P-methoxybenzylamine as well as preparation method and application thereof

Abstract

The invention discloses p-methoxybenzylamine as well as a preparation method and application thereof, and belongs to the field of acyclic or carbocyclic compounds. The preparation method comprises the following steps: (1) adding p-methoxybenzaldehyde into a reaction container, sequentially adding an ethanol solution and ammonia water, heating and stirring, and reacting at 50-90 DEG C in a normal pressure environment; after the reaction, carrying out reduced pressure distillation to obtain p-methoxybenzylimine; the molar ratio of the p-methoxybenzaldehyde to the ammonia water is 1: (1-1.3); (2) dissolving p-methoxybenzylimine in methanol, adding a sodium hydroxide solution and 4-dimethylaminopyridine, then adding sodium borohydride, and reacting at the temperature of 0-30 DEG C under normal pressure; after the reaction is completed, adding acid into a product for hydrolysis; and adjusting the product to be alkalescent, extracting, drying, filtering and distilling to obtain the p-methoxybenzylamine. A new strategy for synthesizing p-methoxybenzylamine is introduced, the reaction does not involve high temperature, and the reaction conditions are milder and more controllable.

Description

Technical Field

[0001] This invention relates to the field of acyclic or carbocyclic compounds, and more particularly to p-methoxybenzylamine, its preparation method, and its uses. Background Technology

[0002] p-Methoxybenzylamine, also known as 4-methoxybenzylamine, CAS number 2393-23-9, possesses multiple functions in the pharmaceutical and biological fields, including antitumor, antibacterial, antioxidant, cardiovascular drug intermediate, and functionalized biomaterials. Currently, there are three main methods for synthesizing p-methoxybenzylamine: The first method uses p-methoxybenzyl alcohol as a raw material. It is first chlorinated in a SOCl2 / DMF system at 0-40 °C to obtain p-methoxybenzyl chloride. Then, it is refluxed with hexamethylenetetramine in n-butanol for 8 h to generate a quaternary ammonium salt. Then, it is hydrolyzed with 6 M HCl-isopropanol and refluxed for 4-6 h. After cooling and adjusting the alkali, it is extracted and distilled to obtain p-methoxybenzylamine. The specific reaction equation is as follows. However, this reaction is complicated and has a low yield.

[0003] .

[0004] The second method involves dissolving p-methoxybenzonitrile in liquid ammonia-methanol and catalyzing it with 60% Ni / SiO2 or Ru(II) complex, ≤10 atm H2, and 120℃ for 6 h. This reaction requires a high-pressure reactor and a flammable catalyst, making it highly hazardous and environmentally unfriendly.

[0005] The third method uses p-methoxybenzaldehyde and ammonium formate as raw materials, and involves a reductive amination reaction under N2 conditions, heated to a molten state. p-Methoxybenzaldehyde and ammonium formate are added simultaneously to a three-necked flask, and the air is replaced with nitrogen. The temperature is slowly raised to 170-180 °C with stirring, until the materials melt into a homogeneous phase, releasing CO2 and NH3 bubbles. After continuing the reaction for 2 hours, the reaction system is cooled to 60-70 °C, ice water is added, and the pH is adjusted to strongly alkaline, releasing p-methoxybenzylamine. After extraction with diethyl ether, the mixture is dried and filtered. The diethyl ether is removed, and the mixture is distilled under reduced pressure to collect the fraction, yielding p-methoxybenzylamine.

[0006]

[0007] This route involves high reaction temperatures and generates significant amounts of waste, making it unsuitable for large-scale production. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing p-methoxybenzylamine, which uses ammonia water instead of the existing liquid ammonia as the nitrogen source and uses sodium borohydride for the reaction. Starting from the raw material p-methoxybenzaldehyde, the reaction proceeds through the intermediate state of p-methoxybenzylimine to obtain the final product p-methoxybenzylamine.

[0009] The present invention also proposes a p-methoxybenzylamine, which is prepared by the above-described method for preparing p-methoxybenzylamine.

[0010] To achieve this objective, the present invention adopts the following technical solution: A method for preparing p-methoxybenzylamine includes the following steps: (1) Add p-methoxybenzaldehyde to the reaction vessel, then add ethanol solution and ammonia water in sequence, heat and stir, and react at 50-90 °C and normal pressure; after the reaction, distill under reduced pressure to obtain p-methoxybenzamide; the molar ratio of p-methoxybenzaldehyde to ammonia water is 1:(1-1.3). (2) Dissolve p-methoxybenzylimine in methanol, add sodium hydroxide solution and 4-dimethylaminopyridine, then add sodium borohydride, and react at a temperature of 0-30 °C and at normal pressure; the molar ratio of p-methoxybenzylimine to sodium borohydride is 1:(1-1.3); after the reaction is completed, add acid to hydrolyze the product; adjust the product to weak alkalinity, and obtain p-methoxybenzylamine by extraction, drying, filtration and distillation.

[0011] Alternatively, in step (2), sodium borohydride is prepared by adding ice water to form a sodium borohydride solution; the reaction vessel for p-methoxybenzyl imine is placed in an ice bath, and the sodium borohydride solution is added dropwise under stirring. After the addition is complete, the reaction continues; the reaction vessel is placed at room temperature, and the reaction continues.

[0012] Alternatively, in step (2), after the reaction is complete, the product is acidified to adjust the pH to 9.5–10.5.

[0013] Alternatively, in step (2), after the reaction is complete, hydrochloric acid is added dropwise to the product under ice bath conditions to adjust the pH to 9.5–10.5.

[0014] Alternatively, in step (2), after the reaction is complete, dilute hydrochloric acid is added dropwise to the product under ice bath conditions.

[0015] A p-methoxybenzylamine, prepared by the above-described method for preparing p-methoxybenzylamine.

[0016] The use of p-methoxybenzylamine in the preparation of pharmaceutical intermediates, wherein the p-methoxybenzylamine is prepared by one of the above-described methods for preparing p-methoxybenzylamine.

[0017] The use of p-methoxybenzylamine in the preparation of biofunctional polymer materials, wherein the p-methoxybenzylamine is prepared by one of the above-described methods for preparing p-methoxybenzylamine.

[0018] Compared with the prior art, one of the above technical solutions has the following beneficial effects: This invention provides a method for preparing p-methoxybenzylamine, which uses ammonia water instead of the existing liquid ammonia as the nitrogen source and utilizes sodium borohydride for the reaction. Starting from the raw material p-methoxybenzaldehyde, the reaction proceeds through the intermediate state of p-methoxybenzylimine to obtain the final product p-methoxybenzylamine. This invention introduces a new strategy for synthesizing p-methoxybenzylamine, which does not involve high temperatures and has milder and more controllable reaction conditions. It solves the problems of complex reaction operations, low yield, harsh synthesis, and serious waste in the existing p-methoxybenzylamine synthesis. Attached Figure Description

[0019] Figure 1 The 1H NMR spectrum of p-methoxybenzylamine I, the final product of Example 1 of this invention; Figure 2 The carbon NMR spectrum of p-methoxybenzylamine I, the final product of Example 1 of this invention; Figure 3 This is the 1H NMR spectrum of p-methoxybenzylimine M2, the intermediate of Example 1 of the present invention; Figure 4 This is the carbon NMR spectrum of p-methoxybenzylimine M2, the intermediate of Example 1 of the present invention. Detailed Implementation

[0020] Embodiments of the present invention are described in detail below. Examples of these embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0021] To facilitate understanding of the present invention, a more comprehensive description is provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of the present invention. Where specific techniques or conditions are not specified in the embodiments, they are performed in accordance with techniques or conditions described in the literature in the art or according to product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0022] A method for preparing p-methoxybenzylamine includes the following steps: (1) Add p-methoxybenzaldehyde to the reaction vessel, then add ethanol solution and ammonia water in sequence, heat and stir, and react at 50-90 °C and normal pressure; after the reaction, distill under reduced pressure to obtain p-methoxybenzamide; the molar ratio of p-methoxybenzaldehyde to ammonia water is 1:(1-1.3). The chemical reaction formula for p-methoxybenzaldehyde and ammonia is: ; This scheme uses ammonia water (NH3·H2O) as the nitrogen source, mainly because ammonia water has a relatively slow evaporation rate and relatively low toxicity and corrosiveness, making it safer overall. Ammonia water is also cheaper than liquid ammonia. Based on these advantages, this scheme does not require hydrogenation under high pressure, making it relatively safe. Existing technologies use liquid ammonia (NH3) as the nitrogen source. Liquid ammonia is mostly stored in pressure-resistant steel cylinders or tanks, is corrosive, and easily evaporates. Furthermore, liquid ammonia participates in high-pressure hydrogenation, resulting in a high rate of chemical accidents. In step (1), the solution changes from colorless to light yellow. After removing ethanol by vacuum distillation, a pale yellow oily substance, p-methoxybenzamide, is obtained.

[0023] (2) Dissolve p-methoxybenzylimine in methanol, add sodium hydroxide solution and 4-dimethylaminopyridine, then add sodium borohydride, and react at a temperature of 0-30℃ and atmospheric pressure; the molar ratio of p-methoxybenzylimine to sodium borohydride is 1:(1-1.3); after the reaction is completed, add acid to hydrolyze the product; adjust the product to weak alkalinity, and obtain p-methoxybenzylamine by extraction, drying, filtration and distillation.

[0024] The chemical reaction formula for p-methoxybenzylimine and sodium borohydride is as follows: ; In step (2), sodium hydroxide solution and 4-dimethylaminopyridine mainly act as catalysts, and their amounts can be determined according to the required reaction rate. Generally, the molar amount of sodium hydroxide solution can be 0.5 to 0.8 times that of p-methoxybenzylimine, and the molar amount of 4-dimethylaminopyridine can be 0.01 to 0.05 times that of p-methoxybenzylimine. The reaction temperature of p-methoxybenzylimine with sodium borohydride is 0 to 30°C, and the reaction can be carried out at room temperature. The product is hydrolyzed with acid, mainly to remove excess sodium borohydride; and the pH is adjusted to weakly alkaline, mainly to release benzylamine to facilitate subsequent extraction steps.

[0025] This invention provides a method for preparing p-methoxybenzylamine, which uses ammonia water instead of liquid ammonia as the nitrogen source and utilizes sodium borohydride for the reaction. Starting from the raw material p-methoxybenzaldehyde, the reaction proceeds through the intermediate state of p-methoxybenzylimine to obtain the final product p-methoxybenzylamine. This invention introduces a new strategy for synthesizing p-methoxybenzylamine, which does not involve high temperatures or the use of hydrogen gas. The reaction conditions are milder and more controllable, solving the problems of complex reaction operations, low yield, harsh synthesis, and serious waste in the existing p-methoxybenzylamine synthesis.

[0026] Alternatively, in step (2), sodium borohydride is prepared by adding ice water to form a sodium borohydride solution; the reaction vessel for p-methoxybenzyl imine is placed in an ice bath, and the sodium borohydride solution is added dropwise under stirring. After the addition is complete, the reaction continues; the reaction vessel is placed at room temperature, and the reaction continues.

[0027] Sodium borohydride in this scheme can be added to p-methoxybenzylimine in powder form as needed. In the optimal embodiment, sodium borohydride is preferably prepared into a sodium borohydride solution by adding ice water. This is mainly because the solution allows for more uniform dispersion of sodium borohydride in the p-methoxybenzylimine reaction system, avoiding violent reactions caused by excessively high local concentrations and making the reaction process more controllable. Preparing the sodium borohydride solution with ice water lowers the temperature of the reaction system, preventing local overheating or violent hydrogen release with p-methoxybenzylimine, thus making the reaction more stable and reducing the formation of byproducts. Simultaneously, the ice water environment significantly reduces the hygroscopic decomposition of sodium borohydride, prolonging solution stability, especially in slow dropwise addition processes.

[0028] Alternatively, in step (2), after the reaction is complete, the product is acidified to adjust the pH to 9.5–10.5.

[0029] When acid is added to the product, it enables sodium borohydride to react with the acid, thereby removing excess sodium borohydride from the product; and by adjusting the pH to 9.5–10.5, the product is placed in a weakly alkaline environment, which is conducive to the release of benzylamine.

[0030] Alternatively, in step (2), after the reaction is complete, hydrochloric acid is added dropwise to the product under ice bath conditions to adjust the pH to 9.5–10.5.

[0031] In this step, the reaction vessel containing the product is placed in an ice bath, and hydrochloric acid is added slowly. This is mainly to avoid adding an excessive amount of hydrochloric acid to the product at once, thereby avoiding adding excessive water to the reaction system and preventing the reaction from becoming too vigorous. At the same time, the ice bath can lower the reaction temperature, thus making the reaction more stable and reducing the formation of by-products.

[0032] Alternatively, in step (2), after the reaction is complete, dilute hydrochloric acid is added dropwise to the product under ice bath conditions.

[0033] This scheme uses dilute hydrochloric acid instead of concentrated hydrochloric acid, mainly because the reaction rate is faster but controllable in dilute hydrochloric acid due to the moderate hydrogen ion concentration. Combined with the generation of sodium chloride, boric acid and hydrogen gas in an ice bath environment, the reaction process is relatively stable.

[0034] A p-methoxybenzylamine, prepared by the above-described method for preparing p-methoxybenzylamine.

[0035] The use of p-methoxybenzylamine in the preparation of pharmaceutical intermediates, wherein the p-methoxybenzylamine is prepared by one of the above-described methods for preparing p-methoxybenzylamine.

[0036] The use of p-methoxybenzylamine in the preparation of biofunctional polymer materials, wherein the p-methoxybenzylamine is prepared by one of the above-described methods for preparing p-methoxybenzylamine.

[0037] p-Methoxybenzylamine can be applied in the pharmaceutical and biological fields, possessing multiple functions such as anti-tumor, antibacterial, antioxidant, cardiovascular drug intermediate, and functionalized biomaterial.

[0038] Example 1: p-Methoxybenzylamine was synthesized according to the following steps: Step (1): Add 0.53 g of p-methoxybenzaldehyde and 20 mL of anhydrous ethanol sequentially to a 100 mL three-necked flask, and stir at room temperature until completely dissolved. Slowly add 0.55 mL of 25% ammonia solution dropwise over 10 min, and reflux at 60 °C for 3 h. The solution gradually changes from clear to slightly yellow and transparent. After the reaction is complete, cool to room temperature; remove the ethanol by rotary evaporation under reduced pressure to obtain a pale yellow oil. Distill under reduced pressure to obtain 0.48 g of p-methoxybenzamide. The yield of p-methoxybenzamide is 90%, and the purity is ≥ 98%.

[0039] Step (2): Dissolve 1.05 g of p-methoxybenzylimine in 20 mL of anhydrous methanol in a three-necked flask. After purging with nitrogen, add 0.01 g of p-dimethylaminopyridine and 2 mL of 2% NaOH solution, and stir to dissolve. Under ice bath conditions, slowly add NaBH4 aqueous solution (0.95 g of NaBH4 dissolved in 5 mL of ice water to prepare a 5 mL solution). Continue stirring for 30 min, and then react at room temperature for 3 h. After the reaction is complete, slowly add 1 M HCl under ice bath conditions to adjust the pH to ≈10, releasing benzylamine. Extract with ethyl acetate and distill to obtain 0.93 g of p-methoxybenzylamine. The yield of p-methoxybenzylamine is 89%, and the purity is ≥ 98%.

[0040] The chemical reaction formulas for steps (1) and (2) above are: ; Product Analysis: For the above-mentioned compounds, the present invention employs nuclear magnetic resonance spectroscopy including... 1 H and 13 Its structure was determined by C NMR spectroscopy; the compound M2 synthesized in step (1) of Example 1 above is p-methoxybenzamide. 1 H and 13 For detailed C NMR spectra, please refer to the appendix. Figure 3 and Figure 4 The compound I synthesized in step (2) of Example 1 above is p-methoxybenzylamine. 1 H and 13 For detailed C NMR spectra, please refer to the appendix. Figure 1 and Figure 2 : For p-methoxybenzylimine, Figure 3 and Figure 4 middle, 1H NMR (400 MHz, Chloroform-d) δ8.908 (d, J = 5.6 Hz, 1H), 7.845 – 7.588 (m, 2H), 7.442 (d, J = 5.6 Hz, 1H), 7.047 – 6.820 (m, 2H), 3.792 (s, 3H); 13 C NMR (125 MHz, Chloroform-d) δ 161.297, 149.453, 132.419, 128.672, 114.884, 55.312. NMR data (8.908 (d, J = 5.6 Hz, 1H), 7.442 (d, J = 5.6 Hz, 1H)) confirmed the presence of imine.

[0041] For p-methoxybenzylamine, Figure 1 and Figure 2 middle, 1 H NMR (400 MHz, CDCl3) δ 7.21 (dt, J=8.0, 1.2 Hz, 2H), 6.89–6.79 (m, 2H), 4.05 (tt, J = 6.4, 1.2 Hz, 2H), 3.78(s, 3H), 2.54 (dt, J = 7.2, 6.0 Hz, 1H), 2.39 (dt, J= 7.2, 6.0 Hz, 1H); 13 C10 NMR (125 MHz, CDCl3) δ 158.95, 135.47, 128.62, 112.47, 55.32, 45.00. NMR data (2.54 (dt, J = 7.2, 6.0 Hz, 1H), 2.39 (dt, J = 7.2, 6.0 Hz, 1H)) confirmed the presence of the benzylamine group.

[0042] Example 2: p-Methoxybenzylamine was synthesized according to the following steps: Step (1): Add 0.53 g of p-methoxybenzaldehyde and 25 mL of anhydrous ethanol sequentially to a 100 mL three-necked flask, and stir at room temperature until completely dissolved. Slowly add 0.60 mL of 25% ammonia solution dropwise over 15 min, and reflux at 80 °C for 4 h. The solution gradually changes from clear to slightly yellow and transparent. After the reaction is complete, cool to room temperature; remove the ethanol by rotary evaporation under reduced pressure, yielding a pale yellow oil. Distill under reduced pressure yields 0.46 g of p-methoxybenzamide. The yield of p-methoxybenzamide is 86%, and the purity is ≥ 98%.

[0043] Step (2): Dissolve 1.05 g of p-methoxybenzylamine in 20 mL of anhydrous methanol in a three-necked flask. After purging with nitrogen, add 0.01 g of p-dimethylaminopyridine and 2 mL of 2% NaOH solution, and stir to dissolve. Under ice bath conditions, slowly add NaBH4 aqueous solution (1 g of NaBH4 dissolved in 5 mL of ice water to prepare a 5 mL solution). Continue stirring for 40 min, and then react at room temperature for 4 h. After the reaction is complete, slowly add 1 M HCl under ice bath conditions to adjust the pH to ≈ 10, releasing benzylamine. Extract with ethyl acetate and distill to obtain 0.90 g of p-methoxybenzylamine. The yield of p-methoxybenzylamine is 86%, and the purity is ≥98%.

[0044] Example 3: p-Methoxybenzylamine was synthesized according to the following steps: Step (1): Add 0.53 g of p-methoxybenzaldehyde and 25 mL of anhydrous ethanol sequentially to a 100 mL three-necked flask, and stir at room temperature until completely dissolved. Slowly add 0.58 mL of 25% ammonia solution dropwise over 20 min, and reflux at 90 °C for 1 h. The solution gradually changes from clear to slightly yellow and transparent. After the reaction is complete, cool to room temperature; remove the ethanol by rotary evaporation under reduced pressure to obtain a pale yellow oil. Distill under reduced pressure to obtain 0.49 g of p-methoxybenzamide. The yield of p-methoxybenzamide is 92%, and the purity is ≥98%.

[0045] Step (2): Dissolve 1.05 g of p-methoxybenzylimine in 20 mL of anhydrous methanol in a three-necked flask. After purging with nitrogen, add 0.01 g of p-dimethylaminopyridine and 2 mL of 2% NaOH solution, and stir to dissolve. Under ice bath conditions, slowly add NaBH4 aqueous solution (0.98 g of NaBH4 dissolved in 5 mL of ice water to prepare a 5 mL solution). Continue stirring for 35 min, and then react at room temperature for 3.5 h. After the reaction is complete, slowly add 1 M HCl under ice bath conditions to adjust the pH to ≈ 10, releasing benzylamine. Extract with ethyl acetate and distill to obtain 0.89 g of p-methoxybenzylamine. The yield of p-methoxybenzylamine is 85%, and the purity is ≥98%.

[0046] In summary, the intermediate states of p-methoxybenzylamine and p-methoxybenzylamine obtained by this method have good production benefits. The average yield of step (1) is 89%, and the average yield of step (2) is 87%, demonstrating good production efficiency. This method uses ammonia water instead of liquid ammonia as the nitrogen source and utilizes sodium borohydride for the reaction. Starting from the raw material p-methoxybenzaldehyde, the reaction proceeds through the intermediate state of p-methoxybenzylamine to obtain the final product p-methoxybenzylamine. This invention introduces a new strategy for synthesizing p-methoxybenzylamine, which does not involve high temperatures and offers milder and more controllable reaction conditions. It can be a green, safe, and low-cost new strategy for synthesizing p-methoxybenzylamine.

[0047] Although embodiments of the invention have been shown and described, those skilled in the art will understand that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A method for preparing p-methoxybenzylamine, characterized in that, Includes the following steps: (1) Add p-methoxybenzaldehyde to the reaction vessel, then add ethanol solution and ammonia water in sequence, heat and stir, and react at 50-90℃ and normal pressure; after the reaction, distill under reduced pressure to obtain p-methoxybenzamide; the molar ratio of p-methoxybenzaldehyde to ammonia water is 1:(1-1.3). (2) Dissolve p-methoxybenzylimine in methanol, add sodium hydroxide solution and 4-dimethylaminopyridine, then add sodium borohydride, and react at a temperature of 0-30℃ and atmospheric pressure; the molar ratio of p-methoxybenzylimine to sodium borohydride is 1:(1-1.3); after the reaction is completed, add acid to hydrolyze the product; adjust the product to weak alkalinity, and obtain p-methoxybenzylamine by extraction, drying, filtration and distillation.

2. The method for preparing p-methoxybenzylamine according to claim 1, characterized in that, In step (2), sodium borohydride is prepared by adding ice water to form a sodium borohydride solution; the reaction vessel of p-methoxybenzylimine is placed in an ice bath, and the sodium borohydride solution is added dropwise under stirring. After the addition is complete, the reaction continues; the reaction vessel is placed at room temperature and the reaction continues.

3. The method for preparing p-methoxybenzylamine according to claim 1, characterized in that, In step (2), after the reaction is complete, the product is acidified to adjust the pH to 9.5-10.

5.

4. The method for preparing p-methoxybenzylamine according to claim 3, characterized in that, In step (2), after the reaction is complete, hydrochloric acid is added dropwise to the product under ice bath conditions to adjust the pH value to 9.5-10.

5.

5. The method for preparing p-methoxybenzylamine according to claim 4, characterized in that, In step (2), after the reaction is complete, dilute hydrochloric acid is added dropwise to the product under ice bath conditions.

6. A p-methoxybenzylamine, characterized in that, It is prepared by the method for preparing p-methoxybenzylamine according to any one of claims 1-5.

7. The use of p-methoxybenzylamine in the preparation of pharmaceutical intermediates, characterized in that, The p-methoxybenzylamine is prepared by any one of the methods for preparing p-methoxybenzylamine according to claims 1-5.

8. The use of p-methoxybenzylamine in the preparation of biofunctional polymer materials, characterized in that, The p-methoxybenzylamine is prepared by any one of the methods for preparing p-methoxybenzylamine according to claims 1-5.

Images