CA1334102C - Production of aniline compound - Google Patents
Production of aniline compoundInfo
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- CA1334102C CA1334102C CA000616768A CA616768A CA1334102C CA 1334102 C CA1334102 C CA 1334102C CA 000616768 A CA000616768 A CA 000616768A CA 616768 A CA616768 A CA 616768A CA 1334102 C CA1334102 C CA 1334102C
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Abstract
The present invention is directed to a process for preparing a compound of the formula:
(I) which process comprises reducing a compound of the formula:
The compound of the present invention is suitable for use in the preparation of compounds of the formula:
(I) which process comprises reducing a compound of the formula:
The compound of the present invention is suitable for use in the preparation of compounds of the formula:
Description
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~
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.
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.
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%).
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%.
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
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~
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.
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.
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%).
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%.
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
Claims
1. A process for preparing a compound of the formula:
(I) which comprises subjecting a compound of the formula:
(II) to reduction.
(I) which comprises subjecting a compound of the formula:
(II) to reduction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000616768A CA1334102C (en) | 1987-09-01 | 1993-11-09 | Production of aniline compound |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21860887 | 1987-09-01 | ||
| JP218608/1987 | 1987-09-01 | ||
| JP63107008A JPH0825970B2 (en) | 1987-09-01 | 1988-04-27 | Process for producing tetrahydrophthalimide compound, intermediate thereof and process for producing the intermediate |
| JP107008/1988 | 1988-04-27 | ||
| CA000576093A CA1328271C (en) | 1987-09-01 | 1988-08-30 | Production of tetrahydrophthalimide compound |
| CA000616768A CA1334102C (en) | 1987-09-01 | 1993-11-09 | Production of aniline compound |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576093A Division CA1328271C (en) | 1987-09-01 | 1988-08-30 | Production of tetrahydrophthalimide compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1334102C true CA1334102C (en) | 1995-01-24 |
Family
ID=27168035
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000616768A Expired - Lifetime CA1334102C (en) | 1987-09-01 | 1993-11-09 | Production of aniline compound |
| CA000616765A Expired - Lifetime CA1334101C (en) | 1987-09-01 | 1993-11-09 | Production of 4-chloro-2-fluoro-5- (pentyloxycarbonylmethyloxy)nitrobenzene |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000616765A Expired - Lifetime CA1334101C (en) | 1987-09-01 | 1993-11-09 | Production of 4-chloro-2-fluoro-5- (pentyloxycarbonylmethyloxy)nitrobenzene |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1334102C (en) |
-
1993
- 1993-11-09 CA CA000616768A patent/CA1334102C/en not_active Expired - Lifetime
- 1993-11-09 CA CA000616765A patent/CA1334101C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA1334101C (en) | 1995-01-24 |
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