Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to a process for the pre-
paration of substituted aromatic amines, which process is particu-
larly simple and selective, and to the novel compounds produced
by this process.
The çompounds according to the invention are of yreat
interest in the field of "fine chemicals" and, particularly, in
the field of dyestuffs, as they are basic intermediate products
for their synthesis. ~ore particularly, these compounds can be
used for the preparation of azodyes of general formula:
OR4 / R
R - N - N ~ N \
R
NHCOR3 2
Wherein R represents the radical of a diazo-component of the ben-
zenic, naphthalenic or heterocyclic series, variously substituted,
and Rl, R2, R3 and R4 represent alkyl radicals.
The process according to the invention for the prepara-
tion o~ aromatic amines substituted by direct amination with N-
chloro-amlnes in a Redox type system, comprises the step of reading
an aromatic compound 1,4-di-substituted with an etheric and an
acylaminic group with an N-chloro-amine in a reaction medium
acidified with a strong acid.
The compounds according to the invention are covered by
the general formula:
N
NHCOR3
wherein R3 represents an alkyl radical having from 1 to 4 carbon
atoms, optionally substituted with carboxy carboxyalkyl ha.ving
from 1 to 4 carbon atoms, hydroxy, halogen or phenyl; and R4
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represents an alkyl radical having from 1 to 4 carbon atoms,
optionally substituted with carboxy or carboxyalkyl having from
1 to 4 carbon atoms.
It is well known that the N-dialkylation of an aromatic
amine is a poorly selective process due to the contemporaneous
formation of the secondary amine and of the ~uaternary ammonium
salt. In order to avoid this drawback, T. L. Kruger et al.
~Jr. Org. Chem. 40, 77 (1975 ~ have suggested using, in the case
of various similar amines (methoxy-halogen and nitro-anilines),
a complete methylation to quaternary ammonium salt with the suc-
cessive removal of the third methyl group by distillation in a
current of steam in a strongly basic medium.
The synthesis technique for aromatic N-alkylamines by
amination of aromatic substrates with chloroamine in the presence
of a reducing salt (ferrous, cuprous or titanous salt) in an acid
reaction medium, has been described in U.S. patent 3,483,255, in
which are alkylaminated non-substituted aromatic compounds such
as benzene, toluene, naphthalene or t~eir derivatives monosubstitut-
ed with chlorine, bromine, iodine, -OCH3, etc. (column 1, line 25,
and following of the cited patent).
The present invention proposes a new and improved
process for the preparation of substituted aromatic amines. It
also proposes new chemical compounds, ie substituted aromatic
amines.
It has now surprisingly been found that it is possible
to obtain substituted aromatic amines by effecting high selectivity
amination on aromatic compounds 1,4-disubstituted with substltuents
that are different from each other but that have the same activat-
ing effect towards the amination, while the formation of two isomers
was reasonably foreseeable.
The process according to this invention is carried out
by reacting an aromatic compound 1,4-di-substituted in a suitable
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reaction medium of an acidic nature (e.g. concentrated H2SO~,
mixturesoEH2SO4 - solvent in which the solvent may, for instance,
be H20, methanol, acetic acid, etc., and in which the concentration
by weight of the sulphuric acid is at least equal to 25~ of the
total mixture), with a suitable N-chloroamine, in the presence of
a catalyst of the REDOX type, for instance FeSO4, at more or less
low temperatures, for instance around room temperature.
The N-halogen-amine may be, for instance N-chloro-methyl-'
amine, N-chloro-dimethylamine, N-chloro-methyl-ethylamine, N-
chloro-methyl-benzylamine, N-chloro-piperidine, N-chloro-N'-
methylpiperazine and the likes'.
One of the substituents of the benzenic ring is an ethe-
ric or etheric-substituted group such as e.g.: OCH3, OC2H5 and the
like. The other is an amidic or amidic substituted group, for
instance: NHCOCH3, NHCOC2H5, NHCOCH2Cl, NHCOCH2COOH.
This process is particularly effective for the p'roduc-
tion of aromatic substrates para-disubstituted with an etheric
group and an acyl-amide group, the so-obtained aromatic amines
' h`aving the foIlowing general structure:
amines of the general structure:
R
OR4
(r)
- ~ 2
"' ~
NHCOR3
wherein:
Rl represents a hydrogen or an alkyl radical having from 1 to 4
carbon atoms;
R2 is identical to Rl except the hydrogen;
Rl and R2 may also form together with N a piperidine ring;
R3 is an alkyl radical having from 1 to 4 carbon atom, optionally
--3--
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substituted with carboxy, carboxyalkyl having ~rom 1 to 4 carbon
akoms, hydroxy, halogen or phenyl; and
R4 is an alkyl radical having from 1 to 4 carbon atorns, optionally
substituted with carbo~y or carboxyalkyl having from 1 to 4
carbon atoms.
The process according to the invention shows a higher
selectivity for the production of aromatic amine compounds described
above than that obtained using the known method described in
Beilst. 13 II, 1341, involving a final alkylation with alkyl
sulphate or alkyl halide of the intermediate:
i OR4
~ NH2
.. ~
NHCOR3
herein R4 = CH3, R3 = CH3-
A particularly valuable azo-dye, derived from the inter-
mediate~compounds of general formula (I), is for instance the dye
of the following formula:
. OCH3
2Q Cl ~ CN3
NHCOCH3
which has excellent applicative characteristics for polyester .
fibres.
The process of this invention permits the synthesis of
amino-benzenic derivatives trisubstituted in position 1, 2, 4 and
consists in treating an aromatic substrate 1,4-di-substituted with
a suitable N-halogen-amine in a Redox-type system containing salts
such as for instance ferrous, cuprous or titanous salts, and an
inorganic strong acid, such as for instance sulphuric acid, or an
organic strong acid such as for instance trifluoro-acetic acid, or
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mixtures thereof with acetic acid.
The process of this invention is preferably conducted
at room pressure. The tempe,rature range within which the reaction
takes place is very wide; thus, for instance, good results are
obtained between 0 and 40C with acyl derivatives of phenetidine,
and with the alcoxyanilides in general.
The molar ratios be-tween N-chloro-amines and the
aromatic substrates may vary according to the syntheses. Most
common are ratios comprised between 1:3 and 3:1, with preference
for a modest excess of chloroamine.
' The catalyst may vary with respect to the N-chloro-
amine from 1:; to 1:100 in mols, according to the cases, preferably
comprised between 1:1.2 and 1:50.
Also with regard to the quantity of acid mixture ther~
r " ~;
may be used the most various ratios in respect of the aromatic
substrate.
The procedures for carrying out the process are the
following:
Into a reactor fitted with a stirrer and provided with
a thermometer, a funnel with a tap and a coolant, there are intro-
duced in the given order:
A) the acid mixture,
B) the aromatic substrate,
C) a solution of N-chloro-amine in the acid mixture, and
D) the catalyst.
~In the case sulphuric acid of a high concentration is used, care
must be taken that the temperature, during the loading of the aro-
matic substrate charge and of the N-chloro-amine solution, be suf-
ficiently low to avoid the sulphonation of the substrate itself).
The catalyst is admixed gradually, controlling the
development of HCl, which latter may be absorbed according to con-
ventional techniques, (in the case of easily sulphonable substrates,
if one operates with highly concentrated sulphuric acid, it is
preferable to check the increase of temperature during the addition
of the catalyst~.
Once the development of HCl has stopped, the content of
the reactor is discharged on ice, under stirring, and the start-
ing product is extracted, in case this be still present, from the
acid solution by means of a suitable solvent, for instance chloro-
form.
After alkalinization with a concentrated alkaline solu-
tion for instance a 30 % caustic soda, the desired reaction pro-
duct is extracted with a suitable solvent.
The choice of the solvent is essentially bound to the
distribution coefficient of the product between solvent and aque-
ous solution.
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The classes of solvents may vary widely since, accord-
ing to opportunity, there may be used: esters, ketones, ethers,
aliphatic or aromatic chlorinated solvents.
After distillation of the solvent, one obtains the
finished products, in general in a state of purity already useful
for subsequent uses.
In some cases it may be useful to sub~ect the desired
product to a crystallization from a suitable solvent or to a
fractionated precipitation such as chlorohydrate, sulphate,
phosphate, etc.
The new compounds synthesized with the above described
process, have the following general formula (II):
OR4
~ U ~ ~II)
; '
NHCOR3
wherein R3 and R4 have the ~eanings defined by formula (I).
The examples that follow hereunder are given for purely
illustrative purposes and are not to be taken in anyway as limiting
more general aspects of the inventive idea.
In said examples where not otherwise indicated, the
- term "parts" must be understood as expressed in units of weight.
The yield is calculated on the quantity of N-chloroamine used.
EXAMPLE nl:
~ Into a reactor fitted with a stirrer and provided with
a coolant, a thermometer and a dropping funnel, there were loaded:
220 parts of concentrated H2SO4, and, maintaining the temperature
below 10C, there were added:
27 parts of phenacetine (para-acetylphenetidine).
Under stirring, there were the
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68.5 parts of a sulphuric solution of N~chloro-dimethylamine at 17.4%
concentration equal to 11.9 parts at 100%.
Thereupon, in batches, there were loaded:
23 parts of FeSO .7~I O
The resulting mixture was allowed to react for 1 hour, after which
the content of the reactor is poured onto:
500 parts of minced ice.
After alkalinization with a 30% NaOH, extraction with chloroform
was carried out and the solvent was distilled.
Thereby were obtained:
27.7 parts of 4-ethoxy-3-N,N-diethylamino-acetanilide with a titre
of 91%. The yield amounted to abt. 76%.
The product precipitated by means of conventional techniques as
hydrochloride, re-dissolved in water and, after alkalinization, re-
extracted with chloroform, has a titre of 99.2%. The melting point
(m.p.) is equal to 110-112C.
Similar results are achieved when using as a solvent 110 parts or
60 parts of concentrated H2S04.
The reaction proceeds with similar rate and yields when quantities
varying between 4.2 and 23 parts of FeS04.7H20 are used.
E ~ E n 2 :
Into an apparatus like that of example l were loaded:
74 parts of concentrated H2S04, keeping the temperatures below
10C, there were then added:
9 parts of phenacetine.
Under stirring there were then added:
23.8 parts of a sulphuric solution of N-chloro-piperidine at
25.1 % equal to 6 parts at 100%.
In batches, there were finally loaded:
7 parts of FeS04-~H20.
The reaction mass was allowed to react for 30 minutes, after which
the content of the reactor was poured onto:
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150 parts of minced ice.
An extraction is carried out with chloroform and the solvent is
then distilled. Thereby are obtained 4 parts of unreacted
phenatine. After alkalinization of the waters and extraction
with chloroform, the solvent is distilled and there are obtained:
7.4 parts of 3-piperidino-4-ethoxy-acetanilide.
Titre: 93%; yield: 52%; melt point: 141; 5 C - 143.5 C.
EXAMPLE n3:
Into an apparatus like that of example 1, there were
loaded:
73 parts of concentrated sulphuric acid.
Maintaining the temperature below 10C, there were added:
8.25 parts of N-acetyl-para-anisidine.
Thereupon, under stirring, there were slowly added:
23.8 parts of a sulphuric solution of N-chloro-piperidine at
2501% concentration equal to 6 parts of 100%.
In batches, there were then Ioaded:
7 parts of FeSO4.7H20 and the mixture was then allowed to react
for 1 hour.
Thereupon the content of the reactor was poured onto: -
150 parts of minced icej and, after extraction with chloroformand distillation of the solvent there were obtained:
2.7 parts of unreacted starting product.
The waters were then alkalinized with 30~ NaOH and extraction was
- carried out with chloroform.
After distillation of the solvent, there were obtained:
8.3 parts of 4-methoxy-3-piperidino-acetanilide.
Titre-: 92~; yield: 62~; melt point: 156 -159 C.
EXAMPLE n 4:
There was proceeded as in example 3. There varied only
the type of N-chloro-amine.
There were used:
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19.4 parts of a sulphuric solution of N-chloro-dimethyl-amine at
20.5% concentration, equal to 4 parts at 100%.
There were obtained:
11 parts of 4-methoxy-3-N,N~dimethylamino-acetanilide.
Titre: 93.8%; yield: 99~; melting point: 109 - 111 C.
EXAMPLE n 5:
. . .
Into an apparatus like that of example 1 were loaded:
150 parts of concentrated H2SO4.
Maintaining the temperature below 10C, there were then added:
22.3 parts of paramethoxy-succinylanylic acid.
Under stirring, there were then loaded:
37.5 parts of a sulphuric solution of N-chloro-dimethyl-amine at
21.2~ concentration equal to 8 parts at 100%.
Then, in batches, there were loaded:
14 parts of FeSO4.7H20, and the whole mass was then kept under
stirring for 2 hours.
Thereupon the content of the reactor was poured onto:
300 parts o minced ice.
The solution, t~tred according to known methods, contained:
19.5 parts ~yield 73%) of 4-methoxy-3-N,N-dimethylamino-succinylani-
lic acid which, eluted on silicic acid, showed an R.F of 0.3 wlth
eluent chloroform 70, methanol 25, ammonia at 17% conc. 5 parts by
volume.
EXAMPLE n 6~
Into an apparatus like that of example 1, were loaded:
75 parts of concentrated H2SO4.
Maintaining the temperature below 10C, there were added:
9 parts of para-methoxy-propioanilide.
Thereupon there were slowly added:
19.1 parts of a sulphuric solution of N-chloro-dimethylamine at
20.8% conc. equal to ~ parts at 100%.
Then, in batches, there were loaded:
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7 parts of FeSO4.7H20, and the mixture was kept under stirrin~ for
2 hours.
Thereafter the content of the reactor was poured onto:
150 parts of minced ice.
The content was extracted with chloroform, the solvent was distilled
and there were recovered:
2 parts of unreacted starting product.
After alkalinization with NaOH at 30% conc., extraction was carried
out with chloroform. After distillation, there were obtained 10
parts of 4-methoxy-3-N,N-dimethylamino-propioanilide.
Titre: 90.6%i yield: 81.6%.
EXAMPLE n 7:
Into an apparatus like that of ex.l, were loaded:
74 parts of concentrated H2SO4.
Maintaining the temperature below 10C, there were added:
10 parts of 4-methoxy-chloroacetanylide. Then, under stirring,
there were added:
19.1 parts of a sulphuric solution of N-chloro-dimethylamine at
20.8% conc. equal to 4 parts at 100%.
At least, in batches, there were loaded:
7 parts of FeSO4.7~l20 and the whole mass was then allowed to react
for 2 hours, after which the content of the reaction was poured
onto:
lS0 parts of minced iced.
It was then extracted with chloroform and the solvent was distill-
ed.
Therehy were obtained:
3 parts of unreacted starting product.
After alkalinization and extraction, the solvent was distilled
and thereby were obtained:
10.7 parts of 4-methoxy-3-N,N-dimethylamino-chloroacetanilide.
Titre: 86~; yield: 75.5%; melt point: 105 -107C.
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EXAMPL~ n8:
.. _ . ...
Into the apparatus oE example 1 were loaded:
74 parts of concentrated ~l2SO4.
Maintaining the temperature below 10C, there were added:
9 parts of 4-methoxy-hydroxyacetanillde.
Then, under stirring, there were added:
19.1 parts of sulphuric solution of N-chloro-dimethylamine at 20.8%
conc. equal to about 4 parts at 100~.
At last there were loaded, in batches,:
7 parts of FeSO47H20.
This mixture was then allowed to react for 2 hours, after which
the content of the reactor was poured onto 150 parts of minced ice.
This was then extracted with chloroform and the solvent was distill-
ed. Thereby were obtained:
0.6 parts of unreacted starting product.
After alkalinization and extraction, the solvent was extracted and
; ~ there were obtained:
8.9 parts of 4-methoxy-3-N,N-dimethylamino-hydroxy-acetanilide.
Titre: 93.7%; yield: 74.5%.
EX~MPLE n9:
.
Into an apparatus like that of ex.l, were loaded:
74 parts of concentrated H2SO4.
Maintaining the temperature below 10C, there were added:
11.3 parts of 4-methoxy-benzanilide. Under s~irring, there were
then added:
; l9.1 parts of sulphuric solution of N-Cl-dimethylamine at 20.8%
- conc. equal to about 4 parts at 100%.
Then, in batches, there were loaded 7 parts of FeSO4.7H20.
This mixture was then allowed to react for 2 hours, after which
the content of the reactor was poured onto:
150 parts of minced ice. Thereafter the reaction mass was extract-
ed with chloroform and the solvent was distilled.
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; Thereby were obtained:
11.5 parts of 4-methoxy-3-N,N-dimethylamino-benzanilide.
Titre: 95.5%; yield: 81.4%; m.p, = 161 - 162~5 C.
By proceeding in the same way as in example 3, the following prod-
ucts were prepared:
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