A method for preparing 6-phenylthieno[2,3-b]pyrazine

Abstract

The present invention relates to a preparation method of 6-phenylthieno[2,3-b]pyrazine. The preparation method of 6-phenylthieno[2,3-b]pyrazine comprises the following steps: (1) reacting 2-chloro-3-cyanopyrazine with phenylacetylene and cuprous iodide under the action of a base and a catalyst to obtain 3-(phenylethynyl)pyrazine-2-carbonitrile; (2) reacting 3-(phenylethynyl)pyrazine-2-carbonitrile with a sulfide to obtain 6-phenylthieno[2,3-b]pyrazine.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis of chemical and pharmaceutical intermediates, and particularly relates to a preparation method of 6-phenylthieno[2,3-b]pyrazine. Background Art

[0002] Thienopyrazine is a class of nitrogen-containing heterocyclic compounds with electron-rich properties, having a large π-conjugated rigid planar structure. It is a class of classical red phosphors, with excellent optoelectronic properties and is a potential red light material. At the same time, thienopyrazine is also an important pharmaceutical intermediate. According to research, thieno[2,3-b]pyrazine compounds can be used as inhibitors of protein kinase IRAK4 that participates in the innate immune response signal, for the treatment of melanoma and other cancers involving IRAK4; as acetyl-CoA carboxylase inhibitors, etc. In addition, due to their excellent multifunctional pharmacological properties (including antibacterial and anti-avian influenza virus H5N1), thienopyrimidine compounds have been widely studied, so thieno[2,3-b]pyrazine compounds have considerable application prospects.

[0003] Currently, there are mainly the following two reported synthesis methods for 6-phenylthieno[2,3-b]pyrazine compounds. (1) The first method is reported by Professor A. van der Gen of Leiden University in the Netherlands, using 3-methylpyrazine-2-thiol and ethyl benzoate as raw materials, and adding them under the action of n-butyllithium to obtain phenyl-2-(3-thioxo-3,4-dihydropyrazin-2-yl)ethan-1-one (5); then dehydrating and cyclizing with concentrated sulfuric acid at a temperature of 70-80 °C to generate the target product 6-phenylthieno[2,3-b]pyrazine. This synthesis route requires the use of air- and water-sensitive n-butyllithium and concentrated sulfuric acid with strong corrosiveness and strong oxidizing properties, with high operating requirements and great danger. (2) The second method uses 2,3-dichloropyrazine and phenylacetylene as raw materials, and generates 2-chloro-3-(phenylethynyl)pyrazine (7) through a palladium-catalyzed Sonogashira coupling reaction; then heating with sodium sulfide in a DMF solvent to 130 °C to undergo electrophilic substitution and cyclization reactions to obtain the target product 6-phenylthieno[2,3-b]pyrazine. Although this method is easier to operate than Route 1, the reaction temperature is high, and a high-boiling solvent DMF is used. It is relatively difficult to remove the residual high-boiling solvent DMF in the product and completely remove DMF.

[0004]

[0005]

[0006] How to develop a green, efficient and simple method for preparing 6-phenylthieno[2,3-b]pyrazine compounds will greatly promote the application research of thienopyrazine compounds. Nitrile compounds are relatively cheap and easily available, widely present in organic small molecules and drugs. At the same time, cyano groups can be conveniently converted into carboxyl groups and amide groups, making them potential multi-functional groups. If the conversion of cyano groups to other functional groups can be achieved, it will provide broader strategies and ideas for the derivatization reactions of nitrile compounds and the design and synthesis of new organic molecules. Summary of the Invention

[0007] In view of the above problems, the present invention aims to provide a method for preparing 6-phenylthieno[2,3-b]pyrazine. The preparation method provided by the present invention can synthesize 6-phenylthieno[2,3-b]pyrazine compounds inexpensively, simply and efficiently, and can achieve the preparation of such compounds in grams or even larger amounts, greatly promoting the research and application of thieno[2,3-b]pyrazine compounds in the fields of medicine and optoelectronics.

[0008] Specifically, the present invention provides a method for preparing 6-phenylthieno[2,3-b]pyrazine, and the preparation method includes the following steps:

[0009] (1) React 2-chloro-3-cyanopyrazine (1) with phenylacetylene and cuprous iodide under the action of a base and a catalyst to obtain 3-(phenylethynyl)pyrazine-2-carbonitrile (2);

[0010]

[0011] (2) React 3-(phenylethynyl)pyrazine-2-carbonitrile (2) with a sulfide to obtain 6-phenylthieno[2,3-b]pyrazine (3)

[0012]

[0013] Preferably, in step (1), the reaction is carried out under the protection of an inert gas, the inert gas is nitrogen, the solvent is acetonitrile and / or DMF, preferably acetonitrile; the dosage ratio of 2-chloro-3-cyanopyrazine to the solvent is 1 g:(7 - 12) mL.

[0014] Preferably, in step (1), the molar ratio of 2-chloro-3-cyanopyrazine to phenylacetylene is 1:(1 - 1.2); the molar ratio of 2-chloro-3-cyanopyrazine to cuprous iodide is 1:(0.01 - 0.3).

[0015] Preferably, in step (1), the base is triethylamine; the molar ratio of 2-chloro-3-cyanopyrazine to the base is 1:(1 - 3), preferably 1:(1.2 - 3).

[0016] Preferably, in step (1), the catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; the molar ratio of 2-chloro-3-cyanopyrazine to the catalyst is 1:(0.01 - 0.05).

[0017] Preferably, in step (1), the reaction temperature is 60 - 100 °C, and the reaction time is 4 - 18 h; after the reaction is completed, water is added and extraction is carried out with an organic solvent. The organic phases are combined, dried, and the organic solvent is removed by distillation under reduced pressure. Then, purification is carried out by silica gel column chromatography to obtain 3-(phenylethynyl)pyrazine-2-carbonitrile.

[0018] Preferably, in step (2), the solvent is at least one of methanol, ethanol, tert-butanol, tetrahydrofuran, or toluene, and methanol is preferred; wherein, the dosage ratio of 3-(phenylethynyl)pyrazine-2-carbonitrile to the solvent is 1 mmol:(0.5 - 3) mL.

[0019] Preferably, in step (2), the sulfide is sodium sulfide, sodium sulfide nonahydrate, or potassium sulfide, and potassium sulfide is preferred; the molar ratio of 3-(phenylethynyl)pyrazine-2-carbonitrile to the sulfide is 1:(1 - 2).

[0020] Preferably, in step (2), the reaction temperature is 60 - 150 °C, preferably 80 - 100 °C, and the reaction time is 3 - 12 h; after the reaction is completed, the reaction solution is cooled, the solvent is removed by distillation under reduced pressure, and then purification is carried out by silica gel column chromatography to obtain 6-phenylthieno[2,3-b]pyrazine.

[0021] Beneficial Effects

[0022] (1) By designing a new synthetic route, the present invention provides, for the first time, a new method for synthesizing 6-phenylthieno[2,3-b]pyrazine compounds using 2-chloro-3-cyanopyrazine as a raw material;

[0023] (2) The raw materials and reagents used in the present invention are commercially available. The method for synthesizing the target product 6-phenylthieno[2,3-b]pyrazine is simple, efficient, easy to operate, with few side reactions, and easy to purify;

[0024] (3) The reaction solvent can directly use common and easily available organic green solvents such as methanol and ethanol. The operation and post-treatment are simple and convenient, and the yield is as high as 94%, which is suitable for large-scale preparation. Description of the Drawings

[0025] Figure 1 It is the 1H NMR spectrum of compound (2) 3-(phenylethynyl)pyrazine-2-carbonitrile;

[0026] Figure 2 It is the 13C NMR spectrum of compound (2) 3-(phenylethynyl)pyrazine-2-carbonitrile;

[0027] Figure 3 1H NMR spectrum of compound (3) 6-phenylthieno[2,3-b]pyrazine;

[0028] Figure 4 13C NMR spectrum of compound (3) 6-phenylthieno[2,3-b]pyrazine. Specific embodiments

[0029] The present invention will be further described by the following embodiments. It should be understood that the following embodiments are only used to illustrate the present invention and do not limit the present invention.

[0030] The synthesis method of 6-phenylthieno[2,3-b]pyrazine adopted by the present invention adopts the following synthetic route:

[0031]

[0032] That is, using 2-chloro-3-cyanopyrazine (1) as a raw material, the target product 6-phenylthieno[2,3-b]pyrazine (3) is obtained through coupling, electrophilic substitution and cyclization reactions.

[0033] Specifically, the preparation method of 6-phenylthieno[2,3-b]pyrazine provided by the present invention may include the steps:

[0034] (1) Reacting 2-chloro-3-cyanopyrazine (1) with phenylacetylene and copper iodide under the action of a base and a catalyst to obtain 3-(phenylethynyl)pyrazine-2-carbonitrile (2);

[0035] (2) Reacting 3-(phenylethynyl)pyrazine-2-carbonitrile (2) with a sulfide to obtain 6-phenylthieno[2,3-b]pyrazine (3).

[0036] Compared with Route 2 introduced in the background technology, the technical solution provided by the present invention, on the one hand, avoids the generation of chlorine-containing waste and broadens the conversion of the potential multi-functional group - cyano - to functional groups other than amide and carboxylic acid functional groups; on the other hand, Route 2 uses 2,3-dichloropyrazine as a reactant, and the chemical environments of the two chlorine atoms are the same, and it is easy to react with two molecules of phenylacetylene at the same time. In contrast, the reaction site of the raw material 2-chloro-3-cyanopyrazine adopted by the present invention is single and the chemical selectivity is high. At the same time, the technical solution provided by the present invention selects the most common alcohol solvent - methanol as the reaction solvent, which can effectively avoid the use of high temperature and high boiling point solvent DMF and realizes the greening of chemical reactions.

[0037] Among them, the reaction in step (1) is carried out under the protection of an inert gas, and the inert gas can be nitrogen. The solvent can be selected from acetonitrile and / or DMF, preferably acetonitrile; the dosage ratio of 2-chloro-3-cyanopyrazine to the solvent can be controlled to 1 g:(7-12) mL.

[0038] In some embodiments, in step (1), the molar ratio of 2-chloro-3-cyanopyrazine to phenylacetylene can be 1:(1 to 1.2); the molar ratio of 2-chloro-3-cyanopyrazine to cuprous iodide can be 1:(0.01 to 0.3); wherein, cuprous iodide serves as a co-catalyst to cooperate with the palladium catalyst to complete the Sonogashira coupling reaction. If the amount of phenylacetylene used is too low, the reaction will be incomplete and the yield will decrease; if the amount used is too high, in addition to easily generating the by-product of phenylacetylene dimerization, it will also cause waste of raw materials.

[0039] In some embodiments, in step (1), the base can be triethylamine; the molar ratio of 2-chloro-3-cyanopyrazine to the base can be controlled to be 1:(1 to 3), preferably 1:(1.2 to 3).

[0040] The reaction of step (1) can be carried out under catalytic or non-catalytic conditions, preferably under catalytic conditions, and more preferably the catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. Among them, the molar ratio of 2-chloro-3-cyanopyrazine to the catalyst can be controlled to be 1:(0.01 to 0.05).

[0041] In some embodiments, step (1) may include the following steps:

[0042] (a) 2-Chloro-3-cyanopyrazine, the catalyst, cuprous iodide, and phenylacetylene are added with the base and the solvent under the protection of an inert atmosphere, heated to 60 - 100 °C, and mixed and stirred for reaction for 4 - 18 h. If the reaction temperature is too low or the reaction time is too short, the reaction of the 2-chloro-3-cyanopyrazine raw material will be incomplete and the yield will decrease; if the reaction temperature is too high or the reaction time is too long, the selectivity of the reaction will decrease, the by-products will increase, and at the same time, the electric energy will be consumed.

[0043] (b) After the reaction is completed, water is added and extracted with an organic solvent, the organic phases are combined, dried, the organic solvent is removed by reduced pressure distillation, and then separated and purified by silica gel column chromatography to obtain 3-(phenylethynyl)pyrazine-2-carbonitrile.

[0044] In step (2), the solvent can be at least one of methanol, ethanol, tert-butanol, tetrahydrofuran or toluene, preferably methanol; among them, the dosage ratio of 3-(phenylethynyl)pyrazine-2-carbonitrile to the solvent can be controlled to be 1 mmol:(0.5 - 3) mL.

[0045] In some embodiments, in step (2), the sulfide can be sodium sulfide, sodium sulfide nonahydrate or potassium sulfide, preferably potassium sulfide; the molar ratio of 3-(phenylethynyl)pyrazine-2-carbonitrile to the sulfide can be controlled to 1:(1-2). An inappropriate control of the dosage ratio of the two will lead to a significant reduction in the yield of the product.

[0046] In some embodiments, step (2) may include the following steps:

[0047] (a) Heating 3-(phenylethynyl)pyrazine-2-carbonitrile (2) with the sulfide in a solvent to 60-150 °C, preferably 80-100 °C, and reacting for 3-12 h;

[0048] (b) After the reaction is completed, waiting for the reaction solution to cool, distilling off the solvent under reduced pressure, and then separating and purifying by silica gel column chromatography to obtain 6-phenylthieno[2,3-b]pyrazine.

[0049] The following further lists examples to illustrate the present invention in detail. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention all fall within the protection scope of the present invention. The specific process parameters and the like in the following examples are also only an example within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description herein, rather than being limited to the specific values in the following examples.

[0050] Example 1

[0051] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0052] (1) Synthesizing the compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0053] 1.82 g of 2-chloro-3-cyanopyrazine, 1.22 g of phenylacetylene, 190 mg of copper iodide, 351 mg of bis(triphenylphosphine)palladium dichloride were added to a reaction flask. Under nitrogen protection, 1.7 mL of triethylamine and 20 mL of acetonitrile were added. After addition, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. After the reaction was completed, 10 mL of water was added, and extraction was carried out with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, the ethyl acetate was distilled off under reduced pressure, and separation and purification by silica gel column chromatography gave 1.5 g of white solid 3-(phenylethynyl)pyrazine-2-carbonitrile (yield 73%); 1 HNMR(400MHz,CD3OD)δ=8.82(d,J=2.3Hz,1H),8.67(d,J=2.5Hz,1H),7.68(d,J=7.3Hz,2H),7.55-7.38(m,3H)ppm. 13CNMR (101 MHz, CD3OD) δ = 147.1, 143.4, 142.7, 132.5, 132.0, 130.4, 128.6, 120.4, 114.8, 98.2, 83.2 ppm. LC-MS (ESI) [M+H] + = 205.8;

[0054] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0055] 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 111 mg of potassium sulfide were added to a reaction flask, 2 mL of methanol was added, and the reaction was carried out at 100 °C for 8 hours. After the reaction, it was concentrated, and purified by silica gel column chromatography to obtain 200 mg of orange 6-phenylthieno[2,3-b]pyrazine solid (94% yield); 1 1H NMR (400 MHz, CDCl3) δ = 8.61 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.70 (s, 1H), 7.53 - 7.40 (m, 3H) ppm. 13 13C NMR (101 MHz, CDCl3) δ = 156.0, 151.2, 149.5, 142.0, 139.9, 133.3, 129.8, 129.3, 126.7, 117.8 ppm. LC-MS (ESI) [M+H] + = 212.7.

[0056] Figure 1 It is the 1H NMR spectrum of compound (2) 3-(phenylethynyl)pyrazine-2-carbonitrile. Figure 2 It is the 13C NMR spectrum of compound (2) 3-(phenylethynyl)pyrazine-2-carbonitrile. Figure 3 It is the 1H NMR spectrum of compound (3) 6-phenylthieno[2,3-b]pyrazine. Figure 4 It is the 13C NMR spectrum of compound (3) 6-phenylthieno[2,3-b]pyrazine.

[0057] Example 2

[0058] A synthesis method of 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0059] (1) Synthesis of compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0060] Add 1.82 g of 2-chloro-3-cyanopyrazine, 351 mg of bis(triphenylphosphine)palladium dichloride, 190 mg of copper(I) iodide, and 1.22 g of phenylacetylene to a reaction flask. Under nitrogen protection, add 1.7 mL of triethylamine and 20 mL of DMF. After addition, heat to 70 °C and react for 6 hours. After the reaction is completed, add 10 mL of water, extract with ethyl acetate (3 × 20 mL), combine the organic phases, dry over anhydrous sodium sulfate, distill off the ethyl acetate under reduced pressure, and purify by silica gel column chromatography to obtain 1.35 g of white 3-(phenylethynyl)pyrazine-2-carbonitrile solid (yield 66%);

[0061] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0062] Add 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 111 mg of potassium sulfide to a reaction flask, add 2 mL of ethanol, and react at 100 °C for 8 hours. After the reaction is completed, concentrate and purify by silica gel column chromatography to obtain 157 mg of orange 6-phenylthieno[2,3-b]pyrazine solid (yield 74%).

[0063] Example 3

[0064] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0065] (1) Synthesis of compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0066] Add 1.82 g of 2-chloro-3-cyanopyrazine, 578 mg of tetrakis(triphenylphosphine)palladium, 190 mg of copper(I) iodide, and 1.22 g of phenylacetylene to a reaction flask. Under nitrogen protection, add 1.7 mL of triethylamine and 20 mL of acetonitrile. After addition, heat to 70 °C and react for 6 hours. After the reaction is completed, add 10 mL of water, extract with ethyl acetate (3 × 20 mL), combine the organic phases, dry over anhydrous sodium sulfate, distill off the ethyl acetate under reduced pressure, and purify by silica gel column chromatography to obtain 1.3 g of white 3-(phenylethynyl)pyrazine-2-carbonitrile solid (yield 63%);

[0067] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0068] Add 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 111 mg of potassium sulfide to a reaction flask, add 2 mL of tert-butanol, and react at 100 °C for 8 hours. After the reaction is completed, concentrate and purify by silica gel column chromatography to obtain 119 mg of orange 6-phenylthieno[2,3-b]pyrazine solid (yield 56%).

[0069] Example 4

[0070] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0071] (1) Synthesis of the compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0072] 1.82 g of 2-chloro-3-cyanopyrazine, 363 mg of dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), 190 mg of copper(I) iodide, and 1.22 g of phenylethyne were added to a reaction flask. Under nitrogen protection, 1.7 mL of triethylamine and 20 mL of acetonitrile were added. After addition, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the ethyl acetate was removed by distillation under reduced pressure. The product was purified by silica gel column chromatography to obtain 1.3 g of white solid of 3-(phenylethynyl)pyrazine-2-carbonitrile (yield: 63%);

[0073] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0074] 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 111 mg of potassium sulfide were added to a reaction flask. 4 mL of methanol was added, and the reaction was carried out at 100 °C for 8 hours. After the reaction was completed, the mixture was concentrated, and the product was purified by silica gel column chromatography to obtain 121 mg of orange solid of 6-phenylthieno[2,3-b]pyrazine (yield: 57%).

[0075] Example 5

[0076] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0077] (1) Synthesis of the compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0078] 1.82 g of 2-chloro-3-cyanopyrazine, 351 mg of dichlorobis(triphenylphosphine)palladium(II), 190 mg of copper(I) iodide, and 1.02 g of phenylethyne were added to a reaction flask. Under nitrogen protection, 1.7 mL of triethylamine and 20 mL of acetonitrile were added. After addition, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the ethyl acetate was removed by distillation under reduced pressure. The product was purified by silica gel column chromatography to obtain 1.42 g of white solid of 3-(phenylethynyl)pyrazine-2-carbonitrile (yield: 69%);

[0079] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0080] 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 111 mg of potassium sulfide were added to a reaction flask. 1 mL of methanol was added, and the reaction was carried out at 100 °C for 8 hours. After the reaction was completed, the mixture was concentrated, and the product was purified by silica gel column chromatography to obtain 129 mg of orange solid of 6-phenylthieno[2,3-b]pyrazine (yield: 61%).

[0081] Example 6

[0082] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0083] (1) Synthesize compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0084] Add 1.82 g of 2-chloro-3-cyanopyrazine, 351 mg of bis(triphenylphosphine)palladium dichloride, 190 mg of copper(I) iodide, and 1.22 g of phenylethyne into a reaction flask. Under nitrogen protection, add 4.2 mL of triethylamine and 20 mL of acetonitrile. After addition, heat to 70 °C and react for 6 hours. After the reaction is completed, add 10 mL of water, extract with ethyl acetate (3 × 20 mL), combine the organic phases, dry over anhydrous sodium sulfate, distill off ethyl acetate under reduced pressure, and purify by silica gel column chromatography to obtain 1.47 g of white solid of 3-(phenylethynyl)pyrazine-2-carbonitrile (yield 71%);

[0085] (2) Synthesize 6-phenylthieno[2,3-b]pyrazine

[0086] Add 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 166.5 mg of potassium sulfide into a reaction flask, add 2 mL of methanol, react at 100 °C for 8 hours. After the reaction is completed, concentrate and purify by silica gel column chromatography to obtain 104 mg of orange solid of 6-phenylthieno[2,3-b]pyrazine (yield 49%).

[0087] Example 7

[0088] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0089] (1) Synthesize compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0090] Add 1.82 g of 2-chloro-3-cyanopyrazine, 351 mg of bis(triphenylphosphine)palladium dichloride, 96 mg of copper(I) iodide, and 1.22 g of phenylethyne into a reaction flask. Under nitrogen protection, add 1.7 mL of triethylamine and 20 mL of acetonitrile. After addition, heat to 70 °C and react for 6 hours. After the reaction is completed, add 10 mL of water, extract with ethyl acetate (3 × 20 mL), combine the organic phases, dry over anhydrous sodium sulfate, distill off ethyl acetate under reduced pressure, and purify by silica gel column chromatography to obtain 1.08 g of white solid of 3-(phenylethynyl)pyrazine-2-carbonitrile (yield 52%);

[0091] (2) Synthesize 6-phenylthieno[2,3-b]pyrazine

[0092] 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 111 mg of potassium sulfide were added to a reaction flask, 2 mL of methanol was added, and the reaction was carried out at 80 °C for 8 hours. After the reaction was completed, the mixture was concentrated, and the product was purified by silica gel column chromatography to obtain 183 mg of orange 6-phenylthieno[2,3-b]pyrazine solid (yield: 86%).

[0093] Example 8

[0094] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0095] (1) Synthesis of compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0096] 1.82 g of 2-chloro-3-cyanopyrazine, 351 mg of bis(triphenylphosphine)palladium dichloride, 190 mg of copper(I) iodide, and 1.22 g of phenylethyne were added to a reaction flask. Under nitrogen protection, 1.7 mL of triethylamine and 20 mL of acetonitrile were added. After addition, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The product was purified by silica gel column chromatography to obtain 1.5 g of white 3-(phenylethynyl)pyrazine-2-carbonitrile solid (yield: 73%);

[0097] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0098] 205 mg of 3-(phenylethynyl)pyrazine-2-carbonitrile and 111 mg of potassium sulfide were added to a reaction flask, 2 mL of methanol was added, and the reaction was carried out at 120 °C for 8 hours. After the reaction was completed, the mixture was concentrated, and the product was purified by silica gel column chromatography to obtain 128 mg of orange 6-phenylthieno[2,3-b]pyrazine solid (yield: 60%).

[0099] Example 9

[0100] A method for synthesizing 6-phenylthieno[2,3-b]pyrazine, comprising the following steps:

[0101] (1) Synthesis of compound 3-(phenylethynyl)pyrazine-2-carbonitrile

[0102] 1.82 g of 2-chloro-3-cyanopyrazine, 351 mg of bis(triphenylphosphine)palladium dichloride, 190 mg of copper(I) iodide, and 1.22 g of phenylethyne were added to a reaction flask. Under nitrogen protection, 1.7 mL of triethylamine and 20 mL of acetonitrile were added. After addition, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The product was purified by silica gel column chromatography to obtain 1.5 g of white 3-(phenylethynyl)pyrazine-2-carbonitrile solid (yield: 73%);

[0103] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0104] 1.03 g of 3-(phenylethynyl)pyrazine-2-carbonitrile and 0.58 g of potassium sulfide were added to a reaction flask, 10 mL of methanol was added, and the reaction was carried out at 100 °C for 8 hours. After the reaction was completed, it was concentrated, and purified by silica gel column chromatography to obtain 0.97 g of orange 6-phenylthieno[2,3-b]pyrazine solid (yield: 91%).

[0105] By comparing Examples 1 to 8, compared with Example 1 under the preferred reaction conditions, in step (1), changing the type of catalyst or reducing the amount of catalyst used would result in a decrease in the yield of compound (2) 3-(phenylethynyl)pyrazine-2-carbonitrile; in step (2), changing the type and amount of solvent would cause a significant change in the yield of compound (3) 6-phenylthieno[2,3-b]pyrazine, and increasing or decreasing the amount of potassium sulfide used would also significantly reduce the yield of compound (3) 6-phenylthieno[2,3-b]pyrazine.

[0106] Comparative Example 1

[0107] Synthesis of 6-phenylthieno[2,3-b]pyrazine using 2,3-dichloropyrazine, including the following steps:

[0108] (1) Synthesis of compound 2-chloro-3-(phenylethynyl)pyrazine

[0109] 1.94 g of 2,3-dichloropyrazine, 351 mg of bis(triphenylphosphine)palladium dichloride, 190 mg of copper(I) iodide, and 1.22 g of phenylethyne were added to a reaction flask under nitrogen protection. 1.7 mL of triethylamine and 20 mL of acetonitrile were added. After addition, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. After the reaction was completed, 10 mL of water was added, and it was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. Purification by silica gel column chromatography gave 1.45 g of yellow 2-chloro-3-(phenylethynyl)pyrazine oil (yield: 52%);

[0110] (2) Synthesis of 6-phenylthieno[2,3-b]pyrazine

[0111] 214 mg of 2-chloro-3-(phenylethynyl)pyrazine and 111 mg of potassium sulfide were added to a reaction flask, 2 mL of methanol was added, and the reaction was carried out at 100 °C for 8 hours. After the reaction was completed, it was concentrated, and purified by silica gel column chromatography to obtain 55 mg of orange 6-phenylthieno[2,3-b]pyrazine solid (yield: 26%).

[0112] Although the content of the present invention has been described in detail through the above preferred embodiments, it should be recognized that the above description should not be considered as a limitation of the present invention. After those skilled in the art have read the above content, various modifications and alternatives to the present invention will be obvious. Therefore, the protection scope of the present invention should be defined by the appended claims.

Claims

1. A method for preparing 6-phenylthieno[2,3-b]pyrazine, characterized in that, The preparation method comprises the following steps: (1) React 2-chloro-3-cyanopyrazine (1) with phenylacetylene and copper iodide under the action of a base and a catalyst to obtain 3-(phenylethynyl)pyrazine-2-carbonitrile (2); (2) React 3-(phenylethynyl)pyrazine-2-carbonitrile (2) with a sulfide to obtain 6-phenylthieno[2,3-b]pyrazine (3); Wherein: in step (2), the reaction solvent is at least one of methanol, ethanol, tert-butanol, tetrahydrofuran or toluene, and the reaction temperature is 60-120 °C.

2. The preparation method according to claim 1, characterized in that, In step (1), the reaction is carried out under nitrogen protection, and the solvent is acetonitrile and / or DMF; the dosage ratio of 2-chloro-3-cyanopyrazine to the solvent is 1 g:(7-12) mL.

3. The preparation method according to claim 1, wherein In step (1), the molar ratio of 2-chloro-3-cyanopyrazine to phenylacetylene is 1:(1-1.2); the molar ratio of 2-chloro-3-cyanopyrazine to copper iodide is 1:(0.01-0.3).

4. The preparation method according to claim 1, characterized in that, In step (1), the base is triethylamine; the molar ratio of 2-chloro-3-cyanopyrazine to the base is 1:(1-3).

5. The preparation method according to claim 4, characterized in that, The molar ratio of 2-chloro-3-cyanopyrazine to the base is 1:(1.2-3).

6. The preparation method according to claim 1, wherein In step (1), the catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; the molar ratio of 2-chloro-3-cyanopyrazine to the catalyst is 1:(0.01-0.05).

7. The preparation method according to claim 1, characterized in that, In step (1), the reaction temperature is 60-100 °C, and the reaction time is 4-18 h; after the reaction is completed, water is added and extraction is carried out with an organic solvent. The organic phases are combined, dried, and the organic solvent is removed by distillation under reduced pressure, and then separation and purification are carried out by silica gel column chromatography to obtain 3-(phenylethynyl)pyrazine-2-carbonitrile.

8. The preparation method according to claim 1, wherein In step (2), the dosage ratio of 3-(phenylethynyl)pyrazine-2-carbonitrile to the solvent is 1 mmol:(0.5-3) mL.

9. The preparation method according to claim 1, characterized in that, In step (2), the sulfide is sodium sulfide, sodium sulfide nonahydrate or potassium sulfide; the molar ratio of 3-(phenylethynyl)pyrazine-2-carbonitrile to the sulfide is 1:(1-2).

10. The preparation method according to claim 1, characterized in that, In step (2), the reaction time is 3-12 h; after the reaction is completed, the reaction solution is cooled, the solvent is removed by distillation under reduced pressure, and then separation and purification are carried out by silica gel column chromatography to obtain 6-phenylthieno[2,3-b]pyrazine.

11. The preparation method according to claim 1, characterized in that, The reaction temperature is 80-100 °C.

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