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Патент USA US2410791

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Patented Nov. 5, 1946 r
Karl G. Pleger, Rochester, N. Y., and Arthur J.
Hill, New Haven, Conn ., assignors to American
Cyanamid Company, New York, N. Y., ‘a core
poration of Maine
No Drawing. ' Application March 31, 1942,
- Serial No. 436,959
, 5 Claims. (crate-+475)
This case relates to the 'alkamine esters of sym
I metrical diaryl-succinic
- the usefulness of its estersas an anti-spasmodic
and as a mydriatic.
Many different compounds have been synthe
The present invention is particularly concerned
sized in the course of a long. search for a local
with alkamine esters of symmetrical diaryl-sub
anesthetic which would be a satisfactory sub
stitute for‘ cocaine. Although cocaine is the 6 stituted succinic acids which may be represented .
by the following formula:
standard against which, local anesthetics are '
usually compared, it has many undesirable prop
erties. Notable among these are its high tox
"icity and narcotic character, because of which 10
its clinical use has practically disappeared. De
spite the large amount of work which has been '
carried out inattempts to find a suitable sub
stitute, the list of effective and non-toxic com
in which ’Ar represents an aryl radical and E
ingly small, not more than about half a dozen
having gained any wide acceptance. There still
phenyl, tolyl, aminotolyl, anisyl, naphthyl, eth
represents an alkamine radical. Ar may be ‘a
pounds suitable for clinical use remains sur'pris- \ 15 substituted or unsubstituted aryl radical such as
remains a real demand for a compound ‘which
is highly active as a local anesthetic and which
is at the same time free from irritating, toxic
and narcotic properties.
oxynaphthyl and the like.
E preferably represents an alkamine radical
of the type formula:
Most of the satisfactory local anesthetics are
alkamine esters of various acids although the
particular properties of any alkamine ester de-.
in which R1 represents a hydrocarbon residue such
pend upon the particular aminoalcohol and par 25 as that of an alkyl radical and Re and Rh repre
ticular acid from which it is made. For ‘exam
sent the same or different radicals or R2 and .Rs
ple, in the past it has been, believed that the alka
may represent hydrocarbon residues ‘which with
mine esters derived from acids containing an , the N go to make up a heterocyclic ring such as
aromatic group were most effective as local an
that of'piperidine or morpholine. Typical exam
esthetics, followed in descending order of activity 30 ples of the aminoal‘cohols of the type concerned
- by alkamine ‘esters of acids containing groups
in'the present application are: p-diethylamino
such as pyrrol, thiophene, furan and alkyl. Ac
'y-diethylaminopropanol, p~dipropylami
cordingly, for example, the hydrochloride 'of the
_ noethanol, .p-dibutylaminoethanol, t-dipropylam
p-diethylaminoethyl ester of p-aminobenzoic acid
has been widely used although it is not particu 35 inobutanol,
6~dibutylaminobutanol, p-N,N-phenylethylami
larly satisfactory as a surface anesthetic nor of
particularly satisfactory duration as a nerve
noethanol, 4-diethylaminocyclohexanol, p-4-mor-1
pholinoethanol, 3-5-dimethyl - p - 4-morpho1ino
It has been found, however, that’ the’. - ethanol, p-piperidinoethanol and the like.
_ properties can be varied almost at will by proper
Typical of the acids, with the alkamine esters
substitution in the acid _from which the ester is 40 of which the present invention is particularly
derived. Not only do these various substitutions
concerned is diphenyl-succinic acid. In the fol
a?ect the general properties but speci?cally a?ect
lowing disous'sion‘ and examples thisacid will be
- the usefulness of the alkamine esters for various
used to illustrate the invention. However,‘ it is
purposes. Varying the substituents of the acid
to be merely illustrative and not to limit
a?ects'the relative anesthetic activity of esters 45 the inventionv
to this particular acid.
derived from it with a designated aminoalcohol,
Symmetrical 'diphenyl-succinio acid may be
both as a surface anesthetic and as a nerve block.
readily prepared in the form of its vethyl ester
Varying the _substituents oi’ the'acid also affects
by treating the ethyl ester of phenyl acetic acid
Exam“: 1
in an ether, solution with iodine and sodium
ethoxide. The action is readily carried out and
Ethyl-sym-diphenyl succinate
the ester occurs as both the mesovand racemic
forms. Separation of the two may be easily made
by means of their different solubilities. Either
form upon saponi?cation in alcoholic caustic so
lution of sodium or potassium hydroxide gives
a mixture of meso and racemic diphenyl-suc
cinic acid. If desired the two acid forms may
Dry pulverized sodium ethylate fr om 11.4 parts
of sodium was suspended in 140 parts of dry ether
be separated by the, difference in the solubility
in a one liter three neck ?ask supplied with con
of their alkaline earth metal salts.
Since any attempt to form an acid chloride in
denser, stirrer and dropping funnel. To this sus
pension was added 70 parts of phenyl acetic ester
treatment of the acid _
the usual manner, as byproduces
anhydrization ‘
with thionyl chloride,
of the dipheriyl-succinic acid, some form of alco 15
holysis is necessary as a means of forming the
and then over a period of one hour, during stir
ring and cooling, a solution of 54.6 parts of iodine
in 280 parts of dry ether. The reaction mixture
became turbid from formation of an insoluble
alkamine esters. If an alcoholysis is carried out,
white precipitate. The mixture was ?nally stirred
the products are all in the same form whether
for two hours at room temperature. Water and
the mesa or the racemic form is used as a start
sodium thiosulphate were then added. The white
ing material. ~ Since the alkamine esters are the 20
precipitate, now suspended in the water layer was
products which aredesired there is, therefore,
?ltered off and crystallized from 95% alcohol.
little practical advantage in separating either the
A pure white crystalline solid melting at mil-141°
two forms of ester or thetwo forms of the acid.
C. was obtained. This is the ,B- or meso ester.
Direct esteri?cation is highly impractical be
The ether layer of the ?ltrate was then separated,
cause of the low reaction rates and poor yields.
dried over sodium sulfate, the ether distilled off
Our preferred procedure is to form a simple alkyl ~
and the residue recrystallized from alcohol. The
ester and then to carry- out a catalyzed ester
resulting product was washed with ether which
interchange, preferably removing the replaced
dissolved the a- or racemic ester leaving. the meso
alcohol as fast as it is liberated. according to the
processset forth in the Hill and Holmes appli 30Y, ester. To recover the racemic ester, the ether was
evaporated from the ?ltrate and the residue re
cation Serial No. 431,822, filed February 21, 1942..
crystallized from petroleum ether. The ester thus
Eor this process the mixture of meso and racemic
obtained melted at 80-82° C.
- ethyl esters of diphenyl-succinic acid produced
as set forth above is an excellent starting ma 35
The alkamine ester bases are usually clear,
somewhat amber colored oils which distill at fair
ly high temperatures even under reduced pres
sure. They are usually soluble in alcohol, acetone
and ether and usually insoluble in water. These 40
alkamine esters are slightly basic in reaction
and may be readily converted into salts such as
To a solution of 0.2 part of sodium in 32- parts
the hydrochloride, nitrate, sulfate, hydrobromide,
Olmooo omcmNwium
of p-diethylaminoethanol was added 26 parts of _
meso-diphenyl-succinic ester. The mixture was
phosphate, tartrate, citrate andthe like. The
hydrochlorides are probably the easiest to pre
then heated by means ‘of an oil bath at Mil-150°
C. for 44 hours. After completion of the reac
tion, the excess p-diethylaminoethanol was dis
The hydrochlorides, for example, are generally
white crystalline solids having a sharp melting 50 tilled off and the residue shaken with a mixture
of dilute hydrochloric acid and ether until solu
point and being in general very soluble in water,
pare and are usually preferable because of this
tion was complete. The hydrochloric acid layer
was separated, washed twice with fresh portions
of ether and then treated with potassium car
alcohol, acetone, chloroform and benzene. The
hydrochloric acid salts of the base in aqueous
solution exhibit high activity and low toxicity as
bonate until a sludge formed.
The sludge was
. '
If so desired the quaternary compounds such 55 then extracted with ether until removal of the
aminoester was complete. The ether solution of
as the methiodide,‘ ethobromide and the like may
surface anesthetics.
» be readily prepared.
The quaternary compounds
the base was dried over sodium sulfate, the solu
tion ?ltered, the ether distilled off and the residue
vacuum distilled. After-a few drops of foreruns
an amber colored liquid distilled at 220-235° C.
hydrochlorides of high melting point which are
- likely to;be extremely hygroscopic, The quater
(5 mm.) .
nary compounds may be readily prepared by
have a certain advantage in that they are usually
more readily crystallized than are some of the
treating the base in an alcoholic solution with a
compound such as'methyl or ethyl bromide and
the salts may be precipitatedby removing, a. por
tion of the alcohol and adding ether to the resi
- -
due until precipitation stops. The quaternary
compounds have sharp melting points when puri
?ed by recrystallization from a suitable solvent
such as an acetone-ether mixture. ‘
Di- (p-diethyl‘aminoethyl) -sym-driphenyl
- ‘- Ooncooomonmconm,
The present invention will be more fully illus
trated in connection with the following examples ~
The procedure of Example 2 was followed in an
experiment using the racemic dlphenyl-succinic
which are illustrative and not by way- of limita
ester. In this case, the amber colored product
tion. All parts are by weight unless otherwise 75 boiled at 225-230” 0. (5 mm.).
2,410,701- '
The properties of the two aminoesters prepared
Exams: '7
by the above methods, as well as the properties
of their hydrochlorides were identical. Therefore
Dt-(v-diethyldminopropyl) -sym-diphen11l Y‘ succi-i '
the two esters have the same form.
Exzmru 4
Hydrochloride of di-(p-diethylaminoethyl) -sym
diphenyl succinate
I C>l11ooocmo1zmwmmnei
,_In an experiment using the ‘procedure‘of Ex
ample 6 racemic-diphenyl-succinic ester was al
coholized by means of a solution of sodium in
'Y-diethylaminopropyl alcohol.‘ ‘In this case the
A portion of the aminoester obtained by the‘
temperature was kept at 1,45-l55° C. for 44 hours.
alcoholysis of meso-diphenyl-succinic ester with
Subsequent treatment of the reaction product
?-diethylaminoethanol was dissolved in dry ether 15 was
thesame as in the preceding experiment. ~
and treated with dry hydrogen chloride until no
The reddish brown product boiled at 235-255° C.
more precipitate formed. The ether was then de
(5 mm.).
canted and the gummy precipitate shaken with
another portion of dry ether which was in turn 20
decanted. Dry acetone was added to the hydro
of di - (‘Y - diethylammopropyl)
succinate '
chloride. Part of the hydrochloride dissolved, and
part assumed the form of a ?occulent precipitate.
After standing in a refrigerator overnight, the pre
cipitate was ?ltered off, washed with acetone and
dry ether and then dried ina vacuum desiccator
overnight. The hydrochloride was a- white,
friable, _ non-hygroscopic
Glucooomomommoiuotnol. _
A portion of ‘the aminoester obtained by the \
which melted at 188-190‘ C. The salt was soluble
in water and alcohol but insoluble in acetone and
alcoholysis of meso-diphenyl-suc'cinic ester with
. 'v-diethylaminopropanol was dissolved in dry
. ether and treated with dry hydrogen chloride
until precipitation was complete. - The ether was
then decanted and the gummy precipitate shaken
with another portion of dry‘ether which was also
Hydrochloride of di-(s-diethyzammoethyz) -sym
diphenz/l saccinate
35 decanted. ' Dry acetone was added to the hydro
chloride. After it had been shaken, the salt as
sumed the form of a ?occulent precipitate but
would not dissolve to any considerable extent. A
small amount of ether was added to the mixture
A portion of the aminoester obtained by the
alcoholysis of ‘racemic-diphenybsuccinic ester
_with p-diethylaminoethanol was subjected to the
treatment of Example 4. The same observations
were noted. The product was identical with the
hydrochloride obtained in the previous experi
ment; melting point, 189-190° C.
40 which was then allowed to stand in a refrigerator
overnight.’ The solid was ?ltered off, washed
. with acetone and ether and dried in a vacuum
‘ desiccator. ,The hydrochloride was white, dry
‘and friable and melted at 165-170° C. Although
; soluble in water and alcohol, the salt was insolu
ble in'acetone and ether.
Hydrochloride of di - (‘Y - diethyldminopropyl) -
ni-(v-diethylam-inopromll) -sym-dii>henyl succi- _ 50
To a solution of 0.2 part of sodium in 25 parts
@0110 0 o onlonlommcinornoi
@cncobomomommomm _
Ollie 0o CH:CH:CH2N(C:H5):
sym-‘diphenyl saccinate
Gino OOCHrOH2CHzN(G;Hs)2.HCl
A portion of the aminoester obtained by‘the
alcoholy'sis of racemic - diphen'yl - succinic ester
>with 'v-diethylaminopropanol was subjected to
of 'y-diethylaminopropanol was added 12 parts
of meso-diphenyl-succinic ester. The mixture .60 the treatment of Example 8. The same observa
tions were noted. The ?nal product had the
was heated by means of an oil bath at 140-155” C.
same appearance, melting point and solubilities
for 55 hours. The excess 'Y_diethylaminopro
as the hydrochloride obtained in Example 8.
panol was then distilled off under reduced pres
sure and the residue shaken with a. mixture of
dilute hydrochloric acid and ether until solution
was effected. _ The hydrochloric acid layer was
separated, washed twice with fresh portions of
ether and then treated with potassium carbonate
until a sludge formed. ' The sludge was then ex
tracted four times with ether to remove the free
aminoester. ‘The ether solution of the base was
dried over sodium sulfate, ?ltered, the ether dis- *
tilled off and the residue vacuum distilled. After
a few drops of foreruns a reddish brown liquid
distilled at 230-250° C‘. (5v mm.).
65 .Di-(p-di-n-butylaminoethyl) -sym-diphenyl suc
@0110 oocnzommcrum
@Jmc o ocmcmmcinoz Y
To a solution of 0.1 part or sodium in 14 parts
of p-di-n-butylaminoethanol was added 9 parts
75 of meso-diphenyl-succinic ester. The mixture
moved and the residue distilled. At 255-215‘ 0.
'was heated at 180° C. for 44 hours. and at 160°C.
(4 mm.) the aminoester distilled as an amber
' for 24- hours. The excess p-dibutylaminoethanol
' was then dlstilled'o? under reduced pressure and
color oil. _
Hydrochloride of diw-di-n-butylaminopmpull
sym-diphem/Z succinate
two layers were extracted twice with ether to re
move any diphenyl-succinic ester.
Emu: 13
the residue shaken with a mixture of dilute hy
drochloric acid and ether. An oily third layer
formed between the acid and ether layers. The
The‘ two lay- .
ers were then combined and treated with potas
slum carbonate until a sludge formed. The tree 10
aminoester was separated from the sludge by
means of several ether extractions. The "ether
extracts were dried over sodium sulfate, the solu-.
A portion of the di-(v-di-n-but laminopropyl)
tion ?ltered, the ether distilled oil and the resi- . diphenyl suceinate was dissolved i dry ether and
due vacuum distilled. After a few drops of fore 15 treated with dry hydrogen chloride until precipi
runs,v the aminoester distilled over at 230-250° C.
tation was complete. The ether was decanted,
(5 mm.) as a brownish oil.
the hydrochloride vigorously shaken with another
Hydrochloride of di-(p-di-n-butylaiminoethgl)
sym-diphenyl succmate
portion of dry etherto remove any adherent
hydrogen chloride and this other in turn poured
20 o?. Dry acetone caused part of the oil to solidify
and dissolved the remainder. After- standing in
a refrigerator overnight, the mixture was ?ltered,
the solid washed with acetone and ether and then
dried in a vacuum desiccator overnight. The ?nal
25 product was a white amorphous powder which
melted ‘at ,171-‘1'73° C. The hydrochloride dis
solved in alcohol and hot acetone but gave a- .
A portion of the di-(p-di-n-butylaminoethyl) -
somewhat turbid water solution.
sym-diphenyl succinate was dissolved in dry
Several of the alkamine esters, notably the di
ether and treated with dry hydrogen chloride
(p-diethylaminoethyl) diphenyl sucoinate, the di
until precipitation was complete. After the re
action mixture had been shaken the ether was
decanted from the oil, fresh dry ether added, the
mixture again shaken and then allowed to stand
in a refrigerator overnight. The‘ ether was de
(q-diethylaminopropyl) diphenyl succinate, and
the di- ('y-dibutylaminopropyl) diphenyl succinate
in the form of their hydrochloride salts in aqueous
solution are particularly useful as local anesthet
ics. The di- ('y-diethylaminopropyl)
canted‘ and the oily hydrochloride treated with
dry acetone. After it had been shaken for a few
succinate, for example, as a surface anesthetic
is but slightly less active than cocaine, produces
moments a considerable portion of the hydro
anesthesia for three times the duration of cocaine
chloride solidi?ed while the remainder dissolved.
and is only about 115 as toxic. Similarly as a nerve
The solid was ?ltered oil, washed with dry ace 40 block, it is only approximately 1/3 as toxic and has
tone and ether and, dried in a, vacuum desiccator.
a~ duration of about four times that of cocaine. It
The resulting hydrochloride was a white, friable, . has the further advantage that when mixed with
amorphous powder which melted at 158-160° C.
' epinephrine and injected subcutaneously it does
It was fairly soluble in water and alcohol but in
not produce a discoloration.
soluble in acetone and ether.
We claim:
1. Di-(p-diethylaminoethyl) diphenylsuccinate.
2'. Di - (7 - diethylaminopropyl) diphenylsucci
Di- (v-di-n-butylamin0pr0mll) -sym-diphenyl
' nate.
@0110 ooomomommoaim
3. Di - iql-dibutylaminopropyl)
~ Olncooomomcnmmmn
diphenylsucci- '
' 4. As new compositions of matter, the di-esters
v of symetrical dlphenyl succinic acid having the
To a solution of 0.2 part of sodium in 26 parts
of 'y-di-n-butylaminopropanol was added 10 parts
of meso-diphenyl-succinicester. ‘The mixture‘
it Hi
was heated by means of'an oil bath at 180-200“
C. for 48 hours. After the excess 'y-dibutylaminor
propanol had been removed under reduced pres 60
sure, the residue was shaken with a mixture of
wherein R’ represents a divalent aliphatic radical
containing 2 to 4 carbon atoms and R represents
‘mained clear showing that the aminoester had
an alkyl group containing 2 to 4 carbon atoms.
dissolved in the acid. _ The acid layer was sepa 65
v5. As new compositions of matter, the water
rated and treated with potas'siumcarbonate until
soluble addition salts of the di-(dialkylamino
a. sludge formed. The free base was separated
alkyl, symmetrical diphenyl succinates of claim 4.
ether and hydrochloric acid. The acid layer be-.
came brown in color while the ether layer- re
from the sludge by means of several ether ex- ‘
The ether extracts were dried over
sodium sulfate, the solution ?ltered, the ether
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