A method for efficiently synthesizing 3-amino furazan-4-carboxylic acid from 1,2,3-propanetriol

Abstract

The application discloses a method for synthesizing 3-amino furazan-4-carboxylic acid from 1,2,3-propanetriol, and belongs to the technical field of chemical engineering and chemistry.The method solves the problems of the prior art, such as the use of toxic raw materials, highly toxic and flammable and explosive reagents, and the lack of greenness and safety, etc.The 1,2,3-propanetriol and a hydroxylamine solution are dissolved in an alkaline aqueous phase, and through adjustment of the reaction temperature, the 1,2,3-propanetriol successively undergoes catalytic reaction, dehydration reaction and neutralization reaction, and finally 3-amino furazan-4-carboxylic acid is synthesized, with a yield of 55%.The method has the advantages of safe and non-toxic raw materials, short synthesis reaction time, simple reaction steps, easy control of reaction temperature, high product yield, less pollutants, etc.Compared with the traditional method for synthesizing 3-amino furazan-4-carboxylic acid, the method saves production cost, the product preparation process is green and environmentally friendly, and is suitable for the green and sustainable development of industrial production of 3-amino furazan-4-carboxylic acid.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical engineering and chemistry, and particularly relates to a method for efficiently synthesizing 3-amino furazan-4-carboxylic acid from 1,2,3-propanetriol. BACKGROUND

[0002] 3-amino furazan-4-carboxylic acid (AFCA) is an important multifunctional oxidized furazan compound, which has a wide application prospect due to its unique molecular structure, especially in the fields of pharmaceuticals, materials, and industries. Oxidized furazan compounds are an important class of NO donors, which have potential application value in the medical field and can be used to synthesize medicines with functions of preventing leukemia, resisting viruses, and inhibiting AIDS virus, etc. In other industrial applications, furazan compounds are often used as metal polishing agents, preservatives, photographic sensitization accelerators, etc.

[0003] Currently, the synthesis of AFCA mainly relies on two chemical methods. One is to use methyl cyanoacetate as a raw material to synthesize AFCA by reaction with hydroxylamine hydrochloride (literature: Synthesis and Performance Research of Novel Insensitive Energetic Plasticizer 3-Nitrofurazan-4-methyl Ether, Energetic Materials, 2011, 19 (6): 735-738), and the second method is to use cyanoacetamide as a starting material to prepare AFCA through nitrosation, addition, and cyclization (literature: Synthesis and Characterization of 3-Amino Furazan-4-Carboxylic Acid, Chemical Reagents, 2019, 41 (01): 93-95). Although these methods have made progress in the synthesis of AFCA, they use toxic cyanide compounds as raw materials and use highly toxic and flammable and explosive reagents, which brings challenges to the safety and environmental friendliness of the AFCA synthesis process. Therefore, it is necessary to explore new routes and methods for the green synthesis of AFCA to significantly reduce the use of toxic raw materials and solvents in the traditional synthesis of AFCA, so as to promote the industrialization process and the wide application in various fields. SUMMARY

[0004] The present application provides a method for efficiently synthesizing 3-amino furazan-4-carboxylic acid from 1,2,3-propanetriol, which solves the problems of using toxic raw materials, highly toxic and flammable and explosive reagents, and lack of greenness and safety in the existing synthesis method of 3-amino furazan-4-carboxylic acid.

[0005] To solve the above technical problems, the present application realizes the following technical scheme:

[0006] The purpose of the present application is to provide a method for efficiently synthesizing 3-amino furazan-4-carboxylic acid from 1,2,3-propanetriol, which comprises:

[0007] (1) mixed dissolution: 1,2,3-propanetriol, hydroxylamine salt and inorganic base are weighed, and the three raw materials are mixed and dissolved below 40°C to obtain a reaction solution;

[0008] (2) catalytic reaction: the temperature of the reaction solution is controlled below 40°C, and the catalytic reaction is carried out under stirring, then the reaction solution is warmed to a certain temperature, and the catalytic reaction is continued;

[0009] (3) dehydration reaction: the reaction solution after the catalytic reaction in (2) is warmed, and the dehydration reaction is carried out under stirring;

[0010] (4) neutralization reaction: the reaction solution after the dehydration reaction in (3) is cooled, and acid is added under stirring to adjust the pH, then the reaction solution after pH adjustment is cooled to below 20°C to obtain a suspension reaction solution;

[0011] (5) post-treatment: the suspension reaction solution is filtered, and the solid is obtained, then the solid is washed with water, recrystallized and filtered again to obtain 3-amino furazan-4-carboxylic acid.

[0012] Further limitation, in (1), the molar ratio of 1,2,3-propanetriol, hydroxylamine salt and inorganic base is 1:(2~13):(2~20).

[0013] Further limitation, in (1), the hydroxylamine salt is one of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine aqueous solution.

[0014] Further limitation, in (1), the inorganic base is one of sodium hydroxide and potassium hydroxide.

[0015] Further limitation, in (2), the reaction solution is warmed to 40~50°C.

[0016] Further limitation, in (2), the total time of catalytic reaction is 1~24h.

[0017] Further limitation, in (3), the reaction solution is warmed to 60~120°C.

[0018] Further limitation, in (3), the dehydration reaction time is 0.5~12h.

[0019] Further limitation, in (4), the reaction solution is cooled to below 60°C.

[0020] Further limitation, in (4), the pH is adjusted to 1~4.

[0021] Further limitation, in (5), the recrystallization process is: the solid obtained by washing with water is dissolved in a recrystallization solvent to form a solution, the solution is warmed to 80~150°C under stirring to obtain a recrystallization mixture, and the recrystallization mixture is kept at 80~150°C for 0.5~3h and then cooled to 0~50°C.

[0022] The beneficial effects of the present application are:

[0023] The present application uses 1,2,3-propanetriol as the substrate, and synthesizes 3-amino furazan-4-carboxylic acid (AFCA) through chemical conversion. The structure of 1,2,3-propanetriol is simple and non-toxic. Under alkaline conditions, the two aldehyde oxime groups of 1,2,3-propanetriol undergo dehydration reaction (the dehydration here corresponds to the catalytic reaction of (2), not the dehydration reaction in (3)), to generate 2-oxime-1,3-propanedinitrile. The addition reaction of 2-oxime-1,3-propanedinitrile and aqueous hydroxylamine occurs in an alkaline environment, the cyano group and hydroxylamine generate oxime group, to obtain 1,3-diamino-1,2,3-propanetriol intermediate, and the intermediate is dehydrated and cyclized at high temperature to generate 3-amino-4-amidoxime furazan. Finally, acidification is carried out to obtain 3-amino furazan-4-carboxylic acid. The method of the present application avoids the use of traditional cyanogen raw materials which are toxic. The method has the advantages of safe and non-toxic raw materials, short synthesis reaction time, simple reaction steps, easy control of reaction temperature, high product yield, simple purification, less pollutants, etc. Compared with the traditional synthesis method, the production cost and time are saved, the production process is more efficient and fast, the product preparation process is green and environmentally friendly, and it is suitable for industrialized production of green and sustainable development. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 HPLC detection chromatogram of 3-amino furazan-4-carboxylic acid prepared in Example 1;

[0025] Figure 2 UHPLC-MS detection chromatogram (extracted ion chromatogram EIC) of 3-amino furazan-4-carboxylic acid prepared in Example 1;

[0026] Figure 3 UHPLC-MS detection chromatogram (first spectrum) of 3-amino furazan-4-carboxylic acid prepared in Example 1;

[0027] Figure 4 Nuclear magnetic resonance carbon spectrum (deuterated DMSO) of 3-amino furazan-4-carboxylic acid prepared in Example 1;

[0028] Figure 5 Nuclear magnetic resonance hydrogen spectrum (deuterated DMSO) of 3-amino furazan-4-carboxylic acid prepared in Example 1. DETAILED DESCRIPTION

[0029] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application will be described in detail below with reference to the description examples.

[0030] The specific embodiments of the present application will be described in detail below with reference to the description examples.

[0031] Many specific details are set forth in the following description in order to provide a thorough understanding of the present application. However, the present application can be practiced without resorting to the

[0032] This application can also be implemented in a variety of other ways not specifically described herein without departing from the scope of the application. Therefore, the scope of the application should be determined not by the embodiments disclosed herein but by the broadest interpretation of the appended claims and their equivalents.

[0033] Second, the "one embodiment" or "an embodiment" as used in this specification means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one implementation of the present application. The appearances of the phrase "in one embodiment" or "in an embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are they necessarily all referring to a single, special implementation of the present application.

[0034] The experimental methods used in the following examples are conventional unless otherwise specified. The materials, reagents, methods and instruments used are conventional unless otherwise specified, and are available to those skilled in the art through commercial channels.

[0035] The synthesis route of 1,2,3-propanetriol for synthesizing 3-amino furazan-4-carboxylic acid is as follows:

[0036]

[0037] Example 1

[0038] (1) Mixed dissolution: 100 mL of water and 30 g of sodium hydroxide were put into a 500 mL three-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, and dissolved, then 17.5 g of 1,2,3-propanetriol was added, and the temperature of the system was controlled within 20°C, then 46.5 g of hydroxylamine hydrochloride was slowly added, and the raw materials were mixed and dissolved under the condition of controlling the temperature of the system within 40°C and stirring, to obtain a reaction solution;

[0039] (2) Catalytic reaction: the raw materials were mixed and dissolved in (1), and the temperature of the reaction solution was still controlled below 40°C, and the catalytic reaction was carried out at room temperature and under stirring for 2 h, then the temperature was quickly raised to 42°C, and the catalytic reaction was continued under stirring for 2 h;

[0040] (3) Dehydration reaction: the reaction solution after the catalytic reaction in (2) was heated to 90°C, and the dehydration reaction was carried out under stirring for 6 h;

[0041] (4) Neutralization reaction: after the dehydration reaction in (3) was completed, the reaction solution was lowered to 60°C, and the pH of the reaction solution was adjusted to 1 using concentrated hydrochloric acid with a concentration of 36% under the condition of room temperature and stirring, then the reaction solution was cooled to below 20°C, to obtain a suspension reaction solution;

[0042] (5) Filtration separation: the suspension reaction liquid is filtered by using a suction filter bottle to separate the solid from the reaction liquid, and the obtained solid is washed with deionized water to remove most of the inorganic salts to obtain a white solid, which is a 3-amino furazan-4-carboxylic acid crude product. The crude product is dissolved in deionized water, and the mass ratio of the crude product to deionized water is 1:5. The mixture is heated to 100°C under stirring to obtain a recrystallization mixture. After 1 hour, the temperature of the mixture is reduced to 30°C, and the precipitated substance is filtered to obtain 3-amino furazan-4-carboxylic acid containing water, which is dried to obtain the product, i.e., a white solid of 3-amino furazan-4-carboxylic acid.

[0043] All the steps in (1)-(4) are carried out under stirring.

[0044] The product 3-amino furazan-4-carboxylic acid is dissolved in water and deuterated DMSO (dimethyl sulfoxide-d6) respectively to obtain a reaction liquid for testing, which is detected by high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) and nuclear magnetic resonance (NMR). The actual yield of 3-amino furazan-4-carboxylic acid is 40% by calculation, and the purity of the product detected by ultra-high performance liquid chromatography is 99.1%.

[0045] The detection method of high performance liquid chromatography (HPLC) is as follows: 1 mL of the reaction liquid is centrifuged at a centrifugal force of 12000g for 1 min, and the supernatant is filtered through a water phase 0.22μm filter membrane and then placed in a liquid phase vial for detection. The detection conditions are as follows: the HPLC instrument model is Shimadzu LC-20AT; the chromatographic column is Agilent ZORBAX SB-C18 (4.6×250mm); the detection wavelength is 272nm; the column temperature is 30°C; the flow rate is 0.5mL / min; the injection volume is 10μL; the mobile phase A is water, and the mobile phase B is acetonitrile. The gradient elution program is as follows: 0-5min, 5%B liquid; 5-12min, linearly changed to 40% B liquid; 12-20min, 40%B liquid; 20-30min, 5%B liquid.

[0046] UHPLC-MS detection method: 1 mL of the reaction solution was centrifuged at 12000g for 1 min, and the supernatant was filtered and placed in a liquid phase vial for detection. Chromatographic separation conditions: the instrument was Thermo SCIENTIFIC UltiMate 3000 UHPLC, the chromatographic column was Aglient Poroshell 120 SB-Aq, the column temperature was 30°C, the mobile phase A was water, the mobile phase B was acetonitrile, the gradient elution conditions were as follows: 0~2min was 5% B liquid; B liquid 2~6min linearly changed to 95%, and kept for 4min; 10min rapidly decreased to 5% B liquid, kept for 5min. The flow rate was 0.2mL / min. Mass spectrometry conditions: the instrument was Bruker Compact Q-TOF time-of-flight mass spectrometer, electrospray ion source, positive ion mode detection, dry box temperature 200°C, flow rate 2.0 L / min, mass scan range m / z 0~600.

[0047] The HPLC detection results are shown in Figure 1 , and it can be seen from Figure 1 B that the product prepared in this example has a clear peak value at about 4min, and the retention time is completely consistent with the standard product Figure 1 A), which indicates that the 3-aminofurazan-4-carboxylic acid is successfully prepared in this example. The UHPLC-MS detection results are shown in Figure 2 , the parent ion flow of m / z=130.02 is extracted, and the peak time is consistent with the 3-aminofurazan-4-carboxylic acid standard product, which also indicates that the product prepared in this example is indeed 3-aminofurazan-4-carboxylic acid. The primary spectrum of UHPLC-MS detection results is shown in Figure 3 , it can be seen that both the product prepared in this example and the standard product contain sodium salt form ions (m / z=173.988). The NMR detection results (carbon spectrum) are shown in Figure 4 , the chemical shifts and proportions of the three carbons in the carbon spectrum are consistent with 3-aminofurazan-4-carboxylic acid, and in the NMR hydrogen spectrum results Figure 5 , the chemical shifts of the amino hydrogen and carboxyl hydrogen in the product are consistent with the standard product, but the proportions are not consistent. Combined with the sodium salt information of UHPLC-MS detection, it can be known that the proportion difference is due to the presence of sodium salt in the product prepared in this example. This result is mutually confirmed with UHPLC-MS analysis, which further confirms the chemical composition of the product prepared in this example.

[0048] Example 2

[0049] (1) mixed dissolution: 100 mL of water and 10.6 g of sodium hydroxide were put into a 500 mL three-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, and dissolved, then 17.5 g of 1,2,3-propanetriol was added, and the temperature of the system was controlled within 20°C, then 18.5 g of hydroxylamine hydrochloride was slowly added, and the raw materials were mixed and dissolved under stirring at a temperature of 40°C, to obtain a reaction solution;

[0050] (2) catalytic reaction: after the raw materials in (1) were mixed and dissolved, the temperature of the reaction solution was still controlled below 40°C, and the catalytic reaction was carried out at room temperature and under stirring for 2 h, then the temperature was quickly raised to 42°C, and the catalytic reaction was continued under stirring for 2 h;

[0051] (3) dehydration reaction: the reaction solution after the catalytic reaction in (2) was heated to 90°C, and the dehydration reaction was carried out under stirring for 6 h;

[0052] (4) neutralization reaction: after the dehydration reaction in (3) was completed, the reaction solution was cooled to 60°C, and the pH of the reaction solution was adjusted to 1 using concentrated hydrochloric acid with a concentration of 36% under stirring at room temperature, then the reaction solution was cooled to below 20°C, to obtain a suspension reaction solution;

[0053] (5) filtration separation: the suspension reaction solution was filtered using a suction filter bottle, so that the solid was separated from the reaction solution, and the solid obtained by suction filtration was washed with deionized water to remove most of the inorganic salts, to obtain a white solid, which was 3-amino furazan-4-carboxylic acid crude product, the crude product was dissolved in deionized water, and the mass ratio of the crude product to deionized water was 1:5, the mixture was heated to 100°C under stirring, to obtain a recrystallization mixture, the temperature of the mixture was reduced to 30°C after 1 h of reaction, and cooling was performed to precipitate, the precipitated substance was filtered, to obtain 3-amino furazan-4-carboxylic acid containing water, which was dried to obtain the product, i.e. white solid 3-amino furazan-4-carboxylic acid.

[0054] All steps in (1)-(4) were carried out under stirring.

[0055] The product 3-amino furazan-4-carboxylic acid was dissolved in water for high performance liquid chromatography (HPLC) detection, and the actual yield of 3-amino furazan-4-carboxylic acid was calculated to be 23%, and the purity of the product detected by ultra-high performance liquid chromatography was 97.8%.

[0056] Example 3

[0057] (1) mixed dissolution: 100 mL of water and 53.2 g of sodium hydroxide were put into a 500 mL three-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, and dissolved, then 35 g of 1,2,3-propanetriol was added, and the temperature of the system was controlled within 20°C, then 60 g of hydroxylamine hydrochloride was slowly added, and the raw materials were mixed and dissolved under the condition of stirring and the temperature of the system was controlled within 40°C, to obtain a reaction solution;

[0058] (2) catalytic reaction: after the raw materials in (1) were mixed and dissolved, the temperature of the reaction solution was still controlled below 40°C, and the catalytic reaction was carried out at room temperature and under stirring for 2 h, then the temperature was quickly raised to 42°C, and the catalytic reaction was continued under stirring for 2 h;

[0059] (3) dehydration reaction: the reaction solution after the catalytic reaction in (2) was heated to 90°C, and the dehydration reaction was carried out under stirring for 6 h;

[0060] (4) neutralization reaction: after the dehydration reaction in (3) was completed, the reaction solution was cooled to 60°C, and the pH of the reaction solution was adjusted to 1 using concentrated hydrochloric acid with a concentration of 36% under the condition of stirring at room temperature, then the reaction solution was cooled to below 20°C to obtain a suspension reaction solution;

[0061] (5) filtration separation: the suspension reaction solution was filtered using a suction filter bottle to separate the solid from the reaction solution, and the solid obtained by suction filtration was washed with deionized water to remove most of the inorganic salts, to obtain a white solid, which was 3-amino furazan-4-carboxylic acid crude product, the crude product was dissolved in deionized water, and the mass ratio of the crude product to deionized water was 1:5, the mixture was heated to 100°C under stirring to obtain a recrystallization mixture, the temperature of the mixture was reduced to 30°C after 1 h of reaction, and the mixture was cooled to precipitate, and the precipitated substance was filtered to obtain 3-amino furazan-4-carboxylic acid containing water, which was dried to obtain the product, i.e. white solid 3-amino furazan-4-carboxylic acid.

[0062] All steps in (1)-(4) were carried out under stirring.

[0063] The product 3-amino furazan-4-carboxylic acid was dissolved in water for high performance liquid chromatography (HPLC) detection, and the actual yield of 3-amino furazan-4-carboxylic acid was calculated to be 31%, and the purity of the product detected by ultra-high performance liquid chromatography was 92.8%.

[0064] Example 4

[0065] (1) mixed dissolution: 100 mL of water and 30 g of sodium hydroxide were put into a 500 mL three-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, and dissolved, then 17.5 g of 1,2,3-propanetriol was added, and the temperature of the system was controlled within 20℃, then 46.5 g of hydroxylamine hydrochloride was slowly added, and the raw materials were mixed and dissolved under the condition of controlling the temperature of the system within 40℃ and stirring, to obtain a reaction solution;

[0066] (2) catalytic reaction: after the raw materials in (1) were mixed and dissolved, the temperature of the reaction solution was still controlled below 40℃, and the catalytic reaction was carried out at room temperature and under stirring conditions for 2 h, then the temperature was quickly raised to 42℃, and the catalytic reaction was continued under stirring conditions for 2 h;

[0067] (3) dehydration reaction: the reaction solution after the catalytic reaction in (2) was heated to 120℃, and the dehydration reaction was carried out under stirring conditions for 4 h;

[0068] (4) neutralization reaction: after the dehydration reaction in (3) was completed, the reaction solution was reduced to 60℃, and the pH of the reaction solution was adjusted to 1 using concentrated hydrochloric acid with a concentration of 36% under the condition of room temperature and stirring, then the reaction solution was cooled to below 20℃, to obtain a suspension reaction solution;

[0069] (5) filtration and separation: the suspension reaction solution was filtered using a suction filter bottle, so that the solid was separated from the reaction solution, and the solid obtained by suction filtration was rinsed with deionized water to remove most of the inorganic salts, to obtain a white solid, which was 3-amino furazan-4-carboxylic acid crude product, the crude product was dissolved in deionized water, and the mass ratio of the crude product to deionized water was 1:5, the mixture was heated to 100℃ under stirring conditions, to obtain a recrystallization mixture, the temperature of the mixture was reduced to 30℃ after 1 h of reaction, and cooling was carried out to precipitate, the precipitated substance was filtered by suction, to obtain 3-amino furazan-4-carboxylic acid containing water, which was dried to obtain the product, i.e. white solid 3-amino furazan-4-carboxylic acid.

[0070] All the steps in (1)-(4) were carried out under stirring conditions.

[0071] The product 3-amino furazan-4-carboxylic acid was dissolved in water for high performance liquid chromatography (HPLC) detection, and the actual yield of 3-amino furazan-4-carboxylic acid was calculated to be 55%, and the purity of the product detected by ultra-high performance liquid chromatography was 99.3%.

[0072] The above is only a preferred specific embodiment of the present application, but the protection scope of the present application is not limited thereto, any person skilled in the art can make equivalent replacement or change according to the technical scheme and inventive concept of the present application within the technical range disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. A method for the efficient synthesis of 3-aminofuran-4-carboxylic acid from 1,2,3-propanetrioxime, characterized in that, include: (1) Mixing and dissolving: Weigh out three raw materials: 1,2,3-propanetrioxime, hydroxylamine salt and inorganic base, and mix and dissolve the three raw materials at a temperature below 40°C to obtain a reaction solution; (2) Catalytic reaction: The temperature of the reaction solution is controlled below 40°C, and the catalytic reaction is carried out under stirring conditions. Then the temperature of the reaction solution is raised to a certain temperature and the catalytic reaction is continued. (3) Dehydration reaction: The reaction solution after the catalytic reaction in (2) is heated and dehydration reaction is carried out under stirring conditions; (4) Neutralization reaction: After the dehydration reaction in (3) is completed, the reaction solution is cooled down, and acid is added under stirring to adjust the pH. Then the pH-adjusted reaction solution is cooled to below 20°C to obtain a suspension reaction solution. (5) Post-processing: The suspension reaction solution was filtered to obtain a solid. The solid was washed with water and recrystallized and filtered again to obtain 3-aminofuran-4-carboxylic acid. In (2), the reaction solution is heated to 40-50°C, and the total catalytic reaction time is 1-24 hours. In step (3), the reaction solution is heated to 60-120°C, and the dehydration reaction time is 0.5-12h. In step (4), the reaction solution is cooled to below 60°C; the pH is adjusted to 1-4.

2. The method according to claim 1, characterized in that, The molar ratio of 1,2,3-propanetrioxime, hydroxylamine salt and inorganic base in (1) is 1:(2~13):(2~20).

3. The method according to claim 1, characterized in that, The hydroxylamine salt in (1) is one of hydroxylamine hydrochloride or hydroxylamine sulfate.

4. The method according to claim 1, characterized in that, The inorganic base in (1) is either sodium hydroxide or potassium hydroxide.

5. The method according to claim 1, characterized in that, The recrystallization process in (5) is as follows: the solid obtained by washing with water is dissolved in the recrystallization solvent to form a solution, and the solution is heated to 80℃~150℃ under stirring conditions to obtain a recrystallization mixture. The recrystallization mixture is kept at 80~150℃ for 0.5~3h and then cooled to 0~50℃.

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