A preparation method of 1,2,4-benzotriazine derivatives

Abstract

The invention discloses a kind of preparation method of 1,2,4-benzotriazine derivatives, 1-(trifluoromethanesulfonyl)-1H-benzotriazole compound shown in formula II structure, bromoacetophenone compound shown in formula III structure, acid binding agent are added to reaction solvent and react and prepare.The present invention directly obtains 1,2,4-benzotriazine derivative I by the [5+1] cycloaddition tandem reaction of bromoacetophenone compound and 1-(trifluoromethanesulfonyl)-1H-benzotriazole.This reaction raw materials, catalyst and solvent are all commercialized and cheap and easy to obtain, reaction process is green and environmentally friendly, reaction conditions are mild, operation is convenient, substrate application range is wider, applied research is practical, with good application prospect.The method is suitable for industrialized production, solves the defect that reaction conditions are harsh in prior art, reaction reagent is expensive, reaction environment is unfriendly and is difficult to industrialized production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a 1,2,4-benzotriazine derivative. Background Art

[0002] 1,2,4-Triazine derivatives are a class of structurally unique benzo-nitrogen heterocyclic compounds with a wide range of biopharmaceutical activities. In recent years, the synthesis and application of 1,2,4-triazine derivatives have attracted increasing interest among researchers. Significant progress has been made in the research and development of bioactive molecules based on the 1,2,4-benzotriazine backbone, including antitumor and antibacterial activities, and as enzyme inhibitors. For example, SN29751 can be used as an important antitumor agent (Hicks, KO; Siim, BG; Jaiswal, JK; Pruijn, FB; Fraser, AM; Rita Patel, R.; Hogg, A.; Sarath Liyanage, HD; Dorie, MJ; Brown, JM; Denny, WA; Hay, MP; Wilson, WR. Pharmacokinetic / Pharmacodynamic Modeling Identifies SN30000 and SN29751 as Tirapazamine Analogues with Improved Tissue Penetration and Hypoxic Cell Killing in Tumors[J]. Clin. Cancer. Res. 2010, 16, 4946-4957.); indole[1,2-c]-1,2,4-benzotriazole compounds have antifungal activity (Xu H.; Fan LLAntifungal Agents. Part 4: Synthesis and Antifungal Activities of Novel Indole[1,2-c]-1,2,4-benzotriazine Derivatives Against Phytopathogenic Fungi in Vitro[J]. Eur. J. Med. Chem., 2011, 46, 364.); SGLT2 as a sodium-glucose cotransporter 2 (SGLT2) inhibitor has been widely used in the prevention and treatment of metabolic disorders (Dardi, I.; Kouvatsos, T.; Jabbour, SASGLT2 inhibitors[J]. Biochem. Pharma. 2016, 101, 27–39.).

[0003]

[0004] Therefore, studying the synthesis of the structural core of 1,2,4-benzotriazole derivatives is of great significance and value, and provides a preliminary basis for the research and development of various drugs.

[0005] In 2012, Huang et al. (Guo, H.; Liu, J.; Wang, XX; Huang, G.S. Copper-catalyzed Domino Reaction of 2-Haloanilines with Hydrazides: A new route for the synthesis of Benzo[e][1,2,4]triazine Derivatives[J]. Synlett. 2012, 23, 903-906.) utilized a copper-catalyzed coupling reaction of 2-iodoaniline with benzoylhydrazide, followed by a nucleophilic addition ring closure reaction, to synthesize a series of 3-phenyl-1,2,4-benzotriazines. This method offers advantages in terms of broad substrate compatibility and readily available, inexpensive raw materials. However, it requires pre-assembled halogen atoms for the reaction.

[0006]

[0007] In 2019, Jiang et al. (Zhang, TS; Zhang, H.; Fu, R.; Wang, J.; Hao, WJ; Tu, SJ; Jiang, B. Tert-butyl Peroxide (TBHP) / KI-mediated Dual C (sp 2 In the absence of metal oxidants, a series of 1,2,4-benzotriazine derivatives were prepared by free radical-induced tandem reactions of arylamines and diazo compounds. The reaction conditions were mild and the substrates were widely adaptable.

[0008]

[0009] In 2021, Zhu et al. (Wu, WP; Fan, SX; Li, TL; Fang, LL; Chu, BF; Zhu, J. Cobalt-Catalyzed, Directed Intermolecular CH Bond Functionalization for Multiheteroatom Heterocycle Synthesis: The Case of Benzotriazine[J]. Org. Lett. 2021, 23, 5652-5657.) reported the use of cobalt catalysts to activate CH bonds in a directed manner to achieve a tandem reaction of aromatic hydrazines and oxadiazolone to prepare a series of 3-phenyl-1,2,4-benzotriazines.

[0010]

[0011] In 2022, Zhou et al. (Wang XY; Yu JH; Xu MJ; Mao H.; Shan YY; Lv X.; Zhou LJ Metal-Free [5+1] Cycloaddition-Aromatization of Benzotriazoles and Sulfur Ylides to Construct 1,2,4-Benzotriazines [J]. Org. Lett. 2022, 24, 5896-5901.) reported that benzotriazole derivatives reacted with sulfur ylides under transition metal-free conditions to prepare a series of 3-substituted-1,2,4-benzotriazines. This method is simple and efficient, but the sulfur ylide needs to be prepared in advance, and the sulfur ylide itself and the by-product dimethyl sulfide have a certain pungent odor, which is not environmentally friendly.

[0012] Summary of the Invention

[0013] The present invention provides a method for preparing 1,2,4-benzotriazine derivatives and their synthetic applications. This method, based on the [5+1] tandem cyclization reaction of 1-(trifluoromethanesulfonyl)-1H-benzotriazole (or its derivative) and a bromoacetophenone compound, efficiently and environmentally friendly synthesizes a series of 1,2,4-benzotriazine derivatives. This method utilizes commercially available base catalysis, inexpensive commercial raw materials, mild reaction conditions, and a wide range of substrate applicability, providing a new, industrially scalable pathway for the synthesis of 1,2,4-benzotriazine derivatives.

[0014] A method for preparing a 1,2,4-benzotriazine derivative comprises the following steps:

[0015] A 1-(trifluoromethanesulfonyl)-1H-benzotriazole compound represented by formula II, a bromoacetophenone compound represented by formula III, and an acid-binding agent (such as lithium hydroxide) are added to a reaction solvent (such as tetrahydrofuran), and after stirring and reacting, a 1,2,4-benzotriazine derivative represented by formula I is obtained by post-treatment.

[0016]

[0017] Among them, R 1 is H, C1-C3 alkyl, halogen; R 2 It is phenyl, C1-C3 alkoxy substituted phenyl, halogen substituted phenyl, dihalogen substituted phenyl.

[0018] The R 1 It can be one or more. When it is multiple (corresponding to a polysubstituted benzene ring), multiple R 1 Independent of each other, can be different or the same; multiple R 1 Substitution can be carried out on any carbon atom on the benzene ring that can undergo substitution.

[0019] As a preference, R 1 is H, methyl, halogen; R 2 It is phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, or dihalogen-substituted phenyl.

[0020] Furthermore, the 1-(trifluoromethanesulfonyl)-1H-benzotriazole compound represented by the structure of Formula II is selected from the following compounds:

[0021]

[0022] Furthermore, the brominated acetophenone compound represented by the structure of formula III is selected from the following compounds:

[0023]

[0024] As further preferred, the structure of the 1,2,4-benzotriazine derivative is as follows:

[0025]

[0026] When R 1 =H, R 2 is one of o-MeOPh; p-MeOPh; p-FPh; m-ClPh; o-MeOPh; o-BrOPh; o-IPh; 3,4-diClPh; when R 1 =7-CH3, R 2 is 2-Cl-5-BrPh; when R2 =Ph, R 1 The letter or number to the left of “-” represents the substitution position, and the letter or number to the right represents the corresponding substituent.

[0027] The specific synthetic route of the reaction involved in the present invention is as follows:

[0028]

[0029] This preparation method involves reacting a bromoacetophenone compound III with lithium hydroxide, for example, to form a carbon anion, which then attacks 1-(trifluoromethanesulfonyl)-1H-benzotriazole II to open the ring. The nitrogen anion then attacks the α-carbon of the bromoacetophenone, leaving the bromide ion to close the ring. Finally, under alkaline conditions, the trifluoromethanesulfinic acid is removed to yield the aromatized 1,2,4-benzotriazine derivative I.

[0030] Preferably, the reaction temperature is 20-40 degrees Celsius.

[0031] Preferably, the reaction environment is a nitrogen atmosphere, and stirring is carried out at room temperature.

[0032] Preferably, the molar ratio of the 1-(trifluoromethanesulfonyl)-1H-benzotriazole compound represented by the structure of formula II, the bromoacetophenone represented by the structure of formula III, and the acid binding agent (lithium hydroxide) is 1:1~2:1~2; as a further preference, the molar ratio is 1:2:2.

[0033] Preferably, the acid-binding agent is selected from one or more of cesium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, lithium hydroxide monohydrate, and lithium hydroxide. Further preferably, the acid-binding agent is selected from lithium hydroxide.

[0034] The reaction solvent is one or more of dichloromethane, tetrahydrofuran, chlorobenzene, N,N-dimethylformamide, acetone, methanol, and ethanol.

[0035] Preferably, the reaction solvent is tetrahydrofuran, and the amount of tetrahydrofuran used in the reaction is 1.0 mL per 1 equiv.

[0036] The reaction time of the reaction system is 5h to 8h.

[0037] The post-processing: column chromatography separation.

[0038] The column chromatography separation adopts silica gel column chromatography separation.

[0039] The application research of the 1,2,4-benzotriazine derivative I involved in the present invention is as follows:

[0040] The 1,2,4-benzotriazine derivative I described in this invention can be used to prepare a variety of important compounds or intermediates. For example, 1,2,4-benzotriazine compound 3p undergoes a Pd-catalyzed Sonogashira coupling reaction with 1-ethynyl-4-methoxybenzene to afford the corresponding alkynyl-containing 1,2,4-benzotriazine derivative 6 in 90% yield. In refluxing PhCl, compound 6 undergoes an intramolecular Diels-Alder / retro-Diels-Alder reaction to afford polycyclic indeno[2,1-b]quinolin-6-one, widely used in biomedical chemistry, in 75% yield.

[0041] The specific reaction is as follows:

[0042]

[0043] Compared with the prior art, the present invention has the following advantages:

[0044] 1. This method can prepare 1,2,4-benzotriazine derivatives by cycloaddition cascade reaction of bromoacetophenone and 1-(trifluoromethanesulfonyl)-1H-benzotriazole at room temperature using a conventional acid-binding agent such as lithium hydroxide, thereby avoiding the defects of the prior art such as harsh reaction conditions, expensive reaction reagents, unfriendly reaction environment, and difficulty in industrial production.

[0045] 2. The reaction raw materials, catalysts and solvents of this method are all commercially available and cheap. The reaction process is green and environmentally friendly, the reaction conditions are mild, the post-processing is simple, the substrate has a wide range of applicability, and the developed application research is practical and has good application prospects.

[0046] In summary, the present invention directly produces a 1,2,4-benzotriazine derivative I through a [5+1] cycloaddition cascade reaction between a bromoacetophenone compound and 1-(trifluoromethanesulfonyl)-1H-benzotriazole. The raw materials, catalyst, and solvent are all commercially available, inexpensive, and readily available. The reaction process is environmentally friendly, the reaction conditions are mild, the operation is convenient, the substrates have a wide range of applicability, and the applied research is practical, with promising application prospects. This method is suitable for industrial production and overcomes the shortcomings of the prior art, which require harsh reaction conditions, expensive reagents, an unfriendly reaction environment, and difficulty in industrial production. DETAILED DESCRIPTION

[0047] Example 1

[0048] Under nitrogen, a 10 mL Schlenk tube was charged with 1-(trifluoromethanesulfonyl)-1H-benzotriazole 1a (50.2 mg, 0.2 mmol, 1.0 eq.), 2 mL of tetrahydrofuran, bromoacetophenone 2a (79.6 mg, 0.4 mmol, 2 eq.), and lithium hydroxide (9.6 mg, 0.4 mmol, 2 eq.). The reaction was allowed to proceed at room temperature for approximately 6 hours until the starting material disappeared. The product was then purified by rapid column chromatography (petroleum ether:ethyl acetate = 8:1 as the developing solvent) and concentrated under reduced pressure to afford 3a as a yellow solid (36.7 mg, 85% yield). 1 H NMR (400MHz, CDCl3) δ8.66(dd,J=8.4,0.8Hz,1H),8.26–8.19(m,1H),8.14–8.08(m,3H),8.06–8.01(m,1H),7.69–7.63(m,1H),7.55–7.48(m,2H). 13 C NMR(101MHz, CDCl3)δ190.55,158.10,147.60,140.33,136.65,135.16,134.24,132.73,131.23,129.80,129.68,128.69.HRMS(ESI)calcd.for C 14 H 10 N3O[M+H + ]:236.0810,found:236.0819.

[0049] The reaction formula is as follows:

[0050]

[0051] Example 2

[0052] The same procedures were followed as in Example 1, except that 4-methyl-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1b was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3b was isolated in a yield of 65%. 1 H NMR (400MHz, CDCl3) δ8.19–8.13(m,2H),8.08(d,J=8.5Hz,1H),8.03–7.97(m ,1H),7.85–7.81(m,1H),7.71–7.64(m,1H),7.57–7.51(m,2H),3.11(s,3H). 13CNMR(101MHz, CDCl3)δ190.80,158.00,146.89,140.97,139.40,136.79,135.39,134.13,132.45,131.32,128.60,127.40,17.02.HRMS(ESI)calcd.for C 15 H 12 N3O[M+H + ]:250.0975,found:250.0976.

[0053] The reaction formula is as follows:

[0054]

[0055] Example 3

[0056] The same procedures were followed as in Example 1, except that 4-fluoro-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1c was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3c was isolated in a yield of 65%. 1 H NMR (600MHz, CDCl3) δ8.15–8.05(m,4H),7.74–7.66(m,2H),7.60–7.50(m,2H). 13 CNMR (151MHz, CDCl3) δ190.08 (s), 158.56 (s), 157.74 (d, J = 270.2Hz), 141.04 (s), 139.23 (d, J = 12.5Hz), 136.68 (d, J = 8. 4Hz),134.95(s),134.47(s),131.25(s),128.79(s),125.66(d,J=5.2Hz),116.45(d,J=17.7Hz).HRMS(ESI)calcd.forC 14 H9FN3O[M+H + ]:254.0724,found:254.0724.

[0057] The reaction formula is as follows:

[0058]

[0059] Example 4

[0060] The same procedures were followed as in Example 1, except that 5-chloro-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1d was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3d was isolated in a yield of 67%. 1 H NMR (400MHz, CDCl3) δ8.68(d,J=1.9Hz,1H),8.22(d,J=9.0Hz,1H),8.12(d,J= 7.5Hz,2H),8.05(dd,J=9.0,2.1Hz,1H),7.72–7.65(m,1H),7.58–7.52(m,2H). 13 C NMR(101MHz, CDCl3)δ190.17,158.19,147.52,139.12,138.98,137.97,135.08,134.41,131.27,128.79,128.41(1peak is missing).HRMS(ESI)calcd.for C 14 H9ClN3O[M+H + ]:270.0429,found:270.0431.

[0061] The reaction formula is as follows:

[0062]

[0063] Example 5

[0064] The same procedures were followed as in Example 1, except that 6-methyl-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1e was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3e was isolated in a yield of 69%. 1 H NMR (600MHz, CDCl3) δ8.53(d,J=8.6Hz,1H),8.12(d,J=7.6Hz,2H),7.98(s,1 H),7.86(d,J=8.5Hz,1H),7.71–7.63(m,1H),7.58–7.49(m,2H),2.70(s,3H). 13 CNMR(151MHz, CDCl3)δ190.71,158.29,148.63,146.62,140.69,135.31,135.29,134.13,131.22,129.26,128.63,127.86,22.79.HRMS(ESI)calcd.for C 15 H 12N3O[M+H + ]:250.0975,found:250.0976.

[0065] The reaction formula is as follows:

[0066]

[0067] Example 6

[0068] The same procedures were followed as in Example 1, except that 6-fluoro-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1f was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3f was isolated in a yield of 78%. 1 H NMR (600MHz, CDCl3) δ8.74–8.68(m,1H),8.12–8.07(m,2H),7.84–7.79(m,2H),7.70–7.65(m,1H),7.55–7.51(m,2H). 13 C NMR(151MHz, CDCl3)δ190.27,166.64(d,J=264.1Hz),158.39,145.61,142.28(d,J=14.8Hz),135.01,134.4 1,132.96(d,J=10.9Hz),131.22,128.77,124.19(d,J=27.3Hz),112.82(d,J=21.9Hz).HRMS(ESI)calcd.for C 14 H9FN3O[M+H + ]:254.0724,found:254.0726.

[0069] The reaction formula is as follows:

[0070]

[0071] Example 7

[0072] The same procedures were followed as in Example 1, except that 6-chloro-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1g was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. 3 g of a yellow solid was isolated in a yield of 58%. 1H NMR(400MHz, CDCl3)δ8.63(d,J=9.0Hz,1H),8.23(d,J=2.0Hz,1H),8.14–8.0 6(m,2H),7.97(dd,J=9.0,2.1Hz,1H),7.73–7.65(m,1H),7.59–7.48(m,2H). 13 C NMR(151MHz, CDCl3)δ190.20,158.56,146.26,143.37,140.86,134.99,134.45,134.19,131.24,131.19,128.80,128.40.HRMS(ESI)calcd.for C 14 H9ClN3O[M+H + ]:270.0429,found:270.0431.

[0073] The reaction formula is as follows:

[0074]

[0075] Example 8

[0076] The same operating steps were followed as in Example 1, except that 5,6-dimethyl-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1h was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3h was isolated in a yield of 63%. 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),8.15–8.11(m,2H),7.97(s,1H),7.69–7.64(m,1H),7.56–7.50(m,2H),2.63(s,3H),2.60(s,3H). 13 C NMR (101MHz, CDCl3) δ190.91,157.91,149.03,147.02,144.46,139.74,135.48 ,134.05,131.31,128.63,128.18,128.13,21.34,20.91.HRMS(ESI)calcd.for C 16 H 14 N3O[M+H + ]:264.1131,found:264.1131.

[0077] The reaction formula is as follows:

[0078]

[0079] Example 9

[0080] The same procedures were followed as in Example 1, except that 5,6-difluoro-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1i was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3i was isolated in a yield of 55%. 1 H NMR (600MHz, CDCl3) δ8.42(t,J=8.4Hz,1H),8.09(d,J=7.5Hz,2H),8.02–7.93(m,1H),7.69(t,J=7.4Hz,1H),7.54(t,J=7.8Hz,2H). 13 C NMR (151MHz, CDCl3) δ189.91, 158.33 (d, J = 2.4Hz), 157.12 (dd, J = 269.4, 16.9Hz), 153.99 (dd, J = 265.7, 17.0Hz), 145.54 (d, J = 10.4 Hz),139.15(d,J=12.6Hz),134.91,134.45,131.19,128.77,115.47(d,J=2.3Hz),115.34(dd,J=9.8,7.8Hz).HRMS(ESI)calcd.forC 14 H8F2N3O[M+H + ]:272.0630,found:272.0639.

[0081] The reaction formula is as follows:

[0082]

[0083] Example 10

[0084] The same procedures were followed as in Example 1, except that 5,6-dichloro-1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1j was used instead of 1-(trifluoromethanesulfonyl)-1H-benzotriazole of structural formula 1a in Example 1. A yellow solid 3j was isolated in a yield of 57%. 1 H NMR (600MHz, CDCl3) δ8.81(s,1H),8.37(s,1H),8.09(d,J=7.7Hz,2H),7.71–7.67(m,1H),7.54(t,J=7.7Hz,2H). 13C NMR(151MHz, CDCl3)δ189.86,158.44,146.09,142.57,139.10,138.18,134.90,134.53,131.22,130.34,130.19,128.83.HRMS(ESI)calcd.for C 14 H8Cl2N3O[M+H + ]:304.0039,found:304.0042.

[0085] The reaction formula is as follows:

[0086]

[0087] Example 11

[0088] The same steps were followed as in Example 1, except that o-methoxybromoacetophenone represented by structural formula 2b was used instead of bromoacetophenone represented by structural formula 2a in Example 1. A yellow solid 3k was isolated in a yield of 60%. 1 H NMR(400MHz, CDCl3)δ8.63(dd,J=8.4,0.7Hz,1H),8.23(d,J=8.1Hz,1H),8.11–8.04(m,1H), 8.02–7.94(m,2H),7.63–7.56(m,1H),7.19–7.13(m,1H),6.95(d,J=8.4Hz,1H),3.41(s,3H). 13 C NMR (151MHz, CDCl3) δ192.09,159.84,159.46,147.31,140.74,136.15,135.29,132 .06,131.53,129.82,129.76,126.51,121.37,112.01,55.81.HRMS(ESI)calcd.for C 15 H 12 N3O2[M+H + ]:266.0924,found:266.0925.

[0089] The reaction formula is as follows:

[0090]

[0091] Example 12

[0092] The same steps were followed as in Example 1, except that p-methoxybromoacetophenone represented by structure 2c was used instead of bromoacetophenone represented by structure 2a in Example 1. A yellow solid 31 was isolated in a yield of 56%. 1H NMR (400MHz, CDCl3) δ8.68(d,J=8.3Hz,1H),8.24(d,J=8.4Hz,1H),8.18–8.08(m,3H),8.07–7.99(m,1H),7.01(d,J=8.9Hz,2H),3.92(s,3H). 13 C NMR(101MHz, CDCl3)δ188.98,164.64,158.70,147.62,140.47,136.54,133.84,132.51,129.86,129.72,128.22,114.12,55.76.HRMS(ESI)calcd.for C 15 H 12 N3O2[M+H + ]:266.0924,found:266.0926.

[0093] The reaction formula is as follows:

[0094]

[0095] Example 13

[0096] The same steps were followed as in Example 1, except that p-fluorobromoacetophenone represented by structural formula 2d was used instead of bromoacetophenone represented by structural formula 2a in Example 1. A yellow solid 3m was isolated in a yield of 64%. 1 H NMR (400MHz, CDCl3) δ8.69 (dd, J = 8.4, 0.5Hz, 1H), 8.29–8.19 (m, 3H), 8.17–8.12 (m, 1H), 8.10–8.04 (m, 1H), 7.26–7.19 (m, 2H). 13 C NMR (101MHz, CDCl3) δ188.86,166.52(d,J=257.3Hz),157.87,144.04(d,J=731.1Hz),136.78,134.20 ,133.50(d,J=121.9Hz),131.65(d,J=3.0Hz),129.87,129.74,116.14,115.92.HRMS(ESI)calcd.for C 14 H9FN3O[M+H + ]:254.0724,found:254.0726.

[0097] The reaction formula is as follows:

[0098]

[0099] Example 14

[0100] The same steps were followed as in Example 1, except that m-chlorobromoacetophenone represented by structural formula 2e was used instead of bromoacetophenone represented by structural formula 2a in Example 1. A yellow solid 3n was isolated in a yield of 57%. 1 H NMR (400MHz, CDCl3) δ8.70 (dt, J=8.48, 0.62Hz, 1H), 8.27 (d, J=8.5Hz, 1H), 8. 19–8.13(m,2H),8.11–8.02(m,2H),7.68–7.62(m,1H),7.50(t,J=7.9Hz,1H). 13 C NMR (151MHz, CDCl3) δ189.18,157.45,147.70,140.37,136.82,134.98,134.10,133.02,131.05,130.01,129.87,129.78,129.43(1peak is missing).HRMS(ESI)calcd.for C 14 H9ClN3O[M+H + ]:270.0429,found:270.0431.

[0101] The reaction formula is as follows:

[0102]

[0103] Example 15

[0104] The same steps were followed as in Example 1, except that o-bromoacetophenone represented by structural formula 2f was used instead of bromoacetophenone represented by structural formula 2a in Example 1. A yellow solid 3o was isolated in a yield of 59%. 1 H NMR (400MHz, CDCl3) δ8.67(d,J=8.3Hz,1H),8.27(d,J=8.4Hz,1H),8.16–8.10(m,1H),8.09–8.03(m ,1H),7.82–7.74(m,1H),7.65(d,J=7.9Hz,1H),7.54(t,J=7.4Hz,1H),7.47(td,J=7.6,1.3Hz,1H). 13 CNMR(101MHz,CDCl3)δ192.86,156.67,147.36,140.74,139.12,136.62,133.34 ,133.13,133.05,131.37,130.02,129.82,127.76,121.26.HRMS(ESI)calcd.for C14 H9BrN3O[M+H + ]:313.9924,found:313.9926.

[0105] The reaction formula is as follows:

[0106]

[0107] Example 16

[0108] The same steps were followed as in Example 1, except that o-iodobromoacetophenone represented by structural formula 2g was used instead of bromoacetophenone represented by structural formula 2a in Example 1. A yellow solid 3p was isolated in a yield of 60%. 1 H NMR (400MHz, CDCl3) δ8.67(d,J=8.3Hz,1H),8.26(d,J=8.4Hz,1H),8.13(t,J=7.5Hz,1H)8.07(t,J=7 .6Hz,1H),7.94(d,J=7.9Hz,1H),7.68(d,J=7.6Hz,1H),7.56(t,J=7.5Hz,1H),7.28(t,J=7.7Hz,1H). 13 C NMR (101MHz, CDCl3) δ193.77,155.94,147.25,142.63,140.70,139.85,136.65, 133.22,132.75,131.09,130.02,129.80,128.29,93.47.HRMS(ESI)calcd.forC 14 H9IN3O[M+H + ]:361.9785,found:361.9786.

[0109] The reaction formula is as follows:

[0110]

[0111] Example 17

[0112] The same steps were followed as in Example 1, except that 3,4-dichlorobromoacetophenone represented by structural formula 2h was used instead of bromoacetophenone represented by structural formula 2a in Example 1. A yellow solid 3q was isolated in a yield of 77%. 1 H NMR (400MHz, CDCl3) δ8.70 (dd, J=8.4, 0.7Hz, 1H), 8.30 (d, J=2.0Hz, 1H), 8.27 (d,J=8.4Hz,1H),8.18–8.13(m,1H),8.11–8.02(m,2H),7.63(d,J=8.4Hz,1H).13 C NMR (101MHz, CDCl3) δ188.14,157.10,147.75,140.41,139.02,136.97,134.86, 133.45,133.23,133.08,130.86,130.33,129.92,129.83.HRMS(ESI)calcd.for C 14 H8Cl2N3O[M+H + ]:304.0039,found:304.0041.

[0113] The reaction formula is as follows:

[0114]

[0115] Examples 18 to 27

[0116] The remaining conditions are the same as those in Example 1, except for the base and reaction solvent:

[0117] Example alkali Reaction solvent Yield Example 18 Cesium carbonate dichloromethane 16％ Example 19 Cesium carbonate Tetrahydrofuran 34％ Example 20 Cesium carbonate chlorobenzene 15％ Example 21 Cesium carbonate acetone 26％ Example 22 Cesium carbonate N,N-Dimethylformamide 20％ Example 23 potassium carbonate Methanol 32％ Example 24 Sodium hydroxide ethanol 22％ Example 25 Lithium hydroxide monohydrate Tetrahydrofuran 68％ Example 26 lithium hydroxide Tetrahydrofuran 78％ Example 27 Sodium methoxide Tetrahydrofuran 12％

[0118] As can be seen from the above examples, the method of the present invention is used to prepare 1,2,4-benzotriazine derivatives, and the yield is higher when lithium hydroxide or lithium hydroxide hydrate is used, and no toxic or hazardous solvents are used.

Claims

1. A method for preparing a 1,2,4-benzotriazine derivative, characterized in that: The following steps are involved: The 1-(trifluoromethanesulfonyl)-1H-benzotriazole compound represented by the structure of formula II, the bromoacetophenone compound represented by the structure of formula III, and an acid binding agent are added to the reaction solvent. After the reaction is completed, the 1,2,4-benzotriazine derivative represented by the structure of formula I is obtained by post-treatment; ； Among them, R 1 is H, C1~C3 alkyl, halogen, R 1 It can be one or more. When it is multiple, multiple R 1 Independent of each other, can be different; R 2 is phenyl, C1~C3 alkoxy substituted phenyl, halogen substituted phenyl, dihalogen substituted phenyl; The acid binding agent is selected from one or more of potassium carbonate, lithium hydroxide monohydrate, lithium hydroxide, cesium carbonate, sodium hydroxide, and sodium methoxide; The reaction temperature is 20~40 degrees Celsius.

2. The method for preparing 1,2,4-benzotriazine derivatives according to claim 1, characterized in that: R 1 is H, methyl, halogen; R 2 It is phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, or dihalogen-substituted phenyl.

3. The method for preparing 1,2,4-benzotriazine derivatives according to claim 1, characterized in that: ； When R 1 =H, R 2 It is one of o-MeOPh, p-MeOPh, p-FPh, m-ClPh, o-BrOPh, o-IPh, and 3,4-diClPh. When R 2 =Ph, R 1 It is one of 8-H; 8-Me; 8-F; 6-Me; 6-F; 6-Cl; 7-Cl; 6-Me, 7-Me; 6-F, 7-F; 6-Cl, 7-Cl.

4. The method for preparing 1,2,4-benzotriazine derivatives according to claim 1, characterized in that: The molar ratio of the 1-(trifluoromethanesulfonyl)-1H-benzotriazole compound represented by the structure of formula II, the brominated acetophenone compound represented by the structure of formula III, and the acid binding agent is 1:1~2:1~2.

5. The method for preparing 1,2,4-benzotriazine derivatives according to claim 1, characterized in that: The reaction solvent is one or more of dichloromethane, tetrahydrofuran, chlorobenzene, acetone, N,N-dimethylformamide, methanol, and ethanol.

Images