Preparation method of N-methylmaleimide

Abstract

The invention relates to the technical field of chemical synthesis, and particularly provides a preparation method of N-methylmaleimide, which comprises the following steps: S1, carrying out ring-opening reaction on maleic anhydride and methylamine to generate 4-(methylamino)-4-oxobutyl-2-olefine acid; and S2, carrying out a condensation reaction on the 4-(methylamino)-4-oxobutyl-2-olefine acid, so as to generate the N-methylmaleimide. According to the preparation method disclosed by the embodiment of the invention, methylamine is used for carrying out ring-opening reaction, the obtained intermediate is good in purity and high in yield, and post-treatment is simple and easy to operate.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound preparation, and more specifically, relates to a preparation method of N-methylmaleimide. Background Art

[0002] Due to its unique chemical structure and reactive chemical properties, N-methylmaleimide plays an irreplaceable and important role in many fields.

[0003] In the field of polymer material modification, as an efficient modification monomer, N-methylmaleimide can significantly improve the performance of materials. Take polyvinyl chloride (PVC) as an example. Traditional PVC materials have problems such as poor thermal stability and insufficient mechanical strength. When N-methylmaleimide is introduced, it can react chemically with the PVC molecular chain and be connected to the molecular chain by covalent bonds, thereby changing the structure and properties of the molecular chain.

[0004] In the field of biomedical intermediates, N-methylmaleimide also plays a key role. In the synthesis process of many drug molecules, N-methylmaleimide participates in the reaction as an important intermediate. Take the synthesis of certain anti-cancer drugs as an example. N-methylmaleimide can react with compounds containing amino or mercapto groups to construct drug precursors with specific structures and functions.

[0005] It is particularly worth mentioning that in the targeted drug delivery system, N-methylmaleimide shows great application potential as a thiol reaction reagent. In cancer treatment, how to accurately deliver drugs to tumor cell sites while reducing damage to normal cells has always been the focus of research in the medical field.

[0006] Currently, the reported preparation methods of N-methylmaleimide mainly fall into the following two categories.

[0007] The first one: Using maleic anhydride as the starting material, reacting with methylamine under the condition of dichloromethane as the solvent to obtain a 4-(methylamino)-4-oxobut-2-enoic acid intermediate; further carrying out a ring-closure reaction with acetic acid as the condensation reagent. During the reaction process, the reaction temperature needs to be raised above 110°C, and even around 140°C in some special cases. Such high-temperature conditions will cause N-methylmaleimide to polymerize, resulting in low yield and high purification difficulty; at the same time, the high-temperature conditions pose high requirements for the reaction equipment. Special high-temperature-resistant materials are required to manufacture the reaction kettle and related pipelines, which not only greatly increases the equipment purchase cost but also makes the equipment maintenance and repair difficult. Regular inspections and repairs are required to ensure the safe operation of the equipment, thereby further increasing the production cost.

[0008] The second method: Starting from maleic anhydride as the raw material, it undergoes a ring-opening reaction with methylamine in acetic acid as the solvent to obtain the intermediate 4-(methylamino)-4-oxobut-2-enoic acid; further, intramolecular dehydration reaction is carried out with 2 equivalents of concentrated sulfuric acid at 60 °C to obtain N-methylmaleimide. Although this synthesis method can reduce the harshness of the reaction temperature, the concentrated sulfuric acid used has strong corrosiveness, which poses high requirements for the reaction equipment; at the same time, there are certain safety risks in the reaction under strong acid conditions. Once the equipment fails or the operation is improper, serious accidents such as leakage may occur, causing great harm to personnel and the environment. Summary of the Invention

[0009] In view of this, the purpose of the present invention is to provide a preparation method of N-methylmaleimide with high safety, simple operation and suitable for industrial production.

[0010] To solve the above technical problems, the present invention adopts the following technical solutions:

[0011] The preparation method of N-methylmaleimide according to the embodiment of the present invention includes:

[0012] Step S1, making maleic anhydride and methylamine undergo a ring-opening reaction to generate 4-(methylamino)-4-oxobut-2-enoic acid;

[0013] Step S2, making the 4-(methylamino)-4-oxobut-2-enoic acid undergo a condensation reaction to generate N-methylmaleimide. The condensation reaction is carried out under the action of a condensing agent, and the condensing agent is selected from one or more of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, tripyrrolidinophosphonium bromide hexafluorophosphate, and n-butylphosphoric anhydride.

[0014] In some embodiments of the present invention, the ring-opening reaction is carried out in a first solvent in the presence of an inorganic base. Among them, the first solvent is one or more of methanol, ethanol, water, etc., and the inorganic base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, etc.

[0015] In some embodiments of the present invention, step S1 includes:

[0016] Adding maleic anhydride and sodium hydroxide to water and dissolving them fully, and adding an aqueous solution of methylamine thereto to carry out the ring-opening reaction.

[0017] Furthermore, the molar ratio of maleic anhydride, methylamine, and sodium hydroxide is 1:(2 - 4):(1 - 2), the reaction temperature of the ring-opening reaction is 10 - 30 °C, and the reaction time is 1 - 4 hours.

[0018] In some embodiments of the present invention, step S1 further includes:

[0019] After the ring-opening reaction is completed, cool the reaction system of the ring-opening reaction, and perform suction filtration. Wash the filter cake with ethanol and then dry it to obtain the 4-(methylamino)-4-oxobut-2-enoic acid.

[0020] In some embodiments of the present invention, step S2 includes:

[0021] Add the 4-(methylamino)-4-oxobut-2-enoic acid to dichloromethane, and dropwise add the condensing agent to the reaction system at a dropping temperature of 5-10°C; after the condensing agent is added dropwise, raise the temperature to 20-30°C to carry out the condensation reaction, and the reaction time is 2-8 hours.

[0022] In some embodiments of the present invention, the molar ratio of 4-(methylamino)-4-oxobut-2-enoic acid to the condensing agent is 1:(1.05-1.1).

[0023] In some embodiments of the present invention, step S2 further includes:

[0024] After the condensation reaction is completed, pour the reaction solution into water, and stir at 20-30°C for 1-3 hours and then separate the liquid. Extract the aqueous phase with dichloromethane, then dry it with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain the crude product;

[0025] Recrystallize the crude product with ethyl acetate / petroleum ether to obtain purified N-methylmaleimide.

[0026] At least one of the above technical solutions of the present invention has the following beneficial effects:

[0027] According to the preparation method of the embodiment of the present invention, the second-step condensation reaction is carried out under the action of a condensing agent, the reaction conditions are mild, the yield is high, and the post-treatment and purification are convenient, with few impurities;

[0028] Furthermore, the first-step ring-opening reaction is carried out in an aqueous sodium hydroxide solution, avoiding the use of organic solvents, reducing the generation of three wastes, and being environmentally friendly;

[0029] Furthermore, the chemicals used in the synthesis route are all conventional reagents, greatly improving the safety of the reaction and operation. Specific Embodiments

[0030] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the described embodiments of the present invention fall within the scope of protection of the present invention.

[0031] First, the preparation method of N-methylmaleimide according to the embodiments of the present invention will be specifically described below.

[0032] The preparation method of N-methylmaleimide according to the embodiments of the present invention includes:

[0033] Step S1: React maleic anhydride with methylamine to undergo a ring-opening reaction to form 4-(methylamino)-4-oxobut-2-enoic acid;

[0034] Step S2: React the 4-(methylamino)-4-oxobut-2-enoic acid to undergo a condensation reaction to form N-methylmaleimide. The condensation reaction is carried out under the action of a condensing agent, and the condensing agent is selected from one or more of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, tripyrrolidinylphosphonium bromide hexafluorophosphate, and n-butylphosphoric anhydride.

[0035] According to the preparation method of the embodiments of the present invention, starting from maleic anhydride, first react it with methylamine to obtain an intermediate, and then make the intermediate undergo a condensation reaction under the action of a condensing agent to obtain the target product N-methylmaleimide. The reaction conditions of the second-step condensation reaction are mild, the yield is high, and the post-treatment is simple and easy to operate.

[0036] Next, a detailed description will be given of the ring-opening reaction (i.e., step S1) and the condensation reaction (i.e., step S2).

[0037] (I) Ring-opening reaction

[0038] That is to say, in the preparation method of the present invention, first react maleic anhydride with methylamine to undergo a ring-opening reaction to form 4-(methylamino)-4-oxobut-2-enoic acid as an intermediate.

[0039] In some embodiments of the present invention, the ring-opening reaction is carried out in a first solvent in the presence of an inorganic base.

[0040] Among them, the first solvent is one or more of methanol, ethanol, water, etc.

[0041] The inorganic base may be, for example, one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, etc. The use of an inorganic base aqueous solution can avoid the use of an organic solvent while ensuring the ring-opening reaction, thereby reducing three wastes and being environmentally friendly.

[0042] Among them, sodium hydroxide is preferred. Sodium hydroxide is used as a base, the alkalinity is suitable, and the yield is significantly improved compared to other bases; at the same time, the price of sodium hydroxide is relatively cheap.

[0043] In some embodiments of the invention, the ring-opening reaction comprises:

[0044] Maleic anhydride and sodium hydroxide are added to water to fully dissolve, and a methylamine aqueous solution is added thereto to cause the ring-opening reaction.

[0045] Specifically, the reaction formula of the ring-opening reaction is shown in the following formula (1):

[0046]

[0047] In some embodiments of the present invention, the molar ratio of maleic anhydride, methylamine, and sodium hydroxide is 1:(2-4):(1-2). Using excess methylamine and sodium hydroxide is beneficial to promote the reaction and improve the yield, preferably 1:3:1.5.

[0048] The reaction temperature of the ring-opening reaction can be set to 10-30°C, for example, room temperature; the reaction time is 1-4 hours, for example, 3 hours. The reaction conditions are mild and easy to operate, and there is no special requirement for equipment, which is suitable for industrial production needs.

[0049] In some embodiments of the present invention, after the ring-opening reaction is completed, post-treatment is also performed to separate the intermediate. The post-treatment may specifically include:

[0050] After the ring-opening reaction is completed, the reaction system of the ring-opening reaction is cooled and filtered, and the filter cake is washed with ethanol and then dried to obtain 4-(methylamino)-4-oxobut-2-enoic acid.

[0051] That is, the present invention uses methylamine to cause a ring-opening reaction, and the ring-opening reaction is carried out in an aqueous solution, so that the obtained intermediate 4-(methylamino)-4-oxobut-2-enoic acid can be easily separated, and has good purity and high yield.

[0052] (ii) Condensation reaction

[0053] That is, after the intermediate 4-(methylamino)-4-oxobut-2-enoic acid is obtained through the ring-opening reaction, it only needs to undergo an intramolecular condensation reaction to obtain the target product N-methylmaleimide.

[0054] In some embodiments of the present invention, the condensation reaction is carried out under the action of a condensing agent. By using a condensing agent, the progress of the condensation reaction can be promoted, the reaction conditions are milder, high temperature can be avoided, and the yield is also higher.

[0055] Among them, as the condensing agent, one or more of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, tripyrrolidinophosphonium bromide hexafluorophosphate, and n-butylphosphoric anhydride can be selected. Among them, n-butylphosphoric anhydride (50% ethyl acetate solution) has low danger, high activity, is easy to operate, and is convenient for post-treatment purification with few impurities, so it is preferred.

[0056] In some embodiments of the present invention, the condensation reaction specifically includes:

[0057] Add 4-(methylamino)-4-oxobut-2-enoic acid to dichloromethane, and dropwise add the condensing agent to the reaction system at a dropping temperature of 5-10 °C; after the addition of the condensing agent is completed, raise the temperature to 20-30 °C for the condensation reaction, and the reaction time is 2-8 hours. The reaction conditions are mild and easy to control, and the reaction cost is low.

[0058] The reaction formula is specifically shown as the following formula (2):

[0059]

[0060] In some embodiments of the present invention, the molar ratio of 4-(methylamino)-4-oxobut-2-enoic acid to the condensing agent is 1:(1.05-1.1). A slightly excessive condensing agent is beneficial to improving the yield.

[0061] In some embodiments of the present invention, post-treatment is also included after the condensation reaction. Specifically, the post-treatment includes:

[0062] After the completion of the condensation reaction, pour the reaction solution into water, stir at 20-30 °C for 1-3 hours and then separate the liquid. The aqueous phase is extracted with dichloromethane, then dried with anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product;

[0063] Recrystallize the crude product with ethyl acetate / petroleum ether to obtain purified N-methylmaleimide.

[0064] That is to say, after the reaction is completed, the crude product can be obtained only by simple liquid-phase separation and other treatments, and the purified N-methylmaleimide can be obtained by simply recrystallizing the crude product without complex operations such as column chromatography.

[0065] Next, the preparation method of N-methylmaleimide of the present invention will be further described in detail through specific examples.

[0066] Example 1

[0067] (1) Maleic anhydride (100 g, 1.02 mol, 1.0 eq.), sodium hydroxide (61.2 kg, 1.53 mol, 1.5 eq.) were added to water (200 g, 2-fold weight). The temperature was lowered to 10 °C in an ice-water bath, and an aqueous solution of methylamine (237.6 g, 3.06 mol, 40% (wt%), 3 eq.) was added dropwise while controlling the temperature at 10 - 20 °C. After the addition, the mixture was kept at a constant temperature for reaction for 3 hours.

[0068] After the reaction was completed, the reaction system was cooled to 5 °C. After 1 hour, filtration was carried out by suction. The filter cake was washed with a small amount of ethanol and then dried to obtain 113.2 g of 4-(methylamino)-4-oxobut-2-enoic acid (water content 0.3%, melting point 143 - 144 °C), and the yield was 88%.

[0069] (2) 4-(Methylamino)-4-oxobut-2-enoic acid (113.2 g, 0.88 mol, 1.0 eq.) was added to dichloromethane (566.0 g, 5-fold weight). The temperature was lowered to 5 °C in an ice-water bath, and n-butylphosphoric anhydride (50% ethyl acetate solution) (697.0 g, 0.968 mol, 50% (wt%), 1.1 eq.) was added dropwise while controlling the temperature at 10 °C. After the addition, the reaction temperature was raised, and the reaction was carried out at 30 °C for 4 hours.

[0070] The reaction solution was poured into water (566.0 g, 5-fold weight), and the mixture was stirred at 30 °C for 1 hour. Liquid separation was carried out. The aqueous phase was extracted twice with dichloromethane (113.2 g, 1-fold weight), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product.

[0071] The crude product was recrystallized with ethyl acetate:n-heptane 1:10 (total 1245.2 g) to obtain 78.7 g of N-methylmaleimide, and the yield was 80.5%.

[0072] The obtained product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the data were as follows:

[0073] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz): δ 7.02 (s, 2H), 2.86 (s, 3H).

[0074] The detection results were consistent with the structure of N-methylmaleimide.

[0075] Example 2:

[0076] (1) Add maleic anhydride (1.0 kg, 10.19 mol, 1.0 eq.), sodium hydroxide (0.61 kg, 15.29 mol, 1.5 eq.) to water (2 kg, 2-fold weight), cool the mixture to 10 °C in an ice-water bath, and dropwise add aqueous methylamine solution (2.37 kg, 30.57 mol, 40% (wt%), 3 eq.). Control the temperature at 10 °C, and keep the mixture reacting for 3 hours after dropping.

[0077] After the reaction is completed, cool the system to 5 °C. After 1 hour, perform suction filtration. Wash the filter cake with a small amount of ethanol, and dry the filter cake to obtain 1.19 kg of 4-(methylamino)-4-oxobut-2-enoic acid intermediate (water content 0.6%, melting point 142 - 144 °C), with a yield of 90.5%.

[0078] (2) Add 4-(methylamino)-4-oxobut-2-enoic acid intermediate (1.19 kg, 9.23 mol, 1.0 eq.) to dichloromethane (5.95 kg, 5-fold weight), cool the mixture to 5 °C in an ice-water bath, and dropwise add n-butylphosphoric anhydride (50% ethyl acetate solution) (6.99 kg, 9.69 mol, 50% (wt%), 1.05 eq.). Control the temperature at 5 °C. After dropping, raise the reaction temperature, and keep the reaction temperature at 20 - 30 °C for 4 hours.

[0079] After the reaction is completed, pour the reaction solution into water (5.95 kg, 5-fold weight), and stir at 30 °C for 1 hour. Separate the layers. Extract the aqueous phase twice with dichloromethane (1.19 kg, 1-fold weight), then dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product.

[0080] Recrystallize the crude product with ethyl acetate:n-heptane 1:10 (total 13.09 kg) to obtain 0.86 kg of N-methylmaleimide, with a yield of 82.5%.

[0081] Perform nuclear magnetic resonance experiments on the obtained product to confirm the product structure. The data are as follows:

[0082] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz): δ 7.05 (s, 2H), 2.90 (s, 3H).

[0083] The test results are consistent with the structure of N-methylmaleimide.

[0084] In summary, the N-methylmaleimide of the present invention uses maleic anhydride as the starting material. First, it undergoes a ring-opening reaction with methylamine to obtain an intermediate, and then the intermediate undergoes a condensation reaction under the action of a condensing agent to obtain the target product N-methylmaleimide. The reaction conditions of the second-step condensation reaction are mild, the yield is high, and the post-treatment is simple and easy to operate.

[0085] The above are the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of N-methylmaleimide, characterized in that, Comprising: Step S1, causing maleic anhydride to undergo a ring-opening reaction with methylamine to form 4-(methylamino)-4-oxobut-2-enoic acid; Step S2, causing the 4-(methylamino)-4-oxobut-2-enoic acid to undergo a condensation reaction to form N-methylmaleimide, wherein the condensation reaction is carried out under the action of a condensing agent, and the condensing agent is selected from one or more of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, tripyrrolidinophosphonium bromide hexafluorophosphate, and n-butylphosphoric anhydride.

2. The preparation method according to claim 1, wherein The ring-opening reaction is carried out in a first solvent in the presence of an inorganic base, wherein the first solvent is one or more of methanol, ethanol, water, etc., and the inorganic base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, etc.

3. The preparation method according to claim 2, wherein The said Step S1 includes: Adding maleic anhydride and sodium hydroxide to water and dissolving them fully, and adding an aqueous methylamine solution thereto to carry out the said ring-opening reaction.

4. The preparation method according to claim 3, wherein The molar ratio of maleic anhydride, methylamine, and sodium hydroxide is 1:(2 - 4):(1 - 2), the reaction temperature of the ring-opening reaction is 10 - 30°C, and the reaction time is 1 - 4 hours.

5. The preparation method according to claim 3, wherein The said Step S1 further includes: After the ring-opening reaction is completed, cooling the reaction system of the ring-opening reaction, and performing suction filtration. The filter cake is washed with ethanol and then dried to obtain the 4-(methylamino)-4-oxobut-2-enoic acid.

6. The preparation method according to claim 1, characterized in that, The said Step S2 includes: Adding the 4-(methylamino)-4-oxobut-2-enoic acid to dichloromethane, dropping the condensing agent into the reaction system, and the dropping temperature is 5 - 10°C; after the condensing agent is dropped, raising the temperature to 20 - 30°C to carry out the condensation reaction, and the reaction time is 2 - 8 hours.

7. The preparation method according to claim 6, characterized in that, The molar ratio of 4-(methylamino)-4-oxobut-2-enoic acid to the condensing agent is 1:(1.05 - 1.1).

8. The preparation method according to claim 6, characterized in that, The said Step S2 further includes: After the condensation reaction is completed, pouring the reaction solution into water, and stirring at 20 - 30°C for 1 - 3 hours and then separating the layers. The aqueous phase is extracted with dichloromethane, then dried with anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product; Recrystallizing the said crude product with ethyl acetate / petroleum ether to obtain purified N-methylmaleimide.

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