A quinoxaline drug molecule and its preparation method

Abstract

The present invention discloses a quinoxaline drug molecule and a method for preparing the same. The method comprises: using a cobalt salt as a catalyst, mixing an alkynyl-containing drug molecule, an o-phenylenediamine compound, an oxidant, and an organic solvent, and heating the mixture to obtain the quinoxaline drug molecule. The method 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 relates to the synthesis of quinoxaline drug molecules, and in particular to a quinoxaline drug molecule and a preparation method thereof. Background Art

[0002] Quinoxaline compounds are a very important class of heterocyclic compounds with a wide range of applications. For example, they have anti-inflammatory and bactericidal properties, can be used as antibiotics and insecticides, and can be used as herbicides in agriculture. Quinoxaline compounds also possess important biological activities and pharmaceutical properties, and can be used as antiviral and anticancer drugs.

[0003] However, few synthetic methods have been developed for synthesizing quinoxaline drug molecules. The limited methods that have been reported mainly use multi-step reactions and cross-coupling methods. These methods have disadvantages such as long synthetic steps, low overall yield, and poor synthesis efficiency. Summary of the Invention

[0004] To address the technical problems in the prior art, the present invention provides a quinoxaline drug molecule 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 drug molecule as starting materials to synthesize the quinoxaline drug molecule 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 drug molecule comprises: using a cobalt salt as a catalyst, mixing an alkynyl-containing drug molecule, an o-phenylenediamine compound, an oxidant and an organic solvent, and heating the mixture to react;

[0007] Wherein, the alkynyl-containing drug molecule 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 alkynyl-containing drug molecule, and the o-phenylenediamine compound is 1-100:1-6000:1-2000.

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

[0010] Further preferably, in order to improve the product yield, the molar ratio of the cobalt salt, the alkynyl-containing drug molecule, and the o-phenylenediamine compound is 1-10:1-300:1-100.

[0011] Preferably, the molar concentration of the cobalt salt is 1-50 mol%.

[0012] Preferably, in order to improve the yield, 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·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 drug molecule is provided. The quinoxaline drug molecule is obtained by the preparation method of the quinoxaline drug molecule.

[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 uses cobalt salt as a catalyst, adds an oxidant, and uses o-phenylenediamine compounds and alkynyl-containing drug molecules as starting materials to synthesize quinoxaline drug molecules for the first time. 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 a short preparation route, good universality of the substrate, mild reaction conditions, high synthesis yield, and simple and easy-to-obtain raw materials and catalysts. It has the potential for large-scale production and is expected to be introduced to the market. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0026] Figure 2b This is the C NMR spectrum of the quinoxaline drug molecule 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] Quinoxaline compound is connected with another biologically active drug molecule, is a kind of concise and effective synthetic method for preparing quinoxaline drug molecule, but the synthetic method that is currently developed for synthesizing quinoxaline drug molecule is few. Further, quinoxaline compound is directly connected with another biologically active drug molecule, for drug molecule and other compound synthesis, it is generally known in the industry that there is a technical difficulty, mainly that drug molecule has very complex functional group, therefore drug molecule is reacted with other compounds, has many reactive sites, has very large challenging, also have the relevant report that quinoxaline compound is directly connected with drug molecule. Especially by adding a small amount of cheap and environmentally friendly catalyst, under mild reaction conditions, by one-step reaction, quinoxaline compound and biologically active drug molecule are directly connected, the method for preparing new quinoxaline drug molecule has not been reported.

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

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

[0031] Wherein, the alkynyl-containing drug molecule 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 alkynyl-containing drug molecule, and the o-phenylenediamine compound is 1-100:1-6000:1-2000, more preferably 1-50:1-3000:1-1000, and even more preferably 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 drug molecule 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) calcd forC 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). 13C NMR (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). 13C 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 (101 MHz, 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: 1 H 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: 1 H 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 for C 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: 1 H 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 alkynyl-containing drug molecule, 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 drug molecule, characterized in that: include: Using cobalt salt as a catalyst, an alkynyl-containing drug molecule, an o-phenylenediamine compound, an oxidant and an organic solvent are mixed, heated, and reacted at a temperature of 50-100°C; Wherein, the alkynyl-containing drug molecule 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; 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, wherein X is an integer of 1-6; 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; 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.

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

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

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

5. The method for preparing the quinoxaline drug molecule according to claim 1, wherein The molar concentration of the cobalt salt is 1-50 mol %.

6. The method for preparing the quinoxaline drug molecule according to claim 1, characterized in that: The reaction temperature in the preparation method is 70°C.

7. The method for preparing a quinoxaline drug molecule according to claim 1, wherein: 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 ... any one or more of 1,2-diamino-1,6-diamine, 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 4,5-dichloro-1,2-phenylenediamine.

8. The method for preparing a quinoxaline drug molecule according to claim 1, wherein: The oxidant is oxygen.

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