Note: Descriptions are shown in the official language in which they were submitted.
1 3341 02
Production of Aniline ComPound
This application has been divided out of Canadian Patent
Application Serial No. 576,093 filed August 30, 1988.
The present invention relates to the production of an
aniline compound. More particularly, it relates to the
production of an aniline compound of the formula (I):
Cl ~ NH2 (I)
2 5 ll(n)
The aniline compound of the formula (I) is suitable for
use in the production of N-[4-chloro-2-fluoro-5-(pentyloxy-
carbonylmethyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide
represented by the formula:
Cl ~ N ~ (A)
O
2 5 11( )
This compound is described in U.S. patent 4,670,046, and is
Per se useful as a herbicide. In the U.S. patent, the
compound (A) is produced by reacting N-(4-chloro-2-fluoro-5-
hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide with n-pentyl
haloacetate in an inert solvent. On the other hand,
EP-B-0049508 discloses production of some tetrahydro-
phthalimide compounds by the reaction of an aniline compound
with 3,4,5,6-tetrahydrophthalic anhydride in an inert solvent.
However, these conventional processes cannot provide the
compound (A) in a satisfactorily high yield with a
sufficiently high purity. Hence, a troublesome operation,
~ - 2 - 1 3 3 4 1 02
e.g. chromatography, is needed to separate or purify the
product. In addition, use of a large amount of an organic
solvent which is not easily recovered or has an unpleasant
odour is required. Accordingly, the conventional processes
are not suitable for practical adoption on an industrial
scale.
As a result of extensive study, it has been found that
the compound (A) can be obtained in high yield with a high
purity by reacting an aniline compound of the formula (I):
Cl~ NH
~ (I)
CH2COOC5Hll (
with 3,4,5,6-tetrahydrophthalic anhydride in the presence of a
catalyst system consisting of a nitrogen-containing base and a
lower aliphatic acid.
The reaction is carried out in an organic solvent, for
example, hydrocarbons (e.g. toluene, xylene, benzene),
halogenated hydrocarbons (e.g. l,2-dichloroethane,
chlorobenzene, chloroform, carbon tetrachloride) or ketones
(e.g. methyl isobutyl ketone) at a temperature of about 50C
to the boiling temperature of the solvent, preferably about
80 to 120C, for a period of about 1 to 10 hours.
As the nitrogen-containing base, there may be exemplified
secondary amines (e.g. diethylamine, dibutylamine, diethanol-
amine), tertiary amines (e.g. triethylamine, tributylamine,
triethanolamine, N,N-dimethylaniline, N,N-diethylaniline),
nitrogen-containing heterocyclic compounds (e.g. pyridine,
piperidine, imidazole, morpholine, quinoline, N,N-dimethyl-
aminopyridine), etc. Examples of the lower aliphatic acid are
acetic acid, propionic acid, butyric acid, etc.
The amount of 3,4,5,6-tetrahydrophthalic anhydride to be
used is usually from about 1.0 to 2.0 equivalents, preferably
~ 334~ 0~
-- 3
from about 1.0 to 1.3, to one equivalent of the compound (I).
The amount of nitrogen-containing base may be from about 0.01
to 0.5 equivalents, preferably from about 0.05 to 0.1
equivalents, to 1 equivalent of the compound (I), and that of
the lower aliphatic acid may be from about 1.0 to 5.0
equivalents, preferably from about 1.0 to 2.0, to one
equivalent of the nitrogen-containing base.
The reaction vessel may be equipped with a water
separator so as to remove water produced as a by-product in
the reaction by its azeotropic distillation with the solvent,
thereby resulting in acceleration of the reaction. In that
case, the reaction may be effected under reduced pressure so
that the boiling temperature of the solvent is lowered, and
azeotropic distillation may be achieved at any desired
temperature.
After completion of the reaction, the reaction mixture
may be subjected to ordinary post-treatment, e.g. addition of
water, extraction with a water-immiscible solvent and
concentration to recover the compound (A). Further, after
removal of the solvent from the extract containing the
compound (A), the crude product may be crystallized from water
or its mixture with an alcohol (e.g. methanol, ethanol,
isopropanol), followed by collection of the crystals.
The aniline starting compound (I) of the present
invention is produced by subjecting the corresponding nitro
compound of the formula:
/F
Cl~No2
O (II)
I
CH2COOC5 11 (
to reduction. The present invention is directed to this
process.
1334102
-- 4
The reduction may be accomplished by a Per se
conventional procedure to convert the nitro group into an
amino group, e.g. iron reduction or catalytic reduction.
In the case of iron reduction, the compound (II) is
reacted with iron powder in the presence of an acid catalyst
in an inert solvent, usually at a temperature of room
temperature to the boiling temperature of the solvent,
preferably of about 60 to 90C, for a period of about 0.5 to
24 hours to give the compound (I). Examples of the acid
catalyst include a mineral acid (e.g. hydrochloric acid,
sulfuric acid), an aliphatic acid (e.g. formic acid, acetic
acid), an iron chloride (e.g. ferrous chloride, ferric
chloride), etc. As the solvent, there may be used water or
water mixed with an organic solvent chosen from aromatic
hydrocarbons (e.g. benzene, toluene, xylene), halogenated
hydrocarbons (e.g. dichloroethane, carbon tetrachloride,
chlorobenzene), ketones (e.g. acetone, methyl isobutyl
ketone), ethers (e.g. diethyl ether, tetrahydrofuran,
dioxane), esters (e.g. ethyl acetate), aliphatic hydrocarbons
(e.g. hexane, heptane), aliphatic acids (e.g. formic acid,
acetic acid), etc. The amount of iron powder may be from
about 2.2 to 10 equi~alents, preferably from about 3 to 5
equivalents, to one equivalent of the compound (II). The
amount of the acid catalyst is usually from about 0.01 to 6.0
equivalents to one equivalent of the compound (II). When the
acid catalyst is chosen from mineral acids and aliphatic
acids, it may be used in an excessive amount so that it can
play not only the role of catalyst but also the role of
solvent.
After completion of the reaction, the reaction mixture is
subjected to a per se conventional post-treatment procedure.
For instance, the reaction mixture is filtered, the filtrate
is extracted with an organic solvent and the extract is
concentrated. If desired, the resultant product may be
purified, for instance, by distillation, recrystallization,
silica gel column chromatography or the like.
~ 5 ~ 133410~
In the case of catalytic reduction, the compound (II) is
reduced with hydrogen in the presence of a catalyst in an
inert solvent under a pressure from atmospheric pressure to
30 kg/cm2. Hydrogen is normally used in an amount of 3 to 10
equivalents to one equivalent of the compound (II). The
catalyst may be chosen from nickel, palladium, platinum,
platinum dioxide, rhodium, etc., and its amount is normally
from about 0.001 to 10% by weight, preferably from about
0.1 to 5~ by weight, to the compound (II). When desired,
the catalyst may be used on a carrier material, e.g. activated
carbon or alumina, or in the form of a complex, for instance,
with triphenylphosphine. Examples of the solvent are alcohols
(e.g. methanol, ethanol, isopropanol), aromatic hydrocarbons
(e.g. benzene, toluene, xylene), ketones (e.g. acetone, methyl
isobutyl ketone), ethers (e.g. tetrahydrofuran, dioxane),
aliphatic acids (e.g. acetic acid, propionic acid),
esters (e.g. ethyl acetate), halogenated hydrocarbons
(e.g. dichloroethane, chlorobenzene), water, and their
mixtures. Generally, the reduction is conducted at a
temperature from room temperature to the boiling point of the
solvent, preferably room temperature to 80C, for a period of
about 0.5 to 24 hours. These reaction conditions are,
however, not limitative; for instance, the reaction conditions
may be autogenic when it is performed in an autoclave.
After completion of the reaction, the reaction mixture
is, for instance, filtered to remove the catalyst, and the
filtrate is concentrated to recover the compound (I). When
desired, any purification procedure, e.g. distillation,
recrystallization or column chromatography may be applied to
the product thus obtained.
The compound (II) is novel and may be produced, for
instance, by reacting 2-chloro-4-fluoro-5-nitrophenol with a
haloacetic ester of the formula:
Y-cH2cooc5H11(n) (III)
wherein Y is a chlorine atom or a bromine atom in the presence
of a base, usually in an inert solvent at a temperature from
- 6 - l 3 3 4 1 02
room temperature to the boiling point of the solvent,
preferably about 50 to 90C, for a period of about
0.5 to 24 hours. The compound (III) and the base may be used
respectively in about 1.0 to 2.0 equivalents, preferably about
1.0 to 1.3 equivalents, and in about 1.0 to 2.0 equivalents,
preferably about 1.0 to 1.3 equivalents, to one equivalent of
2-chloro-4-fluoro-5-nitrophenol. Examples of the solvent are
alcohols (e.g. methanol, ethanol, isopropanol), aromatic
hydrocarbons (e.g. benzene, toluene, xylene), halogenated
hydrocarbons (e.g. dichloroethane, carbon tetrachloride,
chlorobenzene), ketones (e.g. acetone, methyl isobutyl
ketone), ethers (e.g. diethyl ether, tetrahydrofuran,
dioxane), nitriles (e.g. acetonitrile), aliphatic hydrocarbons
(e.g. hexane, heptane), dimethylsulfoxide, dimethylformamide,
water, etc. Among them, preferred are polar solvents, e.g.
nitriles and dimethylformamide, mixed solvents, e.g. water-
aromatic hydrocarbons, etc. Examples of the base are alkali
metal hydroxides (e.g. sodium hydroxide, potassium hydroxide),
alkali metal carbonates (e.g. sodium carbonate, potassium
carbonate), alkali metal bicarbonates (e.g. sodium hydrogen
carbonate), alkali metal hydrides (e.g. sodium hydride),
alkali metal alkoxides (e.g. sodium methoxide), organic bases
(e.g. triethylamine, pyridine, dimethylaminopyridine), etc.
When desired, the reaction may be performed in the presence of
a catalyst, for example, a metal salt (e.g. sodium bromide,
potassium bromide, sodium iodide, potassium iodide) or a
quaternary ammonium salt (e.g. tetrabutylammonium chloride) in
an amount of about 0.001 to 0.2 equivalents to one equivalent
of 2-chloro-4-fluoro-5-nitrophenol.
After completion of the reaction, the reaction mixture
may be, for instance, admixed with water and extracted with an
organic solvent, followed by concentration. When desired, any
purification procedure, e.g. distillation or silica gel column
chromatography, may be applied to give the resulting product.
Still, 2-chloro-4-fluoro-5-nitrophenol is known as
disclosed in U.S. patent 4,670,046.
~ ~ 7 - l 3 3 4 1 0 2
Practical and presently preferred embodiments of the
invention and the invention set out in the parent application
are illustratively shown in the following Examples and
Comparative Examples.
Example 1
Preparation of the compound (II):-
A mixture of 2-chloro-4-fluoro-5-nitrophenol (100 g),
anhydrous potassium carbonate (86.6 g) and dimethylformamide
(500 g) was heated at 50C, and amyl 2-chloroacetate (90.2 g)
lo was dropwise added thereto over 30 minutes. The mixture was
allowed to stand at 60C for 4 hours. The reaction mixture
was cooled to room temperature, and water (1500 g) was added
thereto, followed by extraction with ethyl acetate (1500 g).
The organic layer was separated, washed with water and
concentrated under reduced pressure. The residue was
distilled under reduced pressure to give 4-chloro-2-fluoro-5-
(pentyloxycarbonylmethyloxy) nitrobenzene (Compound (II))
(129 g) as a pale yellow oil.
Yield: 77%.
b.p., 160 - 165C/0.7 mmHg.
NMR~ (CDCl3, TMS) (ppm): 7.58 (lH, d, J = 7 Hz),
7.39 (lH, d, J = 10 Hz), 4.80 (2H, s), 4.22 (2H, t, J = 6 Hz),
1.10 - 2.00 (6H, m), 0.91 (3H, t, J = 6 Hz).
Example 2
Preparation of the compound (I):-
A mixture of iron powder (115 g), acetic acid (29 g) and
water (551 g) was heated at 80C, and a solution of the
compound (II) (132 g) in acetic acid (200 g) was dropwise
added thereto over 1 hour, followed by heating under reflux
for 5 hours. The reaction mixture was filtered to remove
insoluble materials, and the filtrate was extracted with ethyl
acetate. The extract was concentrated under reduced pressure.
The residue was distilled off under reduced pressure to give
4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)aniline
(compound (I)) (90 g).
Yield: 75~.
b.p., 145 - 149~C/0.4 mmHg.
-- - 8 - I 334 1 02
m.p., 32 - 34C.
NMR~ (CDCl3, TMS) (ppm): 7.00 (lH, d, J = lO Hz), 6.37
(lH, d, J = 7 Hz), 4.60 (2H, s), 4.20 (2H, t, J = 6 Hz), 3.75
(2H, brs), 1.10 - 1.90 (6H, m) , 0.92 (3H, t, J = 6 Hz).
Example 3
Preparation of the compound (I):
Hydrogen gas (1.3 litres) was introduced into a
mixture of the compound (II) (6.4 g), 5% palladium-carbon
(0.32 g) and toluene (64 g) at room temperature in 1 hour with
stirring. After removal of the catalyst from the reaction
mixture, the solvent was removed under reduced pressure, and
the residue was purified by silica gel column chromatography
to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)-
aniline (3.6 g).
Yield: 62%.
Example 4
Preparation of the compound (A):-
A mixture of the compound (I) (12.0 g), 3,4,5,6-tetra-
hydrophthalic anhydride (7.56 g), piperidine (0.18 g),
propionic acid (0.30 g) and toluene (24 g) was heated under
reflux for 5 hours, during which water, produced as a by-
product, was azeotropically removed. To the reaction mixture,
toluene (24 g) and water (24 g) were added, and the organic
layer was separated and concentrated under reduced pressure.
To the residue, water (18 g) and methanol (33 g) were added,
and the precipitated crystals were collected by filtration to
give N-[4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)-
phenyl]-3,4,5,6-tetrahydrophthalimide (Compound (A)) (16.1 g).
By the use of high speed liquid chromatography, the purity of
the compound (A) as the major product and the amount of the
by-product 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)-
acetanilide (hereinafter referred to as "N-acetyl compound")
as a contaminant were determined according to the inner
standard method and the area comparison method, respectively.
Yield: 92.0%.
Purity: 92.3% (N-acetyl compound content, less
than 0.1%).
1 3341 02
g
NMR~ (CDCl3, TMS) (ppm): 7.22 (lH, d, J = 10 Hz), 6.75
(lH, d, J = 7 Hz), 4.6 (2H, s), 4.1 (2H, t, J = 6 Hz),
2.40 (4H, m), 1.80 (4H, m), 1.10 - 1.80 (6H, m),
0.85 (3H, t, J = 6 Hz).
IR (Nujol*): 1750, 1720 (cm~1).
m.p.: gO - 91C.
ExamPle 5
Preparation of the compound (A):-
A mixture of the compound (I) (12.0 g), 3,4,5,6-
tetrahydrophthalic anhydride (7.56 g), triethylamine
(9.42 g), acetic acid (0.75 g) and 1,2-dichloroethane (24 g)
was heated under reflux for 8 hours. The reaction mixture was
washed with water (24 g). The organic layer was separated and
treated as in Example 4 to give the compound (A) (16.2 g).
Yield: 92.5%.
Purity: 94.7% (N-acetyl compound content, 0.1%).
Example 6
Preparation of the compound (A):-
A mixture of the compound (I) (12.0 g), 3,4,5,6-tetra-
hydrophthalic anhydride (7.56 g), piperidine (0.36 g), acetic
acid (0.5 g) and toluene (24 g) was refluxed at 88 to 92C
under a pressure of about 300 mmHg for 4 hours, during which
water was azeotropically removed. The reaction mixture was
then treated as in Example 4 to give the compound (A)
(16.7 g).
Yield: 95.2%.
Purity: 97.0% (N-acetyl compound content, less
than 0.1%).
ComParative Example 1
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-
3,4,5,6-tetrahydrophthalimide (3 g) in dimethylformamide
(100 ml), anhydrous potassium carbonate (0.8 g) and then amyl
chloroacetate (1.9 g) were added, and the resultant mixture
was heated at 70 to 80~C for 3 hours. The reaction mixture
was cooled to room temperature, admixed with water and
*Trade mark
- - lo - 1 334 1 0~
extracted with diethyl ether. The etheral layer was washed
with water, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography to give the compound (A)
(1.8 g).
Yield: 42.0%.
Purity: 98.0%.
Comparative Example 2
A mixture of the compound (I) (12.0 g), 3,4,5,6-
tetrahydrophthalic anhydride (7.56 g) and acetic acid (50 g)
was heated at 90 to 95C for 7 hours. The reaction mixture
was cooled to room temperature, and water (75 g) was added
thereto. The precipitated crystals were collected by
filtration to give the compound (A) (15.7 g).
Yield: 89.3%.
Purity: 88.7% (N-acetyl compound content, 5.1%).
ComParative Example 3
A mixture of the compound (I) (12.0 g), 3,4,5,6-
tetrahydrophthalic anhydride (7.56 g) and acetic acid (50 g)
was heated under reflux for 2 hours. The reaction mixture was
cooled to room temperature, and water (75 g) was added
thereto. The precipitated crystals were collected by
filtration to give the compound (A) (15.4 g).
Yield: 88.0%.
Purity: 87.0% (N-acetyl compound content, 7.2%).
ComParative ExamPle 4
A mixture of the compound (I) (12.0 g), 3,4,5,6-tetra-
hydrophthalic anhydride (7.56 g) and toluene (50 g) was heated
under reflux for 12 hours. Analysis by high speed liquid
chromatography revealed the presence of 20% of the compound
(I) as unreacted. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by silica gel
column chromatography to give the compound (A) (10.9 g).
Yield: 62.0%.
Purity: 98.0%.
11 - 1 334 1 02
ComParative ExamPle 5
A mixture of the compound (I) (12.0 g) and 3,4,5,6-
tetrahydrophthalic anhydride (7.56 g) was heated at 85 to 90C
for 10 hours. Analysis by high speed liquid chromatography
revealed the presence of 72% of the compound (A) and 9% of the
compound (I) as unreacted together with many other impurities.
The reaction mixture was purified by silica gel column
chromatography to give the compound (A) (11.4 g).
Yield: 65.0%.
Purity: 98.2%.
Comparative Example 6
A mixture of the compound (I) (12.0 g), 3,4,5,6-tetra-
hydrophthalic anhydride (7.56 g), triethylamine (0.4 g) and
toluene (50 g) was heated under reflux for 10 hours. The
reaction mixture was cooled to room temperature and washed
with water. The toluene layer was separated and concentrated
under reduced pressure. Analysis of the resulting product
revealed that it contained the compound (A) in a purity of
about 77% and a large amount of a compound of the following
formula as the impurity:
~ F
o
O
2 5 ll(n)
Purification of the above product by silica gel column
chromatography gave the compound (A) (13.7 g).
Yield: 77.9%.
Purity: 98.2%.
comParative Example 7
A mixture of the compound (I) (12.0 g), 3,4,5,6-tetra-
hydrophthalic anhydride (7.56 g), p-toluenesulfonic acid
~ - 12 - l 334 1 0~
(0.4 g) and toluene (24 g) was refluxed for 10 hours, during
which water was azeotropically removed. The reaction mixture
was treated in the same manner as in Example 4 to give
the compound (A) (15.6 g).
Yield: 88.9%.
Purity: 80.9~.
Still, the product contained a large amount of a compound
of the formula as the impurity:
cl~NH-co-cH2o~
CH2COOC5 11( ) F o
