Preparation method of triazene derivative

Abstract

The invention discloses a preparation method of a triazene derivative, and belongs to the technical field of synthesis of triazene compounds. Arylazo sulfone and a secondary amine or primary amine compound are used as raw materials, and a solvent and alkali are added for reaction to obtain the triazene derivative. According to the invention, aryl azo sulfone which can be stably stored under a room temperature environment condition is used as a basic azo source, and under the promotion of a cheap alkali reagent, the aryl azo sulfone and an amine compound are subjected to a nucleophilic addition-elimination reaction without transition metal participation to obtain the triazene derivative. The method has the characteristics that the raw materials are easy to obtain, the preparation method is simple to operate, the reaction is efficient and the method is environment-friendly. The triazene derivative prepared by the invention has important application value in the fields of chemical synthesis, drug research and development and the like; the unique pharmacological and physiological activity of the compound has great potential development value in clinical application of treating diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of triazene compound synthesis, and particularly relates to a method for preparing triazene derivatives. Background Art

[0002] Triazenes, also known as diazoamino compounds, are compounds containing an N=NN structure. Due to their unique structure, they have broad applications in a wide range of fields, including anticancer therapy, materials science, and organic synthesis (e.g., as directing groups, cross-coupling reagents, traceless linkers, precursors of azo compounds and diazonium salts, and starting materials for cyclization and rearrangement reactions). Triazenes have been used in clinical research as anticancer drugs. Temozolomide (TMZ) and dacarbazine (DTIC) are currently used in clinical treatments for diseases such as melanoma, Hodgkin's lymphoma, and soft tissue sarcomas. In recent years, with the continued advancement of research, it has been discovered that these compounds possess a variety of biological activities, including antibacterial, antiviral, and antitumor activities. Given the broad application prospects of triazenes, the development of synthetic methods for their use has attracted the interest of chemists and pharmacologists.

[0003] Currently, the development of efficient methods for the construction of triazene compounds is still relatively limited. Traditional synthetic methods mainly involve the coupling reaction of aryl diazonium salts with secondary amines (for example: (a) Nwajiobi, O.; Verma, AK; Raj, M. J. Am. Chem. Soc. 2022, 144 , 4633-4641; (b) Zarei, A.; Khazdooz, L.; Aghaei, H.; Azizi, G.; Chermahini, AN; Hajipour, AR Dyes Pigments 2014, 101 , 295-302), and this type of research has mostly focused on the synthesis of 1-aryl-3,3-dialkyltriazene derivatives. However, the inherent low stability and low solubility of diazonium salts have limited their storage and large-scale application to a certain extent (for details, see: (a) Ullrich, R.; Grewer, T. Thermochim. Acta, 1993, 225, 201–211; (b) Sheng, M.;Frurip, D.; Gorman, D. J. Loss Prev. Process Ind. 2015, 38, 114–118; (c) Xie, C.;Yuan, Y.; Wang, B.; Du, L. Thermochim. Acta 2022, 709, 179156). Another approach is to couple an alkyl magnesium or lithium compound with an azide to generate a disubstituted triazene, which is then alkylated. A limitation of this approach is that both isomers are generated in approximately equal proportions (e.g., (a) Sieh, DH; Wilbur, DJ; Michejda, CJ J. Am. Chem. Soc. 1980, 102 , 3883-3887; (b) Sieh, DH;Michejda, CJ J. Am. Chem. Soc. 1981, 103 , 442-445). In 2015, Severin et al. described an innovative reaction to synthesize triazenes by reacting N2O with secondary amide lithium and Grignard reagents. Subsequently, the same research group also used Grignard reagents and 1-azido-4-iodobutane or 4-azidobutyl-4-methylbenzenesulfonate to synthesize triazenes (Kiefer, G.; Riedel, T.; Dyson, PJ; Scopelliti, R.; Severin, K. Angew. Chem. Int. Ed. 2015, 54 , 302-305; Suleymanov, AA; Scopelliti, R.; Tirani, FF; Severin, K. Org. Lett. 2018, 20 , 3323-3326). Potential drawbacks of these two methods are the use of gaseous N2O, which is not easily available in synthetic chemistry laboratories, or the use of lithium amide reagents and Grignard reagents, which are air-sensitive.

[0004] In summary, despite remarkable achievements, there is still an urgent need to develop a method for synthesizing triazenes that is easy to operate and uses reagents that are stable in air and easy to store. Summary of the Invention

[0005] In response to the problems existing in the prior art, the present invention provides a method for preparing triazene derivatives, which synthesizes triazene derivatives based on arylazosulfone as an azo source. The synthesis method is insensitive to air and can be carried out in an air atmosphere. It is simple to operate, does not require harsh reagents, has a high reaction efficiency, and is suitable for large-scale applications.

[0006] The present invention is achieved through the following technical solutions: The present invention provides a method for preparing triazene derivatives. An arylazosulfone and a secondary amine or a primary amine compound are used as raw materials, and a solvent and a base are added to react to obtain the triazene derivatives.

[0007] Furthermore, the structural formula of the arylazosulfone is , X is , Y is a short-chain aliphatic hydrocarbon group or an alkylphenyl group having 1 to 3 carbon atoms; 2 is an aryl group or an aromatic heterogroup.

[0008] Furthermore, the Y is methyl or p-methylphenyl; the R 2 for or .

[0009] Furthermore, the molar ratio of the arylazosulfone to the secondary amine nitrogen or primary amine nitrogen in the secondary amine or primary amine compound is 1-5:1; and the molar ratio of the secondary amine or primary amine compound to the base is 1:1-4.

[0010] Furthermore, the molar ratio of the arylazosulfone to the secondary amine nitrogen or primary amine nitrogen in the secondary amine or primary amine compound is 1.2:1.

[0011] Furthermore, the base is one or more of sodium bicarbonate, cesium carbonate, sodium carbonate, sodium hydroxide and triethylamine; and the solvent is one or more of methanol, ethanol, tert-butanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran and dichloromethane.

[0012] Furthermore, the solvent is methanol.

[0013] Furthermore, the reaction temperature is 15-40° C., and the reaction time is 2-24 hours.

[0014] Furthermore, the secondary amine or primary amine is 、 、 or .

[0015] Furthermore, the triazene derivative is in the form of a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments of the present invention with better effects, the representative compound structures of the above triazene derivatives are as follows: The compound IA was reported to have good reactivity in the presence of trifluoroacetic acid and could be reacted with acetonitrile to synthesize acetanilide (similar process see: Suleymanov, AA; Scopelliti, R.; Tirani, FF; Severin, K. Org. Lett. 2018, 20,3323-3326); Compound IB has been reported to have rearrangement and coupling reaction activity and can be used in the synthesis of aminoazobenzene and 1-phenylpyrazole (e.g.: He, L.; Chao, D.; Jia, X.; Liu,H.; Yao, L.; Liu, X.; Wang, C. J. Mater. Chem. 2011, 21 , 1852–1858; Fabre, I.;Perego, LA; Bergès, J.; Ciofini, I.; Grimaud, L.; Taillefer, M. Eur. J. Org. Chem. 2016, 5887–5896). IB has also been reported to have a strong inhibitory effect on cytochrome P450 1A1 and 1B1, with half inhibitory concentration (IC50) values ​​of 8 uM and 2 uM, respectively (see: Moran, R.; Nakamura, R.; Isovitsch, R.; Iimoto, D. Bioorg. Med. Chem. Lett. 2022, 59 , 128570).

[0017] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention provides a method for preparing triazene derivatives. Triazene derivatives have important application value in the fields of chemical synthesis and drug development. The unique pharmacological and physiological activities of these compounds (such as antibacterial, antiviral, and antitumor activities) have great development value in the clinical application of treating diseases. Currently, temozolomide (TMZ) and dacarbazine (DTIC) are used in clinical treatment, mainly for the treatment of melanoma, Hodgkin's lymphoma, and soft tissue sarcoma. Therefore, it is of great significance to provide a more economical and simple method for preparing triazene compounds.

[0018] (2) The method for preparing triazene derivatives provided by the present invention uses arylazosulfone as the azo source for the reaction without the use of a catalyst, and uses a cheap and easily available alkaline reagent as a reaction promoter to promote the nucleophilic addition and elimination of arylazosulfone with an amine compound to obtain a triazene derivative. The arylazosulfone is prepared from cheap aromatic amine and can be stably stored at room temperature. The raw materials used in the method of the present invention are easily available, the preparation method is simple to operate, the reaction is efficient, and it is environmentally friendly. In addition, the present invention also provides a non-radical utilization method for arylazosulfone compounds, providing a new idea and providing an important technical reserve for the preparation of triazene derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1This is the X-ray single crystal diffraction pattern of the triazene derivative prepared in Example 1. DETAILED DESCRIPTION

[0020] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0021] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0022] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0023] Example 1 To a 50 mL reaction tube under air atmosphere, sodium bicarbonate (0.34 g, 4 mmol), dibenzylamine (0.77 mL, 4 mmol), methanol (30 mL), and methanesulfonyl-substituted phenylazosulfone (0.88 g, 4.8 mmol) were added in sequence. The mixture was stirred at room temperature (25°C) for 18 hours. The solvent was removed under reduced pressure and the mixture was purified by column chromatography to obtain a triazene derivative as a white solid in an isolated yield of 87% (mp: 85-86°C). The structural characterization information of the triazene derivative prepared above is as follows, and it is confirmed to be Compound IA ((E)-3,3-dibenzyl-1-phenyltriazene-1-ene): NMR data: 1 H NMR (500 MHz, CDCl3): δ 7.54-7.52 (m, 2H), 7.39-7.36 (m,2H), 7.34-7.27 (m, 6H), 7.24-7.18 (m, 5H), 4.91 (s, 4H); 13 C NMR (125 MHz,CDCl3): δ 150.6, 136.7, 129.0, 128.7, 128.4, 127.6, 125.9, 121.0, 57.3, 48.6; High-resolution mass spectrometry data: HRMS (ESI) m / z [M+Na] + Calcd for C20 H 19 N3Na: 324.1471, Found324.1470; X-ray single crystal diffraction pattern of IA is as follows Figure 1 As shown; The chemical reaction formula involved in the above reaction is: .

[0024] Example 2 Under air atmosphere, sodium carbonate (53 mg, 0.5 mmol), aniline (36 uL, 0.4 mmol), THF (3 mL) and methylsulfonyl-substituted phenylazosulfone (88 mg, 0.48 mmol) were added sequentially to a 25 mL reaction tube. The mixture was stirred at room temperature (25°C) for 14 hours. The solvent was removed under reduced pressure and purified by column chromatography to obtain a triazene derivative as a yellow solid with an isolated yield of 59% and mp: 96-98°C. The structural characterization information of the triazene derivative prepared above is as follows, which is confirmed to be Compound IB ((E)-1,3-diphenyltriazene-1-ene): NMR data: 1 H NMR (500 MHz, acetone- d 6): δ 11.52 (s, br, 1H), 7.52-7.50 (m, 4H), 7.41-7.38 (m, 4H), 7.17-7.14 (m, 2H); 13 C NMR (125 MHz, acetone- d 6): δ128.7, 124.2, 117.2 (delocalization occurs, and the carbon spectrum shows only three peaks, which is consistent with known literature); high-resolution mass spectrometry data: HRMS (ESI) m / z [M+Na] + Calcd for C 12 H 11 N3Na: 220.0845, Found 220.0843; The chemical reaction formula involved in the above reaction is: .

[0025] Example 3 To a 25 mL reaction tube under air atmosphere, sodium bicarbonate (34 mg, 0.4 mmol), 4-methoxy-N-methylaniline (55 mg, 0.4 mmol), MeOH (3 mL), and p-toluenesulfonyl-substituted phenylazosulfone (125 mg, 0.48 mmol) were added in sequence. The mixture was stirred at room temperature (approximately 30°C) for 10 hours. The solvent was removed under reduced pressure and purified by column chromatography to obtain a triazene derivative as a yellow oily liquid with an isolation yield of 80%.

[0026] The characterization information of the triazene derivative prepared above is as follows, and it is confirmed to be compound IC ((E)-3-(4-methoxyphenyl)-3-methyl-1-phenyltriazene): NMR data: 1 H NMR (500 MHz, DMSO- d 6): δ 7.51-7.49 (m, 2H), 7.45-7.39 (m,4H), 7.23-7.20 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H), 3.58 (s, 3H); 13 CNMR (125 MHz, DMSO- d 6): δ 156.1, 150.1, 138.3, 129.1, 126.2, 120.8, 118.9,114.5, 55.3, 33.2; High-resolution mass spectrometry data: HRMS (ESI) m / z [M+Na] + Calcd for C 14 H 15 N3NaO:264.1107, Found 264.1104; The chemical reaction formula involved in the above reaction is: .

[0027] Example 4 To a 25 mL reaction tube under air atmosphere, sodium bicarbonate (34 mg, 0.4 mmol), dibenzylamine (77 uL, 0.4 mmol), MeOH (3 mL), and heteroarylazosulfone (108 mg, 0.48 mmol) were added sequentially. The mixture was stirred at room temperature (approximately 25°C) for 5 hours. The solvent was removed under reduced pressure and purified by column chromatography to obtain a triazene derivative as a white solid with an isolated yield of 95% (mp: 134-135°C).

[0028] The characterization information of the triazene derivative prepared above is as follows, and it is confirmed to be compound ID ((E)-3-(3,3-dibenzyltriaze-1-en-1-yl)-1H-indazole): NMR data: 1 H NMR (500 MHz, CDCl3): δ 10.35 (s, br, 1H), 8.17 (d, J = 8.2Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.35-7.26 (m, 11H), 7.16-7.13 (m, 1H), 5.00(s, br, 4H); 13 C NMR (125 MHz, CDCl3): δ 153.3, 142.1, 135.9, 128.8, 128.3,127.2, 123.3, 121.4, 115.0, 110.2, 57.3, 48.0; HRMS (ESI) m / z [M+Na] + Calcd for C 21 H 19 N5Na: 364.1533, Found 364.1535; The chemical reaction formula involved in the above reaction is: .

[0029] Example 5 To a 25 mL reaction tube under air atmosphere, sodium bicarbonate (34 mg, 0.4 mmol), dibenzylamine (77 uL, 0.4 mmol), MeOH (5 mL), and a vitamin E-derived arylazosulfone (301 mg, 0.48 mmol) were added sequentially. The mixture was stirred at room temperature (approximately 25°C) for 12 hours. The solvent was removed under reduced pressure and purified by column chromatography to obtain a triazene derivative as a colorless oily liquid with an isolation yield of 45%.

[0030] The characterization information of the triazene derivative prepared above is as follows, and it is confirmed to be Compound IE ((E)-3,3-dibenzyl-1-[3-({[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl]oxy}methyl)phenyl]-1-triazene): NMR data: 1 H NMR (500 MHz, CDCl3): δ7.66 (s, 1H), 7.52 (d, J= 7.1 Hz, 2H), 7.43-7.40 (m, 2H), 7.38-7.30 (m, 6H), 7.25-7.23 (m, 3H), 5.30 (s, 1H), 4.93 (s, 4H), 4.75 (s, 2H), 2.62 (t, J = 6.7 Hz, 2H), 2.27 (s, 3H), 2.24 (s,1H), 2.22 (s, 3H), 2.19 (s, 1H), 2.13 (s, 4H), 1.88-1.76 (m, 3H), 1.57-1.46(m, 4H), 1.44-1.37 (m, 4H), 1.18-1.13 (m, 4H), 1.10-1.07 (m, 3H), 0.89-0.87(m, 14H), 0.86 (s, 2H); 13 C NMR (125 MHz, CDCl3): δ 150.8, 148.3, 148.0, 139.0,129.1, 128.7, 128.6, 128.4, 128.1, 127.8, 127.7, 126.2, 125.1, 123.0, 120.3,117.7, 74.9, 74.8, 53.6, 40.2, 39.5, 37.6, 37.6, 37.6, 37.4, 32.9, 32.9,31.5, 28.1, 25.0, 24.6, 24.0, 22.9, 22.8, 21.2, 20.8, 19.9, 19.8, 13.1, 12.2, 12.0; High-resolution mass spectrometry data: HRMS (ESI) m / z [M+Na] + Calcd for C 50 H 69 N3NaO2: 766.5282, Found 766.5276; The chemical reaction formula involved in the above reaction is (Ms represents methylsulfonyl): .

[0031] Example 6 To a 25 mL reaction tube under air atmosphere, sodium bicarbonate (134 mg, 1.6 mmol), cyclopentane (i.e., 1,4,7,10-tetrachlorocyclododecane, 69 mg, 0.4 mmol), MeOH (12 mL), and phenylazosulfone (354 mg, 1.92 mmol) were added in sequence. The mixture was stirred at room temperature (approximately 25°C) for 24 hours. The solvent was removed under reduced pressure and purified by column chromatography to obtain a triazene derivative as a white solid with an isolated yield of 88% and mp: 190-191°C.

[0032] The characterization information of the triazene derivative prepared above is as follows, and it is confirmed to be Compound IF (1,4,7,10-tetrakis[(E)-phenyldiazenyl]-1,4,7,10-tetraazacyclododecane): NMR data: 1 H NMR (500 MHz, CDCl3): δ 7.43 (d, J = 8.1 Hz, 8H), 7.33-7.30 (m, 8H), 7.19-7.16 (m, 4H), 4.06 (s, 16H); 13 C NMR (125 MHz, CDCl3): δ150.4, 129.0, 126.3, 121.0, 51.7; High-resolution mass spectrometry data: HRMS (ESI) m / z [M+Na] + Calcdfor C 32 H 36 N 12 Na: 611.3078, Found 611.3070; The chemical reaction formula involved in the above reaction is: .

[0033] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A method for preparing a triazene derivative, characterized in that: Aryl azosulfone and secondary or primary amine compounds are used as raw materials, and a solvent and a base are added to react to obtain triazene derivatives.

2. The method for preparing triazene derivatives according to claim 1, characterized in that: The structural formula of the arylazosulfone is , X is , Y is a short-chain aliphatic hydrocarbon group or an alkylphenyl group having 1 to 3 carbon atoms; 2 is an aryl group or an aromatic heterogroup.

3. The method for preparing triazene derivatives according to claim 2, characterized in that: The Y is methyl or p-methylphenyl; the R 2 for or .

4. The method for preparing triazene derivatives according to claim 1, characterized in that: The molar ratio of the arylazosulfone to the secondary amine nitrogen or primary amine nitrogen in the secondary amine or primary amine compound is 1-5:1; the molar ratio of the secondary amine or primary amine compound to the base is 1:1-4.

5. The method for preparing triazene derivatives according to claim 1, characterized in that: The molar ratio of the arylazosulfone to the secondary amine nitrogen or the primary amine nitrogen in the secondary amine or primary amine compound is 1.2:

1.

6. The method for preparing triazene derivatives according to claim 1, characterized in that: The base is one or more of sodium bicarbonate, cesium carbonate, sodium carbonate, sodium hydroxide and triethylamine; the solvent is one or more of methanol, ethanol, tert-butanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran and dichloromethane.

7. The method for preparing triazene derivatives according to claim 6, characterized in that: The solvent is methanol.

8. The method for preparing triazene derivatives according to claim 1, characterized in that: The reaction temperature is 15-40° C., and the reaction time is 2-24 hours.

9. The method for preparing triazene derivatives according to claim 1, characterized in that: The secondary amine or primary amine is 、 、 or .

10. The method for preparing triazene derivatives according to claim 1, characterized in that: The triazene derivatives are in the form of tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof.

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