Synthesis method of 3, 5-dibromo-2-aminopyrazine

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a synthetic method of 3, 5-dibromo-2-aminopyrazine. The preparation method comprises the following steps: by taking 2-cyanopyrazine as an initial raw material, carrying out hydrolysis reaction to obtain 2-amide pyrazine; then, under the condition of a specific catalyst, 2-amide pyrazine and bromine are subjected to a Hofmann degradation reaction under the alkaline condition, and 2-aminopyrazine is prepared; finally, under the condition of a specific catalyst, the 2-aminopyrazine is subjected to a bromination reaction, and the 3, 5-dibromo-2-aminopyrazine is prepared. The 3, 5-dibromo-2-aminopyrazine with the total yield of 86% or above and the purity of 99% or above is finally prepared, a brand new process route is provided for synthesis of the 3, 5-dibromo-2-aminopyrazine, the industrial production prospect is high, meanwhile, powerful support is provided for synthesis and development of follow-up drugs (such as upatinib and the like), and the method has high application and popularization value.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing 3,5-dibromo-2-aminopyrazine. Background Art

[0002] 3,5-Dibromo-2-aminopyrazine can be used as a synthetic intermediate for upadacitinib, a selective JAK inhibitor developed by AbbVie. It is the third Janus kinase inhibitor approved for rheumatoid arthritis after baricitinib and tovastatinib. The launch of upadacitinib provides more options for the treatment of patients with atopic dermatitis. In addition, 3,5-dibromo-2-aminopyrazine can also be used as a substrate in organic synthesis, especially in the reaction of four-component synthesis of imidazolidinidines. In addition, 3,5-dibromo-2-aminopyrazine is also a key intermediate for imidazopyrazine anti-tumor drugs. With the continuous deepening of research on the pathogenesis of tumors, this type of drug with 3,5-dibromo-2-aminopyrazine as a key intermediate is expected to open up new treatment strategies in the field of tumor treatment in the future and bring more hope to cancer patients.

[0003] At present, the process for synthesizing 3,5-dibromo-2-aminopyrazine is mainly as follows: using 2-cyanopyrazine as the starting material, obtaining 2-aminopyrazine by hydrolysis, rearrangement, and hydrolysis in one pot, and then obtaining 3,5-dibromo-2-aminopyrazine by bromination reaction. This method has a long and complicated synthesis route, low selectivity of bromination reaction, and a large number of by-products, which have an adverse effect on the subsequent industrial production of upadacitinib. Therefore, it is necessary to develop a synthesis method of 3,5-dibromo-2-aminopyrazine that is efficient, low-cost, green and environmentally friendly, and easy to industrialize. Summary of the invention

[0004] In view of the problems of lengthy reaction route, low reaction selectivity, low yield, etc. in the prior art process for preparing 3,5-dibromo-2-aminopyrazine, the present invention provides a method for synthesizing 3,5-dibromo-2-aminopyrazine. The method has short reaction time and mild reaction conditions, is conducive to the industrial production of 3,5-dibromo-2-aminopyrazine, and has high application value.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] A method for synthesizing 3,5-dibromo-2-aminopyrazine comprises the following steps:

[0007] S1, hydrolyzing 2-cyanopyrazine to obtain 2-amidepyrazine;

[0008] S2, in the presence of catalyst a and a strong base, 2-amidopyrazine and bromine undergo a Hofmann degradation reaction to obtain 2-aminopyrazine; the catalyst a is at least one of iron powder, copper powder, sodium bromide, potassium bromide, tetramethylammonium bromide or tetraethylammonium bromide;

[0009] S3, under the condition of catalyst b, 2-aminopyrazine and bromide undergo bromination reaction to obtain 3,5-dibromo-2-aminopyrazine; the catalyst b is at least one of ferric bromide, aluminum bromide or sodium carbonate.

[0010] Compared with the prior art, the present invention provides a novel synthesis method of 3,5-dibromo-2-aminopyrazine by designing a new synthesis route. The method uses 2-cyanopyrazine as a starting material, firstly obtains 2-amide pyrazine through a hydrolysis reaction; then, under specific catalyst conditions, 2-amide pyrazine and bromine are subjected to a Hofmann degradation reaction under alkaline conditions to prepare 2-amino pyrazine; finally, under specific catalyst conditions, 2-amino pyrazine is subjected to a bromination reaction to prepare 3,5-dibromo-2-amino pyrazine.

[0011] The synthesis process of 3,5-dibromo-2-aminopyrazine provided by the present invention has relatively mild reaction conditions in each step, and no special conditions such as high temperature and high pressure are required for hydrolysis reaction, Hofmann degradation reaction and bromination reaction, thereby reducing the requirements for equipment and the safety risks in the production process, and the selectivity of each step of the reaction is high. The total yield of 3,5-dibromo-2-aminopyrazine can reach more than 86%, the purity can reach more than 99%, and the raw material cost is low, which is conducive to reducing production costs and improving the competitiveness of products in the market. It is more suitable for industrial production, has very important significance for expanding the application scope of 3,5-dibromo-2-aminopyrazine, and can also provide high-quality key intermediates for subsequent drug synthesis, and has high application value.

[0012] As a specific embodiment of the present invention, the synthesis method of 3,5-dibromo-2-aminopyrazine specifically comprises the following steps:

[0013] S1, hydrolyzing 2-cyanopyrazine in an acid solution, cooling and crystallizing to obtain 2-amidepyrazine;

[0014] S2, adding 2-amidopyrazine to a bromine and strong base solution, then adding a catalyst a, heating and performing a Hofmann degradation reaction to obtain 2-aminopyrazine;

[0015] S3, dissolving 2-aminopyrazine in an organic solvent, adding a bromide and a catalyst b, and carrying out a bromination reaction to obtain 3,5-dibromo-2-aminopyrazine.

[0016] The reaction equation of the above preparation process is as follows:

[0017]

[0018] As a specific implementation of the present invention, S1 specifically includes the following steps:

[0019] Add 2-cyanopyrazine to the acid solution, mix well, heat up for hydrolysis reaction, monitor by TLC, after the reaction is finished, cool down for crystallization, separate the solid and liquid, add water to the obtained solid for slurrying, separate the solid and liquid, and dry to obtain 2-amidepyrazine.

[0020] Preferably, in S1, the acid solution is an aqueous hydrochloric acid solution with a concentration of 11 mol / L to 12 mol / L, and the volume mass ratio of the acid solution to 2-cyanopyrazine is (1 to 4) mL:1 g.

[0021] Preferably, in S1, the temperature of the hydrolysis reaction is 30°C to 50°C, and the hydrolysis time is 0.5h to 1.5h.

[0022] Preferably, in S1, the temperature of the cooling and crystallization is 0°C to 10°C, and the time of the cooling and crystallization is 20min to 90min.

[0023] Specifically, in S1, stirring is performed while the temperature is lowered to crystallize, so as to promote sufficient precipitation of 2-amidepyrazine.

[0024] The preferred reaction conditions of S1 can promote the full progress of the hydrolysis reaction and increase the rate and yield of the hydrolysis reaction.

[0025] As a specific implementation of the present invention, S2 specifically includes the following steps:

[0026] The bromine and strong base solution are mixed evenly, cooled, and 2-aminopyrazine is added. After the addition is completed, catalyst a is added, and the temperature is raised to carry out Hofmann degradation reaction. TLC is monitored until the reaction is completed, and the temperature is lowered, the pH is adjusted to neutral, and extraction is performed. The extract is concentrated to obtain 2-aminopyrazine.

[0027] Preferably, in S2, the strong alkaline solution is a sodium hydroxide aqueous solution with a concentration of 1 mol / L to 4 mol / L, and the volume mass ratio of the strong alkaline solution to 2-amidopyrazine is (15 to 20) mL:1 g.

[0028] Preferably, in S2, the molar ratio of the 2-amide pyrazine to bromine is 1:(1-2).

[0029] Preferably, in S2, the added amount of the catalyst a is 1% to 10% of the mass of 2-amidopyrazine.

[0030] Preferably, in S2, the catalyst a is iron powder or copper powder.

[0031] Preferably, in S2, the 2-amide pyrazine is added in batches over a period of 30 to 60 minutes, and the temperature of the reaction system when the 2-amide pyrazine is added is 0°C to 10°C.

[0032] Preferably, in S2, the temperature of the Hofmann degradation reaction is 10° C. to 70° C., and the reaction time is 40 min to 60 min.

[0033] Specifically, in S2, the extraction uses dichloromethane or ethyl acetate as the extraction solvent, preferably dichloromethane.

[0034] The preferred reaction conditions in S2 can promote the Hofmann degradation reaction of 2-amidopyrazine and improve the yield of 2-aminopyrazine.

[0035] As a specific implementation of the present invention, S3 specifically includes the following steps:

[0036] The 2-aminopyrazine prepared above is dissolved in an organic solvent, and a bromide and a catalyst b are added to carry out a bromination reaction. The reaction is monitored by TLC until the end. An alkaline solution is added to remove bromine, and water is added to separate the solid and the liquid. The obtained solid is slurried in dichloromethane, separated from the solid and the liquid, and dried to obtain 3,5-dibromo-2-aminopyrazine.

[0037] Preferably, in S3, the brominated compound is one or more of N-bromosuccinimide (NBS), dibromohydantoin or pyridinium tribromide.

[0038] Further preferably, in S3, the brominated compound is one or both of N-bromosuccinimide (NBS) and dibromohydantoin.

[0039] Preferably, in S3, the molar ratio of 2-aminopyrazine to bromide is 1:(1-3).

[0040] Preferably, in S3, the brominated compound is added in batches over a period of 20 to 30 minutes, and the system temperature during the addition is 20° C. to 30° C.

[0041] Preferably, in S3, the organic solvent is one or more of dichloromethane, dichloroethane, ethyl acetate, N,N-dimethylformamide, ethanol or acetone.

[0042] Preferably, in S3, the volume mass ratio of the organic solvent to 2-aminopyrazine is (10-20) mL:1 g.

[0043] Preferably, in S3, the catalyst b is ferric bromide.

[0044] Preferably, in S3, the added amount of the catalyst b is 1% to 10% of the mass of 2-aminopyrazine.

[0045] Preferably, in S3, the temperature of the bromination reaction is 20°C to 50°C, and the reaction time is 0.5h to 1h.

[0046] Specifically, in S3, the alkaline solution is one or more of saturated sodium sulfite, saturated sodium carbonate, saturated sodium bisulfite, sodium thiosulfate and saturated potassium carbonate, preferably saturated sodium sulfite.

[0047] It should be noted that the prepared 3,5-dibromo-2-aminopyrazine can be subjected to conventional coupling reactions, cyclization reactions, and coupling reactions in the art to prepare the key intermediate ethyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-yl) carbamate of upadacitinib, and the synthesis route thereof is as follows. For details, reference can be made to the document Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib. The key intermediate can be used to prepare upadacitinib according to the prior art.

[0048]

[0049] The method for synthesizing 3,5-dibromo-2-aminopyrazine provided by the present invention has the advantages of reasonable process design, simple steps, mild reaction conditions, high product yield and purity, low production cost, high process safety, etc. The total yield of 3,5-dibromo-2-aminopyrazine can reach more than 86%, and the purity can reach more than 99%. A new process route is provided for synthesizing 3,5-dibromo-2-aminopyrazine, and the industrial production prospect is high. At the same time, strong support is provided for the synthesis and development of subsequent drugs (such as upadacitinib, etc.), and the method has high promotion and application value. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0051] The concentrated hydrochloric acid used in the following examples and comparative examples refers to commercially available concentrated hydrochloric acid with a concentration of 12 mol / L.

[0052] Example 1

[0053] This embodiment provides a method for synthesizing 3,5-dibromo-2-aminopyrazine, comprising the following steps:

[0054] Step 1. Synthesis of 2-amidopyrazine

[0055]

[0056] Add 2-cyanopyrazine (20 g, 0.19 mol) and concentrated hydrochloric acid (40 mL) to a 250 mL three-necked flask, heat to 40 ° C, react for 1 h, and monitor by TLC. After the reaction is completed, cool to 5 ° C, stir for 35 min, filter, slurry the filter cake with water (20 mL), filter with suction, and dry to obtain a white solid, i.e., 2-amide pyrazine, with a yield of 98.2% and a purity of 99.2%.

[0057] Step 2: Synthesis of 2-aminopyrazine

[0058]

[0059] A 250mL three-necked flask was added with aqueous sodium hydroxide solution (concentration 2mol / L, 190mL) and bromine (15.98g, 0.1mol), cooled to 5°C, 2-aminopyrazine (10g, 0.081mol) was added in batches, the addition time was 45min, and then 10wt% copper powder was added. After the addition was completed, it was stirred at 10°C for 15min, heated to 40°C for reaction for 15min, and then heated to 70°C for reaction for 10min. The reaction was monitored by TLC. The reaction was completed, cooled to 13°C, adjusted to pH=7 with concentrated hydrochloric acid, and dichloromethane (160mL) was added for extraction and separation. The organic phase was concentrated to obtain 2-aminopyrazine with a yield of 90.2% and a purity of 98.2%.

[0060] Step 3: Synthesis of 3,5-dibromo-2-aminopyrazine

[0061]

[0062] 2-Aminopyrazine (20 g, 0.21 mol) and dichloromethane (300 mL) were added to a 500 mL three-necked flask, stirred and dissolved, and the temperature was raised to 25 ° C. NBS (93.44 g, 0.525 mol) was added in batches, the temperature was controlled at 30 ° C, the addition time was 25 min, and 10 wt% ferric bromide (2 g) was added. The reaction was carried out at 25 ° C for 45 min and monitored by TLC. After the reaction was completed, a saturated aqueous sodium sulfite solution (200 mL) was added and stirred, and then water (200 mL) was added and stirred. The filter cake was slurried with dichloromethane (100 mL), filtered, and dried to obtain 3,5-dibromo-2-aminopyrazine with a yield of 98.5% and a purity of 99.6%.

[0063] 1 H NMR (400MHz, CDCl3): δ = 8.04 (s, 1H), 5.16 (br s, 2H).

[0064] Example 2

[0065] This embodiment provides a method for synthesizing 3,5-dibromo-2-aminopyrazine, comprising the following steps:

[0066] Step 1, Preparation of 2-amidopyrazine

[0067]

[0068] Add 2-cyanopyrazine (20 g, 0.19 mol) and concentrated hydrochloric acid (20 mL) to a 250 mL three-necked flask, heat to 30 ° C, react for 1.5 h, and monitor by TLC. After the reaction is completed, cool to 0 ° C, stir for 20 min, filter, slurry the filter cake with water (20 mL), filter with suction, and dry to obtain a white solid, i.e., 2-amide pyrazine, with a yield of 96.5% and a purity of 99.1%.

[0069] Step 2: Preparation of 2-aminopyrazine

[0070]

[0071] A 250mL three-necked flask was added with an aqueous sodium hydroxide solution (concentration 1mol / L, 150mL) and bromine (12.94g, 0.081mol), cooled to 0°C, 2-aminopyrazine (10g, 0.081mol) was added in batches, the addition time was 30min, and then 1wt% tetraethylammonium bromide was added. After the addition was completed, it was stirred at 10°C for 15min, heated to 40°C for reaction for 15min, and then heated to 70°C for reaction for 10min. The reaction was monitored by TLC. The reaction was completed, cooled to 10°C, and the pH was adjusted to 7 with concentrated hydrochloric acid. Ethyl acetate (160mL) was added for extraction and separation. The organic phase was concentrated to obtain 2-aminopyrazine with a yield of 84.2% and a purity of 93.0%.

[0072] Step 3: Preparation of 3,5-dibromo-2-aminopyrazine

[0073]

[0074] 2-Aminopyrazine (20 g, 0.21 mol) and acetone (200 mL) were added to a 500 mL three-necked flask, stirred and dissolved, and the temperature was raised to 20 ° C. Dibromohydantoin (54.38 g, 0.21 mol) was added in batches, the temperature was controlled at 30 ° C, the addition time was 20 min, and 1 wt% aluminum bromide (0.2 g) was added. The reaction was carried out at 25 ° C for 30 min and monitored by TLC. After the reaction was completed, a saturated sodium thiosulfate solution (200 mL) was added and stirred, and then water (200 mL) was added and stirred. The filter cake was slurried with dichloromethane (100 mL), filtered, and dried to obtain 3,5-dibromo-2-aminopyrazine with a yield of 92.5% and a purity of 94.2%.

[0075] 1H NMR (400MHz, CDCl3): δ = 8.04 (s, 1H), 5.16 (br s, 2H).

[0076] Example 3

[0077] This embodiment provides a method for synthesizing 3,5-dibromo-2-aminopyrazine, comprising the following steps:

[0078] Step 1, Preparation of 2-amidopyrazine

[0079]

[0080] Add 2-cyanopyrazine (20 g, 0.119 mol) and concentrated hydrochloric acid (80 mL) to a 250 mL three-necked flask, heat to 50 ° C, react for 0.5 h, and monitor by TLC. After the reaction is completed, cool to 10 ° C, stir for 90 min, filter, slurry the filter cake with water (20 mL), filter with suction, and dry to obtain a white solid, i.e., 2-amide pyrazine, with a yield of 97.3% and a purity of 99.3%.

[0081] Step 2: Preparation of 2-aminopyrazine

[0082]

[0083] A 250 mL three-necked flask was added with sodium hydroxide aqueous solution (concentration 4 mol / L, 200 mL) and bromine (25.89 g, 0.162 mol), cooled to 10°C, 2-aminopyrazine (10 g, 0.081 mol) was added in batches, the addition time was 60 min, and then 5 wt% sodium bromide was added. After the addition was completed, it was stirred at 10°C for 15 min, heated to 40°C for reaction for 15 min, and then heated to 70°C for reaction for 10 min. The reaction was monitored by TLC. The reaction was completed, cooled to 15°C, and the pH was adjusted to 7 with concentrated hydrochloric acid. Dichloromethane (160 mL) was added for extraction and separation. The organic phase was concentrated to obtain 2-aminopyrazine with a yield of 75.1% and a purity of 85.3%.

[0084] Step 3: Preparation of 3,5-dibromo-2-aminopyrazine

[0085]

[0086] 2-Aminopyrazine (20 g, 0.21 mol) and 1,2-dichloroethane (400 mL) were added to a 500 mL three-necked flask and stirred to dissolve. The temperature was raised to 30 ° C. Pyridinium tribromide (201.49 g, 0.63 mol) was added in batches. The temperature was controlled at 30 ° C. The addition time was 30 min. Then 5 wt% sodium carbonate (1 g) was added. The reaction was carried out at 25 ° C for 60 min and monitored by TLC. After the reaction was completed, saturated potassium carbonate aqueous solution (200 mL) was added and stirred. Then water (200 mL) was added and stirred. The filter cake was slurried with dichloromethane (100 mL), filtered, and dried to obtain 3,5-dibromo-2-aminopyrazine with a yield of 87.3% and a purity of 88.9%.

[0087] 1 H NMR (400MHz, CDCl3): δ = 8.04 (s, 1H), 5.16 (br s, 2H).

[0088] Comparative Example 1

[0089] The difference between this comparative example and Example 1 is that no catalyst copper powder is added in step 2, and the other steps are exactly the same as those in Example 1. The yield of 2-aminopyrazine prepared in step 2 is 45.3% and the purity is 56.3%.

[0090] Comparative Example 2

[0091] The only difference between this comparative example and Example 1 is that the catalyst copper powder in step 2 is replaced by an equal amount of nickel powder, and the other steps are exactly the same. The yield of 2-aminopyrazine prepared in step 2 is 48.2% and the purity is 50.3%.

[0092] Comparative Example 3

[0093] The difference between this comparative example and Example 1 is that the catalyst ferric bromide is not added in step 3, and the other steps are exactly the same as Example 1. The yield of 3,5-dibromo-2-aminopyrazine finally prepared is 60.3% and the purity is 70.2%.

[0094] Comparative Example 4

[0095] The difference between this comparative example and Example 1 is that the catalyst ferric bromide in step 3 is replaced by an equal amount of copper powder, and the other steps are exactly the same. The yield of 3,5-dibromo-2-aminopyrazine finally prepared is 70.5% and the purity is 65.4%.

[0096] Examples 1 to 3 may also use other catalysts a and catalysts b defined in the present invention. As long as the same type of catalysts are added in an amount within the range defined in the present invention, they can achieve technical effects that are substantially equivalent to those of the corresponding examples.

[0097] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 3,5-dibromo-2-aminopyrazine, characterized in that: The steps include: S1, hydrolyzing 2-cyanopyrazine to obtain 2-amidepyrazine; S2, in the presence of catalyst a and a strong base, 2-amidopyrazine and bromine undergo a Hofmann degradation reaction to obtain 2-aminopyrazine; the catalyst a is at least one of iron powder, copper powder, sodium bromide, potassium bromide, tetramethylammonium bromide or tetraethylammonium bromide; S3, under the condition of catalyst b, 2-aminopyrazine and bromide undergo bromination reaction to obtain 3,5-dibromo-2-aminopyrazine; the catalyst b is at least one of ferric bromide, aluminum bromide or sodium carbonate.

2. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 1, characterized in that: The specific steps include: S1, hydrolyzing 2-cyanopyrazine in an acid solution, cooling and crystallizing to obtain 2-amidepyrazine; S2, adding 2-amidopyrazine to a bromine and strong base solution, then adding a catalyst a, heating and performing a Hofmann degradation reaction to obtain 2-aminopyrazine; S3, dissolving 2-aminopyrazine in an organic solvent, adding a bromide and a catalyst b, and carrying out a bromination reaction to obtain 3,5-dibromo-2-aminopyrazine.

3. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S1, the acid solution is an aqueous solution of hydrochloric acid with a concentration of 11 mol / L to 12 mol / L, and the volume mass ratio of the acid solution to 2-cyanopyrazine is (1 to 4) mL:1 g; and / or In S1, the temperature of the hydrolysis reaction is 30°C to 50°C, and the hydrolysis time is 0.5h to 1.5h; and / or In S1, the temperature of the cooling and crystallization is 0°C to 10°C, and the time of the cooling and crystallization is 20min to 90min.

4. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S2, the strong alkaline solution is a sodium hydroxide aqueous solution with a concentration of 1 mol / L to 4 mol / L, and the volume mass ratio of the strong alkaline solution to 2-amide pyrazine is (15 to 20) mL: 1 g; and / or In S2, the molar ratio of 2-amide pyrazine to bromine is 1:(1-2); and / or In S2, the added amount of the catalyst a is 1% to 10% of the mass of 2-amidopyrazine.

5. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S2, the 2-amide pyrazine is added in batches over a period of 30 to 60 minutes, and the temperature of the reaction system when the 2-amide pyrazine is added is 0°C to 10°C.

6. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S2, the temperature of the Hofmann degradation reaction is 10°C to 70°C, and the reaction time is 40min to 60min.

7. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S3, the brominated compound is one or more of N-bromosuccinimide, dibromohydantoin or pyridinium tribromide; and / or In S3, the molar ratio of 2-aminopyrazine to bromide is 1:(1-3); and / or In S3, the brominated compound is added in batches over a period of 20 to 30 minutes, and the system temperature during the addition is 20°C to 30°C.

8. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S3, the organic solvent is one or more of dichloromethane, dichloroethane, ethyl acetate, N,N-dimethylformamide, ethanol or acetone; and / or In S3, the volume mass ratio of the organic solvent to 2-aminopyrazine is (10-20) mL:1 g.

9. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S3, the added amount of the catalyst b is 1% to 10% of the mass of 2-aminopyrazine.

10. The method for synthesizing 3,5-dibromo-2-aminopyrazine according to claim 2, characterized in that: In S3, the temperature of the bromination reaction is 20°C to 50°C, and the reaction time is 0.5h to 1h.

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