
ylic acid esters may be prepared; thus theremay
be cited the derivatives of the 1-(2'¢methylphenyl)-cyclopropyl-l-carboxylic acid, of the 1-6‘
in form of a bright oil being well soluble in acids.
methylphenyl) -cyclopropy1'-1-carboxylic acid, of
In high vacuo it boils under a pressure of 0.1 mm. {50 the ' 1-(4'-methylphenyl)-cyclopropyl-l-carboxe
at 155°-160° C.
Example 5'
Moreover, also the alkylated'cyclopropane- or‘
'cyclobutane- or cyclopentane-phenylcarboxylic
V 20.8 parts of l-phenyl-cyclopentyl-l-carboxylic
acids respectively may be used, such as for in-'
acid'chloride are dissolved in 200 parts of abso 0", stance: 1-phenyl -2--methyl-cyclopropyl-lécar
lute benzene. While stirring and cooling, a
lboxylic acid or 1-(2'—methyl-phenyl) -2'-'m'ethyl
solution of 11 parts of 'y-dimethylaminopropanol
cyclopropyl-l-carboxylic acid or l-(3'émethyl
in 50parts of absolute benzene is caused to’ drop
phenyl)-2-methyl-cyclopropyl-1-carboxylic acid
thereinto and the whole is subsequently heated P or 1-(4’-methyl-phenyl)eZ-methyl-cyclopropyl
to boiling, for 1 hour. The mixture is twice ‘0 l-carboxylic or 1-phenyl-2-ethyl-cyclopropyl-1
shakenwith water and once with dilute hydro
carboxylic acid or the like.
chloric; acid.
The collected . aqueous solutions
are extracted with ether,'the base freed by means
of potassium carbonateand taken up‘ "in ether. . ~
1 23.7 parts of 1-phenyl-cyc1oheptyl¢l-carboxylic
The ethereal solution is washed with water, dried 75 acid chloride are dissolved in 300 parts by volume '
of absolute ether, then, while stirring and well
being a colorless liquid boiling at 112°-115° C. at
cooling with a freezing mixture, a solution of 12
0.07 mm. pressure.
3. The 1-(3’ :4’-dimethylpheny1) -cyclopentyl
parts of diethylaminoethanol in 50 parts by vol
l-carboxylic acid diethylamino ethanol ester of
the formula
ume of absolute ether is caused to drop thereinto,
the temperature being maintained below 0° C.
Then the whole is further stirred for 2 hours at
room temperature, shaken twice with water and
once with dilute hydrochloric acid, the collected
aqueous solutions are made alkaline by means
of potassium carbonate and shaken with ether. 10
Ila- H:
The ethereal solution is washed with water, dried
over potassium carbonate and the solvent is dis
being a colorless liquid boiling at 126°-128° C. at
tilled o?. The so-obtained base boils at a pres
0.05 mm. pressure.
sure of 0.07 mm. at 140° C.
4. The 1-(4'-methylphenyl) -cyc1ohexyl-1-car
All of the tertiary amines thus obtained can 15 boxylic acid diethylaminoethanol ester of the for- I
easily be quaternised by heating with diethyl sul
fate, dimethyl sulfate, benzyl chloride or halogen
alkyl, thus yielding the corresponding ammonium
What we claim is:
1. A basic ester of the formula
370-0 o-o—<cH,) ..—N(alky1) ,
wherein R stands for a member selected from 25 ‘ being a liquid boiling at 138°—140° C‘. at 0.08 mm.
the group consisting of phenyl and methylphenyl,
m stands for one of the integers 3, 4 and 5, and
n stands for one of the integers 2 and 3.
2. The 1-phenyl-cyclopentyl-l-carboxylic acid
diethylamino ethanol ester of the formula
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