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Патент USA US3075988

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United States Patent 0
1
1
3,075,978
PROCESS FOR MAKING AMINO-ALKYL-PARA
3,075,978
Patented Jan. 29, 1963
2
amine sulfate, and the like, in a suitable solvent such as
a pyridine-alcohol solution, to form the corresponding
AMINO-ORTHG SUBSTilTUTED-BENZOIC ACID
hindered 4-oximin0-2-cyclohexene-l-carboxylic acid ester.
Merrill E. Specter, Kalamazoo Township, Kalamazoo
County, Mich., assignor to The Upjohn Company,
Kalamazoo, Mich, a corporation of Michigan
No Drawing. Filed May 24, 1954, Ser. No. 432,033
2 Claims. (Cl. 260—247.1)
such as, for example, a lower-alkyl pyridine, quinoline,
isoquinoline, and the like. The conversion of the hindered
4-oxo-2-cyclohexene-l-carboxylic acid ester to the cor
ESTERS ANT) AMTDES
Solvents other than pyridine can be used in the reaction
responding hindered 4-oximino-2-cyclohexene-l-carbox
ylic acid ester may likewise be effected by reacting the
10 ketone with a hydroxylarnine salt in alcohol in the pres
This invention rel-ates to a process for preparing benzoic
ence of an acid~binding agent such as sodium acetate,
acid derivatives and to novel products thereof. More
potassium acetate, lithium propionate, and the like. 1
particularly, the invention relates to a process for pre
paring hindered 4-aminobenzoic acid derivatives and to
The hindered 4-oximino-2-cyclohexene - 1 - carboxylic
able therapeutic properties, especially as local anesthetics.
acid ester is then aromatized and acylated to form the
corresponding hindered 4-acylamidobenzoic acid ester.
This is preferably accomplished in an acidic medium con
taining an anhydride of a lower-aliphatic acid such as
Thus, B~diethylaminoethyl 4-aminobenzoate, commonly
known as procaine, is particularly useful as a local
the like; a hydrogen halide such as hydrogen chloride or
anesthetic. These esters, however, have the disadvantage
of being relatively easily hydrolyzed. It has been found
that this disadvantage is largely avoided if the carboxylate
tic acid, propionic acid, butyric acid, isobutyric acid, and
novel hindered 4-aminobenzoic acid derivatives so pro
duced.
Esters of 4-aminobenzoic acid are known to have valu
group is hindered, i.e., if at least one of the carbon atoms
ortho to the carboxylate group in the 1-position bears
a substituent such as R1 or R2, as set forth in greater de
tail hereinafter. Thus, 2,6-dimethylprocaine, for exam
ple, is more stable to hydrolysis than procaine. This and
acetic, propionic, butyric, and isobutyric anhydride, and
hydrogen bromide; and a lower-aliphatic acid such as ace
the like. In this reaction, it is ordinarily preferable to use
an acid together with its anhydride. For example, if
acetic anhydride is used, acetic acid is preferred and
likewise, if propionic anhydride is used, propionic acid is
preferred. While aromatization and acylation of the
hindered 4-oxirnino-2-cyclohexene-l-carboxylic acid ester
can be effected in the absence of a lower-aliphatic acid,
other hindered 4-aminobenzoic acid derivatives, however,
cannot be prepared by the methods known for the prep 30 superior results are obtained when a lower-aliphatic acid
is present in the reaction mixture. Further, although
aration of procaine.
concentration of the acylating agent may be varied, at
Furthermore, by the novel procedure of the invention,
least an equimolar amount of the acylatin-g agent with
new and therapeutically useful hindered 4-aminobenzoic
respect to the starting material is employed and prefer
acid derivatives which were unavailable hitherto are pre
ably, a molar ratio between about 3:1 and about 8:1.
pared.
At least one mole of the lower-aliphatic acid must be
It is an object of the invention, therefore, to provide
present to secure optimum results. Still further, highly
a new process for the preparation of hindered 4-amino
satisfactory results are obtained when the reaction mix
benzoic acid derivatives. Another object of the inven
ture is substantially saturated with the hydrogen halide.
tion is to provide new and novel hindered 4-aminobenzoic
acid derivatives. Other objects and features of the inven~ 40 It is ordinarily preferred to maintain the temperature of
the reaction between about 100 degrees and about 120
.tion will be apparent to those skilled in the art to which
this invention pertains.
These objects are accomplished in the present inven
degrees centigrade although temperatures between about
sixty degrees centigrade and about 200 degrees centi
grade can also be utilized. The reaction mixture is
tion by subjecting a hindered 4-oxo-2-cyclohexene-1
carboxylic acid ester to oximation; aromatizing and acylat~ 45 vheated for a period of at least one hour. Upon comple
tion of the reaction, the mixture is worked up by any
ing the resulting hindered 4-oximino-2-cyclohexene-1
convenient procedure. Advantageously, the reaction
carboxylic acid ester; hydrolyzing the resulting hindered
mixture is added to ice or water, and the hindered 4-‘
4-acylamidobenzoic acid ester followed by acylation to
acylamidobenzoic acid ester is recovered and recrystal
obtain a hindered 4-acylarnidobenzoic acid; reacting the
lized from a suitable solvent.
hindered 4-acylamidobenzoic acid with an inorganic acid
halide to obtain a hindered 4-acylamidobenzoyl halide,
reacting the hindered 4-acylamidobenzoyl halide with a
compound of the formula:
HYCnHznR
wherein Y is a member selected from the group consisting
of oxygen, sulfur, imino, and lower-alkylimino, R is a
secondary-amino radical, and n is an integer from one to
six inclusive, to obtain a hindered 4-acylamidobenzoic
_ Alternatively, aromatization and acylation can likewise
be effected by reacting a pyridine solution of the starting
hindered 4-oximino-2-cyclohexene-l-carboxylic acid ester
with a solution containing an equimolar quantity of a
lower-aliphatic acid halide dissolved in a lower-aliphatic
acid anhydride, ‘at a temperature between about ?fty
degrees and about 100 degrees centigrade. When the re
action moderates, the mixture is re?uxed for at least one
hour. After re?ux, the mixture is poured into water or
ice and worked up, for example, by the aforedescribed
acid compound; and hydrolyzing said compound to form
the corresponding hindered 4-aminobenzoic acid com
convention-a1 procedure, to obtain the desired 4-acyl
pound.
amidobenzoic acid ester.
The term “secondary-amino radical" as used in the
speci?cation and claims refers to a radical obtained by
The hindered 4-acylamidobenzoic acid ester is hydro
lyzed, i.e., deacylated and de-esteri?ed, and then acylated.
removing the hydrogen atom attached to the nitrogen 65 This ordinarily involves hydrolysis of both the ester func
atom of a secondary amine.
tion and the 4-acylamido group, followed by acylation of
In accordance with a speci?c embodiment of the proc
the resulting 4-amino group to reconstitute the 4-acyl
ess of the invention, a hindered 4-oxo-2-cyclohexene-l
amido group. The acyl group in the resulting 4-acyl
carboxylic acid ester is converted to its oxime by any
suitable procedure. Ordinarily, this is conveniently ac
complished by reacting the 4-oxo group with a hydroxyl
amine salt such as hyroxylamine hydrochloride, hydroxyl
amidobenzoic acid, therefore, may or may not be the same
as that of the starting hindered 4-acylamidobenzoic acid
ester. It has been found advantageous to effect the hy
drolysis by heating the 4-acylamidobemoic acid ester at
3,075,978
4
a temperature between about 125 degrees and about 200
like. The conversion of the hindered 4-acylamidobenzoic
degrees centigrade, in a mixture containing an alkali such
as potassium hydroxide, sodium hydroxide, and the like,
and a glycol such as ethylene glycol, propylene glycol,
conventional procedures for forming acyl halides, e.g.,
acid to the acid halide can be accomplished by any of the
in the presence of an inert solvent such as benzene,
toluene, and the like. Ordinarily, the hindered 4-acyl
amidobenzoyl halide is obtained sufticiently pure ‘for
reaction ‘purposes ‘merely by removing the inert solvent,
although if desired, further puri?cation can be e?ected
by conventional procedures such as vacuum distillation
and the like; and to effectrac'ylation of the hydrolyzed
compound in the presence of water, ata temperature be
tween about Zero degrees centigrade and about 75 degrees
centigrade, by reaction with an acylating agent such as
ananhydride of a lower-aliphatic acid, ‘e.g., acetic an
hydride, propionic anhydride, butyric anhydride and the
like; an arylsultonyl halide such as tosyl, chloride, tosyl
10 o‘r recrystallization.
bromide, benzenesulfonyl chloride, and the like; or an
aroyl? halide such as benzoyl chloride, benzoyl bromide,
and the like. In the hydrolysis reaction, between about
/
The resulting hindered 4-ac‘ylamidobenzoyl halide is
reacted with a compound of the’f'o'r'mula:
three and about ‘ten moles of alkali per mole of starting 15 wherein Y, R and n are as‘de?ned above. The ‘reaction
of the hindered 4-acyl-amidobenzoyl halide with ‘a sec
4-ac‘ylamidobenzoic acid ester are preferred, although
ondaryeamino'a‘lkylamine, or a secondary-amino‘alkanol,
satisfactory results are likewise obtained by the use of
or a, secondaryaamino alkyl mercaptan, is similar to the
larger amounts of alkali such as ‘up to ‘about ?fteen or
reaction of an alkyl amine, alkanol, or alkyl mercaptan
even about twenty moles of ‘alkali per mole of starting
4-acylamidobenzoic acid ester. The reaction tempera 20 withran acyl halide. Preferably, the reaction is conduct
ed between about zero degrees centigrade and about ‘forty
ture should not substantially exceed 200_‘de'grees centi
degrees
centigr‘ade in thepres‘ence of an inert solvent such
grade to prevent decarboxylation of the hindered 4-acyl
as benzene, toluene, and the like. Upon completion of
amidobenzoic acid product. In the acylation reaction,
at least one mole of acylating agent per ‘mole of ester 25 the reaction, the resulting 4-acylamidobenzoic acid com
pound is ‘isolated‘by removal‘o'f the solvent, and can ‘be
is ‘used, although ordinarily, van excess will be used ‘such
further ‘puri?ed‘by conventional means e.g., vacuum distil
as from ‘about ?ve to about ten moles of acylatingv agent
per rnolejof ester. The acylating agent can ‘be preseut'in
the‘mixturein equimolar amounts with the alkali material
used. Upon ‘completion of the reaction, ‘the mixture is
lation.
The hindered 44acylamidobenzoic acid compound thus
obtained is then selectively hydrolyzed to ‘the correspond
workedvu‘prby ‘a‘ny convenient procedure. Advantageous
ing hindered 4-aminobenzoic acid compound by reaction
ly, a- mineral ‘acid is added, ‘the hindered ‘4‘-‘acylamido
benz‘oi‘c‘acid is extracted ‘with a suitable solvent, e;g.,
ether, the solvent is evaporated, the‘; "residue is extracted
with ‘an alkali such as sodium ‘hydroxide, potassium hy
water with'a lower-aliphatic alcohol,‘e.g., methyl alcohol,
cipitate the free organic v‘acid. The‘latt‘er can be further
puri?ed ifso desired, such as by recrystallization from a
the like. The hydrolysis is carried ‘out'at a temperature
dioxide, ‘and the‘ like, ‘in ‘a solvent‘sueh as a mixture of
with caustic solution to obtain ‘a water solution of a ‘salt 35 ethyl alcohol, propyl alcohol, and the like, or with a water
soluble 'ketone such as acetone, methyl ethyl ketone, and
of ‘t'lie‘or'ganic acid, and‘ this solution is acidi?ed ‘to pre
between about forty ‘degrees Centigrade and ‘about 100
degrees centigrade, preferably between about ?fty degrees
suitable solvent.
and about 85 'degre'es'centigrade, and for a time
__Deacylation of the hindered 4_‘-acylamidobenzoic acid 40 centigrade'
between about one hour and about'sixhours, preferably
ester can likewise be'accomplishe'd ‘in other ways such as
between ‘about two hours and about four hours. From
by'reac'tion with a dilute alkali for a short period of time,
about one to about eight moles of alkali, and preferably
i1e.,.°a‘bout four hours, or by alcoholysi's, or 'ammonolysis,
from about two to about six moles, are employed per
the alcoholy‘sis' and ammonolysis reactions being con
mole of'startin'g 4-acylamidobenzoic acid compound. In
ducted at temperatures in excess 'of 100 degrees centi 45 this hydrolytic reaction, care must be taken that hydrolysis
g'r‘ade for periods of time varying between ten and 48
of the amide group" in the 4-position is effected without any
hours. On deacylating the hindered4-acylamidobenzoie
substantial‘hydrolysis of the ester group in the l-position.
acid‘es‘ter, the hindered ‘47ar‘ninobenzoic ‘acid ester is‘ ‘ob
Thus, when'a‘higher reaction temperature, e.g., 100 de
tained. This compound is then hydrolyzed by vconven
grees centigrade is employed, and/ or a higher molar ratio
tional means to the corresponding ‘hindered 4-amino 50 of alkali to starting amide-ester, e.g.,‘ 8:1, vis employed,
benzoic acid and the acid is ‘acylated to obtain a hindered
a‘correspondinglyshorter reaction time is employed, all of
4-acyla'rnid‘obe‘nzoi'c 'acid. Acylating agents ‘which can
which will b‘e readily apparent to one skilled in the art.
be used include anhydrides of lower¢aliphatic acids such
‘When an aryls‘ulfonyl halide or aroyl ‘halide has been
as acetic anhyd'ride, ‘propionic anhydride, butyric anhy
the acylati‘ng agent, the corresponding hindered
dride, isobutyric Yanhydr'ide, and the like; arylsulfonyl 55 used'as
4'-acylamidobenzoic acid compound can be hydrolyzed
halides "such‘as tosyl chloride, tosyl wbr'timidre, benzene
by reaction with a mixture of hydrogen bromide and
sulfonyl chloride, and ‘the like; and'aroyl halides such as
phenol in an acetic acid medium, by the procedure set
benzoyl ‘chloride, benzoyl bromide, and the like.
forth'in US. Patent 2,562,222, to form the hindered 4
The hindered 4-acylamidobenzoic‘acid thus obtained is
aminobenzoic acid compound.
60
convertedto an acid halide by‘rea‘ction with'a'n inorganic
The process for the preparation of hindered 4-amino
acid halide such as thionyl chloride, thionyl bromide,
benzoic acid derivatives ‘is set forth in the following
phosphorus trichloride, ‘phosphorus‘pentachloride, phos
phorus tribromide, phosphorus pentabromide, and the
equations:
0
. ll
lYTHC R4
‘ Hydroxyl-
amine salt
Halide
(R40 0M0
__
Ra
_-————>
R2-
R1
0 O O R:
0003s
‘Hydrolysis and
acylat ion
3,075,978
wherein n is an integer from one to six inclusive, R is a
Methyl, benzyl, and phenethyl 2,6-dimethyl-4-oxo-2-cyclo
secondary amino radical, R1 is a member selected from
hexene-l-carboxylates,
'
the group consisting of hydrogen and alkyl, cycloalkyl,
aralkyl, aryl and heterocyclic radicals; R2 is a member
Methyl, ethyl, benzyl, and phenethyl 2-methyl-6-ethyl~4
ing of alkyl and aralkyl radicals; R6 is an acyl radical; X
Ethyl Z-methyl-6-n-hexyl-4-oxo-2-cyclohexene-l-carboxyl
Ethyl 2~methyl-6-phenyl-4-oxo-2-cyclohexene-1~carboxyl
oxo—2-cyclohexene-1-carboxylates,
selected from the group consisting of alkyl and aryl radi 25 Methyl, ethyl, and benzyl Z-methyl-6-isopropyl-4-oxo-2
cals; R3 is a member selected from the group consisting
cyclohexene-l~carboxy1ates,
.
of hydrogen and valkyl and aralkyl radicals; R4 is an alkyl
Methyl,
ethyl,
and
benzyl
2,6-diethyl-4-oxo-2-cyclohexene
radical; R5 is a member selected from the group consist
l-carboxylates,
1
>
is halogen; and Y is a member selected from the group
ate,
consisting of oxygen, sulfur, imino and alkylimino.
Examples of alkyl radicals are methyl, ethyl, propyl,
ate,
butyl, amyl, hexyl, heptyl, octyl, and the like, including
isomeric forms thereof. Cycloalkyl radicals include un
substituted and substituted radicals such as cyclopropyl, 35
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo<
butyl, methylcyclopentyl, methylcyclooctyl, and the like,
including isomeric forms thereof. Aralkyl radicals in~ 40
clude unsubstituted and substituted radicals such as ben
zyl, phenethyl, phenylpropyl, rnethoxyphenethyl, and the
like, including isomeric forms thereof. Aryl radicals in—
clude unsubstituted and substituted radicals such as phen
45
Ethyl Z-methyl-6-cyclobutyl-4-oxo-2-cyclohexene-lrcar
boxylate,
‘
Methyl Z-methyl-6-cyclohexyl-4-oxo-Z-cyclohexene-l-car
boxylate,
4
Ethyl Z-methyl-6-o-methylbenzyl-4-oxo-2-cyclohexene-1
carboxylate,
, _" '
Ethyl Z-methyl-6-p-methoxyphenethyl-4-oxo-2Fcyclohex
ene-l-carboxylate,
Ethyl 2,6-diphenyl-4-oxo-2-cyclohexene-1~carboxylate,
Ethyl 2,6-diphenyl-3-ethyl-4-oxo-2-cyclohexene-1-carbox~
ylate,
Ethyl 2,3-dimethyl-4-oxo-2—cyclohexene-l-carboxylate, '
Ethyl 2-methyl-3-benzyl-6-isopropyl-4-oxo-2-cyclohexene
l-carboxylate,
chlorophenyl, and the like, including isomeric forms 50
thereof. Examples of heterocyclic radicals are furyl, thi
enyl, pyridyl, and the like, including isomeric forms there
of. Examples of acyl radicals are acetyl, propionyl,
butylryl, tosyl, benzenesulfonyl, benzoyl, and the like, in
cluding isomeric forms thereof. Examples of halogens 55
are chlorine, bromine, and the like.
The starting materials of the invention, i.e., esters of
hindered 4-oxo-2-cyclohexene-l-carboxylic acids, are rep
resented by the following formula:
Ethyl 2-rnethyl-6- (2-furyl) -4-oxo-2-cyclohexene- l-carboxé
ylate,
v
octyl, methylcyclohexyl, dimethylcyclohexyl, ethylcyclo
hexyl, amylcyclohexyl, hexylcyclohexyl, methylcyclo
yl, naphthyl, methoxyphenyl, butoxyphenyl, methoxy
naphthyl, chlorophenyl, vbrornonaphthyl, tolyl, xylyl, tri
methylphenyl, ethylphenyl, amylphenyl, methylbutyl
phenyl, methylnaphthyl, butylnaphthyl, di- and trimethyle
naphthyl, dichlorophenyl, dimethoxyphenyl, methoxy
,
60
0
l
R
Methyl 2,3,6-trimethyl-4-oxo-2-cyclohexene-l-carboxylate,
Ethyl 2-methyl-3-ethyl-4-oxo-2-cyc1ohexene-l-carboxylate,
Ethyl 2-methyl-3-(3,7-dimethyloctyl) -4-oXo~2-cyclohex~
ene-l-carboxylate,
>
I
‘
Ethyl Z-methyl-3-m-methoxyphenethyl-4-oxo-2i-cyclohexJ
ene-l-carboxylate,
.
Ethyl 2-methyl-3-ethyl-6-isopropyl~¢oxo-Z-cyclohexene-l
carboxylate,
.
Ethyl 2-ethyl-3~methyl-4~oxo-2-cyclohexene-l-carboxylate,
Ethyl 2Fmethyl-6-p-tolyl-4-oxo-2-cyclohexene-l-carboxyl
ate,
,
Ethyl 2-methyl~6-benzyl-4-oxo-2-cyclohexene-l-carboxyl
ate,
Ethyl 2-methyl-3~benzyl-4-oxo~2-cyclohexene-l-carboxyl
ate, and the like.
65
The esters of hindered 4-oxo-2-cyclohexene-1-carbox
ylic acids which are used as starting materials in the syn
0:6-0 R:
(I)
thesis of the novel compounds of the invention are pre
wherein R1, R2, R3 and R5 are as de?ned above, and in
pared by various known methods.
R
R1
clude, for example:
For example, in one method, Knoevenagel condensa
Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, 70 tion conditions are employed to react aldehydes (e.g.,
formaldehyde, acetaldehyde, phenylacetaldehyde, isobu
n~amyl, l-ethylbutyl, benzyl, and phenethyl 2-methyl-4
tyraldehyde, furfural, hexahydrobenzaldehyde, and the
oxo-2-cyclohexene-l~carboxylates,
like) with esters of p-keto alkanoic acids (e_.g., ethyl aceto
Ethyl 2-ethyl-4—oxo-2-cyclohexene-l-carboxylate,
Methyl 2-n-propyl-4-oxo~2-cyclohexene-l-carboxylate,
75
:acetate, butyl acetoacetate, methyl acetoacetate, benzyl
acetoacetate, ethyl propionylacetate, ethyl 'isobutyryl
3,075,978
7
Ethyl 2,6-diphenyl-4-oxo-2-cyclohexene-l-carboxylate,
Ethyl 2-methyl-6-p-tolyl-4-oxo-2-cyclohexene-l-carboxyl
acetate, and the like) to form esters of a,a.'-diacylglutaric
acids. These “bis-esters," so-called, are then cyclized in
ate, and the like.
The esters of hindered 4-oxo-2-cyclohexene-1-carbox—
various ways, e.g., with sulfuric acid and acetic acid, to
produce esters of hindered 4-oxo-2-cyclohexene-l-carbox
ylic acids. This general method for preparing compounds
of this type has been described in the literature by
ylic acids, the starting compounds for the process and
products of the invention, wherein R3 is hydrogen (For
Hagemann, Ber. 26, 876 (1893),
Horning, Denekas and Field, J. Org. Chem. 9, 547-551
mula 1, supra‘) are alkylated at position 3 to obtain cor
responding compounds in which R3 is an alkyl or aralkyl
radical. Thus, for example, Hagemann’s ester can be
(‘1944),
converted to ethyl 2-methyl-3-p—methoxyphenethyl-4-oxo
Homing, Denekas and Field, Org. Syntheses 27, 24-27
2-cyclohexene-1-carboxylate and ethyl 2,6-dimethyl-4
(1947),
oXo-2-cyclohexene-l-carboxylate can be converted to
(1943), and
ene-l-carboxylate. Suitable alkylation procedures :have
L. I. Smith and Rouault, J. Am. Chem. Soc. 65, 631-635
W. T. Smith and Eftax, ibid. 75, 4356 (1953).
More speci?cally, on reacting 'formaldehyde with ethyl
ethyl 2,6 - dimethyl - 3 - n - butyl - 4 - oxo - 2 - cyclohex
15
been disclosed by
Smith and Rouault, supra,
Bergmann and Weizmann, J. Org. Chem. 4, 266-269
acetoacetate, ethyl 2-methyl-4-oxo-2-cyclohexene-l-car
boxylate (“Hagem-ann’s ester”) is obtained; using acetal
dehyde and ethyl propionylacetate as reactants, ethyl 2
ethyl 3,6-dimethyl-4-oxo-2-cyclohexene-l-canboxylate is
(1939),
20 Horning, Horning and Platt, I. Am. Chem. Soc. 71, 177 l
1'773 (1949),
obtained.
‘
_
l-Iorning, Homing and Walker, ibid. 71, 169-171 (1949),
Hogg, ibid. 70, 161-164 v(194s),
Similarly, other hindered 441xo-2-cyclohexene-l-car
boxylic- acid esters are obtained sue-has:
Ethyl 2,6-dimethyl-4-oXo-2-cyclohexene-l-carboxylate,
Dieckmann, Ber. 45, 2701 (1912), and
US. Patent 72,582,252.
Ethyl 2 - methyl - 6 - n - hexyl-'-=-4 Joxo - 2 -' ‘cyclohe'xene
Thus, by these general ‘procedures, other 'est‘ers‘ofi hindered
Ethyl 2 - methyl - 6 - isopropyl - 4 - oxo - 2 - cyclohexene
as:
Ethyl 2-niethyl-6iethyl=4-oxo;2-cyclohexene-l-carboxylate,
llicar'bo'kylate,
4-oXo-2-cyclohiexen‘e-1écarboxylic acids are obtained "such
30
Ethyl 2 - methyl - 3 ~ (3,7 - dimethyloctyl) - 4 - oxo - 2
Ethyl 2 - methyl - 6 - n - propyl - 4 - oxo - 2 - cyclo
Ethyl 2 - methyl - 6 - p - methoxyphenethyl - 4 - oxo - 2
cyclohe‘xeneilicarboxylate,
Ethyl 2,6-diethyl-4-oxo-2-cyclohexene-l-carboxylate,
Beri'zyl 2,6;diethylllt;oxo-2-cyclohexene-l-carboxylate,
35
Phenethyl 2,6 - dimethyl - 4 - oxo - 2 - cyclohexene - 1
" c'arb'oirylate,
Ethyl 2 - methyl - 6 - (2 - furyl) - 4 - oxo - 2 - cyclohex
40
' ene-l v-<':‘2'i‘rbo>tylate,
Ethyl 2 - methyl - 6 - cyclohexyl - 4 - oxo - 2 - cyclohex~
érielllcar'boxylate,
Methyl 2 - methyl - 6 - cyclohexyl -' 4 -'oxo - 2 - cyclo
_
_
heXene-l-c'arboxylate,
a
cyclohexene-l-carboxylate,
Ethyl 2,3-dimethyl-4-oxo-2-cyclohexene-l-carboxylate,
Ethyl’ 2-r'nethyl-3 -ethyl-4-oxo-2-cyclohexene- l»carboxylate,
Ethyl 2-methyl-3~m-methbxyphénethyl~4-oxo-2-cycldhex
hexene-ldarboxylate,
‘
ene-l-carboxylate,
Ethyl 2,6-dimethyl-3ethyl-4-oxo-2-cyclohexene-l-carbox
.ylate,
Ethyl 2-methyl-3-ethyl-6-isopropyl-4-oxo-2-cyclohexene-1
carboxylate,
_
Ethyl -2—rnethyl-3~phenethyl-6-isopropyl-4-oxoQ-cyclohex
ene-l-carboxylate,
Methyl 2,3,6-trimethyl-4-oxo-2-cyclohexene-l-carboxylate,
Ethyl .2-ethyl-3-methyl-4-oXo-24cyclohexene-1-carboxylate,
Ethyl .2-rnethyl-3~benzyl-4-oxo-Z-cyclohexene-l-carboxyl
ate, and the like.
Ethyl '2 -" methyl -6 -‘ o -' rr'iethylhen'zyl - 4 -‘oxo - 2 - cyclo~
hexene-l-carboxylate,
The following examplesillustrate the process and prod
Butyl "2 -'ineth'yl -“~6 l-‘be'nz’yl - 4 - 'oxo - 2 - cyclohexene
ucts of the present invention but these examples are illus
t'rative only and are not to be construed as limiting.
'licarbo'xylafe, and the'like.
~-NeWman--and-Lloyd,'l'-.~Org. Chem. 17, 577-580 (1952),
utilized the diene synthesis‘ to react 2-methoxybutadiene 50
with - ethyl >2>butynoate to produce a cyclic enol ether
'Example 1.—~Efhy1 2,6-Dimethyl-44Oximin0-2-Cycl0
hexene-l -Carb oxy late
To'a solution {if-2'78, grams (410 moles) of 'hydroxyl
amine vhydrochloride in 800 milliliters of pyridine and
SOOmilliliters of ethanol is‘ added 500 grams (3‘.0imoles)
which was readily converted by mild hydrolysis to Hage
man‘nis ester. -Similarly,- starting vcornpo'unds of the pres
ent invention can likewise be prepared'by this-method
merely by using-other 2-alkynoici‘a‘cid esters as reactants 65 of ethyl 2,6-dirnethyl>4-oXo-2-cyclohexene-l-carboxyl'ate.
The solution is re?uxed for four hours. The solvents are
to obtain compounds such as ethyl 2-ethyl-4-oXo-2-cyclo
removed under reduced pressure and a reddish gum which
is thus obtained is dissolved in benzene. -'Ihe ‘benzene
hexene-‘llcarb'oxylate, ethyl v2-n-p'ropyli4-oxo-Zkyclohex
ene-l-carboxylate, . ethyl 2-n~b~utyl-4-oxo-2>cyclohexene-l
carboxylate, and the like.
3To prepare vesters ' of ‘- hindered 4-oxo-2-cycloheXene-1
solution is washed with several portions of water, dried
60 over magnesium sulfate and concentrated. An oily ma
terial which is thus obtained is distilled under reduced
carboxylic acids having aryl substituents, it is ordinarily
pressure and the fraction of» the desired ethyl 2,6-dimethyl
preferred to employ- procednres‘suchas those described by
4-oximino-2-cyclohexene-l-carboxylate which distils be
Rabe and Spence, Ann. 342, 352 (1905),
tween 155 and 162 degrees centigrade at 0.5 millimeter
Dieckmann and'Von-Fischer, Ber. "44, 966-974 (1911), 65 pressure is collected. A yield of 485 grams (76.5 per
Dieckmann, ibid. 44,975-981 (1911), and
cent) of ethyl 2,6-dimethyl-4-oximino-2-cyclohexene-1
Homing and Field, vJ.
‘Chem. Soc. 68, 387-389
carboxylate is obtained. _
,
(1946).
Analysis-Cale. for'Cnl-ll'fNoa: C, 62.52; H, ‘8.11;
Thus, bythesergeneral procedures, esters of hindered 4
oxo-‘2-cyclohexene-l-carboxylic . acids ' are obtained such
as:
Ethyl
-'-methyl - 6~- p-methoXyphenyl-‘4- -oxo - 2
' cyclohexene-l-carborrylate,
‘
Ethyl va24rnethyll6éphenyle4~01:OLZ-cycIoheXenc-l-carboxyl
‘Fate,
N, 6.63. Found: C, 62.11; H, 8.04; N,~6.49.
70
Example 2.—Ethyl 2-Me'thyl-6-Ethyl-4-Oximin0-2-Cycl0
hexane-1 —Carboxy late
A mixture-of 26 grams (0.1-3 mole) of ethylZ-methyl
6-ethyl - 4 - oXo-Z-cyclohexeneLl-oarboxylate, 103 grams
75 (0.15 mole) of hydroxylamine hydrochloride, and ?fty
9
3,075,978
10
Ethyl 2-methyl-3-m-methoxyphenethyl-4-oximino-2-cyclo—
hexene-l-carboxylate,
Ethyl 2-methyl-6-n-hexyl-4-oximino-Z-cyclohexene-l-car
boxylate,
Ethyl 2-n-butyl-4-‘oximino-2-cyclohexene-l-carboxylate,
milliliters of pyridine are heated on a steam bath for
three hours. The pyridine is removed from the mixture
by distillation under reduced pressure. The residue is dis
solved in ether and the resulting solution is washed with
several portions of water, dried over magnesium sulfate 5
and concentrated. The oily material thus obtained is
Ethyl 2 - methyl-6-o-methylbenzyl-4-oximino-2-cyclohex
distilled under reduced pressure and the fraction of the
ene~1-carboxylate,
desired ethyl Z-methyl-6-ethyl-4-oximino-2-cyc1ohexene-1
Ethyl 2~methyl-6-p-methoxyphenethyl~4-oximino-2-cyclo
hexene-l-carboxylate,
carboxylate which distils between 163 and 165 degrees
Centigrade at 0.9 millimeter pressure is collected.
Analysis.—Calc. for C12H19NO3: N, 6.39. Found:
N, 6.18.
10 Ethyl 2,6-dimethyl-3-ethyl - 4 - oximino-Z-cyclohexene-l
Example 3.—-—Erlzyl 2-Methyl-6-Is0pr0pyl-4-Oximin0-2
hexene-l-carboxylate,
Ethyl 2-ethyl-4-oximino-2-cyclohexene—l-carboxylate,
carboxylate,
Ethyl 2 - methyl-3-benzyl-6-isopropyl-4-oximino-Z-cyclo
Cyclohexene-J -Carb0xylale
15 Ethyl 2 - methyl-6-p-tolyl-4-oximino-Z-cyclohexene-l-car
boxylate,
In a three-later, one-neck ?ask ?tted with a re?ux con
denser are placed 448.6 grams (2.0 moles) of ethyl 2
Ethyl 2,3 - dimethyl-4-oximino-Z-cyclohexene-l-carboxyl
ate, and the like.
methyl - 6 - isopropyl - 4 - oxo - 2 - cyclohexene - 1 - car
boxylate, 278 grams (4.0 moles) of hydroxylamine hy
drochloride, 700 milliliters of anhydrous pyridine and
Example 4.—Ethyl 2,6-Dimethyl-4-Acetamidobenzoate
500 milliliters of absolute ethanol. The mixture is re
?uxed for four hours and then allowed to stand at 23
161 grams (0.76 mole) of ethyl 2,6-dimethyl-4-oximino
2-cyclohexene-l-carboxylate (Example 1) is added to a
cooled solution of 450 milliliters of acetic anhydride.
Accompanied by stirring, the mixture is warmed to room
degrees centrigrade for ?fteen hours. The alcohol and
pyridine are then removed from the mixture by distilla
tion under reduced pressure and the cooled residue dis 25 temperature and then allowed to stand for a period of
solved in two liters of ether. The resulting solution is
about eighteen hours. 200 milliliters of acetic acid is
extracted with six one-liter portions of water, dried over
added to the mixture and a rapid stream of dry hydrogen
magnesium sulfate and then distilled. There is obtained
chloride gas is passed therethrough while heating to gentle
207 grams of ethyl 2-methyl-6-isopropyl-4-oximino-2-oy
re?ux temperature. After six hours, at re?ux tempera
clohexene-l-carboxylate (43 percent yield) boiling be 30 ture, the mixture is cooled and poured, while stirring,
tween 138 and 142 degrees centigrade at 0.3 millimeter
onto ice. After allowing the cooled mixture to stand
pressure and characterized by an index of refraction
for about eighteen hours, a solid material which sep
111325: 1.5070.
arates out is recovered by ?ltration and then dried over
Analysis-Cale for C13H21NO3: N, 5.85. Found:
phosphorus pentoxide. A yield of 170 grams (95.5 per
N, 5.82.
35
Similarly, on replacing ethyl 2,6-dimethyl-4-oxo-2-cy
cent) of ethyl 2,6~dimethyl-4—acetamidobenzoate is ob
tained which melts between 139 and 140 degrees centi
clohexene-l-carboxylate in Example 1 by other hindered
grade after recrystallization from methylcyclohexane.
4-oxo-2-cyclohexene-l-carboxylic acid esters, other hin
Analysis-Cale. for C13H17NO3: C, 66.35; H, 7.28;
dered 4-oximino-2-cyclohexene-l-carboxylic acid esters
N, 5.94. Found: C, 66.52; H, 7.37; N, 6.00.
are obtained. Thus, for example, using ethyl 2-methy1 40
Example 5 .~Ethyl-2-Methyl-6-Ezhyl-4-A cetamido
4-oxo-2-cyclohexene-l-carboxylate as the starting mate
beiizoaie
rial, ethyl 2-methyl-4-oximino-2-cyclohexene-1-carboxyl_
ate is obtained; ethyl 2-ethyl-3,6~dimethyl-4-oximino-2
45 grams of ethyl Z-methyl-6-ethyl-4-oximino-2~cyclo
cyclohexene-l-carboxyla-te is obtained from ethyl Z-ethyl
hexene-l-carboxylate (Example 2) is added to 150 milli
4.5
3,6 - dimethyl-4-oxo-2~cyclohexene~l-carboxylate; benzyl
liters of acetic anhydride. After allowing the mixture to
stand for a period of about eighteen hours, 100 milliliters
of acetic acid is added and a rapid stream of dry hydro
gen chloride gas is passed through the mixture while
heating to gentle re?ux temperature. After about six
hours at re?ux temperature, the mixture is cooled and
poured, while stirring, onto ice. A solid material sepa
rates out which is then recovered by ?ltration, washed
with water and air dried. After recrystallizing from
2,6-diethyl-4-oximino-Z-cyclohexene-l-carboxylate is ob
tained from benzyl 2,6-diethyl-4-oxo-2-cyc1ohexene-1~
carboxylate; ethyl 2-methyl-6-(2-fury1)-4-oximino-2-cy
clohexene-l-carboxylate is obtained from ethyl 2-methyl~
6-(2-furyl)-4-oxo-2-cyclohexene~l-carboxylate; ethyl 2
methyl-6-cyclohexyl - 4 - oximino - 2 - cyclohexene-l-car
boxylate is obtained from ethyl 2-methy1-6-cyclohexyl
4-oxo - 2 - cyclohexene-l-carboxylate; ethyl 2-methyl-6-p
methoxyphenethyl-4-oximino-2-cyclohexene-1-carboxylate
is obtained from ethyl 2~methyl-6-p-methoxyphenethyl
55
4-oxo-2-cyclohexene-1-carboxylate; ethyl 2,6-diphenyl-4
Analysis-Cale for C14H19T‘IO2: C, 67.44; H, 7.68; N,
5.62. Found: C, 67.28; H, 7.60; N, 5.74.
ethyl 2,6 - diphenyl - 4 - oxo-2-cyclohexene-1~carboxylate;
and ethyl 2-methyl-3-p-methoxybenzyl-4-oximino-2-cyclo
60
p-methoxybenzyl-4-oxo-2-cyclohexene-l-carboxylate.
Example 6.——Ethyl 2-Methyl-6-Is0pr0pyl-4-Acetamido
benzoate
151 grams (0.63 mole) of ethyl 2-methyl-6-isopropyl-4
Similarly, using the procedure set forth in Example 1
except for the replacement of ethyl 2,6-dimethyl-4-oxo
2-cyclohexene-1-carboxylate by other hindered 4-oxo-2
cyclohexene-l-carboxylic acid esters, other hindered 4
4-acetamidobenzoate is obtained melting between 110 and
111 degrees centigrade.
oximino-Z-cyclohexene-l-carboxylate is obtained from
hexene-l-carboxylate is obtained from ethyl 2-methyl-3
methylcyclohexane, forty grams or” ethyl 2-methyl-6-ethyl
oximino-2-cyclohexene-1~carboxylate (Example 3) is
65 added to a cooled solution of 450 milliliters of acetic an
hydride. After allowing the mixture to stand for eighteen
oximino-2-cyclohexene-1~carboxylic acid esters are pre
pared such as:
hours, 200 milliliters of acetic acid is added and a stream
Phenethyl 2,6-dimethyl-4-oximino - 2 - cyclohexene-l-car
heating to gentle re?ux temperature. After six hours at
re?ux temperature, the mixture is cooled and poured,
while stirring, onto ice. The cooled mixture is allowed
to stand for about eighteen hours, during which time a
crystalline material separates out. The crystalline ma
terial is recovered by ?ltration, then washed with water,
and recrystallized from isopropanol. A yield of 56
boxylate,
Butyl 2 - methyl-6-benzyl-4-oximino-2-cyclohexene-l-car
boxylate,
of dry hydrogen chloride gas is passed therethrough while
70
Ethyl 2-methyl-3-(3,7-dimethyloctyl)-4-oximino-2-cyclo
hexene-l-carboxylate,
Ethyl 2,6-diethyl-4-oximino-2-cyclohexene-l-carboxylate, 75 grams (34 percent) of ethyl 2-methyl-6-isopropyl-4
3,075,97s
ll‘
A second 25-milliliter portion of acetic anhydride is added
to’ the mixture followed by the addition of about 25 milli
liters of concentrated hydrochloric .acid. The solution
which :is now strongly acidic, is repeatedly extracted with
99 degrees centigrade.
Amzlysis.-—Calc. for C15H21NO3: C, 68.61; H, 7.90; N,
5.99. Found: C, 68.41; H, 8.04; N, 5.95.
Similarly, on replacing ethyl 2,6-dimethyl-4-oximino-Z
cyclohexene-l-carboxylate in Example 4 by other hin~
dered 4-oximino-2-cyclohexene-l-carboxylic acid esters
and ‘by reacting these compounds with acylating agents
ether v‘to give about two liters of extractand the extract is
then ‘dried with anhydrous magnesium sulfate. After
drying foreighteen hours, the solution is ?ltered and con
centnated to form a mixture of a solid material and an
such as anhydrides of lower-aliphatic acids such as, for
example, acetic anhydride, propionic anhydride, butyric
10
anhydride, isobutyric anhydride, and the like, in the
presenceof lower-aliphatic acid such as acetic acid, pro
pionic acid, butyric acid, and the like, and a hydrogen
halide, :other hindered 4-acylamidobenzoic acid esters
are obtained.
12
hydride is added to the solution over a 45-minute period.
acetamidobenzoate is obtained melting between 98 and
oil. The mixture of solid material and oil is dissolved
in .25 ‘milliliters of ?ve percent sodium hydroxide solu
tion, the resulting solution Washed with ether and the
basic layer is acidi?ed. A yield of eight grams (60.5 per
cent) of 2,6-dirnethyl-4-acetamidobenzoic acid is obtained
in the form of 'a‘precipitate. The melting point of this
Thus, for example, on reacting ethyl .2
methyl-4-oximino-2-cyclohexene-l-carboxylate with ‘acetic
compound, after recrystallization from ethyl acetate, is
anhydride, acetic acid, and dry hydrogen chloride,
A;za_lysis.—:Calc. for C11H13NO3: C, 63.76; H, 6.32;
214 to 216 degrees centigrade.
ethyl 2-methyl-4-acetamidobenzoate is obtained. In a
N, 6.76. Found: C, 63.46; H, 6.27; N, 6.75.
like manner, ethyl 2»ethyl-3,6-dimethyl-4-propionamido
8.——2-Methyl-6-Ethyl-4~Acetamidobenzoic Acid
benzoate is obtained from ethyl Z-ethyl 3,6-dirnethyl-4 20 Example
Following
‘the procedure described in Example 7 ex
oximino-Z-cyclohexene-l-carboxylate, propionic anhy
cept
for
the
replacement
of ethyl 2,6-dimethyl-4-acetami
dride, propionic acid, and dry hydrogen bromide; benzyl
dobenzoate by ethyl ,2emcthyl-6-ethyl-4-acetamidobenzo
2,6-diethyl-4-acetamidobenzoate is obtained from benzyl
ate (Example 5), Z-methyl-6-ethyl-4-acetamidobenzoic
2,6-diethyl-4-oximino-2-cyclohexene-l-carboxylate, acetic
acid
is obtained (96 percent yield) melting between 203
anhydride, Valerie acid, and dry hydrogen chloride; ethyl 25 and 204
degrees Centigrade (tube).
2émethyl-6-(Z-furyl)-4-butyramidobenzoate is obtained
Analysis.-—Calc. 'for CmH1‘5NO3: C, 65.14; H, 6.83;
from ethyl Z-rnethyl-6-(2-furyl)-4-oximino-2ecyclohex
N, ‘6.33. ‘Found: C, 65.15; H, 6.68g'N, 6.42.
ene-l-carboxylate, butyric anhydride, butyric acid, and
Example 9.--2-‘Methyls?-lsopropyl-ll-acetamidobenzoic
dry hydrogen chloride; ethyl .2-methyl~6-p-methoxy~
.Acid
phenethyl~4-acetamidobenzoate is obtained from ethyl 2 30
methyl - 6-p#methoxyphenethyl-4-oxirnino-2-cyclohexene
Following the procedure described in Example 7 ex
cept ‘for ‘the replacement of ethyl 2,6-dimethyl-4-acet~
l#carboxylate, acetic anhydride, acetic'acid, and dry hy
drogen chloride; ethyl 2,6-diphenyl-4-acetamidobenzoate
amidobenzoate by ethyl ,2-methyl-6-isopropyl-4-acetami
is obtained from ethyl 2,6-diphenyl-4-oximino-Z-cyclo
(Example6), Z-methyl-6-isopropyl-4-acetami
hexene-l-carboxylate, acetic .anhydride, acetic acid, and 35 dobenzoate
dobenzoicacidis
obtained v(sixty vpercent yield) melting
dry ‘hydrogen chloride; ethyl 2-methyl-6-cyclohexyl-4
between
194
and
.197
degrees centigrade (tube).
acetamidobenzoateis obtained from ethyl 2-methyl-6-cy
Analysis-Called. vfor C13H17NO3: C, 66.58; H, 6.82;
clohexyl - 4#oximino-2-cyclohexene—'l-carboxylate, acetic
N, 5.99. Found: C, 66.36; ‘H, 7.13; N, 5.95.
anhydride, acetic acid, and dry hydrogen chloride; and
the procedure described in Example 7 except for
ethyl Z-methyl-3-p-methoxyphenethyl-4-acetamidobenzo 4-0 the‘Using
replacement of acetic anhydride by other acylating
ate is obtained from ethyl Z-methyl-S-p-methoxyphen
agents such as, acetyl chloride, acetyl bromide, propionyl
ethyl-4-oximino-2-cyclohexene-l-carboxylate, acetic an
chloride,
propionic anhydride, butyric anhydride, butyryl
hydride, acetic acid, and dry hydrogen bromide.
chloride,.isobutyric
anhydride, caproic anhydride, ,caproyl
Similarly, other hindered 4-acylamidobenzoic acid
chloride, heptanoic anhydride, and the like; tosyl chlo
esters are obtained such as:
ride p-toluenesulfonyl chloride), vtosyl bromide (p-tolu
Ethyl 2-methyl-6~n-l1exyl-4-acetamidobenzoate,
ene-sulfonyl bromide),'benzenesulfonyl chloride, and the
Ethyl 2-metl1yl~6-isopropyl-4-propionamidobenzoate,
like; benzoyl 'bromi‘de, benzoyl chloride, and the like,
Ethyl Z-methyl-6-p-methoxyphenethyl-4-butyramido~
benzoate,
Ethyl 2,6-diethyl-4-isobutyrarnidobenzoate,
Phenethyl 2,6-dimethyl-4-acetamidobenzoate,
Ethyl 2~metl1yl-6-o-methylbenzyl-4-acetamidobenzoate,
Butyl 2-methyl-6-benzyl-4-acetamidobenzoate,
Ethyl Z'ethyl-4-acetamidobenzoate,
Ethyl 2-n-butyl-4-acetamidobenzoate,
Ethyl 2-methyl-6-p-tolyl-4-acetarnidobenzoate,
Ethyl 2-rnethyl-3-(3,7-dimethyloctyl)-4-acetamidoben
other 2,6-dimethyl-4-acylamidobenzoic acids are ob
50
tained. In a like manner, ‘2,6-dimethyl-4¢p-toluenesul
ionamidobenzoic acid is obtained by the use of p-tolu
enesulfonyl chloride; 2;6-dimethyl-4#benzenesulfonami
dobenzoic acid is obtained by the use of benzenesulfonyl
chloride; and f2,6-dimethyl-4~benzamidobenzoic acid is
obtained by the use of benzoyl chloride. Ordinarily, it
is preferred toutilize an, acylating agent containing not
zoate,
Ethyl 2,3-dimethyl-4-acetamidobenzoate,
Ethyl 2-methyl-3~m-rnethoxyphenethyl-4-acetamido
benzoate,
Ethyl 2,6-dimethyl-3ethyl-4-acetamidobenzoate,
Ethyl 2-methyl-3-benzyl-6-isopropyl-4-acetamidobenze
tained. Thus,'by using propionic anhydride in the above
reaction, 2,,6-dimethyl44-propionamidobenzoic acid is ob
60
more than seven carbon atoms and more particularly,
an acylating agent derived from a lower-aliphatic mono
carboxylic acid containing not more than seven carbon
atoms such as the anhydrides or.acid halides of .said
lower-aliphatic monocarboxylic acids.
.Similarly, orrreplacing ethyl 2,6-dimethyl-4-acetami
ate, and the like.
dobenzoate. in Example 7. by other hindered 4-acylamido
Example 7.—2,6-Dimethyl~4~Acea‘amidobenzoic Acid
benzoicacid esters, and by the use of an acylating agent
such as described supra, other hinderedA-acylamido
Fifteen grams (0.064 mole) of ethyl 2,6-dimethyl-4
benzoic acids are obtained. Thus, for example, by the
use of ethyl .Z-methyl-4-acetamidobenzoate, 2-methyl-4
of 35 grams (0.62 mole) of potassium hydroxide in 150
milliliters of ethylene glycol. The mixture is heated to 70 acetamidobenzoic acid is obtained; 2-ethyl-3,6,-dirnethyl
4-propionamidobenzoic acid is obtained by the use of
a temperature between 160 and 170 degrees Centigrade
acetamidobenzoate (Example 4) is added to a solution
and maintained within that range for a period of ?ve
hours. The solution is allowed to cool, then poured into
200 milliliters of water and the resulting solution is cooled
ethyl 2-ethyl-3,6-dimethyl-4-propionamidobenzoate; 2,6
diethyl-4-acetamidobenzoic acid is'obtained by the use
of benzyl 2,6-diethyl-4-acetamidobenzoate; 2-methyl-6
in an ice bath. While stirring, 25 milliliters of acetic an 75 (Z-iuryl)~4-butyramidobenzoic acid'is obtained by the
3,075,978
13
14
use of ethyl 2-methyl-6-(2-furyl)-4-butyramidobenzoate;
2-methyl-6-cyc1ohexyl-4-aminobenzoic acid,
2,6-diphenyl-4-aminobenzoic acid,
2-ethyl-3,6-dimethy1-4-andnobenzoic acid,
2 - methyl - 6 - p-methoxyphenethyl - 4 - acetamidobenzoic
acid is obtained by the use of ethyl 2-methyl-6-p-meth
oxyphenethyl - 4 - acetamidobenzoate;
2-methyl-6-n-hexyl-4-aminobenzoic acid,
2,6 - diphenyl - 4
acetamidobenzoic acid is obtained by the use of ethyl 5 2-methyl-4-aminobenzoic acid,
2,6 - diphenyl - 4 - acetamidobenzoate;
2 - methyl - 6
2-methyl-6- (2-furyl) ~4-aminobenzoic acid,
cyclohexyl-4~acetamidobenzoic acid is obtained by the use
of ethyl 2-methyl-6-cyclohexyl~4-acetarnidobenzoate; and
2 - methyl - 3 - p - methoxyphenethyl - 4 - acetamidoben
zoic acid is obtained by the use of ethyl 2-m-ethyl-3~p-meth- 10
oxyphenethyl-4-acetamidobenzoate.
' In the same manner, i.e., by replacing ethyl 2,6-dimeth
2-n-butyl-4-aminobenzoic acid,
yl-4-acetamidobenzoate in Example 7 by other hindered
2-methyl~3-benzyl-6-isopropyl-4-aminobenzoic acid,
4-acylamidobenzoic acid esters, and by the use of an
acylating agent such as described supra, other hindered
4-acylamidobenzoic acids are obtained such as:
2-ethyl-4-aminobenzoic acid,
Z-methyl-6-p-tolyl-4-aminobenzoic acid,
2,3-dimethyl-4-amin0benzoic acid,
2-methyl-3-(3,7-dimethylocty1) -4-aminobenzoic acid,
2-methyl-6-n-hexyl-4-acetamidobenzoic acid,
2-methyl-6-isopropyl-4-propionamidobenzoic acid,
2 methyl-3-m-methoxyphenethyl-4-aminobenzoic acid,
2-methyl-6-p-methoxyphenethyl-4-butyramidobenzoic
2,6-dimethyl-3-ethy1-4-aminobenzoic acid, and the like.
acid,
20
~2,6-diethyl-4-isobutyramidobenzoic acid,
2-methyl-6-o-methylbenzyl-4-acetamidobenzoic acid,
2-methyl-6-benzyl-4-acetamidobenzoic acid,
The hindered 4-aminobenzoic acids thus obtained are
then acylated with conventional acylating agents such as
anhydrides of lower-aliphatic acids such as acetic anhy
dride, propionic anhydride, butyric anhydride, and the
2-ethyl-4-acetamidobenzoic acid,
2-n-butyl-4-acetamidobenzoic acid,
25 like, arylsulfonyl halides such as p-toluenesulfonyl chlo
ride, p-toluenesulfonyl bromide, benzenesulfonyl chloride,
2-methyl-6-p-tolyl-4-acetamidobenzoic acid,
2-rnethyl-3- ( 3 ,7-dimethyloctyl ) -4-acetamidobenzoic acid,
2,3-dimethyl-4-acetamidobenzoic acid,
2-methyl-3-m-n1ethoxyphenethyl-4-acetamidobenzoic acid,
2,6-dimethyl-3-ethyl-4-acetamidobenzoic acid,
2-methyl~3-benzyl-6-isopropyl-4-acetamidobenzoic acid,
'
2-methyl-3-p-methoxyphenethyl-4-aminobenzoic acid,
2-methyl-6-o-methylbenzyl-Al-aminobenzoic acid,
2-methyl-6-benzyl—4-aminobenzoic acid,
Z-methyl-6-p-rnethoxyphenethyl-4-aminozoic acid,
Z-methyl-6-isopropyl-4-aminobenzoic acid,
and the like.
‘
i
benzenesulfonyl bromide, and the like, aroyl halides such
as benzoyl chloride, benzoyl bromide, and the like, to
obtain the corresponding hindered 4-acylamidobenzoic
acids.
Example 10.—2,6-Dimethyl-4-Acetamid0benz0yl
> Chloride
’
. The deacylation step in Example 7 can be effected with
In a dry, 2-liter, three-neck ?ask ?tted with stirrer and
reflux condenser are placed 207 grams (1.01 mole) of
out producing any change in other positions on the ring 35
2,6-dlmethyl-4-acetamidobenzoic acid (Example 7), one
by three alternative procedures such as (l), reacting the
liter of dry benzene and 179 grams (1.5 mole-110
hindered 4-acylamidobenzoic acid ester with a dilute
milliliters) of thionyl chloride. The mixture is stirred
aikali for a short period of time, e.g., about four hours,
and slowly heated to re?ux. When re?ux temperature is
or (2), alcoholysis or (3), ammonolysis, the alcoholysis
reached, the reaction becomes somewhat violent and must
andv ammonolysis procedures being conducted at‘ a tem
be controlled by cooling the container in an ice-bath.
perature higher than 100 degrees centigrade ‘for periods
After the reaction has subsided, stirring and re?uxing are
of time varying between ten and 48 hours. By such pro
continued for an additional 45 minutes. The mixture is
cedures, hindered 4-aminobenzoic acid esters are obtained
cooled in an ice-bath for one hour and ?ltered. The solid
such as:
material is washed with cold, dry benzene and dried in
Ethyl 2,6-dimethyl-4-aminobenzoate,
Methyl 2,6-dimethyl-4-aminobenzoate,
Benzyl 2,6-diethyl-4-aminobenzoate,
Ethyl 2-methyl-6-cyclohexyl~4-aminobenzoate,
Ethyl 2,6-diphenyl-4-aminobenzoate,
45 a vacuum desiccator.
Example 11.~—2~Mez‘hyl-6-Ethyl-4-Acetamidobenzoyl
Ethyl 2-methyl-6-p-methoxyphenethyl~4-aminobenzoate,
Chloride
Ethyl 2-methyl-6-n-hexyl-4-aminobenzoate,
Ethyl 2-methyl-4-aminobenzoate,
-
-
-
.
.
'
Ethyl 2-methyl-6-p-methoxyphenethyl-4-aminobenzoate,
Ethyl 2-methyl-3-p-methoxyphenethyl-4-aminobenzoate,
Ethyl 2-methyl-6-isopropyl-4-aminobenzoate,
Ethyl 2, 6-diethyl-4-aminobenzoate,
Phenethyl 2, 6-dimethyl-4-aminobenzoate,
Ethyl 2-n-butyl-4-aminobenzoate,
Ethyl 2-methyl-3-(3,7-dimethyloctyl) -4-aminobenzoate,
Ethyl 2-methyl-3~m-methoxyphenethyl-4-aminobenzoate,
Ethyl 2,6-dimethyl-3-ethyl-4raminobenzoate,
Ethyl Z-methyl-3-benzyl-6-isopropyl-4-aminobenzoate,
Ethyl 2-ethyl-4-aminobenzoate,
'
'
Following the procedure described in Example 10 ex
cept for the replacement of 2,6-dimethyl-4-acetamido—
Ethyl 2-methyl-6-(2-furyl)-4-aminobenzoate,
Ethyl 2-ethyl-3,6-dimethyl-4-aminobenzoate,
Ethyl 2-methyl-6-o-methylbenzyl-4-arninoben2oate,
Butyl 2-methyl-6-benzyl-4-aminobenzoate,
A yield of 192 grams (85 per
cent) of 2,6-dimethyl-4-acetamidobenzoyl chloride is ob
tained melting between 110 and 118 degrees centigrade.
benzoic acid by 2-methyl-6-ethyl-4-acetamidobenzoic
acid (Example 8), 2-methyl-6-ethyl-4-acetamidobenzoyl
55 chloride is obtained.
.
Example 12.-—2-Methyl-6-Is0pr0pyl-4-Acetamidobenzoyl
'
Chloride
Following the procedure described in Example 10 ex
60 cept for the replacement of 2,6-dimethyl-4-acetamido
benzoic acid by 2-methyl-6-isopropy1-4-acetamidobenzoic
acid (Example 9), 2-methyl-6-isopropyl-4-acetamido
benzoyl chloride is obtained.
Similarly, using the procedure of Example 10 except
65 for the replacement of 2,6-dimethyl-4-acetamidobenzoic
acid by other hindered 4-acy1amindobenzoic acids, other
hindered 4-acylamidobenzoyl chlorides are obtained.
Ethyl 2-methyl-6-p-tolyl-4-aminobenzoate,
Thus, for example, on reacting 2,6adirnethyl-4-propion
Ethyl 2,3-dimethyl-4-aminobenzoate, and the like.
amidobenzoic acid with an inorganic acid chloride, 2,6;
' The hindered 4-aminobenzoic acid esters thus obtained
In a like manner, 2,6-dimethyl-4-p-toluenesulfonamido
are hydrolyzed to obtain the corresponding hindered
4-arninobenzoic acid such as:
2,6-dimethyl-4-aminobenzoic acid,
2,6-diethyl-4eaminobenzoic acid,
>
~
dimethyl-4-propionamidobenzoyl chloride is obtained.
benzoyl chloride is obtained by reacting 2,6-dimethyl-4
p-toluenesulfonamidobenzoic acid with an inorganic acid
chloride;
2,6-dimethyl - 4 - benzenesulfonamidobenzoyl
75 chloride is obtained by reacting 2,6-dimethyl-4-benzene
3,9761???
15
16
Example 14.—-N-B-Diethylamin0ethyl-2-Methyl-6
sulfonamidobenzoic acid with an inorganic acid Chlo—
Ethyl-4-Agetamid0benzqmide
ride; 2,6-dimethyl-4-benzamidobenzoyl chloride is ob
tained by reacting 2,6-dimethyl-4rbenzamidobenzoic acid
'
Following the procedure described in Example 13 ex
cept for the substitution of 2,6-dfmethyl-4-acetamido
with an inorganic acid chloride; 2-methyl-4-acetamido
benzoyl chloride is obtained by reacting 2-rnethyl-4
acetamidobenzoic acid with an inorganic acid chloride;
benzoyl chloride by 2-methyl-6-ethyl—4-acetamidobenzoyl
chloride (Example 11), N-B-diethylaminoethyl-Z-rnethyl
6-ethyl-4-acetaniidobenzamide is obtained.
2-ethyl-3,6-dimethyl-4-propionamidobenzoyl chloride is
obtained by reacting 2-ethyl-3,6idimethyl-llepropionamido
Example l5.--N-5-Diethylaminoetlzyl-Z-Methyl-?
benzoic acid with an inorganic acid chloride; 2,6-methyl,
lsopropyl-47Acetqmidobenzamide
4-acetamidobenzoyl chlonde is obtained by reacting 2,6,, 1.0
diethyl-4-acetamidobenzoic acid with an inorganic acid
Following the procedure described in Example 13 ex
cept for the substitution of 2,6-dimethyl-4-acetamido
chloride; 2-methyl-6-(Z-furyl)r-4ebutyrarnidobenzoyl chlo
ride isobtained by reacting ~2-methyl-6-(2-furyl)ell-bntyl:
amidobenzoic acid with an inorganic acid chloride; 2;
methyl~6-p-methoxyphenethyl-4 - acetamidobenzoyl chlo 15
bénzoyl chloride’ by 12-methyl-?-isopropyl-4-acetamido
benioyl chloride (Example 12.), N-B-diethyIannnQethyl-Z
methyl-6-isopropyl-4-acetamidobenzamide is obtained.
Following the procedure described in Example 13 ex
ride is obtained by reacting 2-rnethyl-6-p-methoxyphen
ethyl-4-acetamidobenzoic acid with an inorganic acid
cept for the replacement of B-diethylaminoethylamine by
other secondary'ainino alkylamines, other hindered 4
chloride; 2,é-diphenyl-4-acetarnidobenzoyl chloride ‘is ob:
acylamidobenzamides“ are obtained. Thus, for example,
tained by reacting 2,6-diphenyl-4-acetamidobenzoic ‘acid
with an inorganic acid chloride; 2-rnethyl-?-vcyclohexyle4 20 on reacting 2,?-dirnethyl-4-acetainidobenzoyl chloride with
diethylaminomethylamine, _N-diethylarninomethyl-2,6-di
aeetamidobenzoyl chloride vis obtained by reacting >2
methyl-6-cyclohexyl~4¢acetamidobenzoic acid with an in
organic acid chloride; and 2-rnethyl-3-p-rnethoxyphen
ethyl-4-acetamidobenzoyl chloride is obtained by reacting
2-methyl-3-p-methoxyphenethyl-47acetamidobenzoic acid
rnethyl-4-acetamidobenzamide is obtained. In a like
manner, N-zeta-dietl'iylaminohexyl-2,?-dimethyl - 4 - acet
amidobenzamide 'is obtained .by reacting 2,6-dimethyl
25
with an inorganic acid chloride.
'In the same manner, on replacing "2,6-dimethyl-4-acet
amidobenzoic acid in 'jEXample 10 by other hindered 4
aeylamidobenzoic acids there are obtained:
2-methyl-6-n-hexyl-4-acetamidobenzoyl chloride,
2-methyl-6-isopropyl-4-propionarnidobenzoyl chloride,
4-acetamidobenzoyl chloride with 'ae‘ta-diethylamino
hexylamine; N?emethylcyclohexylaminoethyl-2,6-dimeth
ylA-acetamidoberizamide is' obtained by ‘reacting 2,6-di
methyl-4-acetamidobenaoyl chloride with ?p-rnethylcyclo
hegrylaminoethylamingN.-.methy1,- N -'e- diethylamirio
30 ethyl-2,6-dirnethylé4eacetamidobenzamide is obtained by
reacting ;2,_6-;dirnethy1-4-acetarnidoben2oyl chloride with
2-methyl-6-p-methoxyphenethyl-4-butyramidobenzoyl
N - methyl - N - B - dieth'ylaminoethylamine; .N - (B
methylcyclohexylaminoethyl) ,- N - ethyl - 2,6 - diinethyl
chloride,
2,6~diethyl-4-isobutyramidobenzoyl chloride,
2-methyl-6-o-methylbenzyl-4-acetamidobenzoyl chloride,
Z-methyl-6ebenzyl-4-acetamidobenzoyl chloride,
2-ethyl-4-acetamidobenzoyl chloride,
Z-n-butyl-4-acetamidobenzoyl . chloride,
2-methyl-6-p-tolyl-4-acetamidobenzoyl chloride,
Z-methyl-3e(3,7-dimethyloctyl)-4-acetamidobenzoy1
4,-acet-amidobenzarnide is obtained by reacting 2,6-di
methyl-4éacetamidobenzoyl chloride with N-ethyl-N-(pé
methylcyclohexylaminoethyl) - amine; N - 6 - (1 - pyr
40
chloride,
chloride with Y?-(2,27dirnethyl—l'lpyrrolidyl)-ethylamine;
2,3-dimethyl-4-acetamidobenzoyl chloride,
2-methyl-3-m-rnethoxyphenethyl-4-acetamidobenzoyl
chloride,
2,6-dimethyl-3-ethyl-4-acetamidcbenzoyl chloride,
Z-rnethyl-3—benzyl-6-isopropyl-4-acetamidobenzoyl. chlo
rolidyl)Tethyl-Z,6-dimethyl-4-acetamidobenzamide is ob
tainedby reacting 2,6-dimethyb4-acetamidobenzoyl chlo
ride with {Hl-pyrrolidyD-ethylamine; N-?-(LZ-dimethyl
l-pyrrolidyl1ethyl-2,6édimethyl-4-acetamidobenzarnide is
obtained‘ by reacting2,6-dimethyl-4-acetamidobenzoyl
N - B - (1 - piperidyl)ethyl - 2,6 -‘ dimethyl - 4 - acetamido
benzamide is obtained by reacting 2,6-dimethyl-4-acet
45
amidobenzoyl chloride with ?-(l-piperidyl)ethylamine;
N - i3 - (2 - methyl - .1 - piperidyl)ethyl ‘ 2,6 - dimethyl-4
acetamidobenzamide is obtained by reacting 2,6-dimethyl
ride, and the like.
4-acetamidobenzoyl chloride with B-(Z-methyl-l-piper
It should be noted that by replacing thionyl chloride
idy1)ethylamine; N - bntyl ~ N - q’ - (1 - piperidyl)
in the above indicated procedure by phosphorus trichlo 50 propyl-2,6-dimethyl-4-acetarnidobenzamide is obtained by
n'de, phosphorus,pentachloride, or the like, hindered 4
reacting 2,6-dimethyla4-acetamidobenzoyl chloride with
acylamidobenzoyl chlorides are also obtained.
N - bntyl - N - 'y - (1 - piperidyDpropylamine; N - ,3 - (4
Similarly, by vusing thionyl bromide, phosphorus tri
bromide, phosphorus pentabrornide, or the like, the cor
morpholinyl)ethyl-2,6édimethyl-4eacetamidobenzamide is
obtained by reacting 2,6-dimethyl-4-acetamidobenzoyl
responding hindered 4-acylamidobenzoyl bromides are 55 chloride .with '?—(4.-morpholinyl)eethylamine; N-;8(-2
obtained.
methyl - 4 - morpholinyl)ethyl - 2,6 - dirnethyl-4eacet
Example 13.--N-?-Diethy_lamin0ethy[-2,6-Dimethyl
4_-Acetamid0benzamide
Inga dry SOO-milliliter, three-neck ?ask ?tted with a
stirrer, re?ux-condenser and droppingifunnel areplaced
forty »grams,(0.l7>8 mole) of 2,6-dimethyl-4-acetamido
benzoyl chloride (Example 10) and 200 milliliters of
dry benzene. The mixture is stirred and cooled in an ice
bath while adding dropwise, over a one hour period, 65
46.5 grams (0.4 mole). of .fi-diethylaminoethylamine dis
solved in 100 milliliters of ‘dry benzene. The mixture is
amidobenzamide is obtained by reacting 2,6-dimethyl-4
acetamidobenzoyl chloride .with 1&(2-methyl-4-rnorpho
IinyDethyIamine; N -p’ - .methylethylaminoethyl - 2,6
dimethyl-4-acetarnidobenzamide is .obtained by reacting
2,6-dirnethyl-4-acetamidobenzoyl chloride with p-methyl
ethylaminoethylamine; and N-?-diisopropylaminopropyl
2,6-dimethyl-4-acetamidobenzamide is obtained by re
acting 2,6-dimethyl-tacetamidobenzoyl chloride with ,3
diisopropylaminopropylamine.
'
Similarly, on reacting >?-diethylaminoethylarnine with
other 2,6-dimethyl-4-acylamidobenzoyl halides in the
manner set forth in Example’ 13, other N-substituted 2,6
centigrade, for twentyhours. Thebenzene is_.rernoved
dimethyl-4-acylamidobeniamides are obtained. Thus,
by distillation and .a viscous, .oily product is» obtained. 70 for
‘example, on reacting 2,6-dimethyl¢4-propionamido
This material is distilled in vacuo and the main fraction
benzoyl
bromide with ?-diethylaminoethylamine, N-?-di
boiling between 190 and 210 degrees centigrade at- 0.01
ethylaminoethyl - 2,6 - dimethyl - 4 - propionamidobenz
millimeter pressure, which is identi?ed byinfrared analysis
amide is obtained. In a-liltemanner, N-?-diethylamino
as N-?-diethylaminoethyl-2,6edimethyl-4-acetamidobenz
ethyl - 2,6 - dimethyl - 4 - p-toluenesulionamidobenzaniide
75
amide, is recovered.
stirred, while maintained at a temperature of 25»_degrees
3,075,978
17
is obtained from 2,6-dimethyl-4-p-toluenesulfonamido
benzoyl chloride; N- -diethylaminoethyl~,6-dimethyl-4
18
benzoyl chloride (Example 10). Over a thirty minute
period, 44 grams of e-diethylaminoethanol is added there—
benzenesulfonamidobenzamide is obtained from 2,6-di
to.
methyl-4-benzenesulfonarnidobenzoyl chloride; and N- -
diethylaminoethyl-Z,6-dimethyl-4-benzamidobenzamide is
obtained from 2,6-dimethyl-4-benzarnidobenzoyl chloride.
Following the procedure described in Example 13 ex
cept for the substitution of 2,6-dimethyL4-acetamido
benzoyl chloride by other hindered 4-acylamidobenzoyl
tion and the brown, viscous oily residue solidi?es upon
cooling. There is obtained 18.8 grams (85 percent yield)
halides, other hindered 4-acylamidobenzamides are ob
tained. Thus, for example, on reacting ,G-diethylamino
of ?-diethylaminoethyl 2,6-dimethyl~4~acetamidobenzoate
ethylamine with 2-methyl-4-acetamidobenzoyl chloride,
N - ,6 - diethylaminoethyl - 2 - methyl - 4 - acetamido
benzarnide is obtained. In a like manner, N-B-diethyl
aminoethyl - 2 - ethyl - 3,6 - dimethyl - 4 - propionamido
15
benzamide is obtained by reacting ,B-diethylaminoethyl
amidobenzoate
acetamidobenzamide is obtained by reacting B-diethyl
Following the procedure described in (Example 16 ex
aminoethylamine with 2,6-diethyl-4-acetamidobenzoyl
20 cept for the replacement of ?-diethylaminoethanol by
chloride; N - ,6 - diethylaminoethyl - 2 - methyl - 6 - (2—
?-4-morpholinylethanol, there is obtained ,8-4-morpholinyl
ethyl 2,6-dimethyl-4-acetamidobenzoate melting between
furyl)-4-butyramidobenzamide is obtained by reacting B
2-methyl-6~(2-furyl) - 4
115 and 116 degrees centigrade (tube) after recrystalliza
butyramidobenzoyl chloride; N-?-diethylaminoethyl-Z
tion from methylcyclohexane.
methyl ~ 6 - p - methoxyphenethyl - 4 - acetamidobenz
Analysis.—Calc. for C1-7H24N2O4: C, 63.72; H, 7.55;
30
N, 8.74. Found: C, 63.76; H, 7.74; N, 8.88.
Example J8.—13-1-Piperidylethyl 2,6-D im etlzyl-4-A cetam i
dobenzoate
Following the procedure described in Example 16
35
?-l-piperidylethanol, there is obtained ,B-l-piperidylethyl
2,6-dimethyl-4-acetamidobenzoate melting between 134
and 135 degrees centigrade (tube) after recrystallization
from methylcyclohexane.
amide is obtained by reacting B-diethylaminoethylamine
chloride; N - ,8 - diethylaminoethyl - 2,6 - diphenyl - 4
acetamidobenzamide is obtained by reacting B-diethyl
aminoethylamine with 2,6-diphenyl~4-acetamidobenzoyl
chloride; N - 13 - diethylaminoethyl - 2 - methyl - 6 - cyclo
except for the substitution of ?-diethylaminoethanol by
hexyl-ll-acetamidobenzamide is obtained by reacting B
diethylaminoethylamine with 2-methyl-6-cyclohexyl-4
acetamidobenzoyl chloride; and N-?-diethylaminoethyl
2-methyl-3-p-n1ethoxyphenethyl-4-acetamidobenzamide is
methyl-3-p-rnethoxyphenethyl-4-acetamidobenzoyl chlo
ride.
obtained by reacting ,B-diethylaminoethylamine with 2_
Example 19.--—B-Diethylaminocthyl 2-l/Iethyl-6-Ethyl-4
Acetamidobenzoare
Similarly, on replacing 2,6-dimethyl-4-acetamidoben
Following the procedure described in Example 16 ex
zoyl chloride in Example 13 by other hindered 4-acylami
cept for the replacement of 2,6-dimethyl-4-acetamido
dobenzoyl halides, other hindered 4-acylamidobenzamides
benzoyl chloride by Z-methyl-6~ethyl-4-acetarnidobenzoyl
are obtained such as:
chloride (Example 11), ,B-diethylaminoethyl 2-methyl-6
N-?-diethylaminoethyl-Z-methyl-6-n—hexyl-4
acetamidobenzamide,
N-?-diethylaminoethyI-Z-methyl-6-isopropyl-4
propionamidobenzamide,
ethyl-4-acetamidobenzoate is obtained.
Example 20.—,B-Dietlzylaminoethyl Z-Methyl-tS-Isopropyl
4-Acetamidobenzoate
N-B-diethylaminoethyl-Z-methyl-6-p-methoxyphenethyl
4-butyramidobenzamide,
Following the procedure described in Example 16 ex
cept for the replacement of 2,6-dimethyl-4-acetamido
N-,8-diethylaminoethyl-Z,6-diethyl-4-isobutyramido
benzamide,
N-B-diethylaminoethyl-Z-methyl-6-o-methylbenzyl-4
acetamidobenzamide,
50
acetamidobenzamide,
N-B-diethylaminoethyl-Z-ethy1-4~acetamidobenzamide,
N-?-diethylaminoethyl-2-n-butyl-4-acetamidobenzamide,
N-?-diethylaminoethyl-Z-methyl-6-p-tolyl-4
55
acetamidobenzamide,
4-acetamidobenzamide,
teger from one to six inclusive, the corresponding 2,6
dimethyl-4-acylamidobenzoic acid esters are obtained,
60
acetamidobenzamide,
N-;3-diethylaminoethyl-Z-methyl-3—m-methoxyphenethyl
4‘acetamidobenzamide,
_
acetamidobenzamide,
N-?-diethylaminoethyl~2-rnethyl-3-benzyl-6-isopropyl
4-acetamidobenzamide, and the like.
Example J6.—,8-Diethylamz'noethyl 2,6-Dz'metIzyl-4-Ace‘t
amidobenzoate
In a dry IOU-milliliter, one-neck ?ask ?tted with a re
?ux condenser, dropping funnel and drying tube is placed
twenty grams (0.0885 mole) of 2,6-dimethyl-4-acetamido
ncnnznon
wherein R is a secondary-amino radical, and n is an in—
N-?-diethylaminoethyl-Z-methyl-3- ( 3,7-dimethyloctyl) -
N-?-diethylaminoethyl-2,3-dimethyl-4~
benzoyl chloride by 2-methyl-6-isopropyl-4-acetamido
benzoyl chloride (Example 12), ,B-diethylaminoethyl 2
methyl-6-isopropyl-4-acetamidobenzoate is obtained.
Following the procedure described in Example 16 ex~
cept for the replacement of ,B-diethylaminoethanol by
other secondary-amino alkanols of the formula:
N-?-diethyiaminoethyl-2-methyl-6-benzyl-4
.
’
25
with 2-methyl-6-methoxyphenethyl - 4 - acetamidobenzoyl
N-e-diethyIaminoethyI-Z,6-dimethyl-3-ethyl-4-
melting between 89 and 91 degrees centigrade (tube)
after recrystallization from methylcyclohexane.
Analysis.——Calc. for ‘C17H26N2O3: C, 66.63; H, 8.55;
N, 9.14. Found: C, 66.67; H, 8.65; N, 8.93.
Example 17.—,B-4-M0lph0linylethyl 2,6-Dimethyl-4-Acet
amine with 2-ethyl-3,6-dimethyl-4-propionamidobenzoyl
bromide; N - B - diethylaminoethyl - 2,6 - diethyl - 4
diethylaminoethylamine with
The mixture is heated on a steam bath for twenty
hours at a temperature of 190 degrees centigrade, cooled
to twenty degrees centigrade and 200 milliliters of water
is added thereto. The solution is made basic with sodi
um hydroxide pellets, then extracted with ether and the
ether layer then dried. The ether is removed by distilla
65
Suitable secondary-amino alkanols include dialkylamino
alkanols suchlas, for example, B-diinethylamincethanol,
dimethylaminomethanol, diethylaminomethanol, B-diethyl
aminopropanol, 'y-diethylaminopropanol, ,8—diethylamino
Ibutanol, B-diethylaminobutanol, e-diethylarninopentanol,
zeta-diethylaminohexanol, B-dipropylaminoethanol, e-di
isopropylaminoethanol, ?-dipropylaminopropanol, 'y-di
propylaminopropanol, e-dibutylaminoethanol, ,B-dibutyl~
aminopropanol, ?-methyle-thylaminoethanol, ?-methylpro
pylaminoethanol, ,e-methylhexylaminoethanol, and the
70 like; dicycloalklaminoalkanols such as, for example, ?-di
cyclopentylaminoethanol,
,8 ~ dicyclohexylaminoethanol,
and the like; alkyl aralkylaminoalkanols such as, for ex
ample, methylbenzylaminornethanol, ?-ethylbenzylamino
ethanol, p-propylbenzylaminoethanol, and the like; alkyl~
75 cycloalkylaminoalkanols such as, for example, ,B-methyh
8,075,978
3%
cyclohexylaminoethanol, and the like; diaralkylamino
alkanols such as, for example, AB-dibenzylaminoethanol,
{i-diphenethylaminoethanol, and the like; heterocyclic
aminoalkanols such as, for example, l-pyrrolidylmethanol,
?-l-pyrrolidylethanol, ?-l-pyrrolidylbutanol, and the like;
zoa’te,
?-Diethyiaminoethyl 2-methy1-3 - (3,7-dimethylocty1)-4
carbon-substituted pyrrolidylalkanols, piperidylalkanols,
morpholinylalkanols, such as, for example, B-(Z-methyl-l
pyrrolidyl) ethanol, 18- (2,2-dimethyl-l-pyrrolidyl) ethanol,
B-(Z-ethyl-l-pyrrolidyl)ethanol, ;3—(2-, 3-, and 4-methyl
l-piperidyDethanols, ,8-(2-, 3-, and 4-ethy1-1-piperidyl)~
2%
,B-Diethylaminoethyl 2—methyl-6-benzyl-4-acetamidoben
zoate,
B-Diethylaminoethyl 2'ethy1-4-acetamidobenzoate,
ii-Diethylaminoethyl 2-n-butyl-4-acetamidobenzoate,
e-Diethylaminoethyl 2methyl-6-p-tolyl-4-acetamidoben
acetamidobenzoate,
p-Diethylaminoethyl
2,3-dimethyl-4-acetamidobenzoate,
10
ethanols, ?-(2-, and 3-methyl-4-morpholinyl)ethanols, ,8—
?-Diethylaminoethyl 2-methyl-3 -m-methoxyphenethyl
4-acctamidobenzoate,
?-Diethylamiuoet-hyl 2,6-dimethyl-3-ethyl-4- acetamido~
(2-, and 3-ethyl-4-morpholinyl)ethanols, and the like.
Following the procedure described in Example 16 ex
cept for the replacement of ?-diethylaminoethanol by
benzoate,
B-Diethylaminoethyl 2-methyl-3-benzyl-6-isopropyl-4
acetamidobenzoate, and the like.
other secondary-amino alkanols, the following 2,6-dimeth 15
Following the procedure described in Example 13
except for the replacement of p-diethylaminoethylamine
by compounds of the general formula:
yl-4~—acetamidobenzoic acid esters are obtained:
Zeta-diethylaminohexyl 2,6-dimethyl-4-acetamidoben
zoate,
p-Mrethylethylaminoethyl 2,6-dirnethyl-4-acetamidoben 20
zoate,
wherein R is a secondary amino radical, and n is an
?~Dicyclohexylaminoethyl 2,6-dimethy1-4-acetamidoben
integer from one to six inclusive, the corresponding 2,6
zoate,
dirnethyl-4-acylamidothiolobenzoic acid esters are ob
?-Ethylbenzylaminoethyl 2,6-dimethyl-4-acetamidoben
tained. Suitable secondary-amino lower alkyl mereap
zoate,
include, for example, ?-dimethylaminoethyl mer
B-Dibenzylaminoethyl 2,6-dimethyl-4-aeetamidobenzoate, 25 tans
captan,
p-diethylaminoethyl mercaptan, ,B-diethylamino
B-I-pyrrolidylethyl 2,6-dimethyl-4-acetamidohenzoate,
propyl mercaptan, 'y-diethylaminopropyl mercaptan, zeta
p-(2-methyl~1-pyrrolidyl)ethyl 2,6-dimethyl-4-acetamid0: diethylaminohexyl mercaptan, B-dipropylaminoethyl mer
benzoate,
eaptan, ?-rnethylethylaminoethyl mercaptan, ,B-nethyl
18-(2-met'nyl-1-piperidyl)ethy1 2,6-dimethyl-4-acetamido 30 propylaminoethyl
mercaptan, and the like; dicycloalkyl
benzoate,
aminoalkyl mercaptans such as, for example, ?-dicyclo
paQ-rnethyl-4~morpholinyl)ethyl 2,6-di1'nethyl-4-acetami
pentylaminoethyl mercaptan, /3—dicyclohexylaminoethyl
dobenzoate.
mercaptan, and the like; alkyl~aralkylamino mercaptans
such as, for example, methylbenzylaminoethyl mercap
Similarly, on reacting ?-diethylamioethanol with other
2,6-dirnethy1-4-acylamidobenzoyl halides in the manner 35 tan, ?-ethylbenzylaminoethyl mercaptan, and the like;
diaralkylarninoalkyl mercaptans such as, for example,
set forth in Example 16, the following 2,6-dimethyl-4
acylamidobenzoic acid esters are obtained:
?-dibenzylaminoethyl mercaptan, e-diphenethylamino
‘
p—Diethylaminoethyl 2,6-dimethyl-4-propionamidoben
zoa-te,
?-Diethylaminoethyl
2,6-dimethyl-4-butyramidobenzoate,
B-Diethylaminoethyl 2,6-dimethyl-4~p-toluenesulfona
midobenzoate,
(S-Diethylaminoethyl 2,6-dimethyl-4-benzenesulfonamido
benzoate,
?-Diethyla-minoethyl 2,6-dimethyl-4abenzamidobenzoate,
ethyl mercaptan, and the like; heterocyclic aminoalkyl
mercaptans such as, tor example, l-pyrrolidylmethyl
40
mercaptan, ?-l-pyrrolidylethyl mercaptan, a-l-pyrrolidyl
butyl mercaptan, ?-l-piperidylethyl mercaptan, 5-4-rnor‘
pholinylethyl mercaptan, and the like; carbon-substituted
pyrrolidylalkyl-, piperidylalkyl-, and morpholinylalkyl
mercaptans such as, for example, Q-(Z-methyl-l-pyrrol
idyl)ethy1 mercaptan, B-(LZ-dimethyl-l -pyrrolidyl)
ethyl mercaptan, 6-(2-ethyl-1-pyrrolidyl)ethyl mercap
tan, 542-, 3-, and 4-methy1-1-piperidy1)ethyl mercap
tans, B-(2-, 3-, and 4-ethyl-1-piperidyl)ethyl mercaptans,
Following the procedure described in Example 16
except for the substitution of 2,6-dirnethyl-4-acetamido 50 {3-(2- and 3~methyl-4-morpholinyl)ethyl mercaptans,
,8-(2- and 3-ethyl-4-morpholinyl)ethyl mercaptans, and
benzoyl chloride by other hindered 4-acylamidobenzoyl
the like.
halides, other hindered 4-acylamidobenzoic acid esters
Following the procedure described in Example 13
are obtained such as:
except ?or the replacement of B-diethylaminoethylamine
and the like.
p-Diethylaminoethyl 2-methyl-4-acetamidobenzoate,
_ by secondary-amino alkyl mercaptans, the following 2,6
?-Diethylaminoethyl 2-ethyl-3,6 - dimethyl - 4-propion
, dimethyl-4-acetamidothiolobenzoic acid esters are ob
amidobenzoate,
tained :
,B-Diethylaminoethyl 2,6-diethyl-4-acetamidobenzoate,
,B-Diethylaminoethyl 2-methyl-6-(2-furyl)-4-butyramido
B-Diethylaminoethyl 2,6_-dimethyl-4-acetamidothiolo
benzoate,
henzoate,
Zeta-diethylaminohexy-l
2,6-dimethyl-4-acetarnidothiolo
60
?-Diethylaminoethyl Z-methy-l-?-p - methoxyphenethyl-4
ibenzoate,
acetamidobenzoa-te,
,B-Methylethylaminoethyl 2,6-dimethyl-lt-acetamidothiolo
B-Diethylaminoethyl 2,6-diphenyl-itaacetamidobenzoate,
benzoate,
B-Diethylaminoethyl 2-methyl-6-cyclohexy1-4-acetamido
?-Dicyclohexylaminoethyl 2,6-dimethyl-4-acetamido
benzoate,
‘
thiolobenzoate,
B-Diethylaminoethyl 2-n1ethy1-3-p - methoxyphenethyl-4
13-Ethylbenzylaminoethyl 2,6-dimethyl-4-acetamidothiolo
acetamidobenzoate,
benzoate,
?-Diethylaminoethyl Z-methyl - 6-n-hexyl - 4-acetamido
?-Dibenzylaminoethyl 2,6-dimethyl-4-acetamidothiolo
benzoate,
benzoate,
p-Diethylaminoethyl 2-methyl-6-isopropyl - 4-proprion
?-l-vpyrrolidylethyl 2,6-dimethyl-4-acetamidothiolo
70
tamidobenzoate,
benzoate,
?-Diethylaminoethyl 2-methyl-6-p - methoxyphenethyl-4
?-l-piperidylethyl 2,6-dimethyl-4-acetamidothiolo
butyramidobenzoate,
benzoate
B-Diethylaminoethyl 2,6-diethyl-4-isobutyramidobenzoate,
5-4¢morpholinylethyl 2,6-dimethyl-4-acetamidothiolo
?-Diethylaminoethyl 2-methyl—6 - 0-methylbenzyl-4-acet
amidobenzoate,
-
75
benzoate,
3,075,978
22
18~ ( Z-methyl- l-pyrrolidyl) ethyl 2,6-dimethyl-4-acetamido
grams of sodium hydroxide, 125 milliliters of water and
500 milliliters of ethyl alcohol. The mixture is re?uxed
thiolobenzoate,
IS-(Z-methyl-l-piperidyl) ethyl 2,6-dimethyl-4-acetamido
thiolobenzoate,
for three hours ‘and then allowed to cool at room tem
perature overnight. The alcohol and water mixture is
I8~ ( 2-methyl-4-morpholinyl ) ether 2,6-dimethy1-4-acet
evaporated under vacuum on a steam bath and the solid
amidothiolobenzoate, and the like.
Similarly, on reacting B-diethylaminoethyl mercaptan
residue thus obtained is extracted With ether. The ether
extract is ?ltered, dried and then distilled. The frac
tion boiling between 185 and 190 degrees cen'tigrade at
with other 2,6-dimethyl-4-acylamidobenzoyl halides in
0.02 millimeter pressure is collected and identified as N
the manner set forth in Example 13, other 2,6-dimethyl
4-acylamidothiolobenzoic acid esters are obtained such as: 10
,B-diethylarninoethyl-2,6-dirnethyl-4-aminobenzarnide.
On heating a benzene solution of N-?-diethylamino~
e-biethylaminoethyl 2,6-dimethyl-4-propionamidothiolo
benzoate,
p-Diethylaminoethyl 2,6-dimethyl-4-butyrarnidothiolo
benzoate,
?-Diethylaminoethyl 2,6-dimethyl-4-p-toluenesulfon
amidothiolobenzoate,
IS-Diethylaminoethyl 2,6-dimethyl-4-benzenesulfonamido
thiolobenzoate,
p-Diethylaminoethyl 2,6-dimethyl-4-benzamidothiolo
ethyl-2,6-dirnethyl-4-aminobenzamide ‘and methyl bro
mide and cooling and concentrating the resulting solu
tion, N - i9 - diethyl-aminoethyhZ,6-dimethyl-4-arninobenz~
amide methobrornide is obtained.
Similarly, by reacting N-?-diethylaminoethyl-2,6-di
methy1~4-aminobenzamide with other esters such as ethyl
chloride, benzyl chloride, and the like, the correspond.
ing quaternary ammonium salts of N-B-diethylamino
20 ethyl-2,6~dimethyl-4-aminobenzamide are obtained such
beuzoate, and the like.
as, for example, N-B-diethylaminoethyl-Z,6-dimethyl-4
Following the procedure described in Example 13
aminobenzamide ethochloride, N-?-diethylaminoethyl
except for the replacement of ?-diethylarninoethylamine
2,6-dimethyl-4-aminobenzamide benzyl chloride, and the
like.
by ?-diethylaminoethyl mercaptan and the substitution
of 2,6-dimethyl-4-acetamidobenzoyl chloride by other
hindered 4-acylamidobenzoyl halides, other hindered 4
On reacting N - B-diethylaminoethyl-Z,6-dimethyl-4~
aminobenzamide with a suitable acid such as sulfuric
acylamidothiolobenzoic ‘acid esters are obtained such as:
acid, acetic acid, benzoic acid, or the like, in alcohol,
the corresponding acid addition salt of N-?-diethylamino-.
ethyLZ?-dimethyl-A-aminobenzamide is obtained such as
(3-Diethylan1inoethy1 2-methyl-4-acetamidothiolobenzoate,
e-Diethylaminoethyl 2-ethyl-3,6-dimethyl-4-propionami~
dothiolobenzoate,
?-Diethylaminoethyl 2,6-diethyl-4-acetamidothioloben
30 N - B-diethylaminoethyl-Z,6-dimethyl-4—arninobenzamide
sulfate, N-§—diethylaminoethy"-2,6-dimethyl-4-aminobenz
amide acetate, N - ,8 _ diethylaminoethyl-2,6-dimethyl-4—
zoate,
aminobennamide benzoate, and the like.
?-Diethylaminoethyl 2~methyl-6-(2-furyl)-4~butyramido
thiolobenzoate,
?-Diethylaminoethyl Z-methyl-6-p-methoxyphenethyl-4
acetamidothiolobenzoate,
?-Diethylaminoethyl 2,6-diphenyl-4-acetamidothiolo
benzoate,
,B-Diethylaminoethyl 2-methyl-6-cyclohexy1-4-acetamido
thiolobenzoate,
IS-Diethylaminoethyl 2-methyl-3-p-methoxyphenethyl
4-ace-tamidothiolobenzoate,
?-Diethylaminoethyl Z-methyl-6-n-hexy-4~acetamido
thiolobenzoate,
?~Diethylaminoethyl Z-methyl-6-isopropyl-4-propi0narni
dothiolobenzoate,
p-Diethylaminoethyl Z-methyl-6-p-methoxyphenethyl
4-butyramidothiolobenziate,
?-Die'thylaminoethyl 2,6-chethyl-4-isobutynamidothiolo
benzoate,
B-Diethylaminoethyl 2-methyl-6-o-methoxybenzyl~4.
Example 22.-—N-/8-DicthylamirtoethyZ-Z-Methyl
6-Ethyl-4-Aminobenzamide
Following the procedure described in Example 21 ex
cept for the substitution of N-?-diethylaminoethyl-Z,6
40
N - ? - diethylaminoethyl-Z-methyl-6-ethyl-4-aminobenz
amide is obtained.
Example 23.—-N-,6-DiethylaminoethyZ-Z-Methyl
6-Is0pr0pyl-4-Amin0benzamide
45
dimethyl-4-acetamidobenzamide by N-B-diethylaminoeth
50 15) ,
N-,8-diethylaminoethyl-2-methyl—6-isopncpyl~4-ami
nobenzamide is obtained.
Following the procedure described in Example 21 ex
55
?-Diethylaminoethyl 2-methyl-3- ( 3,7-dimethyloctyl) -
60
cept for the replacement of N-e-diethylaminoethyl-2,6-di
benzoa-te,
?-Diethylaminoethyl 2-methyl-3-m-methoxyphenethyl
4-acetamidothiolobenzoate,
I
iS-Diethylam-inoethyl 2,6-dimethyl-3-ethyl-4-acetamido—
thiolobenzoate,
?-Diethylaminoethyl 2-methyl-3-benzyl-6-isopropyl-4
acetamidothiolobenzoate, and the like.
Example 21.—N-[3-Diez‘hylamin0ethyl-2,6-Dimethyl-4
Amiizobenzamide
methyl-4-acetamidobenzamide by other N~secondary-ami
noalkyl-Z,6-dimethyl-4-acetamidobenzamides, other N
s'econdary - aminoalkyl-Z,6-dimethyl-4-aminobenzamides,
including their acid addition and quaternary ammonium
salts, are obtained. Thus, on hydrolyzing N-diethylami
nomethyl-Z,6-dimethyl-4-acetamidobenzamide, N-diethyl
thiolobenzoate,
13~Diethylaminoethyl 2,3-dimethyl~4-acetarnidothioloa
Following the procedure described in Example 21 ex
cept for the substitution of N-?-diethylaminoethyl-2,6~
yl-2-methyl-6-isopropyl-4-acetamidobenzamide (Example
acetamidothiolobenzoate,
?-Diethylaminoethyl Z-methyl-6-benzyl-4-acetamido
thiolobenzoate,
?-Diethylaminoethyl 2-ethy1-4-acetamidothiolobenzoate,
IS-Diethylaminoethyl Z-n-butyl-4-acetamidothioloben
zoate,
e-Diethylaminoethyl 2methyl-6-p-tolyl-4-»acetamido_
4-acetamidothiolobenzoate,
dimethyl-4-acetamidobenzamide by N-re-diethylaminoeth
yl-2-methy1-6-ethyl-4~acetamidobenzamide (Example 14),
aminomethyl-Z,6-dimethyl-4-aminobenzamide is obtained.
In a like manner, N-zeta-diethylaminohexyl-Z,G-dimethyl
4-aminobenzamide is obtained by hydrolyzing N-zeta-di
ethylaminohexyl-2,6-dime-thyl-4—acetam-idobenzamide; N
5 - methylcyclohexylaminoethyl - 2,6-dirnethyl-4-amino
benzamide is obtained by hydrolyzing N-B-methyleyclo
[hexylaminoethyl-Z,6-dimethyl-4~acetarnidobenzamide; N
methyl-N-B-diethylaminoethyl-2,6-dimethyl-4-aminobenz
amide is obtained by hydrolyzing N-methyl-N-?-diethyl
aminoethyl - 2,6 - dimethyl-4-acetamidobenzamide; N-(?
70 methylcyclohexylaminoethyl) - N - ethyl-2,6-dimethyl-4
aminobenzamide is obtained by hydrolyzing N-(?-meth
ylcyclohexylaminoethyl) - N - ethyl - 2,6 - dimethyl-4-a ~
In a two-liter, one-neck ?ask ?tted with a re?ux con
denser are placed the N- -diethylaminoeLhyl-2,6-dimeth
etamidobenzamide; N-?-(l-pyrrolidyl)ethyl-2,6-dirnethyl
4-amiinobenzamide is obtained by hydrolyzing N- -(1
yl-4-acetamidobenzamide obtained in Example 13, forty 75 pyrrolidyDethyl-Z,6-dimethyl-4~acetamidobenzamide;
N
3,075,97'8
,
23
The novel hindered 4-aminobenzamides of the inven
tion, their acid addition and quaternary ammonium salts,
are characterized by pharmacological activity, and more
speci?cally, local anesthetic activity.
B - (2,2 - dimethyl-l-pyrrolidyl)ethyl-2,6--dimethyl-4~ami
nobenzamide is obtained by hydrolyzing N-?-(LZ-dimeth
yl - 1 - pyrrolidyl)ethyl - 2,6 - dimethyl-li'acetamidobenz
a-mide; N - ?-(l-piperidyl)ethyl-2,6-dimethyl-4-aminobenz
Example .24.--,B-Diethyiaminoethyl 2,6-Dimethyl
amide is obtained by hydrolyzing N-?-(l-piperidyl-ethyl
4-Aminobenz0ate
2,6 - dimethyl-li-acetamidobenzamide; N-?-(Z-methyl-b
piperidyDethyl - 2,6 - dimethyl-ll-aminobenzamide is ob
In a 500-milliliter, one-neck ?ask ?tted with a re?ux
tained by hydrolyzing N-?-(Z-Inethyl-l-piperidyl)ethyl—
condenser are placed 26 grams (0.085 mole) of ?-di
2,6 - dimethyl - 4-acetamidobenzarnide; N-butyl-N-y-(l
piperidyl)propyl-2,6-dimethyl-4-aminobenzamide is ob
tained by hydrolyzing N-butyl-‘N-Iy-(I-piperidyl)propyl
ethylarninoethyl 2,6-dimethyl-4-acetamidobenzoate (Ex
10 ample 16), 22 grams of sodium hydroxide, ?fty mil
liliters of water and 200 milliliters of ethyl alcohol. The
mixture is refluxed for four hours at a temperature of
2,6-dimethyl-4~aceta-midobenzamide; N-?-(li-morpholinyl)
ethyl-2,6-dimethyl-4-aminobenzamide is obtained by hy
95 degrees centigrade and then 200 milliliters of solvent
is removed by distillation. The residue is cooled to
15 twenty degrees centigr-ade, 300 milliliters of water added
dimethyl-li-aminobenzarnidc is obtained by hydrolyziug
thereto and ‘the resulting solution is extracted with ether.
N43-(2-methyl-4-morpholinyl)ethyl - 2,6‘ - dimethyl-li-acet
The ether extract is ?ltered, dried and then distilled.
amidobenzamide; and N-p-methylethylaminoethyl-L6-di
There is obtained a light brown oil, identi?ed by in
drolyzing N-p-(4-morpholinyDethyl-2,6-dimethyl-4-acet
amidobenzamide; N-{i-(Z-methyl-4-morpholinyl)ethyl-2,6
methyl-li-aminobenzamide is obtained by hydrolyzing N
13 - methylethylaminoethyl-2,6-dirnethyl-4-acetamidobenz
frared analysis as B-diethylaminoethyl 2,6-dimet'hyl-4
20
amide.
Following the procedure described in Example 21 ex
cept for the substitution of N-)8~diethylamin0ethyl-2,6
dimethyl-4-acetamidobenzamide by other hindered 4
acylamidobenzamides, the following hindered 4-amino
benzamides, including their acid addition and quaternary
aminobenzoate boiling between 155 and 157 degrees cen
tigrade at a pressure of 0.04 millimeter of mercury and
possessing an index of refraction n 25=l.5477.
AnaIysis.--Calculated for C15H24N2o2: N, 10.60.
N, 10.49.
25 Found:
By heating a benzene solution of [i-diethylaminoethyl
2,6-dimethyl-4-aminobenzoate and methyl bromide and
cooling and concentrating the resulting solution, ?-dieth
ammonium salts, are obtained:
N-?-diethylaminoethyl-Z-methyl-4saminobenzamide,
N-?-diethylaminoethyl-Zethyl-3,6-dimethyl-4-aminobenz~
amide,
N-?-diethylaminoethyl-Z,6-diethyl-4-aminobenzamide,
N- B-diethylaminoethyl-2-methyl-6- ( Z-furyl) -4-aminioi
benzamide,
N-?-diethylaminoethyl-Z-methyl-6-p-meth-oxyphen
ethyl-4-aminobenzamide,
N-BniethyIaminOethyI-Z,6-diphenyl-4eaminobenzamide,
N-B-diethylaminoethyl-2-methyl-6-cyclohexyl-Li-amino
'benzamide,
N-?'diethylaminoethyl-2-methyl-3-p-methoxypenethyl
taminobenzamide,
N-?-diethylaminoethyl-Z-methyl-6~n~hexyl-4-arninobenz
ylaminoethyl 2,6-dimethyl-4-am-inobenzoate methobro
mide is obtained.
Similarly, by reacting ?-diethylaminoethyl 2,6-dimeth
yl-4-aminobenzoate with other esters such as, for ex
ample, ethyl chloride, benzyl chloride, and the like, the
corresponding quaternary ammonium salts of ?-diethyl
35 aminoethyl 2,6-dimethyl-4-aminobenzoate are obtained
such as, for example, ?-diethylaminoethyl 2,6-dimethyl
4-aminobenzoate ethochloride, B-diethylaminoethyl 2,6
dimethyl-4-aminobenzoate benzyl chloride, and the like.
Example 25.--,8~Diethylaminoethyl 2,6-Dimethyl
4-Amin0benz0ate Monohydrochloride
One gram of ?-diethyliaminoethyl 2,6-dimethyl-4-ami
40
nobenzoate (Example 24) is dissolved in thirty milliliters
of diethyl ether and gaseous hydrogen chloride is bubbled
into the solution until the precipitation of white solid
amide,
N-?-diethylaminoethyl-Z-methyl-6-isopropyl-4-amino
benzamide,
N-?-diethylaminoethyl-2-methyl-6-p-methoxyphenethyl
4-aminobenzamide,
N-?-diethylaminoethyl-2,6-diethyl—4-aminobenzamide,
N-?-diethylaminoethyl-Z'methyl-6-o-methyibenzyl-4
aminobenzamide,
N-B-diethylaminoethyl-2-methyl-6-benzyl-4-aminobenz
amide,
N-B-diethylaminoethyl-Z-ethyl-4~aminobenza1nide,
N-p-d-iethylaminoethyl-Z-n-butyl-4-aminobenzamide,
N-f3—diethy1aminoethyl»2-rnethyl-6-p-tolyl-4eaminobenz
45 ceases. The solid material is collected by ?ltration, im
mediately dissolved in isopropanol and then recrystallized
therefrom. ?-Diethylaminoethyl 2,6-dimethyl-4-amino
50
Example 26.—-B-Diethylaminoethyl 2,6-Dimethyl-4
Aminobenzoate Dilzydrochloride
55
amide,
ceases. The solid material is collected by ?ltration and
60 exposed to the air. Over 1a period of eight hours, the white
solid material becomes gummy, light tan in color and
[then resolidi?es. Upon recrystallization from isopro
panol, white crystalline e-diethylaminoethyl 2,6-dimethyl
amide,
N-B-diethylaminoethyl-Z~methyl-3
~benzyl-6eisopropyl-4
amino‘oenzamide, and the like.
4-amin0benzoate dihydrochloride is obtained melting be
65 tween 194 and 194.5 degrees centrigrade.
Analysis.--Calc. for C15H25Cl2N2O2: Cl, 21.07; N,
Where arylsulfonyl halides, aroyl halides, and the like,
have been used as 'acylating agents to form the aforemen
tioned N - B-diethylaminoethyl-Z,?-dimethyl-?l-petoiuene
sulfonamidobenzamide, N - B-diethylaminoethyl-2,6-di
methyl-4-benzenesulfonamidobenzamide, N-e-diethylami
noethyl - 2,6-dimethyl-4-benzamidobenzamide, and the
like, these compounds are hydrolyzed to the correspond
ing hindered 4-aminobenzarnide by reaction with a mix
.ture of hydrogen bromide and phenol in ‘an acetic acid
One gram of B-diethylaminoethyl 2,6-dimethyl-4-amino
benzoate (Example 24) is dissolved in thirty milliliters
of diethyl ether and gaseous hydrogen chloride is bubbled
into the solution until the precipitation of white solid
N-ft-diethylaminoethyl-Z-methyl-3 - (3 ,7 -dimethyloctyl) -
4-aminobenzamide,
N-B-diethylaminoethyl-Z,3-dimethy1-4-aminobenzamide,
N-B-diethylaminoethyl-2-methyl-3-m~methoxyphenethyl
4-aminobenzamide,
N-[S-diethylaminoethyl-2,6-dirnethyl-3-ethyl-4-aminobenz
benzoate monohydrochloride is thus obtained melting
between 129 and 130 degrees centigrade.
Analysis-Calculated for C15H25ClN2O2: 01, 11.79.
Found: Ci, 11.67.
8.32. Found: C1, 20.61; N, 8.28.
Example 2 7.—-?-Diethylamin0ethyl 2,6-Dimethyl-4
70
Aminobenzoate Citrate
Following the procedure set forth in Example 25 except
for the replacement of hydrogen chloride by citric acid,
?-diethylaminoethyl 2,6-di1nethyl-4-aminobenzoate- citrate
is obtained in the form of colorless crystals.
medium, in the manner set forth in U. S. Patent 2,5 62,222. 75
25
Example 28.—?-]-Piperidylethyl 2,6-Dimethyl-4
3,076,978
26
V
?-Dirnethylaminoethyl 2-methyl-4-aminobenzoate,
Aminobenzoate
?-Diethylaminoethyl 2-ethyl-3,6-dimethyl-4-aminobenzo
ate,
Following the procedure described in Example 24 ex
cept for the substitution of 18-diethylarninoethyl 2,6-di
?-Diethylaminoethyl 2,i6ediethyl~4-aminobenzoate,
B-Diethylaminoethyl 2-methyl-6-(2-furyl)-,4-raminobenzoe
n1ethyl-4-acet-amidobenzoate by 18-1-piperidylethyl 2,6
dimethyl-4~acetamidobenzoate (Example 18), there is
ate,
obtained a forty percent yield of p-l-piperidylethyl 2,6—
dimethyl-4-aminobenzoate boiling between 175 and 180
?-Diethylaminoethyl 2 ~ methyl-6-p-methoxyphenethyl-4
aminobenzoate,
degrees centigrade at a pressure of 0.03 millimeter of
?-Diethylaminoethyl 2,6-diphenyl-4-a1ninobenz0ate,
mercury.
10 ,B-Diethylaminoethyl 2 ~ methyl-6-cyclohexyl14aaminoben
zoate,
Example 29.—-{3-1 -Piperidylethyl 2,6-Dimetlzyl-4
?-Diethylaminoethyl 2 - methyl-3-p-methoxyphenethyl-4
Aminobenzoate Dihydrochloride
Following the procedure described in Example 26 ex
cept for the substitution of ,B-diethylaminoethyl 2,6-di 15
metl1yl-4-aminobenzoate by p - 1 - piperidylethyl 2,6-di
methyl-4-aminobenzoate (Example 28), there is obtained
j3-l-piperidylethyl 2,6-dimethyl-4-aminobenzoate dihydro
chloride melting between 223 and 225 degrees centigrade
(tube).
Analysis-C?c. for C16H26Cl2N2O2: C, 55.01; H, 7.50;
N, 8.02; Cl, 20.21. Found: C, 55235; H, 7.64; N, 8.19;
20
Cl, 19.83.
Example 30.-—;8-4-M0rpholinylethyl 2,6-Dimethyl-4
Aminobenzoale
25
Following the procedure described in Example 24 ex
pholinylethyl 2,6-dimethyl-4~aminobenzoate is obtained.
aminobenzoate,
?-Diethylaminoethyl 2,3~dimethyl-4-aminobenzoate,
aminobenzoate,
18-Diethylarninoethyl 2,6-dimethyl-3-ethyl-4-aminobenzo
ate,
Ethyl-4A min 0b erzzoare
Following the procedure described in Example 24 ex 35
cept for the replacement of ,G-diethylaminoethyl 2,6-di
obtained.
of hydrogen bromide and phenol in an acetic acid me
rnethyl-6-isopropyl-4-acetamidobenzoate (Example 20),
zoate is obtained.
In the same manner, hindered 4-acylamidobenzoic acid
tained.
The novel hindered 4~aminobenzoic acid esters, their
acid addition and quaternary ammonium salts, are char
esters ‘are hydrolyzed by the procedure described in Ex
ample 24- to form the corresponding hindered 4-amino
acterized by pharmacological activity, and more speci?
cally, local anesthetic activity.
Following the procedure described in Example 24,
benzoic acid esters. Thus, zeta-diethylaminohexyl 2,6
dimethyl-4-aminobenzoate is obtained by the hydrolysis
of zeta-diethylaminohexyl 2,6-dimethyl-4-acetamidoben
hindered 4-acylainidothiolobenzoic acid esters are hy
zoate; ,8 - methylethylaminoethyl 2,6 - dimethyl-4-amino
drolyzed to the corresponding hindered 4~arninothiolo
benzoic acid esters. Thus, for example, ,8-diethylamino~
benzoate is obtained by the hydrolysis of B-methylethyl
aminoethy-l 2,6-=dimethyl-4-acetamido-ber1oate; B-dicyclo
hexylaminoethyl 2,6 - dimethyl - 4-aminobenzoate is ob
60
dimethyl - 4 - acetamidobenzoate; ,B-I-pyrrolidylethyl 2,6
benzoate. In a like manner, zeta-diethylaminohexyl 2,6
drolysis of Zeta~diethylaminohexyl 2,6-dimethyl-4-acet
amidothiolobenzoate; ?-methylethylaminoethyl 2,6 -di
of ?-l-pyrrolidylethyl 2,6-dimethyl-4-acetamidobenzoate.
Similarly, the following hindered 4-ann'nobenzoic acid
methyl-4-aminothiolobenzoate is obtained by the hydroly
sis of ?-methylethylaminoethyl 2,6-dhnethyl-4-acetamido
esters ‘are obtained by hydrolysis of the corresponding
hindered 4-acylamidobenzoic acid esters:
thiolobenzoate; ,B-dicyclohexylaminoethyl 2,6-dimethyl-4
?-Ethylbenzylaminoethyl 2,6-dimethyl-4-aminobenzoate,
B-Dibenzylarninoethyl 2,6-Dimethyl-4-aminobenzoate,
benzoate,
ethyl 2,6-dimethyl-4-acetamidothiolobenzoate is hydro
lyzed to ?-diethylaminoethyl 2,6-dimethyl-4-aminothiolo
dimethyl-4~aminothiolobenzoate is obtained by the hy
dimethyl-4-aminobenzoate is obtained by the hydrolysis
zoate,
?-(2~methyl-4-morpholinyl)ethyl 2,6 - dimethyl-4-amino
sulfonamidobenzoate, ?-diethylaminoethyl 2,6-dimethyl
4-benzenesulfonamidobenzoate, ?-diethylaminoethyl 2,6
dium, in the manner set forth in U.S. Patent 2,562,222.
Similarly, by the procedure set forth in Examples 24
to 27, the acid addition and quaternary ammonium salts
of hindered 4-aminobenzoic acid esters are likewise ob
,8 ~. diethylaminoethyl 2 - methyl-6-isopropyl-4-aminoben
zoate,
Where arylsulfonyl halides, aroyl halides, and the like,
dirnethyl~4-benzamidobenzoate, and the like, these com
pounds are hydrolyzed to the corresponding hindered
4-aminobenzoic acid esters by reaction with a mixture
methyl-4-acetamidobenzoate by ?-diethylaminoethyl 2
IS-(Z-methyl-l-piperidyl)ethyl 2,6 - dimethyl-4-aminoben
aminobenzo ate, and the like.
mentioned ?-diethylaminoethyl 2,6-dimethyl-4- -toluene
40
Following the procedure described in Example 24 ex
cept for the substitution of ,B-diethylaminoethyl 2,6-di
?-(Z-methyl-l-pyrrolidyl)ethyl 2,6-dimethyl-4-aminoben
?-Diethylaminoethyl 2 - methyl - 3 - benzyl-6-isopropyl-4
have been used as acylating agents to form the afore
Example 32.-—B-Diethylaminoelhyl 2-Methyl-6
Is0pr0pyl-4-Aminobenzoate
tained by the hydrolysis of {3-dicyclohexylaminoethyl 2,6
zoate,
B-Diethylaminoethyl Z-methyl-6-o-methylbenzyl-4-amino
benzoate,
[3»Diethylaminoethyl 2methyl-6-benzyl-4-annnobenzoate,
l3~Diethylarrdnoethyl 2-ethyl-4-aminobenzoate,
?-Diethylaminoethyl 2-n~buty-l-4-aminobenzoate,
?-Diethylaminoethyl Z-methyl-6-p-ttolyl-4-aminobenzoate,
30 ?-Diethylaminoethyl 2 - methyl-3-m-methoxyphenethyl-4
Example 31 .~—j3-Diethylaminoethyl 2-Methyl-6
methyl---acetam-idobenzoate by [i-diethylaminoethyl 2~
methyl-6~ethyl-4-acetamidobenzoate (Example 19), f3
diethylaminoethyl 2-methyl-6-ethyl-4-aminobenzoate is
;8-Dimethylaminopropyl 2-metl1yl-6-n-propyl-4-aminoben
zoate,
,B-Dimethylaminoisopropyl 2-methyl-6-n-propyl-4-ainino
benzoate,
v~Dimethylaminopropyl 2-methyl-6-n-propyl-4-aminoben
?-Diethylaminoethyl 2 - methyl-3-(3,7-Dimethylootyl) -4
cept for the substitution of ?-diethylaminoethyl 2,6-di
methyl-4-acetarnidobenzoate by ,B-4-morpholinylethyl 2,6
dimethyl-4-acetamidobenzoate (Example 17), ,B-4-n1or
aminobenzoate,
BDiethylaminoethyl 2-methyl-6-n-hexyl-4~aminobenzoate,
aminothiolobenzoate is obtained by the hydrolysis of
f2 - dicyclohexylaminoethyl 2,6-dimethyl-4-acetamidothio
70
lobenzoate; ,B-I-pyrrolidylethyl 2,6-dimethyl-4-aminothio
lobenzoate is obtained by the hydrolysis of ?-l-pyrrolidyl
ethyl 2,6-dimethyl-4-acetamidothiolobenzoate, ?-l-piper
idylethyl 2,6-dimethyl-4-aminothiolobenzoate is obtained
by the hydrolysis of p-l-piperidylethyl 2,6-dimethyl-4
acetamidothiolobenzoate; and ,8-4-morpholinylethyl 72,6
3,075,978
28
v2'7
dimethyl-ll-aminothiolobenzoate is obtained by the hy
I claim:
>
.
l. A process for preparing compounds of the formula:
drolysis of ?-4-morpholinylethyl 2,6-dimethyl-4-accta’
is
R;- }
midothiolobenzoate.
By the same procedure, the following hindered 4-ami
nothiolobenzoic acid esters are obtained from the corre
sponding hindered 4-acylamidothiolobenzoic acid esters:
'?-Bthylbenzylaminoethyl 2,6-dirnethyl~4-aminothio1oben
zoate,
?-Dibenzylaminoethyl
2,6-dime?1yl-4-aminothiolobenzo
R2‘-
—R1
10 wherein n is an integer from one to six inclusive, R is a
ate,
secondary-amino radical, R1 is a member selected from
thiolobenzoate,
the group consisting of hydrogen and alkyl, cycloalkyl,
aralkyl, aryl' and heterocyclic radicals; R2 is a member
selected from the group consisting of alkyl and aryl radi
6- (2-methyl-l~pyrrolidyl) ethyl 2,6-dimethyl-4-amino
18- (2-methyl-l -piperidyl ) ethyl 2,6-climethyl-4-arnino
thiolobenzoate,
15 cals; R3 is a member selected from the group consisting
thiolobenzoate,
of hydrogen and alkyl and aralkyl radicals; and Y is a
member selected from the group consisting of oxygen,
?-(2-methyl-4-morpholinyl) ethyl 2,6-dimethyl-4-amino
,B-Diethylaminoethyl 2-methyl-4-aminothiolobenzoate,
,B-Diethylaminoethyl 2-ethyl-3,6-dimethyl-4-aminothio
lobenzoate,
?-Diethylaminoethyl 2-methyl-6-(2-furyl) -4-aminothio
sulfur, imino, and alkylirnino; which comprises subject
ing a hindered 4-oXo-2-cyclohexene-l-carboxylic acid
20 ester of the formula:
lobenzoate,
?-Diethylaminoethyl Z-methyl-6—p-methoxyphenethy1-4
aminothiolobenzoate,
?-Diethylaminoethyl 2-methyl-6-cyclohexyl-4-aminothio
lobenzoate,
,B-Diethylaminoethyl Z-methyl-3-p-methoxyphenethyl-4
aminothiolobenzoate,
?-Diethylaminoethyl Z-methyl-6-n-hexyl-4-aminothiolo
benzoate,
?-Diethylaminoethyl Z-methyl-6-isopropyl-4-aminothio
lobenzoate,
p-Diethylaminoethyl Z-methyl-6-o-methylbenzyl-4-amino
thiolobenzoate,
B'DiethylaminOethyl Z-methyl-6-benzyl-4~aminothiolo
25
wherein R5 is a member selected from the group consist
ing of alkyl and aralkyl radicals, and R1, R2 and R3 are
30
as de?ned above, to oximation, aromatizing and acylating
the resulting hindered 4-oximino-2-cyclohexene-l-carbox
yh'c acid ester, hy-drolyzing the hindered 4-acylamidoben
zoic acid ester thus obtained followed by acylation to
35 form a hindered 4-acylamidobenzoic acid, reacting said
acid with an inorganic acid halide, reacting the hindered
benzoate,
?-Diethylaminoethyl 2-ethyl-4-aminothiolobenzoate,
B-Diethylaminoethyl Z-n-butyl-4-aminothiolobenzoate,
4-acylamidobenzoyl halide thus obtained with a com
pound of the formula:
?-Diethylaminoethyl 2-methyl-6-p-tolyl—4-aminothiolo
benzoate,
e-Diethyl'aminoethyl 2-methyl-3 - (3 ,7-dimethyloctyl) -4
40
aminothiolobenzoate,
B-Diethylaminoethyl 2,3-dimethyl-4-aminothiolobenzo
ate,
?-Diethylaminoethyl
2-methyl-3-m-methoxyphenethyl-4
aminothiolobenzoate,
|B-Diethylaminoethyl 2,6-din-rethyl-S-ethyl-4-aminothiolo
benzoate,
?-Diethylaminoethyl
2-methyl-3-benzyl-6-isopropyl-4
wherein Y, R and n are as de?ned above, and then hydro
lyzing the compound thus obtained.
2. A process for preparing compounds of the formula.
aminothiolobenzoate, and the like.
Similarly, by the procedure set forth in Examples 24
to 27, the acid addition and quaternary ammonium salts
of hindered 4-aminothiolobenzoic acid esters are like
wise obtained.
0: —-YCnHmR
wherein R6 is an acyl group, and n, R, R1, R2, R3 and Y
are as de?ned in claim 1, which comprises subjecting a
hindered 4-oXo-2-cyclohexene-l-carboxylic acid ester of
the formula:
Where arylsulfonyl halides, arolyl halides, and the like,
have been used as acylating agents to form the aforemen
tioned B-diethylaminoethyl 2,6-dirnethyl~4-p-toluenesnl
fonamidothiolobenzoate, ?-diethylaminoethyl 2,6-dimeth
115-
yl-4-benzenesulfonarnidothiolobenzoate, B-diethylamino
R3
——R1
ethyl 2,6-dimethyl-Ll-benzamidothiolobenzoate, and the
O=(E—O R5
like, these compounds are hydrolyzed to the correspond
ing hindered 4-aminothiolobenzoic acid esters by reaction
wherein R1, R2, R3 and R5 are as de?ned in claim 1, to
with a mixture of hydrogen bromide and phenol in an
acetic acid medium in the manner set forth in US. Patent
oximation, aromatizing and acylating the resulting hin
dered 4-oximino-2-cyc1ohexene-l—carboxylic acid ester,
hydrolyzing the hindered 4-acylamidobenzoic acid ester
2,562,222.
The novel hindered a-aminothiolobenzoic acid esters,
.their acid addition and quaternary ammonium salts, are
thus obtained following by acylation to form a hindered
4-acylamidobenzoic acid, reacting said acid with an in
organic acid halide and then reacting the hindered 4-acyl
- characterized by pharmacological activity, and more spe
, ci?cally,'local anesthetic activity.
It is to be understood that the invention is not to be
limited to the exact details of operation or exact com
amidobenzoyl halide thus obtained with a compound of
the formula:
HYCnHznR
pounds shown and described herein, as obvious modi?ca
tions and equivalents will be apparent to one skilled in
the art. The invention is therefore to be limited only by
the scope of the appended claims,
wherein Y, R and n are as de?ned in claim 1.
75
(References on following page)
29
3,075,978
39
References Cited in the ?le of this patent
UNZTED STATES PATENTS
2,073,100
2,342,142
Eisleb ________________ __ Mar. 9, 1937
Harris et a1 ___________ __ Feb. 22, 1944
2,821,540
Speeter et a1. _________ __ Ian. 28, 1958
OTHER REFERENCES
Grob: Helvetica Chhnica Acta, volume 33, pages
1787-96, abstracted in Chem. Abstracts, volume 45, col
umn 3804(f), 1950.
Rhodehamel: I our. of the American Chem. Soc., vol
5
ume 73, page 5902, abstracted in Chem. Abstracts, Vol
ume 46, column 11181(b) (1951).
Dvoretsky et a1.: I our. of Org. Chem, volume 18, pages
615-19, June 16, 1952.
Tetracaine: Merck Index, Sixth Edition, p. 939 (1952).
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