JPH0780845B2 - Method for producing N-substituted maleimides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing N-substituted maleimides. More specifically, the present invention relates to maleic anhydride and amines,
Alternatively, the present invention relates to a method for producing N-substituted maleimides in which a maleic acid monoamide obtained therefrom is dehydrated and subjected to ring-closure imidization in an organic solvent in the presence of a catalyst, and the resulting reaction mixture is washed and then isolated and purified.

N-substituted maleimides are compounds having a very wide range of applications as pharmaceuticals, agricultural chemicals, dyes, polymer raw materials or intermediates thereof.

[Prior art]

Various methods have been conventionally known as methods for producing N-substituted maleimides. For example, there is a method of obtaining N-substituted maleimides by heating maleic acid monoamides (maleamic acids), which are easily obtained from maleic anhydride and amines, at 180 ° C. and performing dehydration cyclization (LEColema).
n et al. J. Org. Chem. 24 135-136 (1959)). However, with this method, the yield of the desired product is as low as 15 to 50%.

A well-known method in the laboratory is a method using a dehydrating agent such as acetic anhydride in the presence of sodium acetate catalyst with maleic anhydride and aniline (Org.Sy.
nth.Coll.vol 5 944 (1973)). Although this method can obtain N-substituted maleimides in a relatively high yield (75 to 80%), it has a disadvantage that the cost of the auxiliary material is added and the manufacturing cost is high because the dehydrating agent is used stoichiometrically. Therefore, it is unsuitable as an industrial manufacturing method.

On the other hand, a method considered to be advantageous as an industrial production method is a method of performing dehydration cyclization of maleic acid monoamides under milder conditions using an efficient dehydration catalyst without using a dehydrating agent. Various attempts have also been made to this method, and a method using an acidic catalyst such as sulfuric acid or sulfonic acid (GB Patent 104102
No. 7), a method using a basic catalyst such as sodium hydroxide and triethylamine (Japanese Patent Publication No. 47-24024), and a method using a heterogeneous catalyst such as an ion exchange resin (Japanese Patent Publication No. 61-85359). ) And many other methods have been proposed. According to these methods, the reaction yield reaches 90% or more, but it is not always sufficient in terms of suppressing side reactions, and in addition to the catalyst, unreacted raw materials and intermediates, various side products are contained in the reaction mixture. Reaction products and polymers are included.

On the other hand, N-substituted maleimides are used for applications such as pharmaceuticals, agricultural chemicals, and monomers, so it is necessary to sufficiently remove impurities. Conventionally, as a method for purifying N-substituted maleimides, the reaction product is neutralized with a dilute alkaline aqueous solution, washed, and then isolated by recrystallization or distillation (Japanese Patent Publication No. 55-4639).
4, JP-A-60-100554, JP-A-62-138468
Or the like, or a method in which the by-products are treated with a strong acid such as sulfuric acid after the reaction to form a by-product into a resin and then separated, followed by washing with water and isolation (Japanese Patent Laid-Open No. 61-22065, 61-204166). ) Etc. have been proposed.

However, in the resinification method, since a large amount of acid is used and an adhesive resinous material must be separated, the separation operation is not easy, and there are problems in terms of economy, operability and waste. In addition, the neutralization washing method has a drawback that the interface is emulsified or insoluble matter is deposited during the separation of the washing water layer, which deteriorates the separability of by-products. This is due to the fact that during the dehydration ring-closure imidization reaction, by-products that have an emulsifying action and by-products that are difficult to dissolve in water and organic solvents are generated by the side-reactions, and this is due to poor reaction selectivity. . Therefore, if an isolation operation such as distillation is carried out while such by-products are mixed, polymerization is likely to occur concurrently, resulting in a decrease in yield and a decrease in purity. There is a problem that the washing process is complicated because the emulsion layer is separated by standing still for a long time, or the emulsion layer is forcibly destroyed by centrifugation or filtration and the insoluble matter is removed. . As described above, the conventional refining technology is still insufficient as a method for industrial implementation.

[Problems to be Solved by the Invention]

The present invention has been made to solve the problems in the conventional method, and its object is to establish a method for producing N-substituted maleimides which can be industrially advantageously carried out, and more specifically, By improving the reaction selectivity and preventing the by-product of the substance that causes the deterioration of separability during washing, it is possible to prevent the occurrence of multiple mergers during purification and to obtain high-purity N-substituted maleimides in high yield. -To establish a method for producing substituted maleimides.

[Means for Solving the Problems]

As a result of earnest studies to achieve the above-mentioned objects, the present inventors have found that when maleic anhydride and primary amines or maleic acid monoamides obtained from them are subjected to dehydration ring-closure imidization, at least one of copper and copper compounds is used. The reaction is carried out in the coexistence of N, then neutralized, washed with water, and then isolated, so that highly pure N-substituted maleimides can be highly purified from the reaction operation without insoluble matters and by-products of the emulsion layer. The present invention has been reached by finding that the yield can be obtained.

The gist of the present invention is as follows.
Maleic anhydride and an aromatic or aliphatic primary amine are heated in an organic solvent in the presence of copper or a copper compound and a catalyst to cause a dehydration ring-closing reaction, and the resulting reaction mixture is diluted with a dilute aqueous alkali solution, water or a dilute solution. A method for producing N-substituted maleimides, which comprises isolating N-substituted maleimides from an organic layer after washing with at least one selected from an aqueous acid solution.

The second invention is a dehydration cyclization by heating maleic acid monoamides obtained by reacting maleic anhydride with an aromatic or aliphatic primary amine in an organic solvent in the presence of copper or a copper compound and a catalyst. An N-substituted maleimide characterized by isolating N-substituted maleimides from an organic layer after reacting and washing the resulting reaction mixture with at least one selected from dilute alkaline aqueous solution, water and dilute aqueous acid solution. It is a manufacturing method of a class.

Embodiments of the present invention will be described below.

Maleic anhydride, which is the starting material of the present invention, may be obtained from any source, and it is convenient to use an appropriately selected maleic anhydride commercially available. Also, the reaction proceeds in the same manner when maleic acid is used,
It is not a good idea because of responsiveness and economy. The other raw material, primary amine, is aromatic primary amines,
For example, aniline, naphthylamine, toluidine, dimethylaniline, chloroaniline, dichloroaniline, hydroxyaniline, nitroaniline, phenylenediamine, etc., preferably aniline, toluidine, chloroaniline, dichloroaniline, hydroxyaniline, nitroaniline, etc. Examples of amines include methylamine, ethylamine, propylamine, butylamine, benzylamine, cyclohexylamine,
Allylamine, ethylenediamine, etc., preferably methylamine, butylamine, cyclohexylamine, etc. can be mentioned, respectively. Maleic anhydride is in the range of 0.8 to 1.5, preferably 0.1, based on 1 mol of the primary amines.
It is recommended to use in the range of 9 to 1.2.

The dehydration cyclization reaction in the present invention is carried out in an organic solvent in the presence of copper or a copper compound and a catalyst.

The first invention according to the present invention is to provide maleic anhydride and the above-mentioned aromatic or aliphatic primary amines in an organic solvent,
It consists of heating in the presence of copper or a copper compound and a catalyst. This reaction can be carried out according to various methods, but a reactor is charged with a predetermined amount of maleic anhydride, a primary amine, an organic solvent, copper or a copper compound and a catalyst,
A method of carrying out the reaction by heating to a predetermined temperature, or charging a predetermined amount of maleic anhydride, an organic solvent, copper or a copper compound and a catalyst into a reactor, heating to a predetermined temperature, and then gradually adding primary amines The method is preferable considering the operation method and the like.

The organic solvent used in the present invention may be any one as long as it dissolves maleic anhydride, aromatic or aliphatic primary amines and maleic acid monoamides, and does not participate in the reaction, but preferably benzene, Examples include aromatic hydrocarbon solvents such as toluene, xylene, ethylbenzene, styrene, and cumene. Particularly preferred are benzene, toluene and xylene.

The amount of the organic solvent used is not particularly limited, but considering the operability and economy, it is preferable to use it so that the product concentration is about 10 to 60%, particularly preferably about 15 to 35%. Further, the reaction can be further promoted by using the above-mentioned aromatic hydrocarbon solvent mixed with an aprotic polar solvent as the organic solvent. Examples of the aprotic polar solvent used in this case include formamide, N-methylformamide, dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane, r-butyrolactone and hexamethylphosphotriamide.
Preferred are dimethylformamide, dimethylacetamide and dimethylsulfoxide.

The amount of aprotic polar solvent used is arbitrary, but
50% or less of the total amount of solvent, preferably about 0.5 to 25%.

The copper or copper compound used in the method of the present invention has an effect of improving the reaction selectivity and suppressing the by-product of the substance causing deterioration of separability of the wash water layer during purification. As copper or a copper compound, copper powder, copper metal such as copper foil, cuprous oxide, cupric oxide, copper hydroxide, copper sulfide and other copper oxides, sulfides and hydroxides, cuprous chloride , Copper salts such as cupric chloride, copper sulfate, copper nitrate, copper phosphate, etc., inorganic copper compounds, and copper complexes such as bisacetylacetonato copper, ethylenediaminetetraacetic acid copper, and organic compounds such as copper acetate. Copper compounds may be mentioned. From the viewpoint of thermal stability and economy, it is preferable to use metallic copper and an inorganic copper compound. These copper or copper compounds may be used alone or in combination of two or more kinds.

The amount of copper or copper compound used is not particularly limited, but it is usually preferable to use it in the range of 5 ppm to 5% by weight with respect to the reaction solution. The amount of copper or copper compound used can be further reduced by using an aprotic polar solvent in combination.

Examples of the catalyst used in the present invention include inorganic acids such as sulfuric acid, sulfurous acid, sulfuric anhydride, phosphoric acid, phosphorous acid, polyphosphoric acid, and organic acids such as benzenesulfonic acid, toluenesulfonic acid, benzenephosphonic acid, trichloroacetic acid, and trifluoroacetic acid. Acid, triethylamine, pyridine, dimethylaniline,
Examples thereof include organic bases such as sodium acetate and strongly acidic ion exchange resins, weakly acidic ion exchange resins, ion exchange resins such as weakly basic ion exchange resins, but preferably sulfuric acid, phosphoric acid, benzenesulfonic acid, toluenesulfonic acid. , And ion exchange resins. The amount of catalyst used is not particularly limited, but is usually in the range of 0.05% to 40% by weight, preferably 0.2% to 25% by weight, based on the reaction solution.
It is good to use in the range of.

The reaction temperature in the method of the present invention is usually in the range of 50 to 200 ° C, preferably 70 to 160 ° C. The reaction pressure is
There is no particular limitation, and it is widely used over normal pressure, increased pressure, and reduced pressure. The reaction time depends on the raw material concentration, catalyst amount, solvent,
Although it depends on the conditions such as reaction temperature, it is usually in the range of 0.5 to 10 hours.

The reaction mixture containing the N-substituted maleimides thus obtained is first washed, and then the N-substituted maleimides are isolated and purified from the obtained organic layer.

The washing of the reaction mixture in the present invention is performed once or more with at least one selected from dilute alkaline aqueous solution, water and dilute acidic aqueous solution. As the dilute alkaline aqueous solution, an aqueous solution of an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate can be used, but preferably an aqueous solution of sodium or potassium hydroxide, carbonate or hydrogen carbonate is used. is there. Examples of the dilute acidic aqueous solution include aqueous solutions of sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, hydrochloric acid, benzenesulfonic acid, toluenesulfonic acid, and the like, with sulfuric acid or phosphoric acid being preferred.

The amount of these dilute alkaline aqueous solution, water, and dilute acidic aqueous solution used is not particularly limited, but may be 10 to 10 times the reaction mixture liquid amount.
About 0% is preferable. The pH of the water layer after washing is 0.5-
It is good to carry out so as to be in the range of 8, preferably 1.5 to 7. The washing temperature is in the range of 20 to 90 ° C, preferably 30 to 70 ° C.

As a washing operation, a washing aqueous solution is added to the reaction mixture, and the mixture is mixed and stirred for 5 minutes to 1 hour, and then allowed to stand to separate into two layers. At this time, the conventional method has remarkably poor separability and forms a heterogeneous layer containing a large amount of emulsion and insoluble matter at the bilayer interface. Forced separation of emulsion and insoluble matter due to filtration was necessary. However, according to the method of the present invention, not only is the operability remarkably improved because the two layers are completely separated in a very short time (usually within 1 hour), but also a high yield is obtained and insoluble matter is not mixed. Less N-
A substituted maleimide-containing organic layer can be obtained. Copper or a copper compound has a favorable effect not only on the selectivity of the reaction but also on the separability of the washing water layer, so that it may be added if necessary during washing.

Then, from the organic layer obtained by such a washing operation, N
-The substituted maleimides are isolated according to known recrystallization or distillation methods.

In the case of the recrystallization method, it is preferable to use an alcohol solvent such as methanol, ethanol or isopropanol or an aromatic solvent such as benzene, toluene, xylene or styrene as a solvent for recrystallization separation.

Further, in the case of the distillation method, it is preferable to carry out under normal pressure or reduced pressure. Since N-substituted maleimides have polymerizability, distillation at a temperature as low as possible is preferable, and distillation under a reduced pressure of usually 20 mmHg or less, preferably 10 mmHg or less is preferable.

In a second aspect of the present invention, a maleic acid monoamide obtained by reacting the above-mentioned maleic anhydride with an aromatic or aliphatic primary amine is subjected to a dehydration cyclization treatment. The chemical reaction treatment is carried out in the same manner as in the case of the first invention. In this case, maleic acid monoamides can be subjected to a dehydration cyclization treatment without being isolated from the reaction product.

The synthesis reaction of maleic acid monoamides is preferably carried out in an organic solvent. As the organic solvent, the above-mentioned aromatic hydrocarbon solvent or a mixture thereof with an aprotic polar solvent is used. This reaction easily proceeds at a reaction temperature of about 150 ° C or lower without using a catalyst. The suitable reaction temperature is from room temperature to 100 ° C. The reaction time varies depending on the reaction temperature and solvent, but 0.5 to 24 hours is suitable.

The washing treatment of the reaction mixture obtained by the dehydration cyclization reaction and the isolation treatment of the N-substituted maleimides can be carried out in the same manner as in the case of the first invention.

Since both the raw material and the product in the method of the present invention have a polymerization-active double bond, it is effective to use a polymerization inhibitor in the reaction and purification steps, and the effect of the present invention has no effect. Hydroquinone as a polymerization inhibitor,
Methoxyphenol, t-butylcatechol, phenothiazine, thiourea, hydroxyquinoline, cuperone and N-nitrosodiphenylamine are effective.

Hereinafter, the configuration and effects of the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Maleic anhydride 107.8 gr, toluene 400 ml dimethylformamide 25 ml, p-toluenesulfonic acid 5.0 gr, copper sulfate 0.1 gr were placed in a reactor equipped with a reflux condenser equipped with a water separator, a thermometer, a stirrer and a dropping funnel. And p-methoxyphenol 0.2
Charge gr and dissolve under heating with stirring. Then, 93.1 gr of aniline was dropped from the dropping funnel, and the mixture was reacted for 3 hours under reflux of the solvent. Water generated during the reaction is removed from the water separator.
After the reaction was completed, the reaction solution was analyzed by gas chromatography, and it was confirmed that 172.1 g of N-phenylmaleimide was produced. The reaction yield was 99.4%.

Next, the reaction solution was cooled to 60 ° C., 200 gr of a 6% sodium carbonate aqueous solution was added thereto, and the mixture was stirred and mixed for 20 minutes, and allowed to stand for 20 minutes, and the aqueous layer separated into two layers was removed. 50 organic layers obtained
It was kept at ℃ and washed again with 100 gr of diluted sulfuric acid aqueous solution adjusted to pH 2 in the same manner to separate the aqueous layer. In both of these two washing operations, neither emulsion layer nor insoluble matter was formed at the interface at the time of separation, and both the organic layer and the aqueous layer were uniform transparent liquids. After the organic layer after washing was desolvated at 130 to 20 mmHg, the bath temperature was 160 ° C,
Distillation was performed at a reduced pressure of 9 mmHg for 3 hours. As a result 165.2
N-phenylmaleimide of gr was obtained (melting point 89-90 ° C)
Pale yellow solid, yield 95.4%, purity 99.9% by gas chromatography).

Comparative Example 1 The procedure of Example 1 was repeated except that copper sulfate was not added, and the reaction yield was 96.1%.
N-phenylmaleimide was obtained (pale yellow solid having a melting point of 80 to 90 ° C., yield 74.6%, purity 99.6% by gas chromatography). During the washing operation, an emulsion layer containing insoluble matter was produced in 15 ml in the first washing and 120 ml in the second washing.

Comparative Example 2 The procedure of Example 1 was repeated except that dimethylformamide and copper sulfate were not added, and the reaction yield was 87.4.
%, A yellow slurry reaction solution was obtained, but in the next washing step, the whole became an emulsion solution containing yellow-white insoluble matter, and the experiment was interrupted because the aqueous layer hardly separated.

Comparative Example 3 Example 1 except that dimethylformamide was not added.
When the completely same operation was performed, the reaction yield was 87.9%,
4.4 gr of N-phenylmaleimide was obtained (melting point 89-9)
Light yellow solid at 0 ° C, yield 60.3%, purity 99.8%). In addition,
During the washing operation, the emulsion layer containing insoluble matter was 12 ml in the first washing and 8 ml in the second washing.

Example 2 A reactor similar to that used in Example 1 was charged with maleic anhydride 103.0 gr,
Xylene 200 ml, dimethyl sulfoxide 10 ml, 98% sulfuric acid 3.0
Charge gr, copper powder 0.05gr and hydroquinone 0.1gr and heat to dissolve under stirring. Next, aniline from the dropping funnel
93.1 gr was added dropwise, and the mixture was reacted under solvent reflux for 2 hours. Water generated during the reaction is removed from the water separator. After the reaction was completed, the reaction solution was analyzed by gas chromatography.
Formation of 70.0 g of N-phenylmaleimide was confirmed.
The reaction yield at this time was 98.2%.

Next, the reaction solution was cooled to 50 ° C., 200 gr of 4.5% aqueous sodium hydroxide solution was added, and the mixture was stirred and mixed for 20 minutes, then left standing for 10 minutes, and the aqueous layer separated into two layers was removed. The resulting organic layer is at 50 ° C
Then, the mixture was washed again with 100 gr of dilute phosphoric acid aqueous solution adjusted to pH 1.5, and the aqueous layer was separated. No formation of emulsion layer or insoluble matter was observed during washing and separation. The organic layer after washing is desolvated at 130 to 20 mmHg, 400 ml of isopropanol heated to 70 ° C is added, and the mixture is dissolved at 70 to 75 ° C. Then cool to 10 ° C with slow stirring. The precipitated crystals were separated by filtration and washed with 100 ml of isopropanol.
The reconstituted mother liquor and washed isopropanol were combined, concentrated to about 50 ml, cooled to 10 ° C. again, and the precipitated crystals were filtered and washed to obtain a second crystal. 70 ° C for 1st and 2nd crystals, 1
After drying in hot air for 16 hours, 163.1gr of N-phenylmaleimide was obtained (pale yellow solid with melting point 89-90 ℃, yield 94.2%, purity 9
9.9%).

Examples 3 to 4 The same as Example 1 except that o-chloroaniline 127.6 gr or o-toluidine 107.2 gr was used as the primary amine and cupric oxide 0.1 gr was used as the copper compound, and the distillation pressure was changed. When the operation was performed, the results shown in the following table were obtained.

Example 5 A reactor similar to that of Example 1 was charged with maleic anhydride 107.8 gr,
Ruene 400ml, Dimethylformamide 25ml, Ion exchange tree
Fat Amber List 15 (Made by Rohm & Haas) 50gr, vinegar
Acid copper 0.2gr and p-methoxyphenol 0.2gr were charged,
Heat and dissolve under stirring. Next, from the dropping funnel, n-bu
Chillamine 73.1gr was added dropwise and the mixture was reacted under solvent reflux for 6 hours.
Let Water generated during the reaction is removed from the water separator. reaction
After completion, cool to 60 ° C, separate the catalyst and wash with toluene.
To do. Gas chromatographic analysis gave a reaction yield of 8
It was 4.7%.

Next, the reaction solution was kept at 60 ° C, and a 6% sodium carbonate aqueous solution 30
It was washed twice as in Example 1 using 0 ml and 100 ml of a dilute sulfuric acid aqueous solution adjusted to pH 2. No formation of emulsion layer or insoluble matter was observed during washing and separation. The obtained organic layer was desolvated at 130 to 20 mmHg, and then distilled at a bath temperature of 90 ° C. and a reduced pressure of 6 mmHg for 3 hours. As a result, 123.5gr N-
n-Butylmaleimide was obtained (boiling point 86-89 ° C / 6mmHg
Colorless transparent liquid, yield 80.6%, purity 99.5%).

Example 6 107.8 gr of maleic anhydride, 400 ml of toluene, 25 ml of dimethylformamide, 0.1 gr of copper sulfate and 0.2 gr of p-methoxyphenol were charged into the same reactor as in Example 1 and dissolved with stirring. Then, 93.1 gr of aniline was added dropwise from the dropping funnel at a reaction temperature of 40 ° C. or lower for 1 hour, and further aged under stirring at 40 ° C. for 1 hour. After adding 5.0 g of p-toluenesulfonic acid to the obtained maleaniline acid slurry solution, dehydration reaction was carried out for 3 hours while azeotropically removing produced water under reflux. The reaction yield by gas chromatography analysis is 93.5.
%Met.

Then, the reaction solution was post-treated in the same manner as in Example 1 to obtain 154.4 gr of N-phenylmaleimide (a pale yellow solid having a melting point of 89 to 90 ° C., yield 89.2%, purity 99.8%). .
During the washing operation, no emulsion layer was found in the first and second washings.

Comparative Example 4 The same operation as in Example 6 was carried out except that copper sulfate was not added, and a reaction yield of 90.8% and 116.8 gr of N-phenylmaleimide were obtained (melting point: 88 to 90 ° C.). Pale yellow solid, yield 67.5%, purity 99.1%). In addition, the emulsion layer containing insoluble matter during the washing operation was 60 ml in the first washing,
The second wash produced 120 ml.

〔The invention's effect〕

According to the method of the present invention, highly pure N-substituted maleimides can be obtained in high yield. Further, the present invention has the following advantages.

i) Separability at the time of cleaning is remarkably improved and operability is improved.

ii) The yield in the reaction and purification is improved.

iii) Product purity is improved.

iv) Purification is easy because byproducts are reduced.

v) Polymerization during purification can be prevented.

Front page continuation (72) Inventor Ken Narita 10-1 Daikokucho, Tsurumi-ku, Yokohama-shi, Kanagawa Nitto Chemical Industry Co., Ltd. (72) Yuya Yano 10-1 Daikoku-cho, Tsurumi-ku, Yokohama-shi, Kanagawa Toei Chemical Co., Ltd. Examiner Shoei Hoshino

Claims (2)

[Claims] 1. Maleic anhydride and an aromatic or aliphatic primary amine in the presence of copper or a copper compound and a catalyst,
After dehydration cyclization by heating in an organic solvent, the resulting reaction mixture is washed with at least one selected from dilute aqueous alkali solution, water and dilute aqueous solution, and then N-substituted maleimides are isolated from the organic layer. A method for producing N-substituted maleimides, comprising: 2. A dehydration cyclization reaction by heating maleic acid monoamide obtained by reacting maleic anhydride with an aromatic or aliphatic primary amine in an organic solvent in the presence of copper or a copper compound and a catalyst. N-substituted maleimides characterized by isolating N-substituted maleimides from an organic layer after washing the resulting reaction mixture with at least one selected from dilute alkaline aqueous solution, water and dilute aqueous acid solution. Manufacturing method.