A quinoxaline compound and its preparation method

Abstract

This invention belongs to the field of quinoxaline compound synthesis and discloses a quinoxaline compound molecule and a preparation method thereof. The preparation method comprises: using a cobalt salt as a catalyst, mixing an alkyne compound, an o-phenylenediamine compound, an oxidant, and an organic solvent, and heating to obtain a quinoxaline drug molecule. The invention has the advantages of mild reaction conditions, good substrate universality, high synthesis yield, and the use of an inexpensive and readily available catalyst.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of quinoxaline compounds, and in particular relates to a quinoxaline compound and a preparation method thereof. Background Art

[0002] Quinoxaline compounds are a very important class of heterocyclic compounds with widespread applications in many fields. For example, they exhibit anti-inflammatory and bactericidal properties, serving as antibiotics and insecticides, and as herbicides in agriculture. Quinoxaline compounds also possess significant biological and pharmaceutical properties, and can be used in antiviral and anticancer drugs. They also have extensive applications in advanced functional materials and dyes.

[0003] Due to the wide range of important applications of quinoxaline compounds, numerous synthetic methods have been developed. However, most require multi-step reactions, harsh reaction conditions, and limited availability of raw materials. Using o-phenylenediamine and alkyne compounds to synthesize quinoxaline compounds is a simple and efficient synthetic strategy. However, the currently available synthetic methods have certain disadvantages. For example, Shi, S.; Wang, T.; Yang, W.; Rudolph, M.; Hashmi, ASK Chem. Eur. J. 2013, 19, 6576−6580, used gold as a catalyst to synthesize quinoxaline compounds from o-phenylenediamine and alkyne compounds. However, this reaction has obvious disadvantages: the use of precious metal gold as a catalyst and the need for a large excess of oxidant and additives result in a narrow range of reaction substrates. Another example is Viswanadham, KKDR; Reddy, MP; Sathyanarayana, P.; Ravi, O.; Kant, R.; Bathula, SR Chem. Commun. 2014, 50, 13517−13520; Hazarika, D.; Phukan, P.. Tetrahedron 2017, 73, 1374−41379, using iodine as a promoter or TsNBr2 as a promoter, but this type of synthesis method requires the use of 2 equivalents of iodine or TsNBr2 reagent as a promoter, and 2 equivalents of potassium carbonate reagent as a base and high temperature conditions, resulting in a narrow reaction substrate range and environmental unfriendliness. Summary of the Invention

[0004] To address the technical problems in the prior art, the present invention provides a quinoxaline compound and a method for preparing the same. The method uses a cobalt salt as a catalyst, an oxidant, and o-phenylenediamine and an alkynyl-containing compound as starting materials to synthesize the quinoxaline compound under mild reaction conditions.

[0005] To achieve the above object, the technical solution of the present invention is:

[0006] A method for preparing a quinoxaline compound comprises: using a cobalt salt as a catalyst, mixing an alkynyl compound, an o-phenylenediamine compound, an oxidant and an organic solvent, and heating the mixture to react;

[0007] Wherein, the alkynyl-containing compound is selected from any one or more of mevalynol, levonorgestrel, ethinyl estradiol, linegestrol, desogestrel, mestranol, 4-alkynylquinoline, anordrin, 4,5-dihydro-5α-methoxy D-(-)-norgestrel, 17α-alkynyl dihydrotestosterone, or 3β-5α-tetrahydronorgestrel.

[0008] Preferably, the molar ratio of the cobalt salt, the alkyne compound, and the o-phenylenediamine compound is 1-100:1-6000:1-2000.

[0009] Further preferably, in order to increase the yield of the product, the molar ratio of the cobalt salt, the alkyne compound, and the o-phenylenediamine compound is 1-50:1-3000:1-1000.

[0010] More preferably, in order to obtain a higher yield of the product, the molar ratio of the cobalt salt, the alkyne compound, and the o-phenylenediamine compound is 1-10:1-300:1-100.

[0011] Preferably, in order to obtain a high yield of the product, the molar concentration of the cobalt salt is 1-50 mol %.

[0012] Preferably, in order to obtain a high yield of the product, the reaction temperature in the preparation method is 20-120°C, further, the reaction temperature is 50-100°C, and further, the reaction temperature is 70°C.

[0013] Preferably, the cobalt salt is selected from cobalt oxide CoO, cobalt trioxide Co2O3, cobalt sulfide CoS, cobalt chloride CoCl2, cobalt chloride monohydrate CoCl2·H2O, cobalt bromide CoBr2, hydrated cobalt bromide CoBr2·H2O, xH2O, cobalt acetate Co(OAc)2, cobalt acetate tetrahydrate Co(OAc)2·4H2O, cobalt iodide CoI2, cobalt phosphate Co3(PO4)2, cobalt carbonate CoCO3, cobalt tetrafluoroborate Co(BF4)2, cobalt tetrafluoroborate monohydrate Co(BF4)2·H2O, tetracobalt dodecacarbonyl Co4(CO)12 , cobalt hydroxide Co(OH)2, cobalt tungstate CoWO4, cobalt diiron tetraoxide CoFe2O4, cobalt thiocyanate Co(SCN)2, or cobalt acetylacetonate Co(C5H7O2)2, any one or more thereof.

[0014] Preferably, the o-phenylenediamine compound is selected from 1,2-phenylenediamine, 3-methyl-1,2-phenylenediamine, 4-methyl-1,2-phenylenediamine, 3-methoxy-1,2-phenylenediamine, 4-methoxy-1,2-phenylenediamine, 3-ethyl-1,2-phenylenediamine, 4-ethyl-1,2-phenylenediamine, 3-tert-butyl-1,2-phenylenediamine, 4-tert-butyl-1,2-phenylenediamine, 3-fluoro-1,2-phenylenediamine, 4-fluoro-1,2-phenylenediamine, 3-chloro-1,2-phenylenediamine, 4-chloro-1,2-phenylenediamine , 3-bromo-1,2-phenylenediamine, 4-bromo-1,2-phenylenediamine, 3-trifluoromethyl-1,2-phenylenediamine, 4-trifluoromethyl-1,2-phenylenediamine, 3-methylformate-1,2-phenylenediamine, 4-methylformate-1,2-phenylenediamine, 3-cyano-1,2-phenylenediamine, 4-cyano-1,2-phenylenediamine, 3-cyano-1,2-phenylenediamine, 4-cyano-1,2-phenylenediamine, 4,5-dimethyl-1,2-phenylenediamine, or any one or more of 4,5-dichloro-1,2-phenylenediamine.

[0015] Preferably, the organic solvent is selected from any one or more of ethyl acetate, n-hexane, cyclohexane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, xylene, mesitylene, 1,4-dioxane, methanol, tert-amyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

[0016] Preferably, the oxidant is selected from any one or more of 1,4-benzoquinone, tetrachloro-p-benzoquinone, tert-butyl hydroperoxide, dibenzoyl peroxide, sodium persulfate, potassium persulfate, copper acetate, silver carbonate, silver oxide, silver acetate, oxygen or air.

[0017] Preferably, the oxidant is oxygen.

[0018] Based on the same inventive concept, a quinoxaline compound is provided. The quinoxaline compound is obtained by the above-mentioned preparation method of the quinoxaline compound.

[0019] Due to the adoption of the above technical solution, the present invention has the following advantages and positive effects compared with the prior art:

[0020] First, the present invention is the first to use cobalt salt as a catalyst, by adding an oxidant, and using o-phenylenediamine compounds and alkyne compounds as starting materials to synthesize quinoxaline compounds, and the synthesis method is simple;

[0021] Second, the starting compounds of the preparation method of the present invention are widely compatible, the conditions are mild, and the synthesis yield is high;

[0022] Third, the catalyst and oxidant used in the present invention are commercial chemical reagents, which have many advantages such as high yield, simple operation, and cheap and readily available raw materials;

[0023] Fourth, the preparation method of the present invention has the advantages of short preparation route, good universality of substrates, mild reaction conditions, high synthesis yield, and simple and easy-to-obtain raw materials and catalysts, and has great prospects for industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The synthetic route of the quinoxaline compound of the present invention is as follows;

[0025] Figure 2a This is the H NMR spectrum of quinoxaline compound 1 in Example 1;

[0026] Figure 2b This is the C NMR spectrum of quinoxaline compound 1 in Example 1. DETAILED DESCRIPTION

[0027] The advantages and features of the present invention will become more apparent from the following description, which is in conjunction with the accompanying drawings and specific examples.

[0028] Connecting a quinoxaline compound to another biologically active drug molecule is a simple and effective method for preparing quinoxaline compounds, but few methods have been developed for synthesizing quinoxaline compounds. Furthermore, directly connecting a quinoxaline compound to another biologically active compound is very challenging, and there are currently no reports on this. In particular, there are no reports on methods for preparing new quinoxaline compounds by directly connecting a quinoxaline compound to a biologically active compound through a one-step reaction using a small amount of inexpensive and environmentally friendly catalyst under mild reaction conditions.

[0029] The invention adopts cobalt salt as a catalyst, mixes an o-phenylenediamine compound, an alkyne compound, an organic solvent and an oxidant, and heats the mixture to react to obtain a quinoxaline compound.

[0030] See Figure 1 A method for preparing a quinoxaline compound, comprising: using a cobalt salt as a catalyst, mixing an alkyne compound, an o-phenylenediamine compound, an oxidant, and an organic solvent, and heating the mixture to react;

[0031] Wherein, the alkyne compound is selected from any one or more of mevalynol, levonorgestrel, ethinyl estradiol, linegestrol, desogestrel, mestranol, 4-alkynylquinoline, anordrin, 4,5-dihydro-5α-methoxy D-(-)-norgestrel, 17α-alkynyl dihydrotestosterone, or 3β-5α-tetrahydronorgestrel.

[0032] Preferably, the molar ratio of the cobalt salt, the alkyne compound, and the o-phenylenediamine compound is 1-100:1-6000:1-2000, more preferably the molar ratio is 1-50:1-3000:1-1000, and even more preferably the molar ratio is 1-10:1-300:1-100.

[0033] Preferably, the molar concentration of the cobalt salt is 1-50 mol%.

[0034] Preferably, the reaction temperature in the preparation method is 20-120° C., further, the reaction temperature is 50-100° C., and further, the reaction temperature is 70° C., and oil bath heating can be used.

[0035] Preferably, the cobalt salt is selected from cobalt oxide CoO, cobalt trioxide Co2O3, cobalt sulfide CoS, cobalt chloride CoCl2, cobalt chloride monohydrate CoCl2·H2O, cobalt bromide CoBr2, hydrated cobalt bromide CoBr2·xH2O, cobalt acetate Co(OAc)2, cobalt acetate tetrahydrate Co(OAc)2·4H2O, cobalt iodide CoI2, cobalt phosphate Co3(PO4)2, cobalt carbonate CoCO3, cobalt tetrafluoroborate Co(BF4)2, cobalt tetrafluoroborate monohydrate Co(BF4)2·H2O, tetracobalt dodecacarbonyl Co4(CO) 12 , cobalt hydroxide Co(OH)2, cobalt tungstate CoWO4, cobalt diiron tetraoxide CoFe2O4, cobalt thiocyanate Co(SCN)2, or cobalt acetylacetonate Co(C5H7O2)2, any one or more thereof.

[0036] Preferably, the o-phenylenediamine compound is selected from 1,2-phenylenediamine, 3-methyl-1,2-phenylenediamine, 4-methyl-1,2-phenylenediamine, 3-methoxy-1,2-phenylenediamine, 4-methoxy-1,2-phenylenediamine, 3-ethyl-1,2-phenylenediamine, 4-ethyl-1,2-phenylenediamine, 3-tert-butyl-1,2-phenylenediamine, 4-tert-butyl-1,2-phenylenediamine, 3-fluoro-1,2-phenylenediamine, 4-fluoro-1,2-phenylenediamine, 3-chloro-1,2-phenylenediamine, 4-chloro-1,2-phenylenediamine , 3-bromo-1,2-phenylenediamine, 4-bromo-1,2-phenylenediamine, 3-trifluoromethyl-1,2-phenylenediamine, 4-trifluoromethyl-1,2-phenylenediamine, 3-methylformate-1,2-phenylenediamine, 4-methylformate-1,2-phenylenediamine, 3-cyano-1,2-phenylenediamine, 4-cyano-1,2-phenylenediamine, 3-cyano-1,2-phenylenediamine, 4-cyano-1,2-phenylenediamine, 4,5-dimethyl-1,2-phenylenediamine, or any one or more of 4,5-dichloro-1,2-phenylenediamine.

[0037] Preferably, the organic solvent is selected from any one or more of ethyl acetate, n-hexane, cyclohexane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene, xylene, mesitylene, 1,4-dioxane, methanol, tert-amyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide. Further preferably, the organic solvent is 1,2-dichloroethane, as using 1,2-dichloroethane as the organic solvent can result in a higher product yield.

[0038] Preferably, the oxidant is selected from any one or more of 1,4-benzoquinone, tetrachloro-p-benzoquinone, tert-butyl hydroperoxide, dibenzoyl peroxide, sodium persulfate, potassium persulfate, copper acetate, silver carbonate, silver oxide, silver acetate, oxygen, or air. Furthermore, it is preferred that the target compound be obtained by heating the reaction under an oxygen atmosphere, as the product yield obtained by the reaction under an oxygen atmosphere is the highest.

[0039] Example 1

[0040] Synthesis of quinoxaline compound 1, whose structural formula is:

[0041] .

[0042] Preparation Method 1: In a reaction tube, under an oxygen atmosphere, add 4.4 mg of cobalt bromide, 58.9 mg of methylpentynol, 21.6 mg of o-phenylenediamine, and 2.0 mL of 1,2-dichloroethane. The mixture is reacted in a 60°C oil bath for 24 hours. Purification affords 21.0 mg of the pure product, with a yield of 52%.

[0043] Preparation Method 2: In a reaction tube, under an oxygen atmosphere, add 3.5 mg of cobalt acetate, 58.9 mg of methylpentynol, 21.6 mg of o-phenylenediamine, and 2.0 mL of 1,2-dichloroethane. The mixture is reacted in a 60°C oil bath for 24 hours. Purification yields 8.9 mg of the pure product, with a yield of 22%.

[0044] Preparation Method 3: In a reaction tube, under an oxygen atmosphere, add 4.4 mg of cobalt bromide, 58.9 mg of methylpentynol, 21.6 mg of o-phenylenediamine, and 2.0 mL of 1,2-dichloroethane. The mixture is reacted in a 70°C oil bath for 24 hours. Purification affords 23.5 mg of the pure product, with a yield of 58%.

[0045] Preparation Method 4: In a reaction tube, under an oxygen atmosphere, add 4.4 mg of cobalt bromide, 58.9 mg of methylpentynol, 21.6 mg of o-phenylenediamine, and 2.0 mL of THF. The mixture was reacted in a 70°C oil bath for 24 hours. Purification afforded 16.2 mg of the pure product, with a yield of 40%.

[0046] Preparation Method 5: In a reaction tube, under an oxygen atmosphere, add 4.4 mg of cobalt bromide, 58.9 mg of methylpentynol, 21.6 mg of o-phenylenediamine, 50 mg of 4A molecular sieves (reaction conditions were further optimized), and 2.0 mL of 1,2-dichloroethane. The mixture was reacted in a 70°C oil bath for 24 hours. Purification afforded 25.5 mg of the pure product, with a yield of 63%.

[0047] The results of NMR characterization of the product are: 1 H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.15-8.08 (m, 2H), 7.82-7.75 (m, 2H), 4.90 (s, 1H), 2.07-1.96 (m, 2H), 1.67 (s, 3H), 0.81 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.7, 142.9, 141.7,140.3, 130.5, 129.8, 129.3, 128.9, 74.0, 35.6, 28.7, 8.1. HRMS (ESI) calcdfor C 12 H 15 N2O (M + H) + , 203.1184, found 203.1201.

[0048] Please see the NMR spectrum of the product Figure 2a and Figure 2b.

[0049] Example 2

[0050] Synthesis of quinoxaline drug molecule 2, whose structural formula is:

[0051] .

[0052] Preparation method: In a reaction tube, under an oxygen atmosphere, add 4.4 mg of cobalt bromide, 187.5 mg of levonorgestrel, 21.6 mg of o-phenylenediamine, 50 mg of 4A molecular sieves, and 2.0 mL of 1,2-dichloroethane. The mixture is reacted in a 70°C oil bath for 24 hours. Purification yields 30.1 mg of the pure product, with a yield of 36%.

[0053] The results of NMR characterization of the product are: 1 H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.13-8.05 (m, 2H), 7.81-7.74 (m, 2H), 5.68 (s, 1H), 4.36 (s, 1H), 2.62-2.55 (m, 1H),2.43-2.20 (m, 5H), 2.09-1.95 (m, 2H), 1.89-1.83 (m, 1H), 1.77-1.72 (m, 1H),1.69-1.66 (m, 1H), 1.56-1.43 (m, 3H), 1.36-1.33 (m, 2H), 1.17 (s, 3H), 1.16(s, 3H), 1.11-1.00 (m, 1H), 0.87 (d, J = 7.0 Hz, 1H), 0.65-0.58 (m, 1H). 13 CNMR (101 MHz, CDCl3) δ 199.5, 171.0, 159.7, 144.0, 141.5, 140.4, 130.4,129.9, 129.2, 124.0, 85.4, 53.4, 50.1, 48.5, 38.6, 36.6, 36.1, 35.6, 34.0,33.5, 32.9, 31.8, 24.5, 20.7, 17.5, 15.1, 14.3. HRMS (ESI) calcd for C 27 H 33 N2O2(M + H) + , 417.2542, found 417.2532.

[0054] Example 3

[0055] Synthesis of quinoxaline drug molecule 3, whose structural formula is:

[0056] .

[0057] The preparation method is as follows: In a reaction tube, under an oxygen atmosphere, add 4.4 mg of cobalt bromide, 118.6 mg of ethinyl estradiol, 21.6 mg of o-phenylenediamine, 50 mg of 4A molecular sieves, and 2.0 mL of 1,2-dichloroethane. The mixture is reacted in a 70°C oil bath for 24 hours. Purification yields 46.7 mg of the pure product, with a yield of 58%.

[0058] The results of NMR characterization of the product are: 1 H NMR(400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.94 (s,1H), 8.09-8.06 (m, 2H), 7.82-7.80 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.44-6.39 (m, 2H), 5.78 (s, 1H), 2.85-2.79 (m, 1H), 2.75-2.61 (m, 2H), 2.02-1.94(m, 2H), 1.86-1.82 (m, 1H), 1.74-1.71 (m, 1H), 1.65-1.59 (m, 1H), 1.56-1.45(m, 2H), 1.39-1.31 (m, 1H), 1.27-1.24 (m, 2H), 1.18-1.11 (m, 1H), 1.07 (s,3H), 0.38-0.33 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 161.9, 155.3, 146.8,140.8, 140.4, 137.5, 130.6, 130.3, 129.7, 129.1, 126.4, 115.3, 113.1, 86.1,48.2, 43.4, 36.6, 33.9, 31.4, 29.6, 27.7, 26.4, 24.7, 22.5, 15.1, 14.4. HRMS(ESI) calcd for C 26 H 29 N2O2 (M + H) + , 401.2229, found 401.2231.

[0059] Example 4

[0060] Synthesis of quinoxaline drug molecule 4, whose structural formula is:

[0061] .

[0062] Preparation method: In a reaction tube, under an oxygen atmosphere, add 4.4 mg of cobalt bromide, 91.9 mg of 4-alkynylquinoline, 21.6 mg of o-phenylenediamine, 50 mg of 4A molecular sieves, and 2.0 mL of 1,2-dichloroethane. The mixture is reacted in a 70°C oil bath for 24 hours. Purification yields 14.4 mg of the pure product, with a yield of 28%.

[0063] The results of NMR characterization of the product are: 1 H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 9.11 (d,J = 4.4 Hz, 1H), 8.27-8.20 (m, 4H), 7.92-7.87 (m, 2H), 7.83-7.79 (m, 1H),7.69 (d, J = 4.4 Hz, 1H), 7.62 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H). 13 C NMR (101MHz, CDCl3) δ 151.8, 150.1, 149.1, 145.8, 143.1, 142.2, 142.0, 131.0, 130.9,130.4, 130.0, 129.9, 129.6, 127.9, 126.0, 125.2, 122.1.

[0064] Example 5

[0065] Synthesis of quinoxaline drug molecule 5, whose structural formula is:

[0066] .

[0067] The preparation method is as follows: In a reaction tube, under an oxygen atmosphere, add 2.2 mg of cobalt bromide, 56.9 mg of linegestrol, 10.8 mg of an o-phenylenediamine compound, 25 mg of 4A molecular sieves, and 2.0 mL of 1,2-dichloroethane. The mixture is reacted in a 70°C oil bath for 24 hours. Purification yields 29.7 mg of the pure product, with a yield of 76%.

[0068] The results of NMR characterization of the product are: 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.13-8.05 (m, 2H), 7.80-7.73 (m, 2H), 5.35 (s, 1H), 4.39 (s, 1H), 2.57-2.50 (m, 1H),2.29-2.18 (m, 2H), 2.05-1.96 (m, 2H), 1.84-1.77 (m, 4H), 1.71-1.66 (m, 2H),1.58-1.51 (m, 2H), 1.49-1.42 (m, 2H), 1.37-1.26 (m, 2H), 1.15 (s, 3H), 1.12-1.04 (m, 1H), 0.99-0.79 (m, 3H), 0.38-0.29 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ160.0, 144.1, 141.5, 140.3, 140.2, 130.3, 129.7, 129.2, 120.2, 85.6, 50.0,49.8, 48.9, 41.93, 41.89, 36.1, 35.6, 33.7, 31.9, 28.7, 25.9, 25.5, 24.3,22.1, 15.2. HRMS (ESI) calcd for C 26 H 33 N2O (M + H) + , 389.2593, found 389.2596.

[0069] Example 6

[0070] Synthesis of quinoxaline drug molecule 6, whose structural formula is:

[0071] .

[0072] Preparation method: In a reaction tube, under an oxygen atmosphere, add 1.1 mg of cobalt bromide, 31.0 mg of desogestrel, 5.4 mg of o-phenylenediamine, 12.5 mg of 4A molecular sieves, and 1.0 mL of 1,2-dichloroethane. The mixture is reacted in a 70°C oil bath for 24 hours. Purification yields 14.7 mg of the pure product, with a yield of 71%.

[0073] The results of NMR characterization of the product are: 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.13-8.07(m, 2H), 7.80-7.74 (m, 2H), 5.43 (s, 1H), 4.88 (s, 1H), 4.67 (s, 1H), 4.35(s, 1H), 2.67-2.60 (m, 1H), 2.44-2.33 (m, 2H), 2.23-2.16 (m, 2H), 2.05-1.86(m, 5H), 1.80-1.71 (m, 4H), 1.64-1.57 (m, 1H), 1.49-1.42 (m, 2H), 1.35-1.32(m, 1H), 1.24 (t, J = 7.4 Hz, 3H), 1.00-0.86 (m, 3H), 0.53 (d, J = 12.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 160.0, 147.0, 143.8, 141.5, 140.4, 139.8,130.4, 129.9, 129.2, 121.6, 108.9, 86.9, 54.7, 52.8, 52.1, 42.7, 42.0, 36.8,36.6, 35.6, 32.0, 29.0, 25.7, 23.2, 22.2, 21.9, 9.7. HRMS (ESI) calcd forC 28 H 35 N2O (M + H) + , 415.2749, found 415.2747.

[0074] Example 7

[0075] Synthesis of quinoxaline drug molecule 7, whose structural formula is:

[0076] .

[0077] Preparation method: In a reaction tube, under an oxygen atmosphere, add 1.1 mg of cobalt bromide, 31.0 mg of mestranol, 5.4 mg of o-phenylenediamine, 12.5 mg of 4A molecular sieves, and 1.0 mL of 1,2-dichloroethane. The mixture is reacted in a 70°C oil bath for 24 hours. Purification affords 11.4 mg of the pure product, with a yield of 55%.

[0078] The results of NMR characterization of the product are: 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.14-8.09(m, 2H), 7.82-7.75 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.65-6.60 (m, 2H), 4.43(s, 1H), 3.74 (s, 3H), 2.94-2.80 (m, 2H), 2.64-2.56 (m, 1H), 2.34-2.27 (m,1H), 2.15-1.97 (m, 3H), 1.89-1.52 (m, 5H), 1.48-1.33 (m, 2H), 1.15 (s, 3H),0.32-0.24 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 158.9, 156.5, 143.1, 140.5,139.4, 137.0, 131.5, 129.4, 128.8, 128.23. 128.21, 125.3, 112.9, 110.5, 84.6,54.3, 48.7, 48.0, 42.5, 38.7, 35.2, 32.7, 28.9, 26.6, 25.3, 23.2, 14.2. HRMS(ESI) calcd for C 27 H 31 N2O2 (M + H) + , 415.2386, found 415.2389.

[0079] The treatment proposed in the above embodiment is as follows: after the reaction is completed, the reaction is quenched with a small amount of ethyl acetate, the reaction solution is simply filtered through diatomaceous earth, the filtrate is collected, the solvent is dried, and the residue is separated by column chromatography to obtain a pure product.

[0080] The present invention uses a cobalt salt as a catalyst, mixes an o-phenylenediamine compound, an alkyne compound, and an organic solvent, and produces a quinoxaline drug molecule in high yield under mild reaction conditions. The catalyst, oxidant, and starting materials used in the present invention are all commercially available chemical reagents, offering advantages such as high yield, simple operation, and readily available raw materials.

[0081] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings, but the present invention is not limited to the above embodiments. Even if various changes are made to the present invention, if these changes fall within the scope of the claims of the present invention and their equivalents, they still fall within the scope of protection of the present invention.

Claims

1. A method for preparing a quinoxaline compound, characterized in that: include: Using cobalt salt as catalyst, an alkyne compound, an o-phenylenediamine compound, an oxidant and an organic solvent are mixed and then heated in an oil bath to react; wherein the alkyne compound is selected from mevalynol or 4-alkynylquinoline; The cobalt salt is selected from cobalt bromide CoBr2 or cobalt acetate Co(OAc)2; The o-phenylenediamine compound is selected from 1,2-phenylenediamine, 3-methyl-1,2-phenylenediamine, 4-methyl-1,2-phenylenediamine, 3-methoxy-1,2-phenylenediamine, 4-methoxy-1,2-phenylenediamine, 3-ethyl-1,2-phenylenediamine, 4-ethyl-1,2-phenylenediamine, 3-tert-butyl-1,2-phenylenediamine, 4-tert-butyl-1,2-phenylenediamine, 3-fluoro-1,2-phenylenediamine, 4-fluoro-1,2-phenylenediamine, 3-chloro-1,2-phenylenediamine , any one or more of 4-chloro-1,2-phenylenediamine, 3-bromo-1,2-phenylenediamine, 4-bromo-1,2-phenylenediamine, 3-trifluoromethyl-1,2-phenylenediamine, 4-trifluoromethyl-1,2-phenylenediamine, 3-methylformate-1,2-phenylenediamine, 4-methylformate-1,2-phenylenediamine, 3-cyano-1,2-phenylenediamine, 4-cyano-1,2-phenylenediamine, 4,5-dimethyl-1,2-phenylenediamine or 4,5-dichloro-1,2-phenylenediamine; The organic solvent is 1,2-dichloroethane; The oxidant is oxygen.

2. The method for preparing the quinoxaline compound according to claim 1, wherein The molar ratio of the cobalt salt, the alkyne compound and the o-phenylenediamine compound is 1-100:1-6000:1-2000.

3. The method for preparing the quinoxaline compound according to claim 2, wherein The molar ratio of the cobalt salt, the alkyne compound and the o-phenylenediamine compound is 1-50:1-3000:1-1000.

4. The method for preparing the quinoxaline compound according to claim 3, wherein The molar ratio of the cobalt salt, the alkyne compound and the o-phenylenediamine compound is 1-10:1-300:1-100.

5. The method for preparing the quinoxaline compound according to claim 1, wherein The reaction temperature in the preparation method is 20-120°C.

6. The method for preparing the quinoxaline compound according to claim 5, wherein The reaction temperature is 50-100°C.

7. The method for preparing the quinoxaline compound according to claim 6, wherein The reaction temperature was 70°C.

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