A method for preparing hexacyclopropylhexaazaisowurtzitane using microchannel continuous flow reaction

Abstract

The application belongs to the technical field of non-metallic compounds, and particularly relates to a method for preparing hexacyclopropylhexaazaisowurtzitane by using a micro-channel continuous flow reaction, which comprises the following steps: S1, material A configuration; S2, material B configuration; S3, adjusting the flow rate of the material A by using a metering pump A, adjusting the flow rate of the material B by using a metering pump B, pumping the two into a mixer, and flowing the mixed solution into a micro-channel continuous flow reactor to perform a condensation reaction; after the reaction is completed, pumping the reaction liquid into a filter separator to perform filtration, washing the filter cake with acetonitrile, and then washing with water to obtain a hexacyclopropylhexaazaisowurtzitane pure product; the method realizes efficient synthesis of the hexacyclopropylhexaazaisowurtzitane by using the micro-channel continuous flow reaction, the reaction time is reduced from 24 hours to a retention time of only 5-20 min; the reaction yield and purity are increased, in a kilogram-level experiment, the yield is increased from 61% to 91%, and the purity reaches more than 99.5%.

Description

Technical Field

[0001] This invention belongs to the field of non-metallic compound technology and relates to the synthesis of cyclopropane compounds, specifically a method for preparing hexacyclopropylhexaazaisowulzane using a microchannel continuous flow reaction. Background Technology

[0002] Cyclopropyl groups are widely used in medicinal chemistry, such as in tegafurine and duracil. Simultaneously, due to their high ring strain, they are often used as highly reactive intermediates in organic synthesis. On the other hand, hexaazaisowrtzine, due to its abundant nitrogen content and high ring strain, is a star framework in the field of energetic materials. For example, the core framework of the currently highest energy density energetic compound, hexanitrohexaazaisowrtzine (CL-20), is a cage-like hexaazaisowrtzine. If six highly reactive cyclopropyl groups are arranged within a hexaazaisowrtzine cage-like framework, a series of high-value-added, highly reactive organic synthesis intermediates can be obtained and applied in pharmaceuticals and energetic materials. Recently, an Indian research group reported a batch reaction of hexacyclopropylhexaazaisowrtzine (HCPIW) using cyclopropylamine and glyoxal as raw materials under formic acid catalysis, achieving a yield of up to 85%. Furthermore, the high-energy-density compound CL-20 can be obtained directly from this precursor through a two-step nitration reaction. Asian Journal of Org. Chem. (2022, 11, 335) Compared to traditional methods, this method shortens the process to two steps and avoids the use of precious metal catalysts, thus fully demonstrating the high reactivity and application value of this compound.

[0003] Microchannel continuous flow reactors are made of special glass, ceramics, or other materials. Their key feature is the continuous reaction within tiny channels surrounded by a large-area heat transfer device, allowing for instantaneous heating of reactants or removal of heat, making them suitable for highly exothermic reactions. In the process of preparing hexacyclopropylhexaazaisowroughtane from cyclopropylamine and glyoxal via a formic acid catalysis, significant exothermic reaction occurs, especially during the feeding process, where the temperature can rise sharply by more than 10°C, accompanied by a large amount of fumes, easily leading to overflow. However, currently, no literature reports the preparation of hexacyclopropylhexaazaisowroughtane using microchannel continuous flow reactions.

[0004] Currently, only the aforementioned Indian article reports a gram-scale batch reaction process for preparing hexacyclopropylhexaazaisowulzane. Using glyoxal and cyclopropylamine as raw materials, and acetonitrile and water as solvents, a one-step condensation reaction is carried out under the catalysis of formic acid, with a reported yield of up to 85%. However, our team repeatedly found that the highest yield was only 73%. The reason for this is that the product obtained by the literature method does not consider purity, and the impurity content is greater than 10%, thus exhibiting the following technical defects:

[0005] 1. During the feeding process, even under the control of an ice-salt bath, the temperature will still rise suddenly by more than 10°C, accompanied by a large amount of smoke, which can easily cause overflow. Therefore, the feeding time of the batch reactor is long. It is acceptable for small-scale reactions, but when scaled up to the kilogram level, it takes about 6 hours. With the reaction time of 24 hours, the total time required is about 30 hours, which is time-consuming and detrimental to the uniformity of the reaction and the purity of the product, making it impossible to scale up production.

[0006] 2. The mass and heat transfer efficiency of batch reactors is low, and there is significant room for improvement in product purity and yield.

[0007] 3. The process is unstable. When scaled up to the kilogram level, the yield will decrease by 5-10% further, and the production rate will drop to about 60%, thereby increasing production costs. Summary of the Invention

[0008] This invention addresses the technical problems of current methods for preparing hexacyclopropylhexaazaisowrutzane, such as material overflow during the reaction process, long reaction time, high cost, low product purity and yield, and inability to achieve large-scale production. It provides a method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction.

[0009] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows: a method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction, comprising the following steps:

[0010] S1. Preparation of Material A: Add cyclopropylamine to a mixture of acetonitrile and water, stir until homogeneous to obtain Material A;

[0011] S2, Material B preparation: At 0℃, add methanesulfonic acid or trifluoromethanesulfonic acid in batches to glyoxal solution, stir evenly to obtain material B;

[0012] S3. The flow rate of material A is adjusted by metering pump A, and the flow rate of material B is adjusted by metering pump B. The two are pumped into the mixer, and the mixed solution flows into the microchannel continuous flow reactor for condensation reaction. After the reaction is completed, the reaction solution is pumped into the filter separator for filtration. The filter cake is washed with acetonitrile and then washed with water to obtain the pure product of hexacyclopropylhexaazaisowrtzane.

[0013] As a further limitation of the technical solution of the present invention, the volume ratio of acetonitrile to water in step S1 is 10:1, and the mass-volume ratio of the mixture of cyclopropylamine, acetonitrile and water is 1467g:8745mL.

[0014] As a further limitation of the technical solution of the present invention, the mass percentage of the glyoxal solution in step S2 is 40%.

[0015] As a further limitation of the technical solution of the present invention, the equivalent ratio of cyclopropylamine, methanesulfonic acid and glyoxal is 2.6:0.23:1.

[0016] As a further limitation of the technical solution of the present invention, the equivalent ratio of cyclopropylamine, trifluoromethanesulfonic acid and glyoxal is 2.6:0.23:1.

[0017] As a further limitation of the technical solution of the present invention, the material flow rate ratio between metering pump A and metering pump B in step S3 is 1:1-10:1, wherein the material flow rate in metering pump A is 7-20 mL / min and the material flow rate in metering pump B is 1-7 mL / min.

[0018] As a further limitation of the technical solution of the present invention, the temperature of the mixer in step S3 is 25-45℃, and the microchannel continuous flow reactor is a channel reactor made of silicon carbide, with an inner diameter of 2-3mm.

[0019] As a further limitation of the technical solution of the present invention, the time for the mixed solution to undergo condensation reaction in the microchannel continuous flow reactor in step S3 is 5-20 min.

[0020] As a further limitation of the technical solution of the present invention, in step S3, the reaction solution is pumped into the filter separator at a flow rate of 16 mL / min.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. This invention utilizes a microchannel continuous flow reaction to achieve the efficient synthesis of hexacyclopropylhexaazaisowrutzane. Compared to the reported batch reaction conditions, the amount of cyclopropylamine used is reduced to 2.6 equivalents, thereby significantly reducing costs. Replacing the highly corrosive formic acid (0.29 equivalents) with methanesulfonic acid or trifluoromethanesulfonic acid (0.23 equivalents) reduces the reaction's hazard.

[0023] 2. Compared to the previously reported batch reaction, where formic acid is slowly added dropwise to the acetonitrile / water solution of cyclopropylamine before glyoxal is slowly added dropwise to the reaction system, this invention mixes methanesulfonic acid or trifluoromethanesulfonic acid with glyoxal in advance, and then adds the mixture to the acetonitrile / water solution of cyclopropylamine. By changing the order of addition, the entire reaction system is made stable and free from temperature runaway.

[0024] 3. The reaction time is reduced from 24 hours to a residence time of only 5-20 minutes, while avoiding the long material drop-addition time of batch reaction, thus greatly increasing the reaction efficiency.

[0025] 4. The reaction yield and purity were increased. In the kilogram-scale experiment, the yield increased from 61% to 91%, and the purity reached over 99.5%. Attached Figure Description

[0026] Figure 1This is a flowchart of the preparation method of the present invention.

[0027] Figure 2 This is a diagram of the internal structure of the microchannel continuous flow reactor of the present invention.

[0028] Figure 3 This is a typical purity test chart of the product prepared in Example 1 of the present invention.

[0029] Figure 4 This is a typical 1H NMR spectrum of the product prepared in Example 1 of the present invention.

[0030] Figure 5 This is a typical carbon NMR spectrum of the product prepared in Example 1 of the present invention. Detailed Implementation

[0031] The present invention will be further described below with reference to specific embodiments.

[0032] The reaction equation for hexacyclopropylhexaazaisowrutzane of this invention is as follows:

[0033]

[0034] Example 1

[0035] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction includes the following steps:

[0036] Preparation of Material A: Add cyclopropylamine (1467g, 2.6eq.) to a mixed solution of acetonitrile / water (7950mL / 795mL), and stir until homogeneous to obtain Material A.

[0037] Material B preparation: At 0℃, methanesulfonic acid (147.2 mL, 0.23 eq.) was added in batches to 40% glyoxal (1436 g, 1 eq.), and stirred evenly to obtain material B.

[0038] The flow rate of material A is adjusted to 14 mL / min using metering pump A, and the flow rate of material B is adjusted to 2 mL / min using metering pump B. Both are then pumped into a mixer at 35°C. The mixed solution then flows into a silicon carbide channel reactor (i.e., [missing information]) with an inner diameter of 2-3 mm and a temperature of 35°C. Figure 2 The condensation reaction was carried out in the microchannel continuous flow reactor shown, with a residence time of 10 min. After the reaction was completed, the reaction solution was pumped into the filter separator at a flow rate of 16 mL / min for filtration. After all the raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile and then washed with 500 mL of water to obtain the pure product with a yield of 82%.

[0039] High-performance liquid chromatography (HPLC) with reverse-phase column chromatography was used to analyze the purity of the product. The principle of purity calculation is as follows: by integrating the peak area of ​​the target peak and converting it with a standard curve established by an external standard solution of known concentration, the actual content of the target compound in the sample is obtained. Subsequently, this content is compared with the mass spectrometric mass of the sample to finally obtain the sample purity. Figure 3 The chromatogram obtained is shown, and the purity, directly measured by the instrument, can reach over 99.2%. ¹H NMR (400MHz, CDCl₃): δ 4.14 (s, 4H), 3.99 (s, 2H), 2.57–2.62 (m, 2H), 2.38–2.44 (m, 4H), 0.27–0.45 (m, 24H); ¹³C NMR (100MHz, CDCl₃): δ 83.1, 77.2, 33.2, 32.0, 8.0, 7.2, 7.2. Elemental analysis (%) C 24 H 36 Calculated N6 (408.6): C, 70.55; H, 8.88; N, 20.57; Measured: C, 70.53; H, 8.86; N, 20.55.

[0040] Example 2

[0041] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction, with the specific steps being the same as in Example 1, except that the residence time is extended to 20 min:

[0042] The flow rate of material A was adjusted to 14 mL / min using metering pump A, and the flow rate of material B was adjusted to 2 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for condensation reaction, with the residence time varied to 20 min (achieved by adding or reducing the microchannel reactor module). After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 91%. High-performance liquid chromatography (HPLC) analysis of the product purity showed that the purity could reach over 99.5%.

[0043] Example 3

[0044] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction, with the specific steps being the same as in Example 1, except that the residence time is shortened to 5 min:

[0045] The flow rate of material A was adjusted to 14 mL / min using metering pump A, and the flow rate of material B was adjusted to 2 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for a condensation reaction, with the residence time changed to 5 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile and then with 500 mL of water to obtain the pure product, with a yield of 71%. High-performance liquid chromatography (HPLC) analysis of the product purity showed that the purity was above 98.5%.

[0046] Example 4

[0047] A method for preparing hexacyclopropylhexaazaisowulzane using a microchannel continuous flow reaction, with the specific steps being the same as in Example 1, the only difference being a reduction in the material flow rate:

[0048] The flow rate of material A was adjusted to 7 mL / min using metering pump A, and the flow rate of material B was adjusted to 1 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 85%. High-performance liquid chromatography (HPLC) analysis of the product purity showed that the purity could reach over 99.0%.

[0049] Example 5

[0050] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction, the specific steps of which are the same as in Example 1, the only difference being that the material flow rate ratio is changed to 2:1:

[0051] The flow rate of material A was adjusted to 14 mL / min using metering pump A, and the flow rate of material B was adjusted to 7 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 58%. High-performance liquid chromatography (HPLC) analysis of the product purity showed a purity of over 91%.

[0052] Example 6

[0053] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction, the specific steps of which are the same as in Example 1, the only difference being the change in the material flow rate ratio of 1:1:

[0054] The flow rate of material A was adjusted to 7 mL / min using metering pump A, and the flow rate of material B was adjusted to 7 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 50%. High-performance liquid chromatography (HPLC) analysis of the product purity showed a purity of over 85%.

[0055] Example 7

[0056] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction, the specific steps of which are the same as in Example 1, the only difference being the change in the material flow rate ratio to 10:1:

[0057] The flow rate of material A was adjusted to 20 mL / min using metering pump A, and the flow rate of material B was adjusted to 2 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 78%. High-performance liquid chromatography (HPLC) analysis of the product purity showed a purity of over 92%.

[0058] Example 8

[0059] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction, with the specific steps being the same as in Example 1, except that the temperature is changed to 45°C:

[0060] The flow rate of material A was adjusted to 14 mL / min using metering pump A, and the flow rate of material B was adjusted to 2 mL / min using metering pump B. Both were pumped into a mixer at 45°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 45°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 80%. High-performance liquid chromatography (HPLC) analysis of the product purity showed a purity of over 99.1%.

[0061] Example 9

[0062] A method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction, with the specific steps being the same as in Example 1, except that the temperature is changed to 25°C:

[0063] The flow rate of material A was adjusted to 14 mL / min using metering pump A, and the flow rate of material B was adjusted to 2 mL / min using metering pump B. Both were pumped into a mixer at 25°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 25°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 76%. High-performance liquid chromatography (HPLC) analysis of the product purity showed a purity of over 99.0%.

[0064] Example 10

[0065] A method for preparing hexacyclopropylhexaazaisowulzane using a microchannel continuous flow reaction, the specific steps are the same as in Example 1, the only difference being that material B is prepared as follows: trifluoromethanesulfonic acid (201.0 mL, 0.23 eq.) is added in batches to 40% glyoxal (1436 g, 1 eq.) at 0 °C, and the mixture is stirred evenly to obtain material B;

[0066] The flow rate of material A was adjusted to 14 mL / min using metering pump A, and the flow rate of material B was adjusted to 2 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 81%. High-performance liquid chromatography (HPLC) analysis of the product purity showed a purity of over 99.5%.

[0067] Comparative Example 1

[0068] A method for preparing hexacyclopropylhexaazaisowulzane using a microchannel continuous flow reaction, the specific steps are the same as in Example 1, the only difference being that material B is prepared as follows: formic acid (96.6 mL, 0.23 eq.) is added in batches to 40% glyoxal (1436 g, 1 eq.) at 0 °C, and the mixture is stirred evenly to obtain material B;

[0069] The flow rate of material A was adjusted to 14 mL / min using metering pump A, and the flow rate of material B was adjusted to 2 mL / min using metering pump B. Both were pumped into a mixer at 35°C. The mixed solution then flowed into a silicon carbide channel reactor (2-3 mm inner diameter) at 35°C for a condensation reaction, with a residence time of 10 min. After the reaction, the reaction solution was pumped into a filter separator at a flow rate of 16 mL / min for filtration. After all raw materials had reacted completely, the filter cake was washed with 1 L of acetonitrile, followed by washing with 500 mL of water to obtain the pure product, with a yield of 68%. High-performance liquid chromatography (HPLC) analysis of the product purity showed a purity of over 99.2%.

Claims

1. A method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction, characterized in that, Includes the following steps: S1. Preparation of Material A: Add cyclopropylamine to a mixture of acetonitrile and water, stir until homogeneous to obtain Material A; S2, Material B preparation: At 0℃, add methanesulfonic acid or trifluoromethanesulfonic acid in batches to glyoxal solution, stir evenly to obtain material B; S3. The flow rate of material A is adjusted by metering pump A, and the flow rate of material B is adjusted by metering pump B. The two are pumped into the mixer, and the mixed solution flows into the microchannel continuous flow reactor for condensation reaction. After the reaction is completed, the reaction solution is pumped into the filter separator for filtration. The filter cake is washed with acetonitrile and then washed with water to obtain the pure product of hexacyclopropylhexaazaisowrtzane.

2. The method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction according to claim 1, characterized in that, In step S1, the volume ratio of acetonitrile to water is 10:1, and the mass-volume ratio of the mixture of cyclopropylamine, acetonitrile, and water is 1467g:8745mL.

3. The method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction according to claim 1, characterized in that, The mass percentage of the glyoxal solution in step S2 is 40%.

4. The method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction according to claim 1, characterized in that, The equivalent ratio of cyclopropylamine, methanesulfonic acid, and glyoxal is 2.6:0.23:

1.

5. The method for preparing hexacyclopropylhexaazaisowrutzane using a microchannel continuous flow reaction according to claim 1, characterized in that, The equivalent ratio of cyclopropylamine, trifluoromethanesulfonic acid, and glyoxal is 2.6:0.23:

1.

6. The method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction according to claim 1, characterized in that, In step S3, the material flow rate ratio between metering pump A and metering pump B is 1:1-10:1, wherein the material flow rate in metering pump A is 7-20 mL / min and the material flow rate in metering pump B is 1-7 mL / min.

7. The method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction according to claim 1, characterized in that, In step S3, the temperature of the mixer is 25-45℃, and the microchannel continuous flow reactor is a channel reactor made of silicon carbide with an inner diameter of 2-3mm.

8. The method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction according to claim 1, characterized in that, In step S3, the mixed solution undergoes a condensation reaction in a microchannel continuous flow reactor for 5-20 minutes.

9. The method for preparing hexacyclopropylhexaazaisowrtzane using a microchannel continuous flow reaction according to claim 1, characterized in that, In step S3, the reaction solution is pumped into the filter separator at a flow rate of 16 mL / min.

Images