A process for the preparation of hexacyclopropylhexaazaisowurtzitane

Abstract

The application belongs to the technical field of non-metallic compounds, and relates to preparation of cyclopropane compounds, and discloses a preparation method of kilogram-level high-purity hexacyclopropylhexaazaisowurtzitane, which comprises the following steps: in step (1), cyclopropylamine is added into a solution of acetonitrile and water at-15 DEG C to-25 DEG C, and then a mixed solution of mixed acid and glyoxal is added dropwise; in step (2), after the dropwise addition is completed, the reaction is carried out at room temperature for more than 18 hours; or, after the dropwise addition is completed, the reaction is carried out in a gradient heating mode for more than 18 hours; and in step (3), the white pure solid product is obtained through filtration, washing and drying. In the application, the catalyst is changed into a binary acid or ternary acid catalytic system, the amount of cyclopropylamine and the reaction time are reduced, the feeding sequence is changed, the whole dropwise addition process is stable and safe, the condensation reaction is carried out in a gradient heating mode, the process is stable and safe, the yield and purity are improved, and the application has obvious technical advantages.

Description

Technical Field

[0001] This invention belongs to the field of non-metallic compound technology and relates to the preparation of cyclopropane compounds, specifically a method for preparing kilogram-level high-purity hexacyclopropylhexaazaisowulzane. Background Technology

[0002] Cyclopropane compounds are widely used in medicinal chemistry, such as tegafurine and duracil. Simultaneously, due to their high ring strain, they are often used as highly reactive intermediates in organic synthesis, resulting in significant market demand. On the other hand, cage-like nitrogen heterocycles, due to their abundant nitrogen content and high ring strain, are star skeletons in the field of energetic materials. For example, the core skeleton of hexanitrohexaazaisowurtzite (CL-20), currently the energetic compound with the highest energy density, is cage-like hexaazaisowurtzite, with an estimated annual demand exceeding 200 tons. If six highly reactive cyclopropane compounds are configured within a single hexaazaisowurtzite cage-like skeleton, a series of high-value-added, highly reactive organic synthesis intermediates can be obtained for applications in pharmaceuticals and energetic materials. Recently, an Indian research group reported a gram-scale method for obtaining hexacyclopropylhexaazaisowurtzite from cyclopropylamine and glyoxal under formic acid catalysis, achieving a yield of 85%. The high-energy-density compound CL-20 can be obtained directly from this precursor through a two-step nitration reaction (Asian J.Org.Chem.2022,11,335). Compared with the traditional method, this process is shortened to two steps and avoids the use of precious metal catalysts, thus fully demonstrating the high reactivity of this compound and its value for engineering development and application.

[0003] Currently, only one Indian article reports a gram-scale preparation route for hexacyclopropylaminohexaazaisowulzane, using glyoxal and cyclopropylamine as raw materials, acetonitrile and water as solvents, and formic acid as a single acid catalysis, via a one-step condensation reaction, 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 take purity into account, and the impurity content is greater than 10%, thus exhibiting the following technical defects:

[0004] 1. There is significant room for improvement in product purity and yield.

[0005] 2. The feeding process is violent, with thick smoke and material overflow. Even under the control of the ice-salt bath, the system temperature can still rise suddenly by 5-10°C, resulting in poor reaction safety, long feeding time, and inability to scale up production.

[0006] 3. The process is unstable. When scaled up to the kilogram level, the yield will decrease by 5-10%, dropping to around 60%, which increases production costs. Summary of the Invention

[0007] In view of the above technical problems and the need for large-scale production of this compound, the present invention provides a method for preparing kilogram-level high-purity hexacyclopropylhexaazaisowulzane.

[0008] This invention is achieved using the following technical solution:

[0009] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane includes the following steps:

[0010] Step (1): At -15℃ to -25℃, add cyclopropylamine to a solution of acetonitrile and water, and then add a mixed acid and glyoxal solution dropwise.

[0011] Step (2): After the addition is complete, raise the temperature to room temperature and react for at least 18 hours.

[0012] Alternatively, after the addition is complete, perform a gradient temperature increase reaction for more than 18 hours;

[0013] Step (3): After filtration, washing and drying, a white pure solid product is obtained.

[0014] The method of this invention can realize the kilogram-scale reaction of cyclopropylamine and the kilogram-scale production of hexacyclopropylhexaazaisowulzane. Specifically, it adopts a feeding method at -15℃ to -25℃, utilizes a polybasic acid catalytic system, and pre-mixes the mixed acid with glyoxal before adding it dropwise to a solution of cyclopropylamine in acetonitrile and water. Finally, the reaction is carried out at room temperature or by gradient heating for more than 18 hours.

[0015] More preferably, in step (1), the mixed acid is selected from protic acid or Lewis acid.

[0016] The mixed acid is any two or more of formic acid, perchloric acid, trifluoromethanesulfonic acid, and methanesulfonic acid. The amount of cyclopropylamine used is 1467g, and the amount of glyoxal used is 1436g; the ratio of mixed acid to glyoxal used in terms of eq. is (0.3~0.45):1.

[0017] More preferably, the mixed acid is a mixture of formic acid and perchloric acid; the ratio of formic acid, perchloric acid and glyoxal is 0.2:(0.1-0.25):1, calculated in eq.

[0018] Alternatively, the mixed acid is a mixture of formic acid and trifluoromethanesulfonic acid; the ratio of formic acid, trifluoromethanesulfonic acid and glyoxal is 0.2:0.175:1, expressed in eq.

[0019] Alternatively, the mixed acid is a mixture of methanesulfonic acid and perchloric acid; the ratio of methanesulfonic acid, perchloric acid and glyoxal is 0.2:0.175:1, calculated in eq.

[0020] Alternatively, the mixed acid is a mixture of formic acid, perchloric acid, and methanesulfonic acid; the ratio of formic acid, perchloric acid, methanesulfonic acid, and glyoxal, expressed in eq., is 0.2:0.1:0.1:1.

[0021] Alternatively, the mixed acid is a mixture of formic acid, perchloric acid, and trifluoromethanesulfonic acid; the ratio of formic acid, perchloric acid, trifluoromethanesulfonic acid, and glyoxal is 0.2:0.1:0.1:1, calculated in eq.

[0022] In a further preferred embodiment, step (2) involves a two-stage gradient heating reaction, as follows:

[0023] Heat to 0℃, reaction time x1 hour; heat to 35℃, reaction time x2 hours; x1 + x2 ≥ 18;

[0024] Alternatively, maintain the temperature of step (1) for a reaction time of Y1 hours; increase the temperature to 35°C for a reaction time of Y2 hours; Y1+Y2≥18.

[0025] The reaction was carried out in three stages with a gradient temperature increase, as follows: at this temperature, the reaction time was Z1 hours; the temperature was increased to 0℃, and the reaction time was Z2 hours; the temperature was increased to 35℃, and the reaction time was Z3 hours; Z1+Z2+Z3≥18.

[0026] Further preferred, step (3) specifically involves: filtration, pouring the filter cake into acetonitrile and stirring; filtration again, washing the filter cake with ice-cold ethanol, then washing with distilled water, and drying to obtain a white, pure solid product.

[0027] The beneficial effects of the method of the present invention are as follows:

[0028] First, the method of the present invention replaces the single formic acid catalyst with a polyacid catalytic system, which shortens the reaction time and improves the reaction yield.

[0029] Principle: In the aldehyde-amine condensation reaction, acidic hydrogen ions can combine with the aldehyde carbonyl group to form an α salt, or combine with the amino group to form an ammonium salt, causing the amino group to lose its nucleophilicity. Therefore, this reaction is very sensitive to the acidity and amount of acidic catalyst. After screening a large number of single acid catalysts, this invention found no significant improvement. When using a mixed acid such as formic acid, methanesulfonic acid, perchloric acid, and trifluoromethanesulfonic acid as acid catalysts, the reaction yield can reach up to 91%, and the reaction time can be shortened from 24 hours to 18 hours. Compared with the reaction conditions reported in the literature, both the reaction yield and time have been comprehensively improved.

[0030] Second, the method of the present invention changes the feeding method, shortens the feeding time, improves the reaction safety, and enables the reaction to be scaled up for production.

[0031] The existing gram-level process involves slowly adding 88% (mass percentage) formic acid dropwise to a solution of cyclopropylamine in acetonitrile and water, followed by slowly adding 40% (mass percentage) glyoxal dropwise to the reaction system. This invention pre-mixes the acid mixture with 40% glyoxal before adding the entire mixture dropwise to the solution of cyclopropylamine in acetonitrile and water. Compared to existing methods, this is not only safer (stable exothermic reaction, no smoke generation, no overflow), but also significantly shortens the addition time and increases the reaction yield. The main principle is analyzed as follows: In the acetonitrile and water solution, acidic hydrogen ions can combine with the aldehyde carbonyl group to form an ammonium salt, as shown in equation (1), or combine with the amino group to form an ammonium salt, causing the amino group to lose its nucleophilic ability, as shown in equation (2). Both processes involve direct chemical reactions of acidic hydrogen ions, resulting in vigorous reactions and significant exothermic reactions. When mixed in a non-solvent, the acid interacts with the aldehyde carbonyl group in molecular form via hydrogen bonds. The reaction principle is as follows (3), which activates the aldehyde carbonyl group, making it easier for it to react with cyclopropylamine in the system. Therefore, the reaction is stable and the yield is increased.

[0032]

[0033] Third, the method of the present invention uses a gradient heating mode to stabilize the process, with the reaction yield remaining stable at over 82% and the purity remaining stable at over 99%, and good reproducibility in kilogram-scale experiments.

[0034] Existing gram-scale processes involve feeding at 0°C, followed by a 24-hour reaction at room temperature. This invention, through reaction kinetic studies, reveals that this condensation reaction is highly reactive. If the initial reaction temperature is too high, it promotes the formation of byproducts, significantly darkens the system color, and reduces purity and yield. Therefore, this invention employs feeding at -15°C to -25°C and utilizes a two- or three-stage gradient heating mode, achieving a gain effect that increases purity, yield, and stability.

[0035] This invention is reasonably designed and has great practical application value. Attached Figure Description

[0036] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0037] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0038] Figure 1 The image shows the hydrogen NMR spectrum of product I obtained in Example 1.

[0039] Figure 2 The image shows the carbon NMR spectrum of product I obtained in Example 1.

[0040] Figure 3 The graph shows the purity test results for product I obtained in Example 1.

[0041] Figure 4 This diagram shows the single-crystal structure of product I obtained in Example 1.

[0042] Figure 5 The image shows the 1H NMR spectrum of the product obtained in Example 2.

[0043] Figure 6 The image shows the carbon NMR spectrum of the product obtained in Example 2.

[0044] Figure 7 The image shows the 1H NMR spectrum of the product obtained in Example 3.

[0045] Figure 8 The image shows the carbon NMR spectrum of the product obtained in Example 3.

[0046] Figure 9 The image shows the 1H NMR spectrum of the product obtained in Example 4.

[0047] Figure 10 The image shows the carbon NMR spectrum of the product obtained in Example 4.

[0048] Figure 11 The image shows the 1H NMR spectrum of the product obtained in Example 5.

[0049] Figure 12 The image shows the carbon NMR spectrum of the product obtained in Example 5.

[0050] Figure 13 The image shows the 1H NMR spectrum of the product obtained in Example 6.

[0051] Figure 14 The image shows the carbon NMR spectrum of the product obtained in Example 6.

[0052] Figure 15 The image shows the hydrogen NMR spectrum of the product obtained in Example 7.

[0053] Figure 16 The image shows the carbon NMR spectrum of the product obtained in Example 7.

[0054] Figure 17 The image shows the hydrogen NMR spectrum of the product obtained in Example 8.

[0055] Figure 18 The image shows the carbon NMR spectrum of the product obtained in Example 8.

[0056] Figure 19 The image shows the hydrogen NMR spectrum of the product obtained in Example 9.

[0057] Figure 20 The image shows the carbon NMR spectrum of the product obtained in Example 9.

[0058] Figure 21 The image shows the hydrogen NMR spectrum of the product obtained in Example 10.

[0059] Figure 22 The image shows the carbon NMR spectrum of the product obtained in Example 10.

[0060] Figure 23 The graph shows the purity test results of the product obtained in Example 2.

[0061] Figure 24 This graph shows the purity test results of the product obtained in Example 3.

[0062] Figure 25 This graph shows the purity test results of the product obtained in Example 4.

[0063] Figure 26 This graph shows the purity test results of the product obtained in Example 5.

[0064] Figure 27 This graph shows the purity test results of the product obtained in Example 6.

[0065] Figure 28 This graph shows the purity test results of the product obtained in Example 7.

[0066] Figure 29 This graph shows the purity test results of the product obtained in Example 8.

[0067] Figure 30 The graph shows the purity test results of the product obtained in Example 9.

[0068] Figure 31 This graph shows the purity test results of the product obtained in Example 10.

[0069] Figure 32 This graph shows the purity test results of the product obtained in Comparative Example 1.

[0070] Figure 33 The graph shows the purity test results of the product obtained in Comparative Example 3. Detailed Implementation

[0071] To better understand the above-mentioned objectives, features, and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

[0072] Many specific details are set forth in the following description in order to provide a full understanding of the invention, but the invention may also be practiced in other ways different from those described herein; obviously, the embodiments in the specification are only some embodiments of the invention, and not all embodiments.

[0073] The specific embodiments of the present invention will be described in detail below. Example 1

[0074] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0075] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (98mL, 0.175eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0076] After the addition was completed, the reaction was maintained at this temperature for 6 hours, then the temperature was raised to 0°C and reacted for 6 hours, and finally heated to 35°C and reacted for 6 hours, for a total reaction time of 18 hours;

[0077] The mixture was filtered, and the filter cake was poured into 2 L of acetonitrile and stirred for 15–20 min. It was then filtered again, and the filter cake was washed with 50 mL of ice-cold ethanol, followed by two washes with 200 mL of distilled water. After drying, a white, pure solid product I was obtained (yield 88%, purity 99.98%). (1H NMR spectroscopy, 400 MHz, 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); C NMR (100 MHz, CDCl3) δ 83.1, 77.2, 33.3, 32.0, 8.0, 7.3, 7.2. High-resolution mass spectrometry C 24 H 36 N6(M+H) + Theoretical value: 409.3074, Measured value: 409.3078. Elemental analysis (%) Theoretical value: C 24 H 36 N6(408.6):C,70.55;H,8.88;N,20.57;Measured values:C,70.53;H,8.86;N,20.55.

[0078] The reaction principle in this embodiment is as follows:

[0079]

[0080] from Figure 1 It can be seen that in the 1H NMR spectrum of product I, 4.14 (s, 4H) represents the four CH groups on the four lower six-membered rings, 3.99 (s, 2H) represents the two CH groups on the two upper five-membered rings, 2.57-2.62 (m, 2H) represents the two CH groups on the two lower cyclopropyl groups, 2.38-2.44 (m, 4H) represents the four CH groups on the four upper cyclopropyl groups, and 0.27-0.45 (m, 24H) represents the twelve CH2 groups on the six cyclopropyl groups.

[0081] from Figure 2 It can be seen that in the carbon NMR spectrum of product I, there are a total of 7 carbons with different environments, hence the 7 carbons with chemical shifts of 83.1, 76.8, 33.3, 32.1, 8.0, 7.3, and 7.2.

[0082] from Figure 3 It can be seen that, in the purity test of product I, the purity of product I was determined to be 99.98% based on the peak area ratio.

[0083] from Figure 4 As can be seen, the chemical structure and spatial arrangement of product I can be clearly determined directly from the single crystal structure diagram of product I. Example 2

[0084] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0085] At -20°C, cyclopropylamine (1467 g, 2.6 eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950 mL, water: 795 mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84 mL, 0.2 eq.), trifluoromethanesulfonic acid (153 mL, 0.175 eq.) and 40% glyoxal (1436 g, 1 eq.) over a period of 1 hour.

[0086] After the addition was completed, the reaction was maintained at this temperature for 6 hours, then the temperature was raised to 0°C and reacted for 6 hours, and finally heated to 35°C and reacted for 6 hours, for a total reaction time of 18 hours;

[0087] Filter by suction, pour the filter cake into 2L of acetonitrile and stir for 15-20 minutes, then filter again. Wash the filter cake with 50mL of ice-cold ethanol, then wash twice with 200mL of distilled water, and dry to obtain a white pure solid product (yield 89%, purity 99.5%).

[0088] The reaction principle in this embodiment is as follows:

[0089]

[0090] The 1H NMR spectrum of the product obtained in Example 2 is as follows: Figure 5As shown, the carbon NMR spectrum is as follows: Figure 6 As shown.

[0091] from Figure 23 It can be seen that in the purity test of the product obtained in Example 2, the purity of the product was 99.5% as determined by the peak area ratio. Example 3

[0092] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0093] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of methanesulfonic acid (128mL, 0.2eq.), perchloric acid (98mL, 0.175eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0094] After the addition was completed, the reaction was maintained at this temperature for 6 hours, then the temperature was raised to 0°C and reacted for 6 hours, and finally heated to 35°C and reacted for 6 hours, for a total reaction time of 18 hours;

[0095] Filter by suction, pour the filter cake into 2L of acetonitrile and stir for 15-20 minutes, then filter again. Wash the filter cake with 50mL of ice-cold ethanol, then wash twice with 200mL of distilled water, and dry to obtain a white pure solid product (yield 91%, purity 99.6%).

[0096] The reaction principle in this embodiment is as follows:

[0097]

[0098] The 1H NMR spectrum of the product obtained in Example 3 is as follows: Figure 7 As shown, the carbon NMR spectrum is as follows: Figure 8 As shown.

[0099] from Figure 24 It can be seen that in the purity test of the product obtained in Example 3, the purity of the product was 99.6% as determined by the peak area ratio.

[0100] Different gradient heating methods will also affect the yield and purity, see Examples 4 to 6. Example 4

[0101] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0102] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (98mL, 0.175eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0103] After the addition was completed, the reaction was maintained at this temperature for 12 hours, and then directly heated to 35°C for 6 hours, for a total reaction time of 18 hours.

[0104] After filtration, the filter cake was poured into 2L of acetonitrile and stirred for 15-20 minutes. After filtration, the filter cake was washed with 50mL of ice-cold ethanol and then washed twice with 200mL of distilled water. After drying, a white pure solid product was obtained (yield 83%, purity 99.5%).

[0105] The 1H NMR spectrum of the product obtained in Example 4 is as follows: Figure 9 As shown, the carbon NMR spectrum is as follows: Figure 10 As shown.

[0106] from Figure 25 It can be seen that in the purity test of the product obtained in Example 4, the purity of the product was 99.5% as determined by the peak area ratio. Example 5

[0107] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0108] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (98mL, 0.175eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0109] After the addition was completed, the reaction was maintained at this temperature for 12 hours, followed by a reaction at 0°C for 6 hours, for a total reaction time of 18 hours.

[0110] Filter by suction, pour the filter cake into 2L of acetonitrile and stir for 15-20 minutes, then filter again. Wash the filter cake with 50mL of ice-cold ethanol, then wash twice with 200mL of distilled water, and dry to obtain a white pure solid product (yield 63%, purity 81.2%).

[0111] The 1H NMR spectrum of the product obtained in Example 5 is as follows: Figure 11 As shown, the carbon NMR spectrum is as follows: Figure 12 As shown.

[0112] from Figure 26It can be seen that in the purity test of the product obtained in Example 5, the purity of the product was 81.2% as determined by the peak area ratio. Example 6

[0113] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0114] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (98mL, 0.175eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0115] After the addition was completed, the temperature was raised to 0°C and reacted for 6 hours, then heated to 35°C and reacted for 12 hours, for a total reaction time of 18 hours;

[0116] Filter by suction, pour the filter cake into 2L of acetonitrile and stir for 15-20 minutes, then filter again. Wash the filter cake with 50mL of ice-cold ethanol, then wash twice with 200mL of distilled water, and dry to obtain a white pure solid product (yield 83%, purity 99.3%).

[0117] The 1H NMR spectrum of the product obtained in Example 6 is as follows: Figure 13 As shown, the carbon NMR spectrum is as follows: Figure 14 As shown.

[0118] from Figure 27 It can be seen that in the purity test of the product obtained in Example 6, the purity of the product was 99.3% as determined by the peak area ratio.

[0119] Different proportions of mixed acids can affect the reaction results, see Examples 7 and 8. Example 7

[0120] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0121] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (140mL, 0.25eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0122] After the addition was completed, the reaction was maintained at this temperature for 6 hours, then the temperature was raised to 0°C and reacted for 6 hours, and finally heated to 35°C and reacted for 6 hours, for a total reaction time of 18 hours;

[0123] Filter by suction, pour the filter cake into 2L of acetonitrile and stir for 15-20 minutes, then filter again. Wash the filter cake with 50mL of ice-cold ethanol, then wash twice with 200mL of distilled water, and dry to obtain a white pure solid product (yield 85%, purity 99.5%).

[0124] The 1H NMR spectrum of the product obtained in Example 7 is as follows: Figure 15 As shown, the carbon NMR spectrum is as follows: Figure 16 As shown.

[0125] from Figure 28 It can be seen that in the purity test of the product obtained in Example 7, the purity of the product was 99.5% as determined by the peak area ratio. Example 8

[0126] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0127] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (56mL, 0.1eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0128] After the addition was completed, the reaction was maintained at this temperature for 6 hours, then the temperature was raised to 0°C and reacted for 6 hours, and finally heated to 35°C and reacted for 6 hours, for a total reaction time of 18 hours;

[0129] After filtration, the filter cake was poured into 2L of acetonitrile and stirred for 15-20 minutes. After filtration, the filter cake was washed with 50mL of ice-cold ethanol and then washed twice with 200mL of distilled water. After drying, a white pure solid product was obtained (yield 83%, purity 99.3%).

[0130] The 1H NMR spectrum of the product obtained in Example 8 is as follows: Figure 17 As shown, the carbon NMR spectrum is as follows: Figure 18 As shown.

[0131] from Figure 29 It can be seen that in the purity test of the product obtained in Example 8, the purity of the product was 99.3% as determined by the peak area ratio.

[0132] Ternary mixed acids can also catalyze this reaction well, as shown in Examples 9 and 10. Example 9

[0133] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0134] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (56mL, 0.1eq.), methanesulfonic acid (64mL, 0.1eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0135] After the addition was completed, the reaction was maintained at this temperature for 6 hours, then the temperature was raised to 0°C and reacted for 6 hours, and finally heated to 35°C and reacted for 6 hours, for a total reaction time of 18 hours;

[0136] Filter by suction, pour the filter cake into 2L of acetonitrile and stir for 15-20 minutes, then filter again. Wash the filter cake with 50mL of ice-cold ethanol, then wash twice with 200mL of distilled water, and dry to obtain a white pure solid product (yield 89%, purity 99.5%).

[0137] The 1H NMR spectrum of the product obtained in Example 9 is as follows: Figure 19 As shown, the carbon NMR spectrum is as follows: Figure 20 As shown.

[0138] from Figure 30 It can be seen that in the purity test of the product obtained in Example 9, the purity of the product was 99.5% as determined by the peak area ratio. Example 10

[0139] A method for preparing kilogram-scale high-purity hexacyclopropylhexaazaisowrutzane is as follows:

[0140] At -20℃, cyclopropylamine (1467g, 2.6eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950mL, water: 795mL), followed by the slow addition of a freshly prepared mixed solution of 88% formic acid (84mL, 0.2eq.), perchloric acid (56mL, 0.1eq.), trifluoromethanesulfonic acid (87.4mL, 0.1eq.) and 40% glyoxal (1436g, 1eq.) over a period of 1 hour.

[0141] After the addition was completed, the reaction was maintained at this temperature for 6 hours, then the temperature was raised to 0°C and reacted for 6 hours, and finally heated to 35°C and reacted for 6 hours, for a total reaction time of 18 hours;

[0142] Filter by suction, pour the filter cake into 2L of acetonitrile and stir for 15-20 minutes, then filter again. Wash the filter cake with 50mL of ice-cold ethanol, then wash twice with 200mL of distilled water, and dry to obtain a white pure solid product (yield 88%, purity 99.8%).

[0143] The 1H NMR spectrum of the product obtained in Example 10 is as follows: Figure 21As shown, the carbon NMR spectrum is as follows: Figure 22 As shown.

[0144] from Figure 31 It can be seen that in the purity test of the product obtained in Example 10, the purity of the product was 99.8% as measured by the peak area ratio. Comparative Example 1

[0145]

[0146] Based on the operating methods and material ratios reported in existing literature, the heat accumulation in the reaction is more obvious and the reaction is more intense at the kilogram-scale operation, making it difficult to control the temperature. Therefore, the feeding time is about 6 hours, and the pure product yield is only 61%.

[0147] At 0°C, cyclopropylamine (1692.7 g, 3 eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950 mL, water: 795 mL). Formic acid (121.8 mL, 0.29 eq.) was then slowly added dropwise to the system. Finally, a 40% glyoxal solution (1436 g, 1 eq.) was slowly added dropwise to the mixture. Due to the vigorous reaction, the addition took approximately 6 hours. After the addition was complete, the mixture was allowed to rise to room temperature and react for 24 hours. The reaction was confirmed by TLC, and the crude product (78% yield) was obtained by filtration. This crude product was poured into 2 L of acetonitrile and stirred for 15–20 min. The mixture was then filtered, and the filter cake was washed with 50 mL of ice-cold ethanol, followed by two washes with 200 mL of distilled water. After drying, a white, pure solid product was obtained (61% yield, 99.3% purity).

[0148] from Figure 32 It can be seen that in the purity test of the product obtained in Comparative Example 1, the purity of the product was 99.3% as determined by the peak area ratio. Comparative Example 2

[0149] If the proportions of the materials provided in this invention are used, and the amount of cyclopropylamine is reduced to 2.6 equivalents, the reaction time is reduced to 18 hours, and formic acid, as reported in existing literature, is used as the single catalyst, and the operation method is carried out according to existing literature, the yield will be further reduced to 56%. It is evident that the dicarboxylic acid catalytic system provided in this invention significantly improves the yield while reducing the amount of cyclopropylamine and the reaction time, demonstrating outstanding economic benefits for scale-up production.

[0150] At 0°C, cyclopropylamine (1467 g, 2.6 eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950 mL, water: 795 mL). Then, formic acid (157.5 mL, 0.375 eq.) was slowly added dropwise to the system. Finally, a 40% glyoxal solution (1436 g, 1 eq.) was slowly added dropwise to the mixture. Due to the vigorous reaction, the addition took approximately 6 hours. After the addition was complete, the mixture was allowed to rise to room temperature and react for 18 hours. The reaction was confirmed by TLC, and the crude product (78% yield) was obtained by filtration. This crude product was poured into 2 L of acetonitrile and stirred for 15–20 min. The mixture was then filtered, and the filter cake was washed with 50 mL of ice-cold ethanol, followed by two washes with 200 mL of distilled water. After drying, a white, pure solid product (53% yield) was obtained. Comparative Example 3

[0151] The reaction was carried out according to the binary mixed acid catalytic system, feeding sequence, reaction time, and material ratio of the present invention, except that the temperature was according to existing literature reports, instead of the gradient heating mode adopted in the present invention. As a result, the reaction yield decreased from 91% to 82%, and the purity decreased to 99.1%.

[0152] At 0°C, cyclopropylamine (1467 g, 2.6 eq.) was added to a solution of acetonitrile and water (acetonitrile: 7950 mL, water: 795 mL). Then, a freshly prepared mixed solution of methanesulfonic acid (128 mL, 0.2 eq.), perchloric acid (98 mL, 0.175 eq.), and 40% glyoxal (1436 g, 1 eq.) was slowly added over a period of 1 hour. After the addition was complete, the reaction was allowed to proceed at room temperature for 18 hours. The mixture was then filtered, and the filter cake was poured into 2 L of acetonitrile and stirred for 15–20 min. The mixture was then filtered again, and the filter cake was washed with 50 mL of ice-cold ethanol and then washed twice with 200 mL of distilled water. After drying, a white, pure solid product was obtained (yield 82%, purity 99.1%).

[0153] from Figure 33 It can be seen that in the purity test of the product obtained in Comparative Example 3, the purity of the product was 99.1% as determined by the peak area ratio.

[0154] The embodiments of the present invention have the following advantages:

[0155] (1) By changing the catalyst to a dicarboxylic acid or tricarboxylic acid catalytic system, the amount of cyclopropylamine used (reduced to 2.6 equivalents) and the reaction time (shortened to 18 hours) are reduced, while the yield is significantly improved (increased to over 82%, with a maximum of 91%), which has outstanding economic benefits for scale-up production.

[0156] (2) By changing the order of adding materials, the entire dropping process is made stable and safe, and the dropping time is shortened from 6 hours to 1 hour; if the reaction amount continues to increase, the gain effect will be more obvious.

[0157] (3) The condensation reaction is carried out by feeding at -20℃ and using a gradient heating mode, which makes the process stable, safe, and improves the yield and purity, thus having obvious technical advantages.

[0158] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the present invention. Although detailed descriptions have been provided with reference to the foregoing embodiments, those skilled in the art should understand that: synthetic steps similar to the present invention, replacing the mixed acids mentioned in the present invention with common protic acids or Lewis acids, and using gradient heating modes with different time intervals or temperature intervals, should all fall within the protection scope of the present invention.

Claims

1. A method for preparing hexacyclopropylhexaazaisowrutzane, characterized in that: Includes the following steps: Step (1): At -15℃ to -25℃, add cyclopropylamine to a solution of acetonitrile and water, and then add a mixed acid and glyoxal solution dropwise. The amount of cyclopropylamine used was 1467g, and the amount of glyoxal used was 1436g. The mixed acid is a mixture of formic acid and perchloric acid; the ratio of formic acid, perchloric acid and glyoxal, expressed in eq., is 0.2:(0.1~0.25):

1. Alternatively, the mixed acid is a mixture of formic acid and trifluoromethanesulfonic acid; the ratio of formic acid, trifluoromethanesulfonic acid and glyoxal is 0.2:0.175:1, calculated in eq. Alternatively, the mixed acid is a mixture of methanesulfonic acid and perchloric acid; the ratio of methanesulfonic acid, perchloric acid and glyoxal, expressed in eq., is 0.2:0.175:

1. Alternatively, the mixed acid is a mixture of formic acid, perchloric acid, and methanesulfonic acid; the ratio of formic acid, perchloric acid, methanesulfonic acid, and glyoxal, expressed in eq., is 0.2:0.1:0.1:

1. Alternatively, the mixed acid is a mixture of formic acid, perchloric acid, and trifluoromethanesulfonic acid; the ratio of formic acid, perchloric acid, trifluoromethanesulfonic acid, and glyoxal, expressed in eq., is 0.2:0.1:0.1:

1. Step (2): After the addition is complete, raise the temperature to room temperature and react for at least 18 hours; Alternatively, after the addition is complete, a gradient heating reaction is carried out for more than 18 hours; wherein, a two-stage gradient heating reaction is carried out, as follows: heating to 0℃, reaction time X1 hours; heating to 35℃, reaction time X2 hours; X1+X2≥18; or, maintaining the temperature of step (1), reaction time Y1 hours; heating to 35℃, reaction time Y2 hours; Y1+Y2≥18; or, carrying out a three-stage gradient heating reaction, as follows: maintaining this temperature, reaction time Z1 hours; heating to 0℃, reaction time Z2 hours; heating to 35℃, reaction time Z3 hours; Z1+Z2+Z3≥18; Step (3): After filtration, washing and drying, a white pure solid product is obtained.

2. The method for preparing hexacyclopropylhexaazaisowrtzine according to claim 1, characterized in that: X1=6, X2=12; Y1=12, Y2=6.

3. The method for preparing hexacyclopropylhexaazaisowrtzine according to claim 1, characterized in that: Z1=Z2=Z3=6.

4. The method for preparing hexacyclopropylhexaazaisowrtzine according to claim 1, characterized in that: Step (3) is as follows: filter, pour the filter cake into acetonitrile and stir; filter again, wash the filter cake with ice-cold ethanol, then wash with distilled water, dry, and obtain a white pure solid product.

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