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Patented Oct. 29, 1946
Frederick F. Blicke, Washtenaw County, Mich.,
assignor to Regents of the University of Michi
gan, Ann Arbor, Mich c., a, corporation of Michi
No Drawing. Application February 26, 1944, ,
Serial No. 524,083
6 Claims. (Cl. 260-469)
The present invention is directed to certain
novel basic-alkyl esters of para-xenyl-acetic acid
and para-xenyl-aceticv acids substituted with a
hydrocarbon radical on the alphav carbon atom
An alternate method for the preparation con
sists of reacting thionyl chloride with a selected
para-xenyl-acetic or hydrocarbon substituted
and salts thereof, and is particularly concerned
with (a) esters having the formula
chloride. ‘ The latter compound ‘is reacted with
an‘ excess of a suitable dialkylamino-alkanol in‘
an inert solvent, e. g. benzene. This is conven
acetic acid to produce the corresponding acid
iently carried out by heating the ‘mixture to the
boiling temperature ‘of the ‘solvent and under
10 re?ux for the period of ‘time necessary to accom
wherein R represents hydrocarbon‘ or hydrogen,
n is an integer from 2 to 4, inclusive, and m is
plish the reaction. Dialkylamino-alkanol hydro
chloride separates‘from the mixture and ,is re
covered by ?ltration. The ?ltrate from this op
an integer from 1 to 44, inclusive, and (b) tn
acid salts of such basic-alkyl esters. Among the 15 eration may be evaporated under reduced pres
sure to separate the solvent and obtain the free
hydrocarbon radicals represented by “R” are
basic-alkyl ester of the para-xenyl-substituted
lower-alkyl, aryl, cycloalkyl, and aralkyl. Mem
acid. An alternate procedure comprises diluting
bers of this class of compounds have been pre
?ltrate With a low boiling non-polar solvent
pared‘ and found to have value as antispasmcdics
suchras diethyl ether and passing gaseous hydro
and as intermediates in the preparation of more
gen halide therethrough to precipitate the basic
complex organic derivatives. These free basic
ester hydrohalide which maybe separated
alkyl esters of para-xenyl-acetic and ‘substituted
and recrystallized. Where it is‘ desired to pro
acetic acids are commonly obtained as oily liq
duce salts other than the hydrohalides, the free
uids readily soluble in many common organic
solvents, dif?cultly soluble in water, and distill
ing with some decomposition at high tempera
tures and under reduced pressure. The‘acid salts
of these basic-alkyl esters are generally solids at.
ordinary temperatures. '
1 basic-alkyl ester or the benzene solution there
of may be reacted with asuitable free acid,‘ such
as acetic acid, sulfuric acid, methyl-sulfuric acid,
etc. The resulting salt compounds may be puri
?ed by recrystallization from alcohol and ether
or other suitable solvent therefor.
The compounds may be prepared by reacting 30 mixtures
The preferred embodiment of 4 the invention
a suitable acid, e. g. para-Xenyl-acetic acid, alpha
consists of the hydrochlorides of the basic-alkyl
(para-xenyl)-phenylacetic acid, alpha- (para
esters formed according to‘the above methods.
xenyl) -phenylpropionic acid, alpha-(para-Xen
These compounds have the generic formula
yl) -cyclohexylacetic acid, or alpha-(para-xenyl) normalbutyric acid with a suitable dialkylamino
alkyl halide. This‘is conveniently accomplished
by heating substantially equimolecular propor
tions of the acid and halide together, preferably
in the presence of a low boiling organic solvent,
wherein R, n and m ‘have the values heretofore
e. g. isopropyl alcohol, butyl alcohol, benzene, 40 given._ These hydrochlorides are relatively high
melting crystalline ‘solids somewhat soluble in
etc., and thereafter evaporating the solvent un
der reduced pressure, and fractionally recrystal
most organic solvents and soluble in water.
lizing the residue from a suitable solvent or sol-'
vent mixture. This procedure is productive of
the hydrohalide of the dialkyl-amino-alkyl ester
of the acid selected.
The 'free ester may be ob-‘
The para-xenyl-acetic acid and substituted
acetic acidsemployed as reactants in the prep
aration of the compounds of the present inven-v
tion are crystalline compounds of relatively high
melting point. These acids may be synthesized by
tained by treatment of this hydrohalide product
with ammonia‘or other suitable alkaline material.
a number of diiferent methods. Representative
Acid'salts ‘other than the hydrohalides ‘maybe
methods‘ of preparation are set forth in the J our
prepared from the basic-alkyl esters by reaction 50 nal of the American Chemical Society, volume 65,
with the corresponding anhydrous acid or by
pages 1725-1727. Para-xenyl-acetic acid has a‘
treatment of the hydrohalide with a selected salt
melting point of 161°-162° C. "Alpha-(para-xen
of the desired acid, to bring about double de-‘
yl)-phenylacetic acid melts at 168°-17(l° C. Al
composition, but under such conditions as ‘not
pha- (para-xenyl) -cyclohexylacetic acid‘ melts at
to induce hydrolysis'of the ester.‘v
55 202°e2039 C; Alpha-(para-xenyl)-propionic acid
melts at 168°-169° C. Alpha-(para-xenyD-nor
malbutyric acid melts at 175°—l7'7° C. Alpha
(para-xenyl) -normalpentanoic acid melts at
142L143” C. Alpha-(para-xenyl)-normalhex
anoic acid melts at 178°~179° C. The omega-di
acid and gamma-diethylamino-propy1 chloride.
Beta-dibutylamino-ethyl alpha- (para-xenyl) -
phenyl-acetate hydrochloride melting at 128°—130°
This compound was prepared from alpha
(para-xenyl) -phenylacetic acid and beta-dibutyl
alkylamino-alkyl chlorides and omega-dialkyl
amino-ethyl chloride.
Gamma .- diethylamino - propyl alpha - (para
amino-alkanols employed in the preparation of
» xenyD-phenylacetate hydrochloride melting at
the new compounds are known derivatives.
The following examples illustrate the invention
LIT-‘119° C. This compound was prepared by
with respect to the preparation of certain of the 10 reacting together alpha-(para-xenyl)-phenyl
basic-alkyl esters and their salts but are not to
be construed as limiting:
‘ acetic
acid ‘and
iBeta-diethylamino-ethyl alpha- (para-'xenyl) -
Example 1 '
'cyclo-hexylacetate hydrochloride melting at
3.18 grams (0.0150 mole) of para-xenyl-acetic 15 170°~172° C. This compound was prepared by
acid, 2.05 grams (0.0151 mole) of beta-diethyl
reacting together alpha-(para-xenyl) -cyclohex
amino-ethyl chloride, and 75 milliliters of anhy
ylavcetyl chloride and‘ beta-diethylamino-ethanol
drous isopropyl alcohol were mixed together and
to form the free basic-alkyl ester, and passing
the mixture heated to boiling temperature and
gaseous hydrogen chloride in contact with a ben
under re?ux for 12 hours. The isopropyl alcohol 20 zene solution of the ester.
was then recovered by evaporation of the mix
Gamma - diethylamino - propyl alpha - (para
ture under reduced pressure, and the residue
xenyl)-cyclohexylacetate hydrochloride melting
washed with dry ether and recrystallized from a
at 1499-15? C. This compound was prepared by
mixture of diethyl ether and absolute ethanol.
reacting together alpha-(para-xenyl) —cyc1ohex
From this reaction, there was obtained 2.58. grams 25 ylacetic acid and gamma-diethylamino¢propyl
of beta-diethylamino-ethyl para-xenyLacetate
hydrochloride as a crystalline compound melting
at 158°-_l59° C‘.
6 grams of alpha-‘(para-xenyl)-phenylacetic
vThis compound was prepared substantially as
30 described ‘in Example 2 by the reaction of alpha
(para-xenyl) -propionyl chloride with beta-di
acid and 8 milliliters of thionyl chloride were
ethylamino-ethanol to form the free basic-alkyl
ester, and reaction of this ester with hydrogen
_ mixed together and heated to a boiling temper
ature and under re?ux for 1 hour. The excess
thionyl chloride was then distilled o?" under
reduced pressure and several 40 milliliter portions
of dry ‘benzene added to the residue and distilled
out to insure the removal of all traces of thionyl
chloride. The residue from this operation was
cooled and recrystallized from petroleum ether ,
to obtain alpha-(para-xenyl) -phenylacetyl chlo_
1l2°-l14° .C. This salt compound was prepared
substantially according to- the method of Example
1 by reacting together alpha-(para-xenyl)-pro
pionic acid alnd gamim-a-diethylamino-propyl
Beta-diethylamino-ethyl alpha- (para-xenyl) -
dissolved in 30 milliliters of dry benzene and the
solution added portionwise and with agitation to
Gamma - diethylamino - propyl alpha - (para
ride as a crystalline compound melting at 99°-101°
C. 2.6 grams (0.0085 mole) of this. product was
a solution of 6.0 grams (0.051 mole) ‘of beta-di
ethylamino-ethyl alcohol in 10 milliliters of ben
propionate hydrochloride melting at 141°-143° C.
Example 2
Beta-diethylamino-ethyl alpha- (para-xenyl) -
15¢i°-156° C.
This compound was prepared ac
45 cording to the method of Example 2 by reacting
together alpha- (para-xenyl) —normalbutyryl chlo
ride and ‘beta-diethylamino-ethanol to form the
free basic-alkyl ester, and reacting this este
zene. The resulting mixture was heated to boil
ing temperature and under reflux for '1/2 hour,
gaseous hydrogen chloride.
cooled, and precipitated beta-diethylamino-ethyl 50 with
Gamma - diethylamino - propyl alpha - (paras
alcohol hydrochloride removed by ?ltration. A
xenyl)'-normalbutyrate hydrochloride melting at
portion of the‘?ltrate was warmed to evaporate
97°-99° C. This compound was prepared by re.
o? the benzene and obtain beta-diethylamino?
acting together alpha-(para-xenyl)-normalbu
ethyl 'alpha- (para-xenyl) -phenylacetate> as a Vis
tyric acid and gamma-diethylamino-propyl chlo
cous oil dif?cultly soluble ‘in water and of high
boiling temperature. The remainder of the ?l .55
Beta-diethylamino-ethyl alpha- (para-xenyl) trate was washed with water, and the benzene
normal-pentanoate hydrochloride melting at
layer separated and dried with magnesium sul
122°-l24° C. This compound was prepared ac
fate. The dried benzene solution was then diluted
with twice its volume of anhydrous diethyl ether, 60 cording to the method of Example 2 by the reac
tion of alpha-(para-xenyl) -pentanoyl chloride
and hydrogen chloride passed therethrough. A
and beta-diethylamino-ethanol to produce the
hydrohalide product separated andwas recrys
'basic-alkyl ester, and the reaction of the
tallized from a mixture of alcohol and diethyl
latter with gaseous hydrogen chloride.
ether to obtain 23 grams of beta-diethylamino
ethyl alpha-(para-xenyl)-phenylacetate hydro
chloride as colorless needles melting'at 139°-141°
Gamma - diethylamino - propyl alpha-(para
xenyD-normalpentanoate hydrochloride melt
ing at 100°-102° C.
This compound was pre
pared according to the method of ‘Example 1 by
Examplev 3
reacting ‘ together alpha-(para-xenyl) -normal~'
By substituting other suitable reactants for
pentanoic acid and gamma-diethylamino-propyl
those shown in the preceding examples, closely 70 chloride.
related compounds have been prepared. The
In a similar fashion alpha-(para-xenyll-nor-‘
following are representative:
malhexanoic acid or alpha-(para-xenyl) -nor
Gammaediethylamino-propyl para-xenylsacer
malhexanoyl chloride may be reacted with omega;
tate hydrochloride meltinguat 113K115o C. This
dialkylamino-alkyl halides or omega-dialkyl-'
compound was prepared from para-xenyl-acetic 75 vamino-all~:al1ols to obtain such compoundsas
1. A compound selected from the group con
sisting of (a) basic-alkyl esters of the formula
beta - diethylamino-ethyl alpha-(para-xenyD
normalhexanoate and its hydrochloride or beta
dibutylamino - ethyl alpha-(para-xenyD- nor
malhexanoate and its hydrochloride. By sub
stituting other omega-dialkylamino-alkanols and
omega — dialkylamino-alkyl halides for those
shown in the foregoing examples, such com
pounds as the dimethylamino-ethyl ester of
wherein R is selected from the group consisting
of hydrogen and hydrocarbon radicals, n is an
integer from 2 to 4, inclusive, and m is an integer
10 from 1 to 4, inclusive, and (b) acid salts thereof.
2. A compound having the formula
alpha-methyl-para-Xenyl acetic acid (dimethyl
ethyl-alpha- (para-xenyl) -propionate) , gamma
alpha-(para-xenyl) -pro
0 ME: "+1
pionate and its hydrochloride, delta-diethyl
amino - normalbutyl alpha-(para-xenyl)-cyclo
hexylacetate and its hydrochloride, beta-di
propylamino-ethyl alpha-(para-xenyl) - phenyl
acetate and its hydrochloride, etc., may be
wherein w represents an integer from 1 to 4, in
formed. Other salts which may be prepared by
clusive, n is an integer from 2 to 4, inclusive, and
reacting the free basic-alkyl esters obtained ac
m is an integer from 1 to 4, inclusive.
cording to the method of Example 2 with suitable
3. A compound having the formula
acids include beta-diethylamino-ethyl para 20
C “Hindi
xenyl - acetate hydrobromide, gamma-diethyl
amino-propyl alpha- (para-xenyl) -phenylacetate
metho - sulfate, gamma - diethylamino - propyl
alpha-(para-xenyl)-propionate vneutral sulfate,
beta - diethylamino-ethyl alpha-(para-XenyD
phenylpropionate tartrate, delta-dibutylamino
normalbutyl alpha-(para-xenyl) -propionate hy
wherein n is an integer from 2 to 4, inclusive,
25 and m is an integer from 1 to 4, inclusive.
4. A compound having the formula
droiodide, beta - diethylamino - propyl alpha
(para - Xenyl)-hexenoate-delta-4-hydrochloride,
Especially preferred embodiments of the pres
ent invention are the omega-dialkylamino-alkyl
alpha-(para-xenyl)-propionates and normal
butyrates and particularly the hydrochlorides
thereof. While all of the compounds herein dis
closed are adapted to be employed as active con
stituents of antispasmodic compositions, the in
dicated propionate and butyrate derivatives have
been found to be exceptionally effective. Repre
and m is an integer from 1 to 4, inclusive.
5. A compound having the formula
sentative of the results obtained with these de 40
rivatives is the effect exerted upon isolated rabbit
jejunum according to the technique of Magnus.
C “Hum
Thus, beta - diethylamino-ethyl alpha-(para
xenyl) -pr0pionate hydrochloride at a dilution of
between 1 to 1,000,000 and l to 2,000,000 in water
was effective in relaxing the unstimulated jejunal
Gamma - diethylamino-propyl alpha—
(para-xenyD-propio'nate hydrochloride was ef
fective at a similar dilution. Beta-diethylamino
wherein n is an integer from 2 to 4, inclusive,
and m is an integer from 1 to 4, inclusive.
6. Beta - diethylamino - ethyl alpha - (para
xenyl) - propionate hydrochloride melting at
ethyl alpha-(para-xenyl) -butyrate hydrochloride 50 141°-143° C.
was effective at a dilution of 1 to 1,000,000.
I claim:
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