Continuous preparation method of 3, 6-p-(3, 5-dimethylpyrazole)-1, 2-dihydro-1, 2, 4, 5-tetrazine

Abstract

The invention relates to a continuous preparation method of 3, 6-p-(3, 5-dimethylpyrazole)-1, 2-dihydro-1, 2, 4, 5-tetrazine, and the continuous preparation method comprises the following steps: introducing a material I and a material II into a microchannel reactor at different flow rates, and carrying out a reaction to obtain the 3, 6-p-(3, 5-dimethylpyrazole)-1, 2-dihydro-1, 2, 4, 5-tetrazine, wherein the material I is obtained by mixing triaminoguanidine hydrochloride and water; the material II comprises acetylacetone. The preparation method provided by the invention has the advantages of low synthesis cost, low reaction risk coefficient, high conversion rate, stable yield, high product purity and the like, and is beneficial to industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine. Background Art

[0002] Energetic materials are a class of high-energy compounds that can store and release a large amount of energy in a short period of time. Tetrazine compounds have high positive formation enthalpy, have high energy levels while maintaining good thermal stability and low sensitivity, and have become one of the research hotspots for new high-nitrogen compounds. The 3- and 6-positions on the 1,2,4,5-tetrazine ring are more susceptible to substitution reactions, and different 1,2,4,5-tetrazine derivatives can be obtained by direct substitution with a series of energetic groups or indirect substitution through connecting bridges. This feature can regulate the sensitivity and energy level of tetrazine materials, making it easier to find high-energy insensitive compounds with excellent performance.

[0003] At present, there are two main synthetic routes for 1,2,4,5-tetrazine ring reported in the literature: one is a two-step synthesis from nitrile and hydrazine hydrate; the other is a three-step synthesis from carbonyl compound and hydrazine hydrate via amination, cyclization, and oxidation. However, the current synthetic methods for preparing this compound have problems such as high synthetic difficulty, high synthetic cost, low safety, low overall yield, and poor product purity, which seriously limit the possibility of its practical application. Therefore, it is urgent to find a synthetic route with high yield and high safety.

[0004] As a disruptive innovation, continuous flow chemistry has expanded the horizons of chemical reactions and opened up new ideas for chemical reactions. Compared with the traditional intermittent reaction method, the continuous method for preparing energetic materials has many advantages. The continuous flow microchannel reactor has the advantages of large specific surface area, precise control of reaction time and material ratio, fast mass transfer and heat transfer, safe operation, environmental friendliness, continuous operation, no amplification effect, miniaturization and integration of equipment, etc., and the continuous flow reactor can also be connected with other technologies, such as chromatographic analysis and detection, to achieve industrial automated production. In addition, the continuous reaction method is also very suitable for optimizing experimental conditions, and can adjust the reaction conditions in a timely and comprehensive manner in a very precise and automated manner, and can even conduct cross-factor parameter experiments.

[0005] Therefore, it is of great significance to provide a continuous preparation method for 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine. Summary of the invention

[0006] In order to solve the above technical problems, the purpose of the present invention is to provide a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine. Compared with the traditional intermittent reaction method, the method of the present invention is safe, reliable, efficient, stable in yield and has no amplification effect.

[0007] To achieve this object, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, the continuous preparation method comprising the following steps:

[0009] The material I and the material II are introduced into a microchannel reactor at different flow rates to react to obtain the 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine;

[0010] Wherein, the material I is obtained by mixing triaminoguanidine hydrochloride and water;

[0011] The material II includes acetylacetone.

[0012] The main reaction equation of the preparation method provided by the present invention is as follows:

[0013]

[0014] The method provided by the present invention uses triaminoguanidine hydrochloride as a raw material, and continuously prepares 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine (DHBT) by performing a ring-forming reaction with acetylacetone. Among them, the use of triaminoguanidine hydrochloride eliminates the unsafe hidden danger of using triaminoguanidine nitrate as a raw material; the continuous flow preparation process used in the synthesis process of the target product in the present invention can significantly improve the heat exchange efficiency and the upper limit of the reaction temperature, which is not only conducive to accurately controlling the reaction temperature and material ratio to avoid reaction runaway, thereby improving the purity and yield of the synthetic product, but also can significantly shorten the reaction time, thereby improving production efficiency, and at the same time, it also improves the stability of the reaction, can avoid the amplification effect in the traditional preparation process, further improves its practicality, and is conducive to industrial production.

[0015] Preferably, the mass ratio of triaminoguanidine hydrochloride to water in the material I is 1:(3-20), for example, it can be 1:3, 1:5, 1:7, 1:9, 1:10, 1:12, 1:15, 1:17 or 1:19, but is not limited to the listed values. Other unlisted values ​​within the numerical range are also applicable, preferably 1:(3-15).

[0016] Preferably, the water is deionized water.

[0017] Preferably, the material II also includes an organic solvent A.

[0018] Preferably, the volume ratio of acetylacetone to organic solvent A in the material II is (1:4)-(4:1), for example, it can be 1:4, 1.5:3.5, 2:3, 2.5:2.5, 3:2, 3.5:1.5 or 4:1, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0019] Preferably, the organic solvent A comprises any one of petroleum ether, tetrahydrofuran or acetonitrile, preferably tetrahydrofuran.

[0020] Preferably, the molar ratio of triaminoguanidine hydrochloride to acetylacetone is 1:(1-2.5), for example, it can be 1:1, 1:1.2, 1:1.5, 1:1.7, 1:2, 1:2.2 or 1:2.5, but is not limited to the listed values. Other unlisted values ​​within the numerical range are also applicable, preferably 1:(1.9-2.1).

[0021] Preferably, the flow rate of material I is 1-50 mL / min, for example, it can be 2 mL / min, 5 mL / min, 10 mL / min, 15 mL / min, 20 mL / min, 25 mL / min, 30 mL / min, 35 mL / min, 40 mL / min or 45 mL / min, but is not limited to the listed values. Other unlisted values ​​within the numerical range are also applicable, preferably 25-40 mL / min, and more preferably 30-40 mL / min.

[0022] Preferably, the flow rate of material II is 1-50 mL / min, for example, it can be 2 mL / min, 5 mL / min, 10 mL / min, 15 mL / min, 20 mL / min, 25 mL / min, 30 mL / min, 35 mL / min, 40 mL / min or 45 mL / min, but is not limited to the listed values. Other unlisted values ​​within the numerical range are also applicable, preferably 1-20 mL / min, and more preferably 3.7-5 mL / min.

[0023] Preferably, the flow rate ratio of material I to material II is (1-20):1, for example, it can be 1:1, 3:1, 5:1, 7:1, 10:1, 12:1, 15:1, 18:1 or 20:1, but is not limited to the listed values. Other unlisted values ​​within the numerical range are also applicable, preferably (6-11):1.

[0024] Preferably, the reaction temperature is 50°C-90°C, for example, it can be 53°C, 55°C, 58°C, 60°C, 65°C, 70°C, 75°C, 80°C or 85°C, but is not limited to the listed values. Other unlisted values ​​within the numerical range are also applicable, preferably 65°C-80°C.

[0025] Preferably, the residence time of the reaction is 0.5-20 min, for example, 1 min, 3 min, 5 min, 7 min, 10 min, 13 min, 15 min or 18 min, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable, preferably 0.5-10 min.

[0026] Preferably, the step (3) further comprises a post-treatment step after the reaction is completed.

[0027] Preferably, the post-treatment step comprises: cooling the reaction solution to 25° C., filtering, washing and drying.

[0028] Preferably, the cooling method includes natural cooling and indirect water cooling.

[0029] Preferably, the washing is washing the filter cake with an organic solvent B, wherein the organic solvent B comprises any one of petroleum ether, n-hexane or n-heptane or a combination of at least two thereof, and typical but non-limiting combinations include a combination of petroleum ether and n-hexane, a combination of petroleum ether and n-heptane, a combination of n-hexane and n-heptane, a combination of petroleum ether, n-hexane and n-heptane, and preferably petroleum ether.

[0030] Preferably, the drying method includes natural drying and low-temperature drying.

[0031] Preferably, the continuous preparation method specifically comprises the following steps:

[0032] (1) mixing triaminoguanidine hydrochloride and deionized water in a mass ratio of 1:(3-20) to obtain material I;

[0033] (2) mixing acetylacetone and organic solvent A in a volume ratio of (1:4)-(4:1) to obtain material II;

[0034] (3) introducing material I in step (1) and material II in step (2) into a microchannel reactor at different flow rates, reacting at 50° C.-90° C. for a residence time of 0.5-20 min. After the reaction, cooling the reaction solution to 25° C., filtering, washing and drying to obtain the 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine;

[0035] In the step (3), the flow rate of material I is 1-50 mL / min; the flow rate of material II is 1-50 mL / min.

[0036] Compared with the prior art, the present invention has at least the following beneficial effects:

[0037] The present invention uses triaminoguanidine hydrochloride as a raw material, and reacts with acetylacetone to form a ring, and continuously prepares 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine. Compared with the existing synthesis method, the preparation method of the present invention can increase the upper temperature limit of the reaction, is easy to accurately control the reaction temperature and material ratio, has the advantages of low synthesis cost, low reaction risk coefficient, high conversion rate, stable yield, high product purity, etc., and provides a guarantee for its future industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Schematic diagram of the continuous flow device used in Examples 1-5; wherein the numbers in the schematic diagram of the device are: 1, material I; 2, material II; 3, plunger pump; 4, micro-reaction module; 5, heat exchanger; 6, cooling module; 7, automatic filtration module; 8, sample;

[0039] Figure 2 is a sample image of the product 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine obtained in Example 1;

[0040] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the product 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine obtained in Example 1. DETAILED DESCRIPTION

[0041] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0042] The following Examples 1-5 were all carried out using a continuous flow device, the schematic diagram of which is shown in FIG. Figure 1 shown.

[0043] Example 1

[0044] This embodiment provides a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, the method comprising the following steps:

[0045] Mix 200g of triaminoguanidine hydrochloride and 3L of deionized water evenly to obtain material I at a flow rate of 30mL / min; mix 277.5mL of acetylacetone and 222.5mL of tetrahydrofuran evenly to obtain material II at a flow rate of 5mL / min. Use a microchannel reactor and set the reaction temperature to 65°C. The reaction residence time is 1.17min. After the system is stable, take 100mL of sample liquid. Cool to 25°C, filter, wash the filter cake with petroleum ether, and dry naturally to obtain a light yellow 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine pure product (such as Figure 2 shown).

[0046] like Figure 3 As shown, the NMR spectrum of the compound 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine has no obvious impurity peaks, and its characterization data are as follows:

[0047] 1 H NMR (700MHz, DMSO-d6) δ 8.86 (s, 2H), 6.16 (s, 2H), 2.41 (s, 6H), 2.18 (s, 6H).

[0048] Example 2

[0049] This embodiment provides a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, the method comprising the following steps:

[0050] 200g of triaminoguanidine hydrochloride and 3L of deionized water were mixed evenly to obtain material I, with a flow rate of 40mL / min; 291mL of acetylacetone was material II, with a flow rate of 3.88mL / min. A microchannel reactor was used, and the reaction temperature was set to 80°C. The reaction residence time was 0.93min. After the system was stable, 100mL of sample solution was taken. Cooled to 25°C, filtered, the filter cake was washed with petroleum ether, and dried naturally to obtain a light yellow 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine pure product.

[0051] Example 3

[0052] This embodiment provides a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, the method comprising the following steps:

[0053] Mix 200g of triaminoguanidine hydrochloride and 3L of deionized water to obtain material I at a flow rate of 30mL / min; mix 277.5mL of acetylacetone and 222.5mL of petroleum ether to obtain material II at a flow rate of 3.7mL / min. Use a microchannel reactor and set the reaction temperature to 65°C. The reaction residence time is 1.2min. After the system is stable, take 100mL of sample solution. Cool to 25°C, filter, wash the filter cake with petroleum ether, and dry it naturally to obtain a light yellow 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine pure product.

[0054] Example 4

[0055] This embodiment provides a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, the method comprising the following steps:

[0056] 200g of triaminoguanidine hydrochloride and 3L of deionized water were mixed as material I, and the pumping speed was 30mL / min; 277.5mL of acetylacetone and 222.5mL of acetonitrile were mixed as material II, and the pumping speed was 3.88mL / min. A microchannel reactor was used, and the reaction temperature was set to 78°C. The reaction residence time was 1.21min. After the system was stable, 100mL of sample solution was collected. Cooled to 25°C, filtered, the filter cake was washed with petroleum ether, and dried naturally to obtain a light yellow 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine pure product.

[0057] Example 5

[0058] This embodiment provides a continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, the method comprising the following steps:

[0059] 8.67kg triaminoguanidine hydrochloride and 130L deionized water were mixed as material I, and the pumping speed was 30mL / min; 12.2L acetylacetone and 9.8L tetrahydrofuran were mixed as material II, and the pumping speed was 5mL / min. A microchannel reactor was used, and the reaction temperature was set to 65°C. The reaction residence time was 1.17min. After the system was stable, 100mL of sample solution was collected every 30min, and the system was run continuously for 72h. Cooled to 25°C, filtered, the filter cake was washed with petroleum ether, and dried naturally to obtain a light yellow 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine pure product.

[0060] Comparative Example 1

[0061] This comparative example provides a method for preparing 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, which comprises the following steps:

[0062] Add 8g of triaminoguanidine hydrochloride and 56mL of deionized water to a 250mL jacketed reactor, stir mechanically at 320rpm, and heat to 50°C using a thermostatic bath. Add acetylacetone (11.08mL, 1.9eq) using a syringe pump at a drop rate of 0.5mL / min, heat to 70°C, and react for 4h. Cool to 25°C, filter, wash the filter cake with petroleum ether, and dry naturally to obtain a light yellow pure 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine.

[0063] Comparative Example 2

[0064] This comparative example provides a method for preparing 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, which comprises the following steps:

[0065] Add 8g of triaminoguanidine hydrochloride and 56mL of deionized water to a 250mL jacketed reactor, stir mechanically at 400rpm, and heat to 70°C. Use a syringe pump to add acetylacetone (12.25mL, 2.1eq) at a pumping rate of 1.0mL / min and react for 4h. Cool to 25°C, filter, wash the filter cake with petroleum ether, and dry naturally to obtain a light yellow pure 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine.

[0066] Comparative Example 3

[0067] This comparative example provides a method for preparing 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, which comprises the following steps:

[0068] Add 14kg triaminoguanidine hydrochloride and 42L deionized water to a 100L jacketed reactor, stir mechanically, rotate at 600rpm, and heat to 50℃. Use a peristaltic pump to add acetylacetone (19.5L, 1.9eq) at a pumping rate of 0.2L / min, heat to 70℃, and react for 4h. Cool to 25℃, filter, wash the filter cake with petroleum ether, and dry naturally to obtain a light yellow pure 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine.

[0069] The yields of the product 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine obtained in the above Examples 1-5 and Comparative Examples 1-3 are shown in Table 1.

[0070] Table 1

[0071]

[0072] In summary, the present invention uses triaminoguanidine hydrochloride as a raw material, reacts with acetylacetone to form a ring, and continuously prepares 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, and the yield can reach more than 87%. It can effectively overcome the amplification effect of the target product prepared by the traditional process, has the advantages of low reaction risk coefficient, high conversion rate, stable yield, high product purity, etc., and provides a guarantee for its future industrialization.

[0073] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A continuous preparation method of 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine, characterized in that: The continuous preparation method comprises the following steps: The material I and the material II are introduced into a microchannel reactor at different flow rates to react to obtain the 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine; Wherein, the material I is obtained by mixing triaminoguanidine hydrochloride and water; The material II includes acetylacetone.

2. The continuous preparation method according to claim 1, characterized in that: The mass ratio of triaminoguanidine hydrochloride to water in the material I is 1:(3-20), preferably 1:(3-15); Preferably, the water is deionized water.

3. The continuous preparation method according to claim 1 or 2, characterized in that: The material II also includes an organic solvent A; The volume ratio of acetylacetone to organic solvent A in the material II is (1:4)-(4:1).

4. The continuous preparation method according to claim 3, characterized in that: The organic solvent A includes any one of petroleum ether, tetrahydrofuran or acetonitrile, preferably tetrahydrofuran.

5. The continuous preparation method according to any one of claims 1 to 4, characterized in that: The molar ratio of triaminoguanidine hydrochloride to acetylacetone is 1:(1-2.5), preferably 1:(1.9-2.1).

6. The continuous preparation method according to any one of claims 1 to 5, characterized in that: The flow rate of material I is 1-50 mL / min, preferably 25-40 mL / min; Preferably, the flow rate of material II is 1-50 mL / min, preferably 1-10 mL / min; Preferably, the flow rate ratio of material I to material II is (1-20):1, preferably (6-11):

1.

7. The continuous preparation method according to any one of claims 1 to 6, characterized in that: The reaction temperature is 50°C-90°C, preferably 65°C-80°C; Preferably, the residence time of the reaction is 0.5-20 min, preferably 0.5-10 min.

8. The continuous preparation method according to any one of claims 1 to 7, characterized in that: After the reaction is completed, a post-processing step is also included; Preferably, the post-treatment step comprises: cooling the reaction solution to 25° C., filtering, washing and drying.

9. The continuous preparation method according to claim 8, characterized in that: The cooling method includes natural cooling and indirect water cooling; Preferably, the washing is washing the filter cake with an organic solvent B, wherein the organic solvent B comprises any one of petroleum ether, n-hexane or n-heptane, or a combination of at least two thereof; Preferably, the drying method includes natural drying and low-temperature drying.

10. The continuous preparation method according to any one of claims 1 to 9, characterized in that: The continuous preparation method specifically comprises the following steps: (1) mixing triaminoguanidine hydrochloride and deionized water in a mass ratio of 1:(3-20) to obtain material I; (2) mixing acetylacetone and organic solvent A in a volume ratio of (1:4)-(4:1) to obtain material II; (3) introducing material I in step (1) and material II in step (2) into a microchannel reactor at different flow rates, reacting at 50° C.-90° C. for a residence time of 0.5-20 min. After the reaction, cooling the reaction solution to 25° C., filtering, washing and drying to obtain the 3,6-p-(3,5-dimethylpyrazole)-1,2-dihydro-1,2,4,5-tetrazine; In the step (3), the flow rate of material I is 1-50 mL / min; the flow rate of material II is 1-50 mL / min.

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