Process for the preparation of salicylamides or salts thereof

Abstract

The present application relates to a method for preparing saligenin or its salt. Specifically, the method comprises the following steps: reacting benzylamine and salicylaldehyde in an organic solvent at a reduced temperature; adding a catalyst Pd / C to the reaction solution to perform hydrogenation to obtain a reaction product containing 2-(benzylaminomethyl)phenol; then adding water to continue hydrogenation stirring to complete the hydrogenation reaction, allowing the reaction solution to stand, filtering, concentrating under reduced pressure to obtain a concentrated solution; adding glacial acetic acid, stirring at low temperature to crystallize, filtering, drying to obtain saligenin acetate; adjusting the pH of the obtained saligenin acetate to 8-9 with ammonia water in water, stirring at low temperature, filtering, drying to obtain saligenin. In the method, the green chemical synthesis process of palladium-carbon catalytic hydrogenation is used, and no special operation is required, which is particularly suitable for industrial production, and the product has high yield and high purity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to an efficient method for preparing salicylamine or its salts, particularly a method for preparing salicylamine or its salts using palladium-catalyzed hydrogenation on carbon. The salicylamine or its salts prepared using the method of this invention have high yields and high purity. Background Technology

[0002] Salicylamine acetate (also known as Hobamine, 2-hydroxybenzylamine acetate, 2-HOBA) is a novel active ingredient derived from Himalayan buckwheat. The molecular formula of salicylamine acetate is C7H9NO.C2H4O2, and its molecular weight is 183.20 (the molecular formula of salicylamine is C7H9NO, and its molecular weight is 123.16). Its chemical structure is as follows: .

[0003] Salicylamine acetate is believed to be a nutritional supplement ingredient specifically designed to address oxidative stress. It is generally considered not to be a traditional broad-spectrum antioxidant, but rather a selective "active dicarbonyl scavenger," targeting and neutralizing only highly toxic and harmful byproducts produced during oxidation (such as IsoLG and malondialdehyde), without interfering with normal free radical signaling and physiological metabolic processes. This resolves the "antioxidant paradox" commonly found in traditional antioxidants. Related clinical studies have confirmed that it can support healthy immune function, improve multiple inflammatory biomarkers, help protect cellular DNA, and maintain normal cell function. It is often added to health-promoting and anti-aging, and immune-boosting dietary supplements; for example, SRW's Cel1 Cell Guardian Capsules from New Zealand contain this ingredient. Salicylamine acetate has passed the US self-certification GRAS (Generally Recognized As Safe) review and New Zealand dietary supplement use permit. The recommended daily safe intake is 50-100 mg / day. Multiple rounds of human safety testing have been completed, showing good tolerability.

[0004] From a chemical structure perspective, the mechanism of action of salicylamine includes the following aspects: the hydroxyl group (-OH) in its molecular structure enables it to effectively interact with and neutralize active molecules; the amine group (-NH2) in its molecular structure enhances its ability to rapidly bind to and inactivate harmful compounds (such as isoleucine adenosine (IsoLG)), which are harmful byproducts of lipid oxidation; and it specifically targets and neutralizes active dicarbonyl groups, preventing them from damaging cellular proteins, lipids, and DNA.

[0005] Salicylamine acetate's innovative mechanism sets it apart: instead of broadly inhibiting oxidative processes, it specifically neutralizes reactive dicarbonyl groups before they cause cellular damage. This selective approach allows normal cellular processes to continue unimpeded while preventing the accumulation of harmful modified proteins that could lead to cellular dysfunction. Reactive dicarbonyl electrophiles, highly reactive byproducts of oxidative stress and lipid peroxidation, are molecules that rapidly bind to proteins, lipids, and DNA, leading to cellular dysfunction, inflammation, and long-term damage. This selective approach allows normal cellular processes to continue unimpeded while preventing the accumulation of harmful modified proteins that could cause cellular dysfunction. Salicylamine acetate acts as a special kind of "scavenger," rather than a traditional antioxidant. Instead of broadly neutralizing all oxidative reactions (which interfere with normal cellular function), it specifically targets highly reactive lipid-derived molecules, eliminating them before they cause cellular damage. It can selectively neutralize harmful free radicals in the cellular environment, protect proteins and lipids from being modified by electrophilic reagents, thereby ensuring cellular health and promoting normal immune system function. It has significant effects in slowing down cellular aging and repairing cellular function, and has good application prospects in the field of dietary nutrition supplementation.

[0006] Several existing literatures describe methods for preparing salicylamine. For example, Holly's literature (Frederick W. Holly, et al., Journal of the American Chemical Society, 1944, 66:1875-1879) describes the preparation of salicylamine from o-hydroxybenzophenone oxime via hydrogenation of palladium on carbon in ethanol and sulfuric acid. Holly's literature uses relatively large amounts of palladium on carbon and concentrated sulfuric acid. The large amount of concentrated sulfuric acid poses a high risk when scaling up the feed rate, which is not conducive to industrial-scale production. The main reaction process is illustrated below: .

[0007] Most current literature uses salicylaldehyde as the starting material to prepare salicylamine. For example, Yu's literature (Yu, Jinhai, et al; Advanced Synthesis and Catalysis, 2022, 364(2): 380-390) records the preparation of salicylamine using salicylaldehyde as the starting material through an enzyme-catalyzed reaction, with a yield of only 36.5%. The main reaction process is illustrated below: .

[0008] CN109836341A (Chinese application number 201711221319.7, Jiangyin Jiyuan) discloses a method for preparing salicylamine acetate. Taking Examples 1 and 2 as examples, the basic operation is as follows: salicylaldehyde (70.4 g, Mr = 122.12, 0.576 mol) is reacted in a system containing acetonitrile, tert-butyl carbamate, triethylsilane, and trifluoroacetic acid for (12~16) hours + (2~4)*n hours. The reaction is quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. Then, the product is reacted in methanol / water / concentrated hydrochloric acid for 16 hours. After treatment, the obtained solid is dissolved in acetic acid and reacted for another 16 hours to obtain 42 g (0.230 mol) of dry salicylamine acetate, with a molar yield of about 39.9% and a total reaction time of more than 50 hours. In Examples 3 and 4, the molar yield is about 33.6% after appropriately changing the reaction conditions for an even longer time. The main reaction process is illustrated below: .

[0009] Paola's literature (Mestichelli, Paola, et al, Organic Letters, 2013, 15(21): 5448-5451) describes the preparation of salicylamine by reacting salicylaldehyde as a starting material with benzyl carbamate, triethylsilane, and trifluoroacetic acid in acetonitrile, followed by hydrogenation in ethyl acetate via palladium on carbon. This method utilizes triethylsilane, which is highly flammable, releases hydrogen violently upon contact with moisture / acids / alkalis, requires stringent storage and operating conditions, is toxic and irritating, and easily decomposes and becomes ineffective under strong acids and high temperatures, making it unsuitable for large-scale industrial production. The reaction process is illustrated below: .

[0010] Chinese Patent Application No. CN111978185B (201910440439.9, technical source) discloses a method for preparing salicylamine acetate. Starting with salicylaldehyde, it reacts with tert-butyl carbamate, triethylsilane, and trifluoroacetic acid in acetonitrile, followed by deprotection with acetic acid to form hydrochloride, thus preparing salicylamine acetate. This method is similar to that in Paola's literature. However, the triethylsilane used is highly flammable, releases hydrogen gas violently upon contact with moisture / acids / alkalis, requires stringent storage and operating conditions, is toxic and irritating, and easily decomposes and becomes ineffective under strong acids and high temperatures, making it unsuitable for large-scale industrial production. The reaction process is illustrated below: .

[0011] Gokhale's paper (Gokhale, Tejas A., et al., Molecular catalysis, 2021, vol.510, 111667) describes the preparation of salicylamine by hydrogenation of salicylaldehyde with ammonia under Ru / MMT or Ni / MMT catalysts. Both Ru / MMT and Ni / MMT catalysts are used in this reaction, and their limited availability hinders the industrialization of salicylamine. Ni / MMT-catalyzed hydrogenation requires a high temperature of 130°C, which is demanding and poses a serious challenge to the safety of industrial production. The reaction process is illustrated below: .

[0012] Gao's literature (Gao, Mingxia, et al, Green Chemistry, 2021, 23(18): 7115-7121) describes the preparation of salicylamine by hydrogenation of salicylaldehyde with ammonia in methanol using Ru / BN-e catalyst and with salicylamine as a co-catalyst. The Ru / BN-e catalyst is used in this reaction. Ru / BN-e catalyst requires special synthesis, is not commercially available, and is difficult to obtain, which is detrimental to the industrial production of salicylamine. The reaction process is illustrated below: .

[0013] Zhang's literature (Zhang, Xiao, et al., Journal of Catalysis, 2022, vol. 416, pp. 129-138) describes the preparation of salicylamine by hydrogenation of salicylaldehyde with ammonia under Ni / diatomite-400 catalysis. Ni / diatomite-400 catalyst is not a commercially available conventional hydrogenation catalyst and is difficult to obtain, making the industrial production of salicylamine challenging. The main reaction process is illustrated below: .

[0014] However, those skilled in the art still expect a simple, easy, high-yield and / or readily available method to prepare high-purity salicylamine. Summary of the Invention

[0015] The purpose of this invention is to provide a method for preparing high-purity salicylamine or its salts, such as acetate, using salicylaldehyde as a starting material, which offers advantages such as simplicity, ease of implementation, greenness, high yield, high product purity, and readily available raw materials. It has been found that at least one of the aforementioned beneficial effects is achieved by using the method of this invention.

[0016] Therefore, the present invention provides a method for preparing salicylamine or its acetate, comprising the following steps: (1) Benzylamine and salicylaldehyde are reacted completely in an organic solvent at a temperature of 0~10℃ in a reaction vessel; (2) Next, catalyst Pd / C was added to the reaction solution, and hydrogen was added and stirred at a temperature of 60~70℃ and a pressure of 1MPa to make the reaction complete, and the reactant containing the product 2-(benzylaminomethyl)phenol was obtained. (3) Next, add an aqueous solution of dicarboxylic acid to the reaction vessel, and continue to add hydrogen and stir at a pressure of 1 MPa at a temperature of 65~80℃ to make the reaction complete. After the reaction solution is cooled, add sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0, let it stand, filter, and concentrate the filtrate under reduced pressure at 50~60℃ to obtain a concentrated solution; the dicarboxylic acid is selected from: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid.

[0017] (4) Add glacial acetic acid to the concentrate, cool it to 0~10℃, for example 0~5℃, keep it warm and stir to precipitate crystals, filter, wash the filter cake and dry it under vacuum to obtain salicylamine acetate. (5) Add the acetate and purified water obtained in the previous step to the reaction flask, stir and cool to 0~10℃, for example 0~5℃, add ammonia water dropwise to adjust the pH to 8~9, and then continue to keep warm and stir for 3~10h, for example 4~7h, filter, rinse the filter cake with water, and vacuum dry to obtain salicylamine.

[0018] According to the method of the present invention, in step (1), the organic solvent is selected from: isopropanol, tetrahydrofuran, methanol, ethanol, acetone, and acetonitrile.

[0019] According to the method of the present invention, in step (1), the reaction is carried out for 4 to 8 hours.

[0020] According to the method of the present invention, in step (1), the amount of benzylamine added is 0.45~0.60mol, preferably 0.48mol, based on 0.4mol of salicylaldehyde, and the amount of organic solvent used is 400~600ml, for example 500ml.

[0021] According to the method of the present invention, in step (2), the catalyst Pd / C is 10% Pd / C.

[0022] According to the method of the present invention, in step (2), 10% Pd / C is used as a catalyst, with an amount of 0.05g to 0.2g, preferably 0.1g, based on 0.4mol of salicylaldehyde feed. According to the method of the present invention, in step (2), the hydrogenation reaction is carried out for 7 to 10 hours.

[0023] According to the method of the present invention, in step (3), the amount of aqueous solution of dicarboxylic acid is 400-600 ml, for example 450-500 ml, based on 0.4 mol of salicylaldehyde.

[0024] According to the method of the present invention, in step (3), the concentration of the dicarboxylic acid in water is 0.2~0.6 mol / L, for example 0.3~0.5 mol / L.

[0025] According to the method of the present invention, in step (3), the hydrogenation reaction is carried out for 4 to 10 hours, for example 5 to 8 hours.

[0026] According to the method of the present invention, in step (3), the sodium hydroxide solution used is a 2M sodium hydroxide solution.

[0027] According to the method of the present invention, in step (3), the pH of the reaction solution is adjusted with sodium hydroxide solution and then allowed to stand for 15 to 60 minutes, for example, 30 minutes.

[0028] According to the method of the present invention, in step (3), the filtrate is concentrated under reduced pressure at 55°C.

[0029] According to the method of the present invention, in step (3), the filtrate is concentrated under reduced pressure to a remaining volume of 1 / 5 to 2 / 5, for example, a remaining volume of 3 / 10.

[0030] According to the method of the present invention, in step (4), the amount of glacial acetic acid added is 0.5~0.7 mol, for example 0.667 mol, based on 0.4 mol of salicylaldehyde feed.

[0031] According to the method of the present invention, in step (4), crystallization takes 4 to 6 hours.

[0032] According to the method of the present invention, in step (4), the filter cake obtained by crystallization filtration is rinsed with 50-200 ml, for example 100-150 ml, of ethanol, tetrahydrofuran, or isopropanol.

[0033] According to the method of the present invention, in step (4), vacuum drying is performed at 40~60°C.

[0034] According to the method of the present invention, in step (5), the amount of purified water added together with acetate is 800~1200ml, for example 1000ml, based on 0.4mol of salicylaldehyde feed.

[0035] According to the method of the present invention, step (5) involves vacuum drying at 50-60°C.

[0036] The method according to the present invention includes the following steps: (1) Add 500 ml of isopropanol to the reaction vessel, cool down and control the temperature to 0~5℃, then add 0.48 mol of benzylamine, then add 0.4 mol of salicylaldehyde dropwise, and continue to stir at this temperature for 6 h. (2) Next, add 0.1g of 10% Pd / C to the reaction solution, and stir with hydrogen at a temperature of 65~70℃ and a pressure of 1MPa for 7h to obtain the reaction product containing 2-(benzylaminomethyl)phenol. (3) Next, add 500 ml of an aqueous solution containing 0.4 mol / L malonic acid to the reaction vessel, heat to 75~80℃, continue to add hydrogen and stir at a pressure of 1 MPa for 5 h, cool the reaction solution to 25~30℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0, let stand for 30 min, filter, concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume, and obtain the concentrated solution; (4) Add 40g of glacial acetic acid to the concentrate, cool to 0~5℃, keep warm and stir to precipitate crystals for 5h, filter, wash the filter cake with 100ml of isopropanol, and dry under vacuum at 55℃ to obtain a white solid, which is salicylamine acetate. (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0~5℃, add ammonia water dropwise to adjust the pH to 8~9, then continue to keep warm and stir for 5h, filter, rinse the filter cake with 100 ml of purified water and dry it under vacuum at 55℃ to obtain a white solid, which is salicylamine.

[0037] The method according to the present invention includes the following steps: (1) Add 500 ml of tetrahydrofuran to the reaction vessel, cool down and control the temperature to 5~10℃, then add 0.48 mol of benzylamine, then add 0.4 mol of salicylaldehyde dropwise, and continue to stir at this temperature for 4 h. (2) Next, add 0.1g of 10% Pd / C to the reaction solution, and stir with hydrogen at a temperature of 60~65℃ and a pressure of 1MPa for 8h to obtain the reaction product containing 2-(benzylaminomethyl)phenol. (3) Next, add 500 ml of an aqueous solution containing 0.3 mol / L malonic acid to the reaction vessel, heat to 70~75℃, continue to add hydrogen and stir at a pressure of 1 MPa for 7 h, cool the reaction solution to 20~25℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0, let stand for 30 min, filter, concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume, and obtain the concentrated solution; (4) Add 40g of glacial acetic acid to the concentrate, cool to 0~5℃, keep warm and stir to precipitate crystals for 4h, filter, wash the filter cake with 100ml of tetrahydrofuran mixture, dry under vacuum at 60℃ to obtain a white solid, which is salicylamine acetate. (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0~5℃, add ammonia water dropwise to adjust the pH to 8~9, then continue to keep warm and stir for 5h, filter, rinse the filter cake with 200 ml of purified water and dry it under vacuum at 55℃ to obtain a white solid, which is salicylamine.

[0038] The method according to the present invention includes the following steps: (1) Add 450 ml of methanol to the reaction vessel, cool down and control the temperature to 2~6℃, then add 0.48 mol of benzylamine, then add 0.4 mol of salicylaldehyde dropwise, and continue to stir at this temperature for 8 h. (2) Next, add 0.1g of 10% Pd / C to the reaction solution, and stir with hydrogen at 55~60℃ and 1MPa for 10h to obtain the reaction product containing 2-(benzylaminomethyl)phenol. (3) Next, add 500 ml of an aqueous solution containing 0.5 mol / L malonic acid to the reaction vessel, heat to 65~70℃, continue to add hydrogen and stir at a pressure of 1 MPa for 8 hours, cool the reaction solution to 25~30℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0, let stand for 30 min, filter, concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume, and obtain the concentrated solution; (4) Add 40g of glacial acetic acid to the concentrate, cool to 0~5℃, keep warm and stir to precipitate crystals for 4h, filter, wash the filter cake with 100ml of tetrahydrofuran, and dry under vacuum at 45℃ to obtain a white solid, which is salicylamine acetate. (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0~5℃, add ammonia water dropwise to adjust the pH to 8~9, then continue to keep warm and stir for 5h, filter, rinse the filter cake with 200 ml of purified water and dry it under vacuum at 55℃ to obtain a white solid, which is salicylamine.

[0039] The method according to the present invention includes the following steps: (1) Add 500 ml of ethanol to the reaction vessel, cool down and control the temperature to 4~8℃, then add 0.48 mol of benzylamine, then add 0.4 mol of salicylaldehyde dropwise, and continue to stir at this temperature for 8 h. (2) Next, add 0.1g of 10% Pd / C to the reaction solution, and stir with hydrogen at a temperature of 60~65℃ and a pressure of 1MPa for 9h to obtain the reaction product containing 2-(benzylaminomethyl)phenol. (3) Next, add 500 ml of an aqueous solution containing 0.35 mol / L malonic acid to the reaction vessel, heat to 70~75℃, continue to add hydrogen and stir at a pressure of 1 MPa for 7 h, cool the reaction solution to 20~25℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0, let stand for 30 min, filter, concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume, and obtain the concentrated solution; (4) Add 40g of glacial acetic acid to the concentrate, cool to 0~5℃, keep warm and stir to precipitate crystals for 6h, filter, wash the filter cake with 150ml of ethanol, and dry under vacuum at 40℃ to obtain a white solid, which is salicylamine acetate. (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0~5℃, add ammonia water dropwise to adjust the pH to 8~9, then continue to keep warm and stir for 5h, filter, rinse the filter cake with 200 ml of purified water and dry it under vacuum at 55℃ to obtain a white solid, which is salicylamine.

[0040] The present invention also provides other specific examples, such as the technical solutions described in Embodiments 6 and 7, especially the technical solution described in Embodiment 6.

[0041] The method of the present invention exhibits superior effects in one or more aspects as described in the context. Attached Figure Description

[0042] Figure 1 2-(benzylaminomethyl)phenol 1H NMR spectrum.

[0043] Figure 2 : Mass spectrum of 2-(benzylaminomethyl)phenol.

[0044] Figure 3 : Hydrogen NMR spectrum of salicylamine acetate.

[0045] Figure 4 : Liquid chromatography-mass spectrometry of salicylamine acetate.

[0046] Figure 5 Hydrogen NMR spectrum of salicylamine.

[0047] Figure 6 Salicylamine liquid chromatography-mass spectrometry.

[0048] Figure 7 HPLC chromatogram for determining the purity of salicylamine. Detailed Implementation

[0049] The following embodiments provided in this invention are for illustrative purposes only and are not intended to be used, nor should they be construed as limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications can be made to the following embodiments without departing from the spirit or scope of the invention. The materials and methods used in the experiments are described generally and / or specifically in this invention. While many of the materials and methods of operation used to achieve the objectives of this invention are well known in the art, the invention is still described in as much detail as possible herein. It will be apparent to those skilled in the art that, unless otherwise stated, the materials and methods of operation used in this invention are well known in the art.

[0050] Example 1: Preparation of salicylamine and salt

[0051] (1) Add 500 ml of isopropanol to the reaction vessel, cool down and control the temperature to 0~5℃, then add benzylamine (51.44 g, 0.48 mol), followed by dropwise addition of salicylaldehyde (48.85 g, 0.4 mol). Continue stirring at this temperature for 6 h. TLC (30% ethyl acetate / cyclohexane) monitoring showed that the reaction was complete (a small sample was taken to determine the amount of the target product, showing a molar yield greater than 99%; unless otherwise specified, the molar yield mentioned in this article refers to the yield starting from salicylaldehyde); the reaction process is shown in the following diagram: .

[0052] (2) Next, 10% Pd / C (0.1 g) was added to the reaction solution, and the mixture was stirred with hydrogen at 1 MPa and the temperature was 65-70℃ for 7 h. The reaction was monitored by TLC (30% ethyl acetate / cyclohexane) to confirm that the reaction was complete, and the reaction product containing 2-(benzylaminomethyl)phenol was obtained. (A small amount of the product was purified and its 1H NMR and mass spectra were measured. The results are as follows.) Figure 1 and Figure 2 (As shown in the figure) (a small sample was taken to determine the amount of the target product, and the molar yield was greater than 99%); the reaction process is illustrated below: .

[0053] (3) Next, add 500 ml of acid-water solution (containing 0.4 mol / L malonic acid) to the reaction vessel, heat to 75-80℃, and continue to stir with hydrogen at a pressure of 1 MPa for 5 h. TLC (50% ethyl acetate / acetone) shows that the reaction is complete. Cool the reaction solution to 25-30℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5-7.0 (actual pH 6.68), let stand for 30 min, filter, and concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume to obtain a concentrated solution (the product is salicylamine; a small sample was taken for determination, and the molar yield of salicylamine based on the volume of the concentrated solution was about 91.6%). The reaction process is illustrated below: .

[0054] (4) Add 40g of glacial acetic acid to the concentrate, cool to 0-5℃, stir and crystallize for 5h, filter, wash the filter cake with 100ml of isopropanol, and dry under vacuum at 55℃ to obtain 65.31g of white solid as salicylamine acetate (molar yield 89.8%, HPLC purity 99.6%). Its 1H NMR spectrum and HPLC-MS spectrum are shown below. Figure 3 and Figure 4 The reaction process is illustrated below: .

[0055] Numerous experiments have shown that after undergoing step (4), the molar yield of the white solid acetate obtained from the concentrate obtained in step (3) typically decreases by 1.3 to 2.5%. Therefore, the molar yield of salicylamine in the concentrate obtained in step (3) is not determined or provided in this paper because the concentrate is a viscous oil, and its disposal, especially when measuring its volume, is very troublesome. It is more convenient to calculate the process yield using the solid obtained in step (4).

[0056] (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0-5℃, add ammonia dropwise to adjust the pH to 8-9 (pH 8.38), then continue to keep warm and stir for 5 hours, filter, rinse the filter cake with 100 ml of purified water and dry under vacuum at 55℃ to obtain 41.56 g of off-white solid, which is salicylamine (molar yield 85.8%, purity 99.9%). Figure 7 (As shown), its 1H NMR spectrum and HPLC-MS / MS spectrum are shown in the figures below. Figure 5 and Figure 6 The reaction process is illustrated below:

[0057] .

[0058] The above Figures 1-6 The 1H NMR, mass spectrometry, and liquid chromatography-mass spectrometry measurements of the three materials were performed by Kanglong Chemical Co., Ltd. In this application, references to purity, HPLC purity, etc., refer to measurements performed using the method described in Test Example 1 of this invention.

[0059] Example 2: Preparation of salicylamine and salt (1) Add 500 ml of tetrahydrofuran to the reaction vessel, cool down and control the temperature to 5~10℃, then add benzylamine (51.44 g, 0.48 mol), then add salicylaldehyde (48.85 g, 0.4 mol) dropwise, and continue to stir at this temperature for 4 h. TLC (30% ethyl acetate / cyclohexane) monitoring showed that the reaction was complete (the molar yield of the target product was greater than 99%). (2) Next, 10% Pd / C (0.1 g) was added to the reaction solution, and the mixture was stirred at 1 MPa and hydrogenated at 60-65℃ for 8 h. TLC (30% ethyl acetate / cyclohexane) showed that the reaction was complete, and the reactant containing the product 2-(benzylaminomethyl)phenol was obtained. The molar yield of the target product was determined by measuring a small sample. (3) Next, add 500 ml of acid aqueous solution (containing 0.3 mol / L malonic acid) to the reaction vessel, heat to 70~75℃, continue to add hydrogen and stir at 1 MPa for 7 h, and monitor the reaction by TLC (50% ethyl acetate / acetone) to ensure that the reaction is complete. Cool the reaction solution to 20~25℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0 (actual pH 6.92), let stand for 30 min, filter, and concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume to obtain the concentrated solution; (4) Add 40g of glacial acetic acid to the concentrate, cool to 0~5℃ and stir to crystallize for 4h, filter, wash the filter cake with 100ml of tetrahydrofuran mixture, and dry under vacuum at 60℃ to obtain a white solid of salicylamine acetate (molar yield 90.7%, HPLC purity 99.5%).

[0060] (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0~5℃, add ammonia water dropwise to adjust the pH to 8~9 (pH 8.83), then continue to keep warm and stir for 6 hours, filter, rinse the filter cake with 200 ml of purified water and dry it under vacuum at 50℃ to obtain a white solid of salicylamine (molar yield 84.3%, purity 99.7%).

[0061] Example 3: Preparation of salicylamine and salt (1) Add 450 ml of methanol to the reaction vessel, cool down and control the temperature to 2~6℃, then add benzylamine (51.44 g, 0.48 mol), then add salicylaldehyde (48.85 g, 0.4 mol) dropwise, and continue to stir at this temperature for 8 h. TLC (30% ethyl acetate / cyclohexane) monitoring showed that the reaction was complete (the molar yield of the target product was greater than 99%). (2) Next, 10% Pd / C (0.1 g) was added to the reaction solution, and the mixture was stirred at 55-60℃ and 1 MPa for 10 h. TLC (30% ethyl acetate / cyclohexane) showed that the reaction was complete, and the reactant containing the product 2-(benzylaminomethyl)phenol was obtained. The molar yield of the target product was determined by measuring a small sample. (3) Next, add 500 ml of acid aqueous solution (containing 0.5 mol / L malonic acid) to the reaction vessel, heat to 65~70℃, continue to add hydrogen and stir at 1 MPa for 8 h, and monitor the reaction by TLC (50% ethyl acetate / acetone) to ensure that the reaction is complete. Cool the reaction solution to 25~30℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0 (actual pH 6.79), let stand for 30 min, filter, and concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume to obtain the concentrated solution; (4) Add 40g of glacial acetic acid to the concentrate, cool to 0~5℃ and stir to crystallize for 4h, filter, wash the filter cake with 100ml of tetrahydrofuran, and dry under vacuum at 45℃ to obtain a white solid, which is salicylamine acetate (molar yield 91.6%, HPLC purity 99.6%).

[0062] (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0~5℃, add ammonia water dropwise to adjust the pH to 8~9 (pH 8.56), then continue to keep warm and stir for 7h, filter, rinse the filter cake with 200 ml of purified water and dry it under vacuum at 60℃ to obtain a white solid of salicylamine (molar yield 85.7%, purity 99.8%).

[0063] Example 4: Preparation of salicylamine and salt (1) Add 500 ml of ethanol to the reaction vessel, cool down and control the temperature to 4~8℃, then add benzylamine (51.44 g, 0.48 mol), then add salicylaldehyde (48.85 g, 0.4 mol) dropwise, and continue to stir at this temperature for 8 h. TLC (30% ethyl acetate / cyclohexane) monitoring showed that the reaction was complete (the molar yield of the target product was greater than 99%). (2) Next, 10% Pd / C (0.1 g) was added to the reaction solution, and the mixture was stirred at 1 MPa and hydrogenated at 60-65℃ for 9 h. TLC (30% ethyl acetate / cyclohexane) showed that the reaction was complete, and the reactant containing the product 2-(benzylaminomethyl)phenol was obtained. The molar yield of the target product was determined by measuring a small sample. (3) Next, add 500 ml of acid aqueous solution (containing 0.35 mol / L malonic acid) to the reaction vessel, heat to 70~75℃, continue to add hydrogen and stir at 1 MPa for 7 h, and monitor the reaction by TLC (50% ethyl acetate / acetone) to ensure that the reaction is complete. Cool the reaction solution to 20~25℃, add 2M sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0 (actual pH 6.59), let stand for 30 min, filter, and concentrate the filtrate under reduced pressure at 55℃ to about 3 / 10 of the remaining volume to obtain the concentrated solution; (4) Add 40g of glacial acetic acid to the concentrate, cool to 0~5℃ and stir for 6h to crystallize, filter, wash the filter cake with 150ml of ethanol, and dry under vacuum at 40℃ to obtain a white solid of salicylamine acetate (molar yield 89.5%, HPLC purity 99.5%).

[0064] (5) Add the acetate obtained in the previous step and 1000 ml of purified water to the reaction flask, stir and cool to 0~5℃, add ammonia water dropwise to adjust the pH to 8~9 (pH 8.73), then continue to keep warm and stir for 4 hours, filter, rinse the filter cake with 200 ml of purified water and dry it under vacuum at 55℃ to obtain a white solid of salicylamine (molar yield 84.6%, purity 99.8%).

[0065] Examples 1-4 above are typical examples obtained by the applicant after extensive research. It has been found that the method of the present invention can achieve the conversion from salicylaldehyde to salicylamine in a relatively short time using a "one-shot" method under mild reaction conditions. Even more unexpectedly, it has been found that in the hydrogenation reaction of the aqueous mixture in step (3) above, the addition of an appropriate amount of certain dicarboxylic acids can greatly increase the yield of the target material and the product purity is quite high, as detailed below.

[0066] Example 5: Preparation of salicylamine and salt The procedure was carried out according to Example 1, but in step (3), the acidic aqueous solution was replaced with an aqueous solution containing 0.1 mol / L, 0.2 mol / L, 0.8 mol / L, 1.0 mol / L, and 1.5 mol / L malonic acid. The results showed that the molar yields (HPLC purity) of the white solid salicylamine acetate obtained in step (4) were 80.3% (purity 99.8%), 84.7% (purity 99.5%), 91.5% (purity 98.4%), 89.7% (purity 96.2%), and 90.3% (purity 93.2%), respectively. These results show that the yield of the target analyte decreases when the amount of malonic acid decreases, but when the amount of malonic acid is too high, although the molar yield can be maintained at a high level, the HPLC purity of the product is significantly reduced, which is particularly undesirable.

[0067] Example 6: Preparation of salicylamine and salt The procedure was carried out according to Example 1, but in step (3), the acidic aqueous solution was replaced with an aqueous solution containing 0.3 mol / L, 0.35 mol / L, 0.4 mol / L, or 0.5 mol / L succinic acid. The results showed that the molar yields of the white solid salicylamine acetate obtained in step (4) were 89.6%, 90.3%, 91.4%, and 89.9%, respectively, and the HPLC purity of all four products was above 99.3%. In addition, when the succinic acid concentration was changed to 0.1 mol / L, 0.2 mol / L, 0.8 mol / L, and 1.5 mol / L, the trend described in Example 5 was also observed. The product yields in the two low-concentration examples were 79.7% and 84.2%, respectively, while the product yields in the two high-concentration examples were ideal, but the purities were 98.1% and 92.5%, respectively.

[0068] Example 7: Preparation of salicylamine and salt The procedure was carried out according to Example 1, but in step (3), the acidic aqueous solution was replaced with an aqueous solution containing 0.3 mol / L, 0.4 mol / L, or 0.5 mol / L oxalic acid. The results showed that the molar yields of the white solid salicylamine acetate obtained in step (4) were 87.2%, 86.7%, and 88.4%, respectively, and the HPLC purity of the three products was all above 99.3%. The procedure was carried out according to Example 1, but in step (3), the acidic aqueous solution was replaced with an aqueous solution containing 0.3 mol / L, 0.4 mol / L, or 0.5 mol / L glutaric acid. The results showed that the molar yields of the white solid salicylamine acetate obtained in step (4) were 86.4%, 88.1%, and 87.2%, respectively, and the HPLC purity of the three products was all above 99.3%. These results show that although the molar yield was higher when the acidic aqueous solution was replaced with oxalic acid and glutaric acid in step (3), it was slightly lower than that of malonic acid and succinic acid.

[0069] Example 8: Preparation of salicylamine and salt The procedure was carried out in accordance with Example 1, but in step (3), the aqueous acid solution was replaced with an aqueous solution of 0.4 mol / L formic acid, acetic acid and propionic acid; the results showed that the molar yields of the white solid salicylamine acetate obtained in step (4) were 77.4%, 79.6% and 76.7%, respectively.

[0070] The procedure was carried out in accordance with Example 1, but in step (3), the acid aqueous solution was replaced with an aqueous solution of 0.4 mol / L citric acid and fumaric acid; the results showed that the molar yields of the white solid salicylamine acetate obtained in step (4) were 83.4% (purity 98.6%) and 85.8% (purity 98.1%), respectively.

[0071] Example 9: Preparation of salicylamine and salt The procedure was carried out according to Example 1, but in step (3), the acidic aqueous solution was replaced with an aqueous solution containing 0.1 mol / L, 0.3 mol / L, 0.5 mol / L, and 0.7 mol / L hydrochloric acid. The results showed that the molar yields of the white solid salicylamine acetate obtained in step (4) were 74.3%, 76.5%, 73.8%, and 75.2%, respectively. Similarly, if the acidic aqueous solution in step (3) was replaced with the above four concentrations containing sulfuric acid, the molar yield of the product in step (4) was in the range of 72% to 75%. In addition, the procedure was carried out according to Example 1, but in step (3), the acidic aqueous solution was replaced with an equal volume of water, i.e., no acid was added to the water. The results showed that the molar yield of the white solid salicylamine acetate obtained in step (4) was 46.7%.

[0072] In general, the inventors have found that when an appropriate amount of a special type of dicarboxylic acid, such as oxalic acid, is added to the aqueous hydrogenation reaction material in step (3), the product yield and purity are high. However, when the amount of the dicarboxylic acid is too small, the yield decreases, and when the amount is too large, the product purity decreases. When other dicarboxylic acids or other organic acids are used, the yield decreases significantly, and when inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid are used, the yield is also significantly lower.

[0073] Experimental Example 1: Determination of the purity of salicylamine acetate and salicylamine This embodiment provides a method for determining the purity of salicylamine acetate and salicylamine using HPLC, as detailed below.

[0074] (i) Chromatographic conditions: The procedure was performed according to the high-performance liquid chromatography method described in Appendix IV of the 2025 edition of the Chinese Pharmacopoeia. Column: A chromatographic column with octadecylsilane-bonded silica gel as the stationary phase [Phenomenex Gemini C]. 18 [Column, 250×4.6mm, 5µm] Flow rate: 1.0 ml / min Mobile phase A: 0.01 mol / L sodium dihydrogen phosphate solution (pH adjusted to 4.5 with phosphoric acid or sodium hydroxide solution); Mobile phase B: acetonitrile. Linear gradient elution program: isocratic elution with a 60% mobile phase A / 40% mobile phase B mixture from 0 to 20 min; from 20 to 65 min, the elution gradient changes from 60% mobile phase A / 40% mobile phase B to 30% mobile phase A / 70% mobile phase B. Detection wavelength: 254nm Column temperature: 25℃ Injection volume: 20µl Test sample: Prepare a 0.5 mg / ml solution using a mixture of 60% mobile phase A and 40% mobile phase B. The area-normalized purity of the salicylamine obtained in step (5) of Example 1 was measured to be 99.86%. Figure 1 As shown, the retention time of salicylamine is about 36 min; in addition, the area normalized purity of the salicylamine acetate obtained in step (4) of Example 1 was measured to be 99.57%.

[0075] The method for preparing salicylamine or its acetate in this invention uses a green chemical synthesis process of palladium-catalyzed hydrogenation on carbon, which requires no special operations and is particularly suitable for industrial production, resulting in high product yield and high purity.

[0076] The present invention has been illustrated with the above embodiments to explain the detailed method of the present invention. However, the present invention is not limited to the detailed method described above, that is, it does not mean that the present invention must rely on the detailed method described above to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing salicylamine or its acetate, comprising the following steps: (1) In a reaction vessel, at a temperature of 0~10℃, benzylamine and salicylaldehyde are allowed to react completely in an organic solvent; (2) Next, 10% Pd / C catalyst was added to the reaction solution, and hydrogen was added and stirred at 60~70℃ and 1MPa to make the reaction complete, and the reactant containing the product 2-(benzylaminomethyl)phenol was obtained; the amount of 10% Pd / C was 0.1g. (3) Next, add an aqueous solution of dicarboxylic acid to the reactor, and continue to stir with hydrogen at a pressure of 1 MPa at a temperature of 65~80℃ to make the reaction complete. After the reaction solution is cooled, add sodium hydroxide solution to adjust the pH of the reaction solution to 6.5~7.0, let it stand, filter, and concentrate the filtrate under reduced pressure at 50~60℃ to obtain a concentrated solution; the dicarboxylic acid is selected from: oxalic acid, malonic acid, succinic acid; the concentration of the dicarboxylic acid in water is 0.3~0.5 mol / L, and the amount of aqueous solution of dicarboxylic acid is 450~500 ml based on 0.4 mol of salicylaldehyde as feed. (4) Add glacial acetic acid to the concentrate, cool to 0~10℃, keep warm and stir to precipitate crystals, filter, wash the filter cake and dry it under vacuum to obtain salicylamine acetate. (5) Add the acetate and purified water obtained in the previous step to the reaction flask, stir and cool to 0~10℃, add ammonia water dropwise to adjust the pH to 8~9, then continue to keep warm and stir for 3~10h, filter, rinse the filter cake with water, and vacuum dry to obtain salicylamine.

2. The method according to claim 1, wherein in step (1), the organic solvent is selected from: isopropanol, tetrahydrofuran, methanol, and ethanol.

3. According to the method of claim 1, in step (1), the reaction is carried out for 4 to 8 hours.

4. According to the method of claim 1, in step (1), the amount of benzylamine fed is 0.45~0.60 mol per 0.4 mol of salicylaldehyde.

5. According to the method of claim 1, in step (1), the amount of organic solvent used is 400~600 ml based on 0.4 mol of salicylaldehyde.

6. According to the method of claim 1, in step (3), the hydrogenation reaction is carried out for 4 to 10 hours; the sodium hydroxide solution used is a 2M sodium hydroxide solution.

7. According to the method of claim 1, in step (3), the pH of the reaction solution is adjusted with sodium hydroxide solution and then allowed to stand for 15-60 min.

8. According to the method of claim 1, in step (3), the filtrate is concentrated under reduced pressure at 55°C.

9. According to the method of claim 1, in step (3), the filtrate is concentrated under reduced pressure to the remaining 1 / 5 to 2 / 5 of its volume.

10. According to the method of claim 1, in step (4), the amount of glacial acetic acid added is 0.5~0.7 mol based on 0.4 mol of salicylaldehyde.

11. According to the method of claim 1, in step (4), crystallization takes 4 to 6 hours; the filter cake obtained by crystallization filtration is rinsed with 50 to 200 ml of ethanol, tetrahydrofuran or isopropanol.

12. According to the method of claim 1, in step (4), the rinsing is followed by vacuum drying at 40~60℃.

13. According to the method of claim 1, in step (5), the amount of purified water added together with acetate is 800~1200 ml, based on 0.4 mol of salicylaldehyde feed.

14. According to the method of claim 1, in step (5), the material is vacuum dried at 50~60°C after being rinsed.

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