A p-methoxybenzylamine and its preparation method and use

Abstract

A kind of p-methoxy benzylamine and its preparation method and use, belong to acyclic or carbocyclic compound field;Preparation method includes the following steps: (1) in reaction vessel, p-methoxy benzaldehyde is added, ethanol solution and ammonia are added in turn, heated and stirred, and is reacted at 50~90 DEG C and normal pressure environment;After reaction, distillation is carried out under reduced pressure, and p-methoxy benzaldimine is prepared;The molar ratio of p-methoxy benzaldehyde and ammonia is 1: (1~1.3) ;(2) p-methoxy benzaldimine is dissolved in methanol, sodium hydroxide solution and 4-dimethylaminopyridine are added, then sodium borohydride is added, and is reacted at 0~30 DEG C and normal pressure;After reaction is completed, product is hydrolyzed with acid;Product is adjusted to weak alkaline, and p-methoxy benzylamine is prepared after extraction, drying, filtration and distillation.The present application introduces a new strategy for synthesizing p-methoxy benzylamine, and the reaction does not involve high temperature, and the reaction condition is more mild and controllable.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of acyclic or carbocyclic compounds, in particular to a p-methoxybenzylamine and a preparation method and use thereof. BACKGROUND

[0002] P-methoxybenzylamine, also known as 4-methoxybenzylamine, has CAS number 2393-23-9, and has multiple effects in the fields of medicine and biology, such as anti-tumor, antibacterial, antioxidant, cardiovascular drug intermediates and functional biological materials. At present, there are three methods for synthesizing p-methoxybenzylamine:

[0003] The first method is to use p-methoxybenzyl alcohol as a raw material, first chlorinate it in an SOCl2 / DMF system at 0-40 °C to obtain p-methoxybenzyl chloride, then reflux it with urotropine in n-butanol for 8 h to form a quaternary ammonium salt, and then hydrolyze it with 6 M HCl-isopropyl alcohol for 4-6 h, cool it, adjust the alkali, extract and distill it to obtain p-methoxybenzylamine. The specific reaction equation is as follows, but the reaction operation is complex and the yield is low.

[0004] .

[0005] The second method is to dissolve p-methoxybenzonitrile in liquid ammonia-methanol, and catalytically hydrogenate it at 120 °C for 6 h under the catalysis of 60% Ni / SiO2 or Ru(II) complex, ≤10 atm H2. The reaction needs a high-pressure kettle and a flammable catalyst in the presence of hydrogen, which is dangerous and not environmentally friendly.

[0006] The third method is to use p-methoxybenzaldehyde and ammonium formate as raw materials, heat them to a molten state under N2 conditions to undergo reductive amination. Add p-methoxybenzaldehyde and ammonium formate to a three-necked flask at one time, replace the air with nitrogen. Slowly warm it to 170-180 °C under stirring, melt the material into a homogeneous phase, and start to release CO2 and NH3 bubbles. After continuing the reaction for 2 hours, cool the reaction system to 60-70 °C, pour it into ice water, adjust the pH to strong alkaline, and free p-methoxybenzylamine. Extract it with diethyl ether, dry and filter it, remove the diethyl ether, and distill it under reduced pressure to collect the fraction to obtain p-methoxybenzylamine.

[0007]

[0008] This route has a high reaction temperature and serious three wastes, which is not conducive to mass production. SUMMARY

[0009] The purpose of the present application is to provide a preparation method of p-methoxybenzylamine, which uses ammonia water instead of existing liquid ammonia as a nitrogen source, and uses sodium borohydride for reaction. Starting from the raw material p-methoxybenzaldehyde, it goes through the intermediate state of p-methoxybenzaldimine to obtain the final product p-methoxybenzylamine.

[0010] The present application also provides a p-methoxybenzylamine prepared by the above method.

[0011] To achieve the above object, the present application adopts the following technical scheme:

[0012] A method for preparing p-methoxybenzylamine, comprising the following steps:

[0013] (1) adding p-methoxybenzaldehyde into a reaction container, and then adding ethanol solution and ammonia water successively, and stirring under heating, and reacting at 50-90 ℃ and normal pressure; and distilling after the reaction under reduced pressure to prepare p-methoxybenzaldimine; the molar ratio of p-methoxybenzaldehyde to ammonia water is 1: (1-1.3) ;

[0014] (2) dissolving the p-methoxybenzaldimine in methanol, and then adding sodium hydroxide solution and 4-dimethylaminopyridine, and further adding sodium borohydride, and reacting at 0-30 ℃ and normal pressure; the molar ratio of p-methoxybenzaldimine to sodium borohydride is 1: (1-1.3) ; after the reaction is completed, the product is hydrolyzed with acid; the product is adjusted to be weakly alkaline, and then extracted, dried, filtered and distilled to prepare p-methoxybenzylamine.

[0015] Optimally, in step (2), the sodium borohydride is added into ice water to form a sodium borohydride solution; the reaction container of the p-methoxybenzaldimine is placed in an ice bath, and the sodium borohydride solution is added dropwise under stirring, and the reaction is continued after the dropwise addition is completed; the reaction container is placed in a room temperature environment, and the reaction is continued.

[0016] Optimally, in step (2), after the reaction is completed, the product is adjusted to pH 9.5-10.5 with acid.

[0017] Optimally, in step (2), after the reaction is completed, the product is adjusted to pH 9.5-10.5 with hydrochloric acid under ice bath condition.

[0018] Optimally, in step (2), after the reaction is completed, the product is added dropwise with dilute hydrochloric acid under ice bath condition.

[0019] A p-methoxybenzylamine prepared by the above method.

[0020] Use of p-methoxybenzylamine in preparing a pharmaceutical intermediate, wherein the p-methoxybenzylamine is prepared by the above method.

[0021] Use of p-methoxybenzylamine in preparing a biofunctional polymer material, wherein the p-methoxybenzylamine is prepared by the above method.

[0022] Compared with the prior art, one of the above technical solutions has the following beneficial effects:

[0023] The present scheme provides a preparation method of p-methoxybenzylamine, which uses ammonia water instead of existing liquid ammonia as a nitrogen source, and uses sodium borohydride for reaction, starting from the raw material p-methoxybenzaldehyde, passing through the intermediate state of p-methoxybenzaldehyde imine, to obtain the final product p-methoxybenzylamine; the present application introduces a new strategy for synthesizing p-methoxybenzylamine, the reaction condition does not involve high temperature, the reaction condition is more mild and controllable, and solves the problems of complex reaction operation, low yield, harsh synthesis and serious three wastes existing in the synthesis of p-methoxybenzylamine. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of the final product p-methoxybenzylamine I of embodiment 1 of the present application;

[0025] Figure 2 is the nuclear magnetic resonance carbon spectrum of the final product p-methoxybenzylamine I of embodiment 1 of the present application;

[0026] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of the intermediate p-methoxybenzaldehyde imine M2 of embodiment 1 of the present application;

[0027] Figure 4 is the nuclear magnetic resonance carbon spectrum of the intermediate p-methoxybenzaldehyde imine M2 of embodiment 1 of the present application. DETAILED DESCRIPTION

[0028] The embodiments of the present application are described in detail below, examples of which are shown in the accompanying drawings, wherein the same or similar reference signs represent the same or similar elements or elements having the same or similar functions throughout. The embodiments described below by referring to the drawings are exemplary and are only used to explain the present application, and cannot be understood as a limitation of the present application.

[0029] In order to facilitate the understanding of the present application, the present application is described more fully below. The present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive. The specific techniques or conditions not mentioned in the embodiments are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The reagents or instruments not marked with the manufacturer are all conventional products that can be obtained by market purchase.

[0030] A preparation method of p-methoxybenzylamine, comprising the following steps:

[0031] (1) adding p-methoxybenzaldehyde into a reaction container, adding ethanol solution and ammonia water in sequence, heating and stirring, and reacting at 50-90°C and normal pressure; distilling after the reaction under reduced pressure to obtain p-methoxybenzaldimine; the molar ratio of p-methoxybenzaldehyde to ammonia water is 1:(1-1.3);

[0032] The chemical reaction formula of p-methoxybenzaldehyde and ammonia water is as follows:

[0033] ;

[0034] The present scheme uses ammonia water (NH3·H2O) as the nitrogen source, mainly considering that ammonia water has relatively slow volatilization speed, relatively small toxicity and corrosion, is safer as a whole, and is relatively cheaper than liquid ammonia. Based on the above advantages, the present scheme does not need high-pressure hydrogenation reaction, and is relatively safe. The prior art uses liquid ammonia (NH3) as the nitrogen source, which is stored in a pressure-resistant steel bottle or a steel tank, has corrosion and is easy to volatilize, and participates in high-pressure hydrogenation, so the chemical accident rate is high. In step (1), it can be observed that the solution changes from colorless to light yellow, and after removing ethanol under reduced pressure, a light yellow oil, i.e. p-methoxybenzaldimine, can be obtained.

[0035] (2) dissolving p-methoxybenzaldimine in methanol, adding sodium hydroxide solution and 4-dimethylaminopyridine, and then adding sodium borohydride, and reacting at a temperature of 0-30°C and normal pressure; the molar ratio of p-methoxybenzaldimine to sodium borohydride is 1:(1-1.3); after the reaction is completed, the product is hydrolyzed with acid; the product is adjusted to weak alkaline, and p-methoxybenzylamine is obtained after extraction, drying, filtration and distillation.

[0036] The chemical reaction formula of p-methoxybenzaldimine and sodium borohydride is as follows:

[0037] ;

[0038] In the reaction of step (2), sodium hydroxide solution and 4-dimethylaminopyridine mainly play a catalytic role, and their addition amount can be determined according to the reaction rate as needed; generally, the molar amount of sodium hydroxide solution can be 0.5-0.8 times that of p-methoxybenzaldimine, and the molar amount of 4-dimethylaminopyridine can be 0.01-0.05 times that of p-methoxybenzaldimine. The reaction temperature of p-methoxybenzaldimine and sodium borohydride is 0-30°C, and the reaction can be carried out at room temperature. The product is hydrolyzed with acid to remove excess sodium borohydride, and is adjusted to weak alkaline to free benzylamine, so as to facilitate the subsequent extraction step.

[0039] The scheme provides a preparation method of p-methoxybenzylamine, which uses ammonia water instead of existing liquid ammonia as a nitrogen source, and uses sodium borohydride to react, starting from the raw material p-methoxybenzaldehyde, through the intermediate state of p-methoxybenzimidamide, to obtain the final product p-methoxybenzylamine; the present application introduces a new strategy for synthesizing p-methoxybenzylamine, the reaction conditions do not involve high temperature, hydrogen is not used, the reaction conditions are more mild and controllable, and the problems of complex reaction operation, low yield, harsh synthesis and serious three wastes existing in the synthesis of p-methoxybenzylamine are solved.

[0040] Optimally, in step (2), sodium borohydride is added to ice water to prepare a sodium borohydride solution; the reaction container of p-methoxybenzimidamide is placed in an ice bath, and the sodium borohydride solution is added dropwise under stirring, and the reaction continues after the dropwise addition is completed.

[0041] The sodium borohydride of the scheme can be added to the p-methoxybenzimidamide in powder form as needed; in the optimal embodiment, the sodium borohydride is preferably added to ice water to prepare a sodium borohydride solution, mainly because after being prepared into a solution, the sodium borohydride can be more uniformly dispersed in the reaction system of p-methoxybenzimidamide, avoiding the local concentration from being too high to cause a violent reaction, so that the reaction process is more controllable. The sodium borohydride is added to ice water to prepare a sodium borohydride solution, and the ice water reduces the temperature of the reaction system, which can avoid local overheating or violent hydrogen release of p-methoxybenzimidamide, so that the reaction is more stable and the generation of by-products is reduced; at the same time, the ice water environment significantly reduces the hygroscopic decomposition of sodium borohydride, prolongs the stability of the solution, especially the slow dropwise addition process.

[0042] Optimally, in step (2), after the reaction is completed, the product is added to acid to adjust the pH value to 9.5-10.5.

[0043] After the product is added to the acid, the sodium borohydride can react with the acid to remove the excess sodium borohydride in the product; and adjusting the pH value to 9.5-10.5 can make the product in a weak alkaline environment, which is conducive to the free release of benzylamine.

[0044] Optimally, in step (2), after the reaction is completed, the product is added to ice water to adjust the pH value to 9.5-10.5.

[0045] This step places the reaction container of the product in an ice bath and slowly adds hydrochloric acid, mainly to avoid adding too much hydrochloric acid to the product at one time, and then to avoid adding too much water to the reaction system, avoiding the reaction from being too violent; at the same time, the ice bath can reduce the reaction temperature, so that the reaction is more stable and the generation of by-products is reduced.

[0046] Optimally, in step (2), after the reaction is completed, the product is added to ice water to adjust the pH value to 9.5-10.5.

[0047] The present scheme uses dilute hydrochloric acid instead of concentrated hydrochloric acid. In dilute hydrochloric acid, the reaction rate is fast but controllable due to the moderate concentration of hydrogen ions. In addition, sodium chloride, boric acid, and hydrogen gas are generated in an ice bath environment, and the reaction process is relatively stable.

[0048] A p-methoxybenzylamine prepared by the above-mentioned method for preparing a p-methoxybenzylamine.

[0049] The use of a p-methoxybenzylamine in the preparation of a pharmaceutical intermediate, the p-methoxybenzylamine being prepared by the above-mentioned method for preparing a p-methoxybenzylamine.

[0050] The use of a p-methoxybenzylamine in the preparation of a biological functional polymer material, the p-methoxybenzylamine being prepared by the above-mentioned method for preparing a p-methoxybenzylamine.

[0051] The p-methoxybenzylamine can be applied in the field of medicine and biology, and has multiple effects such as anti-tumor, antibacterial, antioxidant, cardiovascular drug intermediates, and functional biological materials.

[0052] Example 1, a p-methoxybenzylamine is synthesized according to the following steps:

[0053] Step (1): In a 100 mL three-necked flask, add p-methoxybenzaldehyde 0.53 g and anhydrous ethanol 20 mL in sequence, and stir at room temperature until completely dissolved. Slowly add 25% ammonia water 0.55 mL dropwise within 10 min, and reflux at 60°C for 3 h. The solution gradually changes from clear to yellow transparent. After the reaction is completed, cool to room temperature; remove ethanol by rotary evaporation under reduced pressure to obtain a light yellow oil. Distill under reduced pressure to obtain p-methoxybenzaldimine 0.48 g. The yield of p-methoxybenzaldimine is 90%, and the purity is ≥ 98%.

[0054] Step (2): Dissolve 1.05 g of p-methoxybenzaldimine in 20 mL of anhydrous methanol in a three-necked flask, and replace with nitrogen. Then add 0.01 g of p-dimethylaminopyridine and 2% NaOH solution 2 mL, and stir to dissolve. Under ice bath conditions, slowly add NaBH4 aqueous solution (0.95 g of NaBH4 is 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 completed, slowly add 1 M HCl dropwise under ice bath to adjust the pH to about 10, and free the benzylamine. Extract with ethyl acetate, and distill to obtain p-methoxybenzylamine 0.93 g. The yield of p-methoxybenzylamine is 89%, and the purity is ≥ 98%.

[0055] The chemical reaction formulas of the above steps (1) and (2) are as follows:

[0056] ;

[0057] Product analysis:

[0058] 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 :

[0059] For p-methoxybenzylimine, Figure 3 and Figure 4 middle, 1 H 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.

[0060] 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); 13C NMR (125 MHz, CDC13) 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.

[0061] Example 2, p-methoxybenzylamine was synthesized according to the following procedure:

[0062] Step (1): In a 100 mL flask, p-methoxybenzaldehyde 0.53 g and absolute ethanol 25 mL were added sequentially, stirred at room temperature until complete dissolution. 25% Ammonia water 0.60 mL was added dropwise slowly within 15 min, refluxed at 80 °C for 4 h, the solution gradually changed from clear to yellow transparent. After the reaction was completed, it was cooled to room temperature; the ethanol was removed by rotary evaporation under reduced pressure, and a light yellow oil was obtained. Distillation under reduced pressure gave p-methoxybenzaldimine 0.46 g. The yield of p-methoxybenzaldimine was 86%, purity ≥ 98%.

[0063] Step (2): 1.05 g of p-methoxybenzaldimine was dissolved in 20 mL of absolute methanol in a flask, and after nitrogen replacement, 0.01 g of p-dimethylaminopyridine and 2% NaOH solution 2 mL were added and stirred to dissolve. Under ice bath conditions, NaBH4 aqueous solution (1 g of NaBH4 was dissolved in 5 mL of ice water to make a 5 mL solution) was added dropwise slowly. After continuing to stir for 40 min, the reaction was carried out at room temperature for 4 h. After the reaction was completed, 1 M HCl was added dropwise slowly under ice bath conditions to adjust the pH to about 10, and the benzylamine was liberated. Extraction with ethyl acetate gave p-methoxybenzylamine 0.90 g. The yield of p-methoxybenzylamine was 86%, purity ≥ 98%.

[0064] Example 3, p-methoxybenzylamine was synthesized according to the following procedure:

[0065] Step (1): In a 100 mL flask, p-methoxybenzaldehyde 0.53 g and absolute ethanol 25 mL were added sequentially, stirred at room temperature until complete dissolution. 25% Ammonia water 0.60 mL was added dropwise slowly within 15 min, refluxed at 80 °C for 4 h, the solution gradually changed from clear to yellow transparent. After the reaction was completed, it was cooled to room temperature; the ethanol was removed by rotary evaporation under reduced pressure, and a light yellow oil was obtained. Distillation under reduced pressure gave p-methoxybenzaldimine 0.46 g. The yield of p-methoxybenzaldimine was 86%, purity ≥ 98%.

[0066] Step (2): 1.05 g of p-methoxybenzaldimine was dissolved in 20 mL of anhydrous methanol in a three-necked flask, and after nitrogen replacement, 0.01 g of p-dimethylaminopyridine and 2% NaOH solution 2 mL were added, and stirring was performed for dissolution. Under ice bath conditions, NaBH4 aqueous solution (0.98 g of NaBH4 was dissolved in 5 mL of ice water to prepare a 5 mL solution) was slowly added dropwise. After 35 min of continuous stirring, the reaction was carried out at room temperature for 3.5 h. After the reaction was completed, 1 M HCl was slowly added dropwise under ice bath conditions to adjust the pH to about 10, and the benzylamine was released. Ethyl acetate was used for extraction, and p-methoxybenzylamine 0.89 g was obtained by distillation. The yield of p-methoxybenzylamine was 85%, and the purity was ≥98%.

[0067] In summary, the intermediate state of the present scheme has good production efficiency for p-methoxybenzaldimine and p-methoxybenzylamine. The average yield of step (1) is 89%, and the average yield of step (2) is 87%, which has good production efficiency. The preparation method of the present scheme uses ammonia water instead of existing liquid ammonia as a nitrogen source, and uses sodium borohydride for reaction. Starting from the raw material p-methoxybenzaldehyde, the intermediate state of p-methoxybenzaldimine is obtained, and the final product p-methoxybenzylamine is obtained. The present application introduces a new strategy for synthesizing p-methoxybenzylamine. The reaction conditions do not involve high temperature, and the reaction conditions are more controllable and mild. It can be a new strategy for green, safe and low-cost synthesis of p-methoxybenzylamine.

[0068] Although the embodiments of the present application have been shown and described, those of ordinary skill in the art can understand that various changes, modifications, replacements and variations can be made to these embodiments without departing from the principles and purposes of the present application, and the scope of the present application 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 as catalyst, and then add sodium borohydride. 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 complete, the product is hydrolyzed with acid. The product is adjusted to a weakly alkaline state, and p-methoxybenzylamine is obtained by extraction, drying, filtration and distillation. 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.

2. 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.

3. The method for preparing p-methoxybenzylamine according to claim 2, 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.

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

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