Preparation method of N-substituent-m-aminobenzylamine

Abstract

The invention discloses a preparation method of N-substituent-m-aminobenzylamine, which comprises the following steps: mixing amine and a solvent to obtain an amine solution; adding m-nitrobenzaldehyde into the amine solution, and reacting to obtain an imine solution; under the action of a catalyst, carrying out catalytic hydrogenation reaction on the imine solution to obtain an N-substituent-m-aminobenzene amine reaction solution; and removing the solvent from the N-substituent-m-aminobenzene amine reaction liquid to obtain a crude product, and rectifying to obtain the target product N-substituent-m-aminobenzene amine. According to the method, m-nitrobenzaldehyde is taken as a raw material, firstly, the m-nitrobenzaldehyde and amine are subjected to pre-reaction, then hydrogenation reduction is performed under the action of the catalyst, the raw materials are low in price and easy to obtain, reaction conditions are mild, byproducts are few, the use amount of solvents is small, products are easy to separate, and the yield of refined products reaches about 90%.

Description

Technical Field

[0001] The invention belongs to the field of chemical industry, and specifically relates to a method for preparing N-substituted-m-aminobenzylamine. Background Art

[0002] N-substituted-m-aminobenzylamine is a class of organic compounds, which are often used as organic synthesis intermediates and have certain biological activity. Therefore, they have certain application potential in drug development and medicine. The most representative compound of N-substituted-m-aminobenzylamine is N-methyl-m-aminobenzylamine, also known as 3-amino-N-methylbenzylamine and 3-amino-benzylmethylamine. It is a colorless to pale yellow solid with a strong amine odor. It can be used as a raw material and intermediate in organic synthesis; it is used to synthesize amides, ketones and alcohol compounds.

[0003] At present, the relevant literature, patents and routes for preparing N-methyl-m-aminobenzylamine are:

[0004]

[0005] The above method (Document Organic Letters, vol.15, #14 p.3734-3737) uses N-methyl-3-bromo-benzylamine as a raw material, and NH3 (3 times the molar amount), NaOtBu (2.2 times the molar amount), and a palladium catalyst, and reacts in 1,4-dioxane at 80°C for 24 hours with a yield of 57%. The catalyst is not easy to obtain, the reaction time is long, the yield is low, and it is not suitable for large-scale production.

[0006] The document (Angewandte Chemie-International Edition, vol.49, #24p.4071-4074) discloses the following technical scheme: N-methyl-3-chlorobenzylamine is selected as a raw material, and NH3 (3 times the molar amount) and NaOtBu (2 times the molar amount) are reacted at 110°C under the action of a catalyst (palladium chloride (π-cinnamyl) dimer), and the final yield is 74%, which is relatively low, and the catalyst is very expensive, which is not suitable for large-scale production. In summary, it is of great significance to provide a method with high yield, low cost, and suitable for large-scale production of N-substituted-m-aminobenzylamine. Summary of the invention

[0007] The technical problem to be solved by the present invention is: in view of the shortcomings of the prior art, a method for preparing N-substituted-m-aminobenzylamine is provided. The method uses m-nitrobenzaldehyde as a raw material, firstly performs a pre-reaction with an amine, and then performs a hydrogenation reduction under the action of a catalyst. The raw material of the method is low in price and easy to obtain, the reaction conditions are mild, the by-products are small, the product purity is high, the solvent usage is small, the product is easy to separate, and the yield of the refined product is as high as about 90%.

[0008] In order to solve the above technical problems, the technical solution of the present invention is:

[0009] A method for preparing N-substituted-m-aminobenzylamine comprises the following steps:

[0010] (1) mixing an amine and a solvent to obtain an amine solution;

[0011] (2) adding m-nitrobenzaldehyde to the above amine solution to react and obtain an imine solution;

[0012] (3) subjecting the imine solution to a catalytic hydrogenation reaction in the presence of a catalyst to obtain an N-substituted-m-aminobenzylamine reaction solution;

[0013] (4) removing the solvent from the above N-substituted-m-aminobenzylamine reaction solution to obtain a crude product, and obtaining the target product N-substituted-m-aminobenzylamine after distillation.

[0014] Preferably, in step (1), the solvent includes one of methanol, ethanol, isopropanol, tetrahydrofuran, and more preferably, one of methanol and ethanol.

[0015] Preferably, in step (1), the amine is monomethylamine, monoethylamine, isopropylamine, or tert-butylamine; further, preferably, it is one of monomethylamine and monoethylamine.

[0016] Preferably, in step (2), the molar ratio of m-nitrobenzaldehyde to amine is 1:(1-10); further, preferably 1:(2-5).

[0017] Preferably, in step (2), the reaction temperature is 0-50°C; more preferably 10-20°C; the reaction time is 1-8h; more preferably 2-4h.

[0018] Preferably, in step (3), the catalyst is one of Raney nickel, palladium carbon, ruthenium carbon and platinum carbon; further preferably, the catalyst is one of palladium carbon and Raney nickel.

[0019] Preferably, in step (3), the amount of catalyst added is 5-50 wt% of the weight of m-nitrobenzaldehyde; more preferably, 10-20 wt%.

[0020] Preferably, in step (3), the temperature of the catalytic hydrogenation reaction is 15-100° C., preferably 30-85° C.; after the hydrogen absorption is completed, the temperature is kept for 1-8 hours, preferably 1-2 hours.

[0021] Preferably, in step (3), the reaction pressure of the catalytic hydrogenation reaction is 0.5-6.5 MPa, and further preferably, 1.0-5.0 MPa.

[0022] Preferably, in step (4), the solvent is removed by atmospheric distillation, and the initial distillation temperature during atmospheric distillation is 60-65° C., which is then gradually increased to 100° C. until no solvent and water are evaporated.

[0023] Preferably, in step (4), a mechanical pump is used for vacuum distillation during rectification, and the liquid phase 140-150°C / -0.1Mpa positive boiling point fraction is collected to obtain the product N-substituted-m-aminobenzylamine.

[0024] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0025] The present invention uses m-nitrobenzaldehyde as a raw material, reacts with amine in a solvent to generate imine, and then performs a hydrogenation reduction reaction under the action of a suitable catalyst to obtain a crude product, and obtains the target compound N-methyl-m-aminobenzylamine through desolventizing and distillation. The solvent, m-nitrobenzaldehyde and amine selected in the above process are cheap and easy to obtain, and the reaction temperature is mild, the reaction time is moderate, and the production cost of the product is reduced. In addition, there are few by-products and a small amount of solvent in the whole reaction, and the product is easy to separate. The present invention greatly improves the purity and yield of the target product by optimizing the reaction conditions.

[0026] The catalyst used in the present invention is cheap, easy to obtain, has good catalytic effect and good reusability. Specifically, in the above preparation method, the catalyst in step (3) is economical, easy to obtain, has excellent catalytic effect and can be applied many times. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0028] Figure 1 This is the GC spectrum of the final target product in Example 1. DETAILED DESCRIPTION

[0029] In order to more clearly understand the above-mentioned objectives, features and advantages of the present invention, the scheme of the present invention will be further described below. It should be noted that the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

[0030] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; it is obvious that the embodiments in the specification are only part of the embodiments of the present invention, rather than all of the embodiments.

[0031] In the following examples and comparative examples, unless otherwise specified, the conditions described are conventional conditions in the art and the products described are commercially available.

[0032] In the following examples and comparative examples, the yield calculation method of the target product is as follows:

[0033] Yield (%) = (actual yield of target product / theoretical yield of target product) × 100%.

[0034] Embodiment 1:

[0035] In a 1000ml reaction bottle, add 600g of methanol solution of monomethylamine (containing 62.1g of monomethylamine, 2mol), add 151g (1mol) of m-nitrobenzaldehyde, stir at 15°C for 2h, take samples for analysis (GC), and when the raw material m-nitrobenzaldehyde remains 0.2%, transfer the reaction solution to a 1000ml hydrogenation kettle, add 15.1g of Raney nickel, seal the reactor, replace with nitrogen three times, replace with hydrogen three times, add hydrogen pressure 2.0Mpa, start hydrogen absorption at 30°C initially, then raise the temperature to 75°C, end hydrogen absorption, maintain pressure and heat for 2 hours, cool down after heat preservation, release pressure, filter the reaction solution, sample and analyze the filtrate (GC): the raw material remains 0.03%; distill the filtrate at room temperature to 100°C, then distill under reduced pressure, collect to 140-150°C / -0.1Mpa, and obtain 122.57g The product N-methyl-m-aminobenzylamine has a purity of 100% and a yield of 89.99%.

[0036] from Figure 1 It can be seen that the N-methyl-m-aminobenzylamine product prepared by the present invention has high purity.

[0037] Embodiment 2:

[0038] In a 1000ml reaction bottle, add 600g of methanol solution of monomethylamine (containing 41g of monomethylamine, 1.3mol), add 100g (0.66mol) of m-nitrobenzaldehyde, stir at 15°C for 2h, take samples for analysis (GC), and when the raw material m-nitrobenzaldehyde remains 0.21%, transfer the reaction solution to a 1000ml hydrogenation kettle, add 10g of Raney nickel, seal the reactor, replace with nitrogen three times, replace with hydrogen three times, add hydrogen pressure 2.0Mpa, start hydrogen absorption at 30°C initially, then raise the temperature to 75°C, hydrogen absorption ends, maintain pressure and heat for 2 hours, cool down after heat preservation ends, release pressure, filter the reaction solution, sample and analyze the filtrate (GC): the raw material remains 0.03%; the above filtrate is first distilled to 100°C at room temperature, then distilled under reduced pressure, collected to 140-150°C / -0.1Mpa, and 81.8g The product N-methyl-m-aminobenzylamine has a purity of 99.79% and a yield of 91%.

[0039] Embodiment 3:

[0040] In a 1000 ml reaction bottle, add 530.8 g of methanol solution of monomethylamine (containing 102 g of monomethylamine, 3.3 mol), add 100 g (0.66 mol) of m-nitrobenzaldehyde, stir at 15 ° C for 2 h, take samples for analysis (GC), and when the raw material m-nitrobenzaldehyde remains 0.1%, transfer the reaction solution to a 1000 ml hydrogenation kettle, add 10 g of Raney nickel, seal the reactor, replace the atmosphere with nitrogen three times, replace the atmosphere with hydrogen three times, add hydrogen pressure 2.0Mpa, initially at 30°C, hydrogen absorption began, then the temperature was raised to 75°C, hydrogen absorption ended, the pressure and heat were maintained for 2 hours, the temperature was lowered after the heat preservation was completed, the pressure was released, the reaction solution was filtered, and the filtrate was sampled and analyzed (GC): the raw material remained 0; the above filtrate was first distilled to 100°C at room temperature, and then distilled under reduced pressure, and collected to 140-150°C / -0.1Mpa to obtain 80.8g N-methyl-m-aminobenzylamine product with a purity of 99.99% and a yield of 89.7%.

[0041] Embodiment 4:

[0042] In a 1000ml reaction bottle, add 600g of methanol solution of monomethylamine (containing 62.1g of monomethylamine, 2mol), add 151g (1mol) of m-nitrobenzaldehyde, stir at 15°C for 2h, take samples for analysis (GC), and when the raw material m-nitrobenzaldehyde remains 0.2%, transfer the reaction solution to a 1000ml hydrogenation kettle, add 30.2g of Raney nickel, seal the reactor, replace with nitrogen three times, replace with hydrogen three times, add hydrogen pressure 2.0Mpa, start hydrogen absorption at 30°C, then raise the temperature to 75°C, end hydrogen absorption, keep warm for 2 hours, cool down after the end of the insulation, release the pressure, filter the reaction solution, and take samples for analysis (GC): the raw material remains 0.01%; the above filtrate is first distilled to 100°C at room temperature, and then distilled under reduced pressure, collected to 140-150°C / -0.1Mpa, to obtain 123g The product N-methyl-m-aminobenzylamine has a purity of 99.9% and a yield of 90.3%.

[0043] Embodiment 5:

[0044] In a 1000ml reaction bottle, add 600g of methanol solution of monomethylamine (containing 62.1g of monomethylamine, 2mol), add 151g (1mol) of m-nitrobenzaldehyde, stir at 15°C for 2h, take samples for analysis (GC), and when the raw material m-nitrobenzaldehyde remains 0.2%, transfer the reaction solution to a 1000ml hydrogenation kettle, add 15.1g of Raney nickel, seal the reactor, replace with nitrogen three times, replace with hydrogen three times, add hydrogen pressure 2.0Mpa, start hydrogen absorption at 30°C initially, then raise the temperature to 75°C, end hydrogen absorption, maintain pressure and heat for 2 hours, cool down after heat preservation, release pressure, filter the reaction solution, and take samples for analysis (GC): the raw material remains 0.02%; the above filtrate is first distilled to 100°C at room temperature, and then distilled under reduced pressure, collected to 140-150°C / -0.1Mpa, to obtain 122.6g The product N-methyl-m-aminobenzylamine has a purity of 99.8% and a yield of 90%.

[0045] Example 6

[0046] Compared with Example 5, the difference is that the catalyst used is Raney nickel applied 5 times, and the other conditions are the same as those in Example 5; 122.5 g of N-methyl-m-aminobenzylamine product is obtained with a purity of 99.8% and a yield of 89.95%.

[0047] In summary, the purity of the target product obtained by the present invention reaches more than 99%, the yield reaches more than 89%, and the reaction conditions are mild, the raw materials are cheap and easily available, and it is suitable for large-scale production.

[0048] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best mode, and also enable any technician in the field to practice the present invention, including making and using any device or system, and implementing any combined method. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, the present invention can also be improved and modified, and these improvements and modifications also fall within the scope of protection of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements similar to the literal expression of the claims, or if they include equivalent structural elements that are not substantially different from the literal expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims

1. A method for preparing N-substituted-m-aminobenzylamine, characterized in that: The following steps are involved: (1) mixing an amine and a solvent to obtain an amine solution; (2) adding m-nitrobenzaldehyde to the above amine solution to react and obtain an imine solution; (3) subjecting the imine solution to a catalytic hydrogenation reaction in the presence of a catalyst to obtain an N-substituted-m-aminobenzylamine reaction solution; (4) removing the solvent from the above N-substituted-m-aminobenzylamine reaction solution to obtain a crude product, and obtaining the target product N-substituted-m-aminobenzylamine after distillation.

2. The method for preparing an N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (1), the solvent includes one of methanol, ethanol, isopropanol and tetrahydrofuran; and / or the amine is monomethylamine, monoethylamine, isopropylamine or tert-butylamine.

3. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (2), the molar ratio of m-nitrobenzaldehyde to amine is 1:(1-10).

4. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (2), the reaction temperature is 0-50°C, and the reaction time is 1-8h.

5. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (3), the catalyst is selected from the group consisting of Raney nickel, palladium carbon, ruthenium carbon, and platinum carbon.

6. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (3), the amount of catalyst added is 5-50wt% of the weight of m-nitrobenzaldehyde.

7. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (3), the temperature of the catalytic hydrogenation reaction is 15-100° C., and the temperature is kept for 1-8 hours after the hydrogen absorption is completed.

8. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (3), the reaction pressure of the catalytic hydrogenation reaction is 0.5-6.5 MPa.

9. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (4), the solvent is removed by atmospheric distillation. The initial distillation temperature during atmospheric distillation is 60-65° C., and then gradually increased to 100° C. until no solvent and water are evaporated.

10. The method for preparing N-substituted-m-aminobenzylamine according to claim 1, characterized in that: In step (4), a mechanical pump is used for vacuum distillation during rectification, and the liquid phase 140-150°C / -0.1Mpa positive boiling point fraction is collected to obtain the product N-substituted-m-aminobenzylamine.

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