An oxotriazine-fused piperazine heterocyclic compound, its preparation method and applications

Abstract

The present invention discloses an oxotriazine-fused piperazine heterocyclic compound, and its structural general formula is shown as formula (I): The present invention also provides a preparation method of the heterocyclic compound. This kind of heterocyclic compound is a novel skeleton heterocyclic compound with a bicyclic parallel connection of a triazine ring and a piperazine ring. The synthesis and preparation of this kind of heterocyclic compound can enrich the types of heterocyclic compounds in nature that can be artificially prepared, and can also be used as a key intermediate for synthesizing some natural products with biological activities. For example, the novel natural alkaloid compound violacein D with good radioprotective effects. Therefore, the preparation of this compound is of great significance for the total synthesis of violacein D.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and more specifically, to an oxotriazine-fused piperazine heterocyclic compound, a preparation method thereof, and an application thereof. Background Art

[0002] A heterocycle refers to a cyclic structure composed of carbon atoms and non-carbon atoms, and the non-carbon atoms in the ring are called heteroatoms. Common heteroatoms include nitrogen, oxygen, sulfur, etc. Heterocyclic compounds play a very important role in the composition of natural substances. Heterocycles can be found in the structures of substances such as alkaloids, nucleic acids, and vitamins in living organisms. The applications of heterocyclic compounds are also very extensive. The biomedical field is a typical application field of heterocyclic compounds. Taking drugs as an example, heterocyclic drugs are the largest category in synthetic drugs, and there are numerous drugs containing heterocyclic structures. Common antibiotics, benzodiazepine sedatives, anticholinergic drugs such as scopolamine, etc. are all heterocyclic drugs. In view of this, scientists have also enriched the types of known heterocyclic compounds through means such as extraction and separation, chemical synthesis, especially the types of heterocyclic compounds that can be artificially synthesized, so that more heterocyclic compounds can be used by people to benefit society.

[0003] Orychophragmine D is a new natural alkaloid compound extracted and separated from Orychophragmus violaceus seeds in recent years. In an in vitro anti-radiation activity screening experiment, using human umbilical vein endothelial cell line HUVEC as a cell model, irradiated with γ-rays generated by 60Co, the irradiation dose was 8 Gy, and the dose rate was 0.8 Gy / min. By comparing with the positive drug 523 control group and the negative control plate, the radiation protection effect of orychophragmine D was calculated. According to the relevant experimental results, orychophragmine D has good in vitro and in vivo anti-radiation activities. In the in vitro anti-radiation activity experiment, the survival rate of umbilical vein endothelial cells in the orychophragmine D group was significantly higher than that of the control group after irradiation; in the in vivo anti-radiation activity experiment, the survival rate of mice in the high-dose orychophragmine D group was 100% after irradiation, while the survival rate of the control group was 0, proving that orychophragmine D has good in vitro and in vivo anti-radiation activities. However, the current preparation methods of orychophragmine D are generally extraction and separation from plants, and this method has problems such as few raw material sources, poor extraction purity, and complex extraction.

[0004] Therefore, in order to solve the above problems, the present invention provides a preparation method of a heterocyclic compound. This type of heterocyclic compound is a new skeleton heterocyclic compound with a bicyclic parallel connection of a triazine ring and a piperazine ring. The synthesis and preparation of this type of heterocyclic compound can enrich the types of heterocyclic compounds in nature that can be artificially prepared, and can also be used as a key intermediate for synthesizing some natural products with biological activities, such as the new natural alkaloid compound orychophragmine D with good radiation protection effects. Therefore, this compound lays a foundation for the total synthesis of orychophragmine D and provides new ideas, which is of great significance. Summary of the Invention

[0005] In view of this, the present invention provides an oxotriazine-fused piperazine heterocyclic compound, a preparation method thereof, and an application thereof.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] An oxotriazine-fused piperazine heterocyclic compound, the structural formula of the compound is shown in formula (I):

[0008]

[0009] A preparation method of the above-mentioned oxotriazine-fused piperazine heterocyclic compound, the synthesis route is:

[0010]

[0011] The preparation method includes the following steps:

[0012] a) Add 1,2-dihydropyran and pyridinium p-toluenesulfonate to the compound shown in general formula (II), and react to obtain the compound shown in general formula (III);

[0013] b) Add N,N'-carbonyldiimidazole to the compound shown in general formula (III), and then dropwise add an ammoniating reagent to the system to obtain the compound shown in general formula (IV);

[0014] c) Subject the compound shown in general formula (IV) to a reduction reaction to obtain the compound shown in general formula (V);

[0015] d) Subject the compound shown in general formula (V) and dimethyl oxalate to an aminolysis reaction of the ester to obtain the compound shown in general formula (VI);

[0016] e) Subject the compound shown in general formula (VI) to an acidification reaction to obtain the compound shown in general formula (VII);

[0017] f) Add imidazole and tert-butyldiphenylchlorosilane to the compound shown in general formula (VII), and react to obtain the compound shown in general formula (VIII);

[0018] g) React the compound shown in general formula (VIII) with Lawesson's reagent to obtain the compound shown in general formula (IX);

[0019] h) The compound shown in general formula (IX) undergoes a nucleophilic reaction to obtain the compound shown in general formula (X);

[0020] i) React the compound shown in general formula (X) with an active carbonyl reagent to obtain the compound shown in general formula (XI);

[0021] j) The compound shown by the general formula (XI) undergoes a deprotection reaction with tetrabutylammonium fluoride to obtain the compound shown by the general formula (XII);

[0022] k) The compound shown by the general formula (XII) reacts with an acidic reagent to obtain an oxotriazine - piperazine heterocyclic compound.

[0023] In the present invention, Boc - L - serine is used as a substrate, and the target oxotriazine - piperazine heterocyclic compound is obtained through 10 steps of reactions. In the initially designed preparation route, the substrate was N - Boc - O - Bn - L - serine. It was intended to remove the benzyl group in the molecule using catalytic hydrogenation after the construction of the triazine - piperazine bicyclic ring. However, the benzyl group in the substrate could not be removed by the classical catalytic hydrogenation method. Due to the presence of the acid - intolerant Boc protecting group in the molecule, the method of using Lewis acid to remove the benzyl group could not be used either. Subsequently, the substrate was replaced with Boc - L - serine without a protecting group on the oxygen atom, a selectively removable tetrahydropyran protecting group was introduced, and then the protecting group was replaced in the preparation route, successfully completing the preparation of the target product. The preparation process is divided into 10 steps.

[0024] Preferably, the oxopiperazine compound shown by the general formula (VIII) is:

[0025]

[0026] Among them, R1 is an oxygen atom or a sulfur atom, and R2 is any one of benzyl, tetrahydropyranyl, and tert - butyldiphenylsilyl;

[0027] The oxopyrazine - piperazine heterocyclic compound shown by the general formula (XI) is:

[0028]

[0029] Among them, R3 is any one of benzyl, tetrahydropyranyl, and tert - butyldiphenylsilyl;

[0030] The oxopyrazine - piperazine heterocyclic compound shown by the general formula (XII) is:

[0031]

[0032] Preferably, in step b), the ammoniating reagent is 30% ammonia water, the molar ratio of the compound shown by the general formula (III) to N,N’ - dicarbonylimidazole is 1:1 - 3, and the molar ratio of the compound shown by the general formula (III) to the ammoniating reagent is 1:3 - 10.

[0033] Preferably, in step c), the reducing agent for the reduction reaction is lithium aluminum hydride, the reaction solvent is diethyl ether or tetrahydrofuran, and the reaction conditions are stirring at room temperature for 36 h or refluxing at 70 °C for 8 h; the molar ratio of the compound represented by the general formula (IV) to the reducing agent is 1:4 - 20.

[0034] Preferably, the molar ratio of the compound represented by the general formula (IV) to the reducing agent is 1:4 - 10.

[0035] Preferably, the molar ratio of the compound represented by the general formula (IV) to the reducing agent is 1:6.

[0036] Preferably, in step d), the ester is any one of dimethyl oxalate, diethyl oxalate, and oxalyl chloride, and the molar ratio of the two is 1 - 10:1;

[0037] The reaction conditions are refluxing at 70 °C for 8 h, and the reaction solvent is any one of ethanol, methanol, dichloromethane, and 1,2 - dichloroethane.

[0038] Preferably, the molar ratio is 2 - 6:1.

[0039] Preferably, the molar ratio is 4:1.

[0040] Preferably, in step e), the acidic reagent for the acidification reaction is any one of hydrochloric acid, p - toluenesulfonic acid, and trifluoroacetic acid, and the molar ratio of the compound represented by the general formula (VI) to the acidic reagent is 1:0.1 - 5; preferably 1:0.2 - 1, more preferably 1:0.5;

[0041] In step f), the molar ratio of the compound represented by the general formula (VII) to tert - butyldiphenylchlorosilane is 1:1 - 1.5, and the molar ratio of the compound represented by the general formula (VII) to imidazole is 1:2 - 5;

[0042] In step g), the molar ratio of the compound represented by the general formula (VIII) to Lawesson's reagent is 1:0.1 - 5, preferably 1:1 - 3, more preferably 1:2; the reaction solvent is any one of tetrahydrofuran, diethyl ether, and n - hexane.

[0043] Preferably, in step h), in the nucleophilic reaction, the molar ratio of the compound represented by the general formula (IX), the nucleophile, and the reaction auxiliary is 1:1 - 10:0.5 - 3; preferably 1:2 - 6:0.5 - 3, more preferably 1:4:2;

[0044] The nucleophile is 1 - Boc - guanidine, the reaction auxiliary is a salt of a transition metal, and the reaction solvent is any one of N,N - dimethylformamide, 1,4 - dioxane, and tetrahydrofuran;

[0045] In step i), the molar ratio of the compound represented by the general formula (X) to the active carbonyl reagent is 1:1 - 10, preferably 1:2 - 6, more preferably 1:4; the reaction solvent is any one of ethyl acetate, dichloromethane, and tetrahydrofuran;

[0046] The active carbonyl reagent is any one of 1,1 - carbonyldiimidazole, triphosgene, and oxalyl chloride.

[0047] Preferably, in step j), the molar ratio of the compound represented by the general formula (XI) to the tetrabutylammonium fluoride is 1:1 - 6, preferably 1:2 - 4, more preferably 1:3;

[0048] The reaction solvent is tetrahydrofuran or diethyl ether.

[0049] Preferably, the acidic reagent added in step k) is any one of trifluoroacetic acid, hydrochloric acid (1 - 6M, preferably 2M), hydrogen chloride methanol solution (1 - 6M, preferably 2M), hydrogen chloride dioxane solution (1 - 6M, preferably 2M), preferably any one of trifluoroacetic acid and hydrogen chloride methanol solution (2M);

[0050] The molar ratio of the compound represented by the general formula (XII) to the acidic reagent is 1:3 - 10;

[0051] The reaction solvent is dichloromethane or 1,2 - dichloroethane.

[0052] Use of the oxotriazine - piperazine heterocyclic compound as described above or the oxotriazine - piperazine heterocyclic compound obtained by the preparation method as described above in the preparation of oryzalin D.

[0053] The present invention provides an oxotriazine - piperazine heterocyclic compound having the same molecular skeleton as oryzalin D. The structure of the oxotriazine - piperazine heterocyclic compound involved in the present invention is shown in the following formula (I), and the structure of oryzalin D is shown in formula (Ia). Therefore, the preparation of this compound is of great significance for the total synthesis of oryzalin D.

[0054]

[0055] As can be seen from the above - mentioned technical solutions, compared with the prior art, the beneficial effects of the present invention are as follows: The present invention provides a preparation method of a heterocyclic compound. This type of heterocyclic compound is a new - skeleton heterocyclic compound with a bicyclic parallel connection of a triazine ring and a piperazine ring. The synthesis and preparation of this type of heterocyclic compound can enrich the types of naturally occurring heterocyclic compounds that can be artificially prepared, and can also be used as a key intermediate for synthesizing certain natural products with biological activities, such as the new natural alkaloid compound oryzalin D with good radioprotective effects. Therefore, the preparation of this compound is of great significance for the total synthesis of oryzalin D. Detailed implementation mode

[0056] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0057] Example 1

[0058] A preparation method of an oxotriazine-piperazine heterocyclic compound, and the synthesis route is as follows:

[0059]

[0060] The specific steps are as follows:

[0061] a) Add 10 g of the substrate Boc-L-serine to a round-bottom flask, add 50 ml of dichloromethane and stir to dissolve. Then continue to add 4.6 g of 3,4-dihydropyran and 1.22 g of pyridinium p-toluenesulfonate to the solution, and stir at room temperature for 12 hours. After the reaction is completed, add 30 ml of 2M sodium hydroxide solution to the system, extract the aqueous phase with dichloromethane (30 ml * 3 times), combine the organic phases and discard them. Dropwise add 2M hydrochloric acid to the aqueous phase to adjust the pH to 2 - 3. Extract the adjusted aqueous phase with dichloromethane (30 ml * 3 times), combine the organic phases, dry over anhydrous sodium sulfate and then concentrate to obtain a crude product. The crude product is directly used for the next reaction without silica gel column chromatography;

[0062] b) Add 8 g of the product from step a) to a round-bottom flask, add 50 ml of ethyl acetate to dissolve. Slowly add 4.93 g of N,N'-carbonyldiimidazole to the solution in batches. After adding, heat the reaction system to 50 °C and stir for 30 minutes. After 30 minutes, dropwise add 10 ml of ammonia water to the system. After adding, stir for 30 minutes. After the reaction is completed, add 30 ml of water to the system, extract the aqueous phase with ethyl acetate (30 ml * 3 times), combine the organic phases, dry over anhydrous sodium sulfate and then concentrate to obtain a crude product. The crude product is separated by silica gel column chromatography to obtain a pure product. The mobile phase is ethyl acetate:petroleum ether 1:30 to 1:3. The two-step yield is 78%. The relevant hydrogen spectrum and carbon spectrum data are as follows: 1 H NMR(400MHz,DMSO-d6)δ:7.30(d,J=7.7Hz,1H),7.07(d,J=9.3Hz,1H),6.64(dd,J=24.0,8.5Hz,1H),4.52(t,J=3.2Hz,1H),4.14–3.91(m,1H),3.73–3.58(m,2H),3.49–3.30(m,2H),1.74–1.38(m,6H),1.34(s,9H).

[0063] 13 13C NMR (101 MHz, DMSO-d6) δ: 172.43, 172.30, 155.66, 98.60, 97.77, 78.62, 67.57, 67.30, 61.64, 61.50, 54.93, 54.45, 30.58, 30.49, 28.66, 25.50, 19.38, 19.28. MS (ESI) m / z: [M+Na] + 301.

[0064] c) Add 5 g of the product from step b) to a round-bottom flask, dissolve it in 30 ml of tetrahydrofuran. Under nitrogen protection and in an ice bath, slowly add 4 g of lithium aluminum hydride to the above solution in portions. After addition, heat the reaction to 70 °C and stir for 24 hours. After the reaction is complete, cool the reaction to 0 °C, slowly add 4 ml of water and 4 ml of 1 M sodium hydroxide solution to the reaction. After addition, filter the insoluble matter. Wash the filter cake with tetrahydrofuran and discard it. Concentrate the filtrate under reduced pressure to obtain a crude product, which is directly used in the next step without silica gel column chromatography;

[0065] d) Add 3 g of the product from step c) to a round-bottom flask, dissolve it in 30 ml of methanol. Add 3.8 g of dimethyl oxalate to the solution. After addition, heat the reaction to 80 °C and stir for 2 hours. After the reaction is complete, cool the reaction to room temperature. Concentrate the system under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain a pure product. The mobile phase is dichloromethane:methanol 1:100 to 1:30. The two-step yield is 62%. The relevant 1H NMR and 13C NMR data are as follows:

[0066] 1 1H NMR (400 MHz, DMSO-d6) δ: 8.37 (dd, J = 10.4, 5.1 Hz, 1H), 4.64–4.48 (m, 1H), 3.76–3.47 (m, 5H), 3.44–3.18 (m, 2H), 2.94 (d, J = 2.8 Hz, 3H), 1.82–1.15 (m, 6H).

[0067] 13 13C NMR (101 MHz, DMSO-d6) δ: 158.28, 157.64, 98.68, 98.13, 66.07, 64.98, 61.62, 61.57, 56.30, 56.14, 34.22, 34.09, 30.51, 30.48, 25.45, 19.19. MS (ESI) m / z: [M+Na] + 265.

[0068] e) Add 2 g of the product from step d) to a round-bottom flask, dissolve it in 20 ml of methanol, slowly add 0.28 g of p-toluenesulfonic acid to the solution, stir at room temperature for 2 hours after addition. After stirring, concentrate the system under reduced pressure to obtain a crude product, which is directly used in the next reaction without silica gel column chromatography;

[0069] f) Add 1 g of the product from step e) to a round-bottom flask, dissolve it in 5 ml of N,N-dimethylformamide. Add 1.9 g of tert-butyldiphenylchlorosilane and 1.3 g of imidazole to the above solution, stir at room temperature for 6 hours after addition. After the reaction is completed, add 10 ml of water to the system, extract the aqueous phase with ethyl acetate (10 ml * 3 times), combine the organic phases, dry over anhydrous sodium sulfate and then concentrate to obtain a crude product. The crude product is separated by silica gel column chromatography to obtain a pure product. The mobile phase is dichloromethane:methanol from 1:100 to 1:30. The two-step yield is 74%. The relevant 1H NMR and 13C NMR data are as follows:

[0070] 1 H NMR(400MHz,DMSO-d6)δ:8.40(d,J=5.0Hz,1H),7.63–7.32(m,10H),5.72(s,1H),3.64(ddd,J=15.2,8.2,3.3Hz,4H),3.36–3.31(m,1H),2.85(s,3H),0.94(s,9H).

[0071] 13 C NMR(101MHz,DMSO-d6)δ:158.20,157.51,135.60,132.80,132.74,130.57,128.55,62.54,57.70,55.45,34.26,27.04,19.18.MS(ESI)m / z:[M+Na] + 419.

[0072] g) Add 1 g of the product from step f) to a round-bottom flask, dissolve it in 5 ml of tetrahydrofuran. Slowly add 0.53 g of Lawesson's reagent to the above solution in batches, stir at room temperature for 6 hours after addition. After the reaction is completed, add 10 ml of water to the system, extract the aqueous phase with ethyl acetate (10 ml * 3 times), combine the organic phases, dry over anhydrous sodium sulfate and then concentrate to obtain a crude product. The crude product is separated by silica gel column chromatography to obtain a pure product. The mobile phase is dichloromethane:methanol from 1:100 to 1:30. The yield is 76%. The relevant 1H NMR and 13C NMR data are as follows: 1 HNMR(400MHz,DMSO-d6)δ:10.94(d,J=4.9Hz,1H),7.65–7.27(m,10H),3.80–3.49(m,4H),3.44–3.33(m,1H),2.89(s,3H),0.95(s,9H).

[0073] 13 C NMR (101 MHz, DMSO-d6) δ: 186.09, 156.44, 135.58, 132.69, 130.56, 128.58, 62.40, 57.73, 41.81, 35.28, 27.10, 19.18. MS (ESI) m / z: [M+Na] + 435.

[0074] h) Add 0.8 g of the product from step g) to a round-bottom flask, dissolve it in 5 ml of N,N-dimethylformamide. Slowly add 0.63 g of mercury(II) chloride and 0.37 g of Boc-guanidine to the above solution. After addition, heat the reaction to 80 °C and stir for 1 hour. After the reaction is complete, add 10 ml of water to the system. Extract the aqueous phase with ethyl acetate (10 ml * 3 times). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is separated by silica gel column chromatography to obtain the pure product. The mobile phase is dichloromethane:methanol 1:100 to 1:30, and the yield is 56%. The relevant 1H NMR and 13C NMR data are as follows: 1 1H NMR (400 MHz, DMSO-d6) δ: 11.41 (s, 1H), 9.05 (s, 1H), 7.57–7.27 (m, 10H), 3.92–3.63 (m, 4H), 2.91 (s, 3H), 2.84 (s, 1H), 2.68 (s, 1H), 1.33 (s, 9H), 0.88 (s, 9H).

[0075] 13 C NMR (101 MHz, DMSO-d6) δ: 162.81, 158.29, 154.69, 147.85, 135.56, 132.74, 132.66, 130.50, 128.47, 77.40, 63.81, 56.82, 46.79, 36.30, 34.00, 31.27, 28.54, 26.92, 19.04. MS (ESI): [M+H] + 538.

[0076] i) Add 0.5 g of the product from step h) to a round-bottom flask, dissolve it in 5 ml of ethyl acetate. Slowly add 1 g of N,N'-carbonyldiimidazole to the above solution. After addition, heat the reaction to 80 °C and stir for 1 hour. After the reaction is complete, add 10 ml of water to the system. Extract the aqueous phase with ethyl acetate (10 ml * 3 times). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is separated by silica gel column chromatography to obtain the pure product. The mobile phase is dichloromethane:methanol 1:100 to 1:20, and the yield is 71%. The relevant 1H NMR and 13C NMR data are as follows:

[0077] 1 1H NMR (400 MHz, DMSO-d6) δ: 10.59 (s, 1H), 7.65–7.23 (m, 10H), 4.50 (d, J = 13.3 Hz, 1H), 4.10–3.86 (m, 2H), 3.70 (s, 2H), 2.92 (s, 3H), 1.39 (s, 9H), 0.80 (s, 9H).

[0078] 13 13C NMR (101 MHz, DMSO-d6) δ: 164.03, 155.92, 155.66, 154.43, 150.17, 135.51, 135.38, 132.41, 132.36, 130.56, 130.51, 128.53, 128.47, 80.76, 63.99, 55.38, 42.33, 34.47, 28.24, 26.87, 18.93. MS (ESI) m / z: [M+Na] + 586.

[0079] j) 0.3 g of the product from step i) was added to a round-bottom flask, dissolved in 3 ml of tetrahydrofuran. 0.64 ml of 1 M tetrabutylammonium fluoride was slowly added to the above solution under an ice bath. After addition, the mixture was stirred at the ice bath for 2 hours. After the reaction was completed, the system was filtered, and the filter cake was washed with tetrahydrofuran to obtain the pure product with a yield of 61%. The relevant 1H NMR and 13C NMR data are as follows: 1 1H NMR (400 MHz, DMSO-d6) δ: 10.55 (s, 1H), 5.16 (t, J = 5.2 Hz, 1H), 4.39–4.18 (m, 1H), 3.98–3.58 (m, 2H), 3.54 (dt, J = 4.7, 4.2 Hz, 2H), 3.02 (s, 3H), 1.39 (s, 9H).

[0080] 13 13C NMR (101 MHz, DMSO-d6) δ: 163.98, 156.05, 155.99, 154.43, 150.20, 80.85, 60.71, 55.94, 42.35, 34.53, 28.25. MS (ESI) m / z: [M+Na] + 348.

[0081] k) 0.1 g of the product from step j) was added to a round-bottom flask and dissolved in 3 ml of dichloromethane. 1 ml of trifluoroacetic acid was slowly added to the above solution under an ice bath. After addition, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and the residue was the trifluoroacetate of the substance shown in general formula I. The relevant nuclear magnetic resonance and high-resolution mass spectrometry data are as follows:

[0082] 1 1H NMR (600 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.61 (s, 1H), 5.15 (s, 1H), 4.32 (d, J = 12.6 Hz, 1H), 3.80–3.72 (m, 2H), 3.55 (d, J = 3.8 Hz, 2H), 3.05 (s, 3H).

[0083] 13 13C NMR (151 MHz, DMSO-d6) δ 166.09, 156.26, 154.67, 154.12, 60.54, 56.21, 41.37, 34.55.

[0084] HRMS (ESI) m / z calcd for C8H 12 N5O3 + [M + H] + 226.0935

[0085] Example 2

[0086] A preparation method of an oxotriazine - piperazine heterocyclic compound, and the synthesis route is as follows:

[0087]

[0088] The specific steps are as follows:

[0089] Steps a) - g) are the same

[0090] h) Add 0.8 g of the product of step g) to a round - bottom flask, dissolve it with 5 ml of N,N - dimethylformamide. Slowly add 0.32 g of zinc chloride and 0.37 g of Boc - guanidine to the above - mentioned solution. After adding, heat the reaction to 80 °C and stir for 1 hour. After the reaction is completed, add 10 ml of water to the system. Extract the aqueous phase with ethyl acetate (10 ml * 3 times). Combine the organic phases, dry over anhydrous sodium sulfate and then concentrate to obtain the crude product. The crude product is separated by silica gel column chromatography to obtain the pure product. The mobile phase is dichloromethane:methanol from 1:100 to 1:30, and the yield is 42.1%. The nuclear magnetic resonance data of the product is the same as that of Example 1;

[0091] i) Add 0.5 g of the product of step h) to a round - bottom flask, dissolve it with 5 ml of ethyl acetate. Slowly add 0.78 g of oxalyl chloride to the above - mentioned solution. After adding, heat the reaction to 80 °C and stir for 1 hour. After the reaction is completed, add 10 ml of water to the system. Extract the aqueous phase with ethyl acetate (10 ml * 3 times). Combine the organic phases, dry over anhydrous sodium sulfate and then concentrate to obtain the crude product. The crude product is separated by silica gel column chromatography to obtain the pure product. The mobile phase is dichloromethane:methanol from 1:100 to 1:20, and the yield is 65%. The nuclear magnetic resonance data of the product is the same as that of Example 1

[0092] Example 3

[0093] A preparation method of an oxotriazine-fused piperazine heterocyclic compound, and the synthetic route is as follows:

[0094]

[0095] The specific steps are as follows:

[0096] The experimental operation is the same as that in Example 1, except that the tetrahydropyran protecting group in the compound shown by the general formula V in d) is replaced by a benzyl group. The nuclear magnetic resonance data of the product are as follows:

[0097] 1 H NMR(400MHz,DMSO-d6)δ:8.38(d,J=4.9Hz,1H),7.34–7.21(m,5H),4.48(q,J=12.2Hz,2H),3.67(dd,J=7.9,3.4Hz,1H),3.62–3.53(m,3H),3.22(ddd,J=13.2,5.4,1.6Hz,1H),2.92(s,3H).

[0098] 13 C NMR(101MHz,DMSO-d6)δ:158.18,157.60,138.48,128.84,128.05,127.85,72.86,68.53,56.18,34.15.MS(ESI)m / z:[M+H] + 249。

[0099] Example 4

[0100] A preparation method of an oxotriazine-fused piperazine heterocyclic compound, and the synthetic route is as follows:

[0101]

[0102] The specific steps are as follows:

[0103] The experimental operation is the same as that in Example 1, except that the tert-butyldiphenylsilyl protecting group in the compound shown by the formula VIII in g) is replaced by a benzyl group. The nuclear magnetic resonance data of the product are as follows: 1 H NMR(400MHz,DMSO-d6)δ:10.93(d,J=4.3Hz,1H),7.46–7.10(m,5H),4.48(q,J=12.1Hz,2H),3.83–3.72(m,1H),3.65–3.52(m,2H),3.47(dd,J=9.8,7.4Hz,1H),3.38–3.28(m,1H),2.95(s,3H).

[0104] 13 13C NMR(101MHz, DMSO-d6) δ: 186.20, 156.51, 138.44, 128.82, 128.05, 127.85, 72.89, 68.33, 56.16, 42.15, 34.95. MS(ESI) m / z: 287。

[0105] In this specification, each embodiment is described in a progressive manner. The key point of each embodiment is to illustrate the differences from other embodiments. For the same or similar parts among the embodiments, reference can be made to each other. For the devices disclosed in the embodiments, since they correspond to the methods disclosed in the embodiments, the description is relatively simple. For the relevant parts, reference can be made to the description in the method section.

[0106] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing an oxotriazine-piperazine heterocyclic compound, characterized in that, The synthetic route is as follows: ； The preparation method comprises the following steps: a) Add 1,2-dihydropyran and pyridinium p-toluenesulfonate to the compound shown by the general formula (II), and react to obtain the compound shown by the general formula (III); b) Add N,N'-carbonyldiimidazole to the compound shown by the general formula (III), and then dropwise add an ammoniating reagent to the system to obtain the compound shown by the general formula (IV); c) Subject the compound shown by the general formula (IV) to a reduction reaction to obtain the compound shown by the general formula (V); d) Subject the compound shown by the general formula (V) to an aminolysis reaction of the ester to obtain the compound shown by the general formula (VI); e) Subject the compound shown by the general formula (VI) to an acidification reaction to obtain the compound shown by the general formula (VII); f) Add imidazole and tert-butyldiphenylchlorosilane to the compound shown by the general formula (VII), and react to obtain the compound shown by the general formula (VIII); g) React the compound shown by the general formula (VIII) with Lawesson's reagent to obtain the compound shown by the general formula (IX); h) The compound shown by the general formula (IX) undergoes a nucleophilic reaction to obtain the compound shown by the general formula (X); i) React the compound shown by the general formula (X) with an active carbonyl reagent to obtain the compound shown by the general formula (XI); j) Subject the compound shown by the general formula (XI) to a deprotection reaction with tetrabutylammonium fluoride to obtain the compound shown by the general formula (XII); k) React the compound shown by the general formula (XII) with an acidic reagent to obtain an oxotriazine and piperazine heterocyclic compound.

2. The preparation method of an oxotriazine-piperazine heterocyclic compound according to claim 1, wherein, In step b), the ammoniating reagent is 30% ammonia water, the molar ratio of the compound shown by the general formula (III) to the N,N'-dicarbonylimidazole is 1:1-3, and the molar ratio of the compound shown by the general formula (III) to the ammoniating reagent is 1:3-10; In step c), the reducing agent for the reduction reaction is lithium aluminum hydride, the reaction solvent is ether or tetrahydrofuran, the reaction conditions are stirring at room temperature for 36 h or refluxing at 70 °C for 8 h; the molar ratio of the compound shown by the general formula (IV) to the reducing agent is 1:4-20.

3. The preparation method of an oxotriazine-fused piperazine heterocyclic compound according to claim 1, wherein In step d), the ester is any one of dimethyl oxalate and diethyl oxalate, and their molar ratio is 1-10:1; The reaction conditions are refluxing at 70 °C for 8 h, and the reaction solvent is any one of ethanol, methanol, dichloromethane and 1,2-dichloroethane.

4. The preparation method of an oxotriazine-piperazine heterocyclic compound according to claim 1, characterized in that, In step e), the acidic reagent for the acidification reaction is any one of hydrochloric acid, p-toluenesulfonic acid and trifluoroacetic acid, and the molar ratio of the compound shown by the general formula (VI) to the acidic reagent is 1:0.1-5; In step f), the molar ratio of the compound shown by the general formula (VII) to the tert-butyldiphenylchlorosilane is 1:1-1.5, and the molar ratio of the compound shown by the general formula (VII) to the imidazole is 1:2-5; In step g), the molar ratio of the compound shown by the general formula (VIII) to the Lawesson's reagent is 1:0.1-5, and the reaction solvent is any one of tetrahydrofuran, ether and n-hexane.

5. The preparation method of an oxotriazine-fused piperazine heterocyclic compound according to claim 1, characterized in that, In step h), in the nucleophilic reaction, the molar ratio of the compound shown by the general formula (IX), the nucleophilic reagent and the reaction auxiliary is 1:1-10:0.5-3; The nucleophile is 1-Boc-guanidine, the reaction auxiliary is a salt of a transition metal, and the reaction solvent is any one of N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran; In step i), the molar ratio of the compound represented by the general formula (X) to the active carbonyl reagent is 1:1-10, and the reaction solvent is any one of ethyl acetate, dichloromethane, and tetrahydrofuran; The active carbonyl reagent is any one of 1,1-carbonyldiimidazole, triphosgene, and oxalyl chloride.

6. The preparation method of an oxotriazine-piperazine heterocyclic compound according to claim 1, characterized in that, In step j), the molar ratio of the compound represented by the general formula (XI) to the tetrabutylammonium fluoride is 1:1-6; The reaction solvent is tetrahydrofuran or diethyl ether.

7. The preparation method of an oxotriazine-fused piperazine heterocyclic compound according to claim 1, characterized in that, In step k), the acidic reagent is any one of trifluoroacetic acid, hydrochloric acid, hydrogen chloride methanol solution, and hydrogen chloride dioxane solution; the molar ratio of the compound represented by the general formula (XII) to the acidic reagent is 1:3-10; The reaction solvent is dichloromethane or 1,2-dichloroethane.

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