A new green method for preparing aminopyrazine and its application in the synthesis of pharmaceutical intermediates

Abstract

The invention discloses a green new method for preparing aminopyrazine and its use in the synthesis of pharmaceutical intermediates. Sodium amide melted at 210-230°C reacts with 2-chloropyrazine, and after purification, aminopyrazine with a content higher than 99.5% is obtained, and the yield reaches 93.39%. The new synthesis method does not require any solvent and is green and efficient. The synthesized aminopyrazine is brominated with 1,3-dibromo-5,5-dimethylhydantoin to obtain 2-amino-3,5-dibromopyrazine, and the bromination reagent has a high active bromine content and good storage stability. 2-amino-3,5-dibromopyrazine is used to synthesize a novel 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate, which can be further used to synthesize kinase inhibitor anti-tumor drugs. The novel 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate of the present invention successfully completes a nucleophilic substitution reaction with the 3-position bromine atom of 2-amino-3,5-dibromopyrazine using 4-aminobenzoic acid, and is mainly used to synthesize Aurora kinase inhibitors. The introduction of a nitrogen atom at the 3-position of 2-amino-3,5-dibromopyrazine has a better effect on the synthesized Aurora kinase inhibitors, and has good application prospects.

Description

Technical Field

[0001] The present invention relates to a new green method for preparing aminopyrazine and its use in the synthesis of pharmaceutical intermediates. Specifically, it involves synthesizing aminopyrazine by a solvent-free melting one-step reaction method, obtaining 2-amino-3,5-dibromopyrazine by a new method, and further synthesizing 2-amino-5-bromo-3-substituted pyrazine. The pharmaceutical intermediate 2-amino-5-bromo-3-substituted pyrazine is mainly used to synthesize Aurora kinase inhibitors. Technical Background

[0002] Cancer seriously threatens human health and life. In the past few decades, many methods for treating cancer have emerged, including surgery, radiotherapy, chemotherapy, gene therapy, etc. Among them, surgery, radiotherapy, and chemotherapy have become the main means of treating cancer. Surgery and chemotherapy are the oldest methods of cancer treatment, but they are also the most effective treatments for many cancers. Although the current cancer treatment methods mainly based on surgery and chemotherapy have made great progress, and modern treatment methods such as radiotherapy have also emerged, the pathogenesis of cancer is complex and changeable, and it is easy to relapse after cure, which brings great difficulties to treatment. Among them, anticancer drugs used in chemotherapy play a very important role in treatment. However, due to the many problems of existing anticancer drugs such as strong hydrophobicity, large toxic side effects, slow efficacy, and poor efficacy [1] ([1] Wang Zixiao. Research on new pyrazinone PI3K / HDAC dual-target inhibitors [D]. Lanzhou University, 2021), their application in tumor treatment is limited. Therefore, it is very necessary to find and develop a safe, efficient and targeted anticancer drug to solve the current problems encountered in cancer treatment. Aurora is frequently overexpressed in many malignant tumors [2] ([2] Bo Yongxin. Design, synthesis and biological activity evaluation of new 3,5-disubstituted-2-aminopyrazine Aurora kinase inhibitors [D]. Lanzhou University, 2017.). This shows that Aurora kinase is an important target for anticancer drug research. The development of Aurora kinase inhibitors is an effective way to discover anticancer drugs. VX-680 / MK0457 developed by Vertex Corporation in the United States is a pan-Aurora kinase inhibitor with pyrimidine as the parent nucleus [3] ([3] Qin WW, Sang CY, Zhang LL, et al. Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors [J]. European Journal of Medicinal Chemistry, 2015, 95: 174-184.). The pyrazine group is probably the best-known heterocycle and is an important common feature of various drugs [4][4]Boggavarapu J, Nannapneni M. Green Synthesis and Antimicrobial Activity of Some Novel N-Arylimidazo[1,2-a]pyrazine-2-Carboxamide Derivatives[J]. Asian Journal of Chemistry, 2020, 32(5): 84-90).

[0003] Aminopyrazine is not only a pharmaceutical intermediate for various anti-tumor drugs [5] ([5] Cheng Wei, Zhang Xianglong, Fan Yafeng, You Tianyu, Yin Xingze, Yuan Wenpeng. Simple synthesis of 6-haloimidazole [1,2-a] pyrazine-3-carboxamide [J]. Chemical Research and Application, 2021, 33 (08): 1614-1621.), plays an important role in the pharmaceutical field. It also plays an important role in chemical products. In the chemical industry, it can be used to make explosives, pesticides, corrosion inhibitors, etc. [6,7] ([6] Jiang Weidong. Synthesis of 2-aminopyrazine derivatives [D]. Hubei University of Technology, 2016. [7] Wang Jinmin. Optimization of the synthesis process of 2,6-diamino-3,5-dinitropyrazine-1-oxide [D]. Nanjing University of Science and Technology, 2017.) Chemical products, ranging from daily chemicals to military chemicals. In summary, 2-aminopyrazine has a huge demand in the pharmaceutical and chemical fields.

[0004] At present, there are two main synthetic routes for aminopyrazine. One is to prepare aminopyrazine from 2-iodopyrazine. Add Cu2O and K2CO3 to the dioxane solution, then add 2-iodopyrazine, and pass ammonia. After reacting at 140°C for 16 hours, cool the reaction mixture to 25°C and filter with diatomaceous earth. The filtrate is extracted with 30% ethyl acetate-n-hexane. The organic layer is washed with saturated NaCl solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-aminopyrazine. [8] ([8]Boggavarapu J, Nannapneni M.Green Synthesis and Antimicrobial Activity of Some Novel N-Arylimidazo[1,2-a]pyrazine-2-Carboxamide Derivatives[J]. Asian Journal of Chemistry, 2020, 32(5):84-90). This synthetic route is complicated to operate, expensive, and difficult to industrialize and mass produce.

[0005] Another method is to prepare aminopyrazine from 2-cyanopyrazine in one pot. Add 10% sodium hypochlorite aqueous solution and 50% sodium hydroxide aqueous solution and stir, add 2-cyanopyrazine at 0-10°C, stir and react for 1h, heat to 60-80°C and react for 4h. After the reaction is completed by TLC tracking, cool to 25°C, centrifuge and filter, and recrystallize with chloroform to obtain aminopyrazine. [9] ([9] Jiang Weidong. Research on the synthesis of 2-aminopyrazine derivatives [D]. Hubei University of Technology, 2016.) This synthetic route has a low product yield, low process stability, and is difficult to achieve industrial large-scale production.

[0006] Based on the above background, the present invention uses 2-chloropyrazine and sodium amide as raw materials, and adopts the method of melting one-step reaction to synthesize aminopyrazine. The product yield and purity are very high, the operation is simple, the process is stable, and the cost advantage is obvious. In particular, this new synthesis method does not require any organic solvent and can be completed by heating and melting reaction. The synthesis method is green and the synthesis reaction is efficient. Using the synthesized aminopyrazine as a raw material, 2-amino-3,5-dibromopyrazine is obtained by bromination of 1,3-dibromo-5,5-dimethylhydantoin. The bromination reagent has a high active bromine content, good storage stability, and economic advantages, which is conducive to the industrial large-scale production of 2-amino-3,5-dibromopyrazine, an important pharmaceutical intermediate. 2-Amino-3,5-dibromopyrazine is reacted to synthesize 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediates, which can be further used to synthesize Chk1 kinase inhibitors, Nek2 kinase inhibitors, PI3K-γ kinase inhibitors, Aurora kinase inhibitors and other anti-tumor drug intermediates. The novel 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate synthesis involved in the present invention is mainly used for synthesizing Aurora kinase inhibitors, has precise uses, and has broad market prospects. Summary of the invention

[0007] In view of the above problems existing in the prior art, the present invention adopts 2-chloropyrazine and sodium amide as raw materials, adopts a solvent-free melting one-step reaction method to propose a new green method for preparing aminopyrazine and for the synthesis of pharmaceutical intermediates. The synthetic route has high synthesis efficiency, high purity, simple operation and obvious cost advantage. The organic matter can be further used to synthesize pharmaceutical intermediates, corrosion inhibitors and other pharmaceutical and chemical products.

[0008] To achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0009] In order to better realize the technical solution of the present invention, the present invention discloses a green new method for preparing aminopyrazine and its application in the synthesis of pharmaceutical intermediates.

[0010] 1. A new green method for preparing aminopyrazine, comprising the following process:

[0011] 2-Chloropyrazine and sodium amide are added into a reaction kettle at a molar ratio of 1:(1.2-1.9), the pressure is controlled at 550-650 KPa, the temperature is controlled at 210-230° C., the reaction is carried out for 5-6 hours, the reaction is cooled to 25° C., a solid is precipitated, and the reaction is filtered. The obtained solid is dissolved in an appropriate amount of chloroform, filtered, and the filtrate is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled to 25° C., a solid is precipitated, and the solid obtained after filtration is recrystallized with pure water. The obtained light yellow crystals are dried at 60° C. for 2-3 hours to obtain aminopyrazine with a content higher than 99.5%.

[0012] 2. The prepared aminopyrazine is further used to synthesize a pharmaceutical intermediate M, the structure of which is shown in Formula I:

[0013]

[0014] 3. The preparation of pharmaceutical intermediate M includes the following process:

[0015] 1) Weigh aminopyrazine and 1,3-dibromo-5,5-dimethylhydantoin in a ratio of 1:(1.0-1.35); dissolve aminopyrazine in an appropriate amount of chloroform, then add 1,3-dibromo-5,5-dimethylhydantoin in batches, stir and react at 25°C for 5-6 hours, concentrate the solution under reduced pressure until the volume is reduced to 1 / 5, cool to 25°C, precipitate solid, centrifuge and filter, recrystallize the solid using ethyl acetate, wash the solid with an appropriate amount of saturated NaCl solution 3 times, and dry the light yellow crystalline solid obtained after filtration at 40°C for 2-3 hours to obtain 2-amino-3,5-dibromopyrazine with a content higher than 99.5%;

[0016] 2) The 2-amino-3,5-dibromopyrazine obtained in step 1) is dissolved in an appropriate amount of N,N-dimethylformamide, and then 4-aminobenzoic acid is added in a molar ratio of 1:(1.1-1.8) to 2-amino-3,5-dibromopyrazine. After complete dissolution, K2CO3 is added in a molar ratio of 1:2 to 2-amino-3,5-dibromopyrazine. The mixture is reacted at 100° C. for 6 h under N2 protection, cooled to 25° C., filtered, and the filtrate is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled to 25° C., solids are precipitated, and centrifuged. The obtained solid is dissolved in an appropriate amount of boiling water, filtered while hot, and the obtained solid is washed 3 times with an appropriate amount of saturated NaCl solution. The solid obtained after filtration is dried at 60° C. for 2-3 h to obtain a pharmaceutical intermediate M.

[0017] Beneficial effects:

[0018] 1. The existing aminopyrazine synthesis methods mainly include: (1) 2-iodopyrazine is used to catalyze the preparation of aminopyrazine with a yield of 90%

[10] (

[10] Boggavarapu J, Nannapneni M. Green Synthesis and Antimicrobial Activity of Some Novel N-Arylimidazo[1,2-a]pyrazine-2-Carboxamide Derivatives[J]. Asian Journal of Chemistry, 2020, 32(5):84-90); (2) 2-cyanopyrazine is used to prepare aminopyrazine in one pot, with a yield of 81.2%

[11] (

[11] Jiang Weidong. Synthesis of 2-aminopyrazine derivatives [D]. Hubei University of Technology, 2016.) The present invention relates to a new green method for preparing aminopyrazine, using 2-chloropyrazine and sodium amide as reaction raw materials. Under the selected pressure and temperature, sodium amide and 2-chloropyrazine can be reacted in a molten state in one step without any solvent. This method has a wide range of raw materials and obvious cost advantages, high synthesis efficiency, and does not require any solvent. The method has the characteristics of green economy, and the product yield is above 90%, up to 93.39%, and the purity reaches 99.5%.

[0019] 2. The existing aminopyrazine is synthesized into 2-amino-3,5-dibromopyrazine by bromination reaction. The bromination reagents used are mainly: N-bromosuccinimide (NBS) and liquid bromine. When N-bromosuccinimide (NBS) is used as the bromination reagent, the molar ratio of aminopyrazine to the bromination reagent is 1:2.6, and the yield is 78%

[12] (

[12] Jiang Weidong. Synthesis of 2-aminopyrazine derivatives [D]. Hubei University of Technology, 2016.). When liquid bromine is used as the bromination reagent, the molar ratio of aminopyrazine to the bromination reagent is 1:1.1, and the yield is 82%

[13] (

[13] Lizano E, Grima J, Pujol M D. Efficient Halogenation of 2-Aminopyrazine[J].Synlett,2019,30(17):2000-2003.), the present invention uses 1,3-dibromo-5,5-dimethylhydantoin as a bromination reagent, the molar ratio of aminopyrazine to the bromination reagent is 1:1.2, the synthesis efficiency is high, the yield is above 86%, the highest can reach 88.84%, and the purity reaches 99.5%. Compared with N-bromosuccinimide (NBS) and liquid bromine, the bromination reagent has high active bromine content, good storage stability, high safety and low hazard, optimizes the bromination pathway of aminopyrazine to synthesize 2-amino-3,5-dibromopyrazine, an important pharmaceutical intermediate, and improves the economic advantage of use while ensuring high synthesis efficiency, which is conducive to large-scale production.

[0020] 3. According to the existing relevant literature

[14] (

[14] Bo Yongxin. Design, synthesis and biological activity evaluation of novel 3,5-disubstituted-2-aminopyrazine Aurora kinase inhibitors [D]. Lanzhou University, 2017.), it is difficult to connect the nitrogen atom at the 3-position of 2-amino-3,5-dibromopyrazine. The present invention relates to a novel 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate. N,N-dimethylformamide is selected as the reaction solvent. 4-aminobenzoic acid is used to react with 2-amino-3,5-dibromopyrazine to complete nucleophilic substitution. The nitrogen atom is connected at the 3-position of 2-amino-3,5-dibromopyrazine. The conditions are mild, the operation is simple, and the yield is good. The 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate can be synthesized and used for synthesizing anti-tumor drugs such as kinase inhibitors. The novel 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate of the present invention is mainly used for synthesizing Aurora kinase inhibitors. Specific implementation plan

[0021] The present invention is further described below by way of examples, but the present invention is not limited by the examples. The raw materials in the present invention are all conventionally commercially available.

[0022] The organic compounds prepared in the examples were characterized by MS (ESI) using a PerkinElmer LLC NexION 1000G inductively coupled plasma mass spectrometer, a 1260 Infinity II high performance liquid chromatograph to detect sample purity, and a Bruker Avance DMX600 nuclear magnetic resonance spectrometer to detect the purity of the samples. 1 H NMR characterization, TMS was used as the internal standard and CDCl3 was used as the solvent.

[0023] Yield = 100% × actual amount of target product produced / theoretical amount of target product produced.

[0024] Embodiment 1:

[0025] 2.291 g (20 mmol) of 2-chloropyrazine and 0.936 g (24 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, and the mixture was cooled to 25° C. to precipitate a solid. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.724 g of aminopyrazine P1 with a content higher than 99.5%, with a yield of 90.62% and a purity of 99.5%.

[0026] Collect 4.755g (50mmol) 2-aminopyrazine P1 and weigh 14.296g (50mmol) 1,3-dibromo-5,5-dimethylhydantoin in a ratio of 1:1.3. Dissolve the aminopyrazine in 50ml chloroform and control the temperature at 25°C. Then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, for a total of 9 times, and complete the feeding in 2h. React at 25°C for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40°C for 2-3h to obtain 11.060g of light yellow powdery solid, 2-amino-3,5-dibromopyrazine Q1, with a yield of 87.47% and a purity of 99.5%.

[0027] The obtained 2.529 g (10 mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50 ml N,N-dimethylformamide, and then 1.509 g (11 mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764 g (20 mmol) K2CO3 was added. The reaction was carried out at 100°C for 6 h under N2 protection. After the reaction was completed, the mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, solids were precipitated, and centrifuged. The obtained solid was dissolved in 100 ml of boiling water and filtered while hot. The obtained solid was washed 3 times with 100 ml of saturated NaCl solution. The filtered solid was dried at 60°C for 2 to 3 h to obtain 2.496 g of intermediate M1 with a yield of 80.73%.

[0028] Embodiment 2:

[0029] 2.291 g (20 mmol) of 2-chloropyrazine and 1.014 g (26 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25° C., and a solid was precipitated. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.735 g of aminopyrazine P2 with a content higher than 99.5%, with a yield of 91.21% and a purity of 99.5%.

[0030] Collect 4.755g (50mmol) 2-aminopyrazine P2 and weigh 15.726g (55mmol) 1,3-dibromo-5,5-dimethylhydantoin in a ratio of 1:1.1. Dissolve the aminopyrazine in 50ml chloroform and control the temperature at 25°C. Then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, for a total of 9 times, and complete the feeding in 2h. React at 25°C for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40°C for 2-3h to obtain 11.150g of light yellow powdery solid, 2-amino-3,5-dibromopyrazine Q2, with a yield of 88.18% and a purity of 99.5%.

[0031] The obtained 2.529g (10mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50ml N,N-dimethylformamide, and then 1.646g (12mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764g (20mmol) K2CO3 was added. The reaction was carried out at 100°C for 6h under N2 protection. After the reaction was completed, the mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, solid was precipitated, and centrifuged. The obtained solid was dissolved in 100ml boiling water and filtered while hot. The obtained solid was washed 3 times with 100ml saturated NaCl solution. The filtered solid was dried at 60°C for 2-3h to obtain 2.531g intermediate M2 with a yield of 81.89%.

[0032] Embodiment 3:

[0033] 2.291 g (20 mmol) of 2-chloropyrazine and 1.092 g (28 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, and the solid was cooled to 25° C. to precipitate a solid. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.749 g of aminopyrazine P3 with a content higher than 99.5%, with a yield of 91.94% and a purity of 99.5%.

[0034] Collect 4.755g (50mmol) 2-aminopyrazine P3 and weigh 17.155g (60mmol) 1,3-dibromo-5,5-dimethylhydantoin according to the ratio of 1:1.2. Dissolve the aminopyrazine in 50ml chloroform, control the temperature at 25℃, and then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, for a total of 9 times, and complete the feeding in 2h. React at 25℃ for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40℃ for 2-3h to obtain 11.233g of light yellow powdery solid, 2-amino-3,5-dibromopyrazine Q3, with a yield of 88.84% and a purity of 99.5%.

[0035] The obtained 2.529 g (10 mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50 ml N,N-dimethylformamide, and then 1.783 g (13 mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764 g (20 mmol) K2CO3 was added. The reaction was carried out at 100°C for 6 h under N2 protection. After the reaction was completed, the mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, a solid was precipitated, and centrifuged. The obtained solid was dissolved in 100 ml of boiling water and filtered while hot. The obtained solid was washed 3 times with 100 ml of saturated NaCl solution. The filtered solid was dried at 60°C for 2 to 3 h to obtain 2.569 g of intermediate M3 with a yield of 83.12%.

[0036] Embodiment 4:

[0037] 2.291 g (20 mmol) of 2-chloropyrazine and 1.170 g (30 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, and the mixture was cooled to 25° C. to precipitate a solid. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.776 g of aminopyrazine P4 with a content higher than 99.5%, with a yield of 93.39% and a purity of 99.5%.

[0038] Collect 4.755g (50mmol) 2-aminopyrazine P4 and weigh 18.585g (65mmol) 1,3-dibromo-5,5-dimethylhydantoin according to the ratio of 1:1.3. Dissolve aminopyrazine in 50ml chloroform, control the temperature at 25℃, then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, a total of 9 times, and complete the feeding in 2h. React at 25℃ for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40℃ for 2-3h to obtain 11.207g of light yellow powdery solid, 2-amino-3,5-dibromopyrazine Q4, with a yield of 88.63% and a purity of 99.5%.

[0039] The obtained 2.529 g (10 mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50 ml N,N-dimethylformamide, and then 1.920 g (14 mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764 g (20 mmol) K2CO3 was added. The reaction was carried out at 100°C for 6 h under N2 protection. After the reaction was completed, the mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, a solid was precipitated, and centrifuged. The obtained solid was dissolved in 100 ml of boiling water and filtered while hot. The obtained solid was washed 3 times with 100 ml of saturated NaCl solution. The filtered solid was dried at 60°C for 2 to 3 h to obtain 2.630 g of intermediate M5 with a yield of 85.08%.

[0040] Embodiment 5:

[0041] 2.291 g (20 mmol) of 2-chloropyrazine and 1.248 g (32 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, and the mixture was cooled to 25° C. to precipitate a solid. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.766 g of aminopyrazine P5 with a content higher than 99.5%, with a yield of 92.83% and a purity of 99.5%.

[0042] Collect 4.755g (50mmol) 2-aminopyrazine P6 and weigh 20.014g (70mmol) 1,3-dibromo-5,5-dimethylhydantoin at a ratio of 1:1.4. Dissolve aminopyrazine in 50ml chloroform, control the temperature at 25°C, then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, a total of 9 times, and complete the feeding in 2h. React at 25°C for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40°C for 2-3h to obtain 11.117g of light yellow powdery solid, 2-amino-3,5-dibromopyrazine Q5, with a yield of 87.92% and a purity of 99.5%.

[0043] The obtained 2.529g (10mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50ml N,N-dimethylformamide, and then 2.057g (15mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764g (20mmol) K2CO3 was added. The reaction was carried out at 100°C for 6h under N2 protection. After the reaction was completed, it was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, solids were precipitated, and centrifuged. The obtained solid was put into 100ml boiling water to dissolve, filtered while hot, and the obtained solid was washed 3 times with 100ml saturated NaCl solution. The filtered solid was dried at 60°C for 2-3h to obtain 2.611g intermediate M5 with a yield of 84.46%.

[0044] Embodiment 6:

[0045] 2.291 g (20 mmol) of 2-chloropyrazine and 1.326 g (34 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25° C., and a solid was precipitated. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.753 g of aminopyrazine P6 with a content higher than 99.5%, with a yield of 92.16% and a purity of 99.5%.

[0046] Collect 4.755g (50mmol) 2-aminopyrazine P6 and weigh 21.444g (75mmol) 1,3-dibromo-5,5-dimethylhydantoin at a ratio of 1:1.5. Dissolve aminopyrazine in 50ml chloroform, control the temperature at 25°C, then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, a total of 9 times, and complete the feeding in 2h. React at 25°C for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the filter residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40°C for 2-3h to obtain 11.032g of light yellow powdery solid, 2-amino-3,5-dibromopyrazine Q6, with a yield of 87.25% and a purity of 99.5%.

[0047] The obtained 2.529 g (10 mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50 ml N,N-dimethylformamide, and then 2.194 g (16 mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764 g (20 mmol) K2CO3 was added. The reaction was carried out at 100°C for 6 h under N2 protection. After the reaction was completed, the mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, solids were precipitated, and centrifuged. The obtained solid was dissolved in 100 ml of boiling water and filtered while hot. The obtained solid was washed 3 times with 100 ml of saturated NaCl solution. The filtered solid was dried at 60°C for 2 to 3 h to obtain 2.583 g of intermediate M6 with a yield of 83.56%.

[0048] Embodiment 7:

[0049] 2.291 g (20 mmol) of 2-chloropyrazine and 1.404 g (36 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, and the mixture was cooled to 25° C. to precipitate a solid. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.746 g of aminopyrazine P7 with a content higher than 99.5%, with a yield of 91.79% and a purity of 99.5%.

[0050] Collect 4.755g (50mmol) 2-aminopyrazine P7 and weigh 22.874g (80mmol) 1,3-dibromo-5,5-dimethylhydantoin according to the ratio of 1:1.6. Dissolve aminopyrazine in 50ml chloroform, control the temperature at 25℃, then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, a total of 9 times, and complete the feeding in 2h. React at 25℃ for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40℃ for 2-3h to obtain 10.959g of light yellow powder solid, 2-amino-3,5-dibromopyrazine Q7, with a yield of 86.67% and a purity of 99.5%.

[0051] The obtained 2.529 g (10 mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50 ml N,N-dimethylformamide, and then 2.331 g (17 mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764 g (20 mmol) K2CO3 was added. The reaction was carried out at 100°C for 6 h under N2 protection. After the reaction was completed, the mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, solids were precipitated, and centrifuged. The obtained solid was dissolved in 100 ml of boiling water and filtered while hot. The obtained solid was washed 3 times with 100 ml of saturated NaCl solution. The filtered solid was dried at 60°C for 2 to 3 h to obtain 2.546 g of intermediate M7 with a yield of 82.37%.

[0052] Embodiment 8:

[0053] 2.291 g (20 mmol) of 2-chloropyrazine and 1.482 g (38 mmol) of sodium amide were added to a high-temperature and high-pressure reactor, and the absolute pressure in the reaction system was controlled at 550-650 KPa and the temperature reached 210-230° C. After reacting for 5-6 hours, the mixture was cooled to 25° C. to precipitate a solid, which was filtered. The obtained solid was dissolved in chloroform and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, and the mixture was cooled to 25° C. to precipitate a solid. The solid obtained after filtration was recrystallized with pure water, and the obtained light yellow crystals were dried at 60° C. for 2-3 hours to obtain 1.734 g of aminopyrazine P8 with a content higher than 99.5%, with a yield of 91.15% and a purity of 99.5%.

[0054] Collect 4.755g (50mmol) 2-aminopyrazine P8 and weigh 24.303g (85mmol) 1,3-dibromo-5,5-dimethylhydantoin according to the ratio of 1:1.7. Dissolve aminopyrazine in 50ml chloroform, control the temperature at 25℃, then add 1,3-dibromo-5,5-dimethylhydantoin in batches, once every 15min, a total of 9 times, and complete the feeding in 2h. React at 25℃ for 6h. After the reaction is completed, the solution is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled, solids are precipitated, centrifuged, and the residue is washed 3 times with 100ml saturated NaCl solution. The filtered solid is dried at 40℃ for 2-3h to obtain 10.886g of light yellow powdery solid, 2-amino-3,5-dibromopyrazine Q8, with a yield of 86.09% and a purity of 99.5%.

[0055] The obtained 2.529g (10mmol) 2-amino-3,5-dibromopyrazine was stirred and dissolved in 50ml N,N-dimethylformamide, and then 2.467g (18mmol) 4-aminobenzoic acid was added. After complete dissolution, 2.764g (20mmol) K2CO3 was added. The reaction was carried out at 100°C for 6h under N2 protection. After the reaction was completed, it was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure until the volume was reduced to 1 / 5, cooled to 25°C, solids were precipitated, and centrifuged. The obtained solid was put into 100ml boiling water to dissolve, filtered while hot, and the obtained solid was washed 3 times with 100ml saturated NaCl solution. The filtered solid was dried at 60°C for 2-3h to obtain 2.501g intermediate M8 with a yield of 80.91%.

[0056] Table 1 Synthesis results of aminopyrazine P1 to P8 samples in Examples 1 to 8

[0057] Table 2 Synthesis results of 2-amino-3,5-dibromopyrazine Q1 to Q8 in Examples 1 to 8

[0058]

[0059] Table 3 Examples Synthesis results of Chinese medicine intermediates M1 to M8 in Examples 1 to 8

[0060]

[0061] A major method for preparing aminopyrazine is to use 2-iodopyrazine as a catalyst to prepare aminopyrazine. The synthetic route is as follows:

[0062]

[0063] The synthesis steps include:

[0064] 1) Add Cu2O and K2CO3 to an appropriate amount of 1,4-dioxane solution and dissolve;

[0065] 2) Add 2-iodopyrazine to the obtained suspension, introduce ammonia gas to make the pressure reach 1034.25 KPa, and react at 140° C. for 16 h;

[0066] 3) After the reaction is completed, the reaction mixture is cooled to 25°C, filtered through diatomaceous earth, the filtrate is extracted with an appropriate amount of 30% ethyl acetate-n-hexane, the organic layer is washed 3 times with an appropriate amount of saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure until the volume is reduced to 1 / 5, filtered, and the obtained solid is dried at 40°C for 2 to 3 hours to obtain aminopyrazine.

[0067] Table 4: Preparation of aminopyrazine from 2-iodopyrazine

[15]

[0068]

[0069]

[15] Boggavarapu J, Nannapneni M. Green Synthesis and AntimicrobialActivity of Som e Novel N-Arylimidazo[1,2-a]pyrazine-2-CarboxamideDerivatives[J]. Asian Journal of Chemis try, 2020, 32(5):84-90.

[0070] Another main method for preparing aminopyrazine is to prepare aminopyrazine from 2-cyanopyrazine in one pot. The synthetic route is as follows:

[0071]

[0072] The synthesis steps include:

[0073] 1) Add 10% sodium hypochlorite aqueous solution into a three-necked flask and cool to 10-20°C;

[0074] 2) At this temperature, slowly add 50% sodium hydroxide aqueous solution into the reaction bottle, then slowly add 2-cyanopyrazine, and stir and react at 10-20°C for 1 hour;

[0075] 3) Then the temperature was raised to 80°C for 5 h and the reaction was monitored by TLC;

[0076] 4) After the reaction is completed, cool to 25°C, centrifuge and filter, recrystallize the obtained solid with chloroform, and dry at 40°C for 2-3h to obtain aminopyrazine.

[0077] Table 5: One-pot preparation of aminopyrazine from 2-cyanopyrazine

[16]

[0078]

[0079]

[16] Jiang Weidong, Wang Yu, Liu Mingxing. Study on the synthesis of 3,5-dibromo-2-aminopyrazine[J]. Guangzhou Chemical Industry, 2016, 44(12):93-94+126.

[0080] From the comparison of data in Table 1, Table 4 and Table 5, it can be seen that the yield of aminopyrazine prepared by 2-iodopyrazine catalysis reaches 92%, the yield of aminopyrazine prepared by 2-cyanopyrazine in one-pot method is 81.2%, and the process route of aminopyrazine P1-P8 synthesized by using 2-chloropyrazine and sodium amide as raw materials of the present invention reaches 93.39% and the purity reaches 99.5%; the preparation of aminopyrazine by 2-iodopyrazine catalysis requires a variety of raw materials and catalysts, which is relatively costly, one of the raw materials is high-pressure ammonia, the operation is complicated, and there are potential safety hazards. The preparation of aminopyrazine by 2-cyanopyrazine in one-pot method requires a variety of raw materials, which is relatively costly and easy to operate. The process route of synthesizing aminopyrazine P1-P8 by using 2-chloropyrazine and sodium amide as raw materials through solvent-free high-temperature melting in one step only requires two raw materials, both of which are solid, and no solvent is required, which is green and economical, stable in storage, and easy to operate. In summary, 2-iodopyrazine is catalyzed to prepare aminopyrazine, and the yield is very high, but the cost is high and the operation is complicated; 2-cyanopyrazine is used to prepare aminopyrazine in one pot, which has low cost and simple operation, but low yield and complex process route; the process route of aminopyrazine P1~P8 synthesized from 2-chloropyrazine and sodium amide as raw materials adopts a solvent-free high-temperature melting one-step reaction, which is green and economical, stable in storage, high in synthesis efficiency, high in purity and simple in operation.

[0081] From the data in Table 2 and Table 3, it can be seen that the synthesis reaction of pharmaceutical intermediate M has mild reaction conditions, high yield, and can be mass-produced. The reaction conditions are mild, the operation is simple, the yield is high, and the yield reaches more than 86%, and the highest can reach 88.84%. The purity is higher than 99.5%. The bromination reagent has high active bromine content, good storage stability, and economic advantages, which meet the conditions for large-scale production. The reaction conditions are mild, the yield is high, and the yield reaches more than 80%, and the highest can reach 85.08%.

[0082] In summary, the process routes for preparing aminopyrazine reported in existing literature have the problems of many reaction raw materials, difficult cost control, complex reaction routes, complex operations, potential safety hazards, etc., which are difficult to meet the requirements of industrial-scale production. In view of the above problems in the prior art, the present invention uses 2-chloropyrazine and sodium amide as raw materials to synthesize aminopyrazine. The process route uses a solvent-free high-temperature and high-pressure melting method, which has stable process, high yield, high purity, simple operation, and cost-effective advantages. Using 1,3-dibromo-5,5-dimethylhydantoin bromination reagent, the bromination pathway of aminopyrazine synthesis of important pharmaceutical intermediate 2-amino-3,5-dibromopyrazine is optimized, and the cost-effective advantages are further improved under the condition of ensuring high synthesis efficiency. N,N-dimethylformamide is selected as the reaction solvent, 4-aminobenzoic acid is reacted with 2-amino-3,5-dibromopyrazine to complete nucleophilic substitution, and the nitrogen atom is connected to the 3-position of 2-amino-3,5-dibromopyrazine to synthesize a novel 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate, which can be further used to synthesize Aurora kinase inhibitor anti-tumor drugs. The synthesis process of the novel 2-amino-5-bromo-3-substituted pyrazine pharmaceutical intermediate is stable, the yield is high, the operation is simple, and the effect is significant. Therefore, the invention patent application of the present invention "A new green method for preparing aminopyrazine and its use in the synthesis of pharmaceutical intermediates" will have a good market prospect.

[0083] Although preferred embodiments of the present invention have been described, additional changes and modifications may be made to these embodiments by those skilled in the art once the basic inventive concepts are known. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention. Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A new green method for preparing aminopyrazine, comprising the following process: 2-Chloropyrazine and sodium amide are added into a reaction kettle at a molar ratio of 1:(1.2-1.9), the pressure is controlled at 550-650 KPa, the temperature is controlled at 210-230° C., after reacting for 5-6 hours, the reaction is cooled to 25° C., a solid is precipitated, and the reaction is filtered. The obtained solid is dissolved in an appropriate amount of chloroform, filtered, and the filtrate is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled to 25° C., a solid is precipitated, and the solid obtained after filtration is recrystallized with pure water. The obtained light yellow crystals are dried at 60° C. for 2-3 hours to obtain aminopyrazine with a content higher than 99.5%.

2. Application of a green new method for preparing aminopyrazine as described in claim 1 in synthesizing a pharmaceutical intermediate M having a structure as shown in formula I 。 3. A method for synthesizing a pharmaceutical intermediate M having a structure as shown in formula I, characterized in that The process includes the following: 1) 2-chloropyrazine and sodium amide are added into a reaction kettle at a molar ratio of 1:(1.2-1.9), the pressure is controlled at 550-650 KPa, the temperature is controlled at 210-230° C., after reacting for 5-6 hours, the reaction is cooled to 25° C., a solid is precipitated, and the reaction is filtered. The obtained solid is dissolved in an appropriate amount of chloroform, filtered, and the filtrate is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled to 25° C., a solid is precipitated, and the solid obtained after filtration is recrystallized with pure water. The obtained light yellow crystals are dried at 60° C. for 2-3 hours to obtain aminopyrazine with a content higher than 99.5%; 2) Weigh the aminopyrazine and 1,3-dibromo-5,5-dimethylhydantoin obtained in step 1) in a ratio of 1:(1.0-1.7); dissolve the aminopyrazine in an appropriate amount of chloroform, then add 1,3-dibromo-5,5-dimethylhydantoin in batches, stir and react at 25° C. for 5-6 hours, then concentrate the solution under reduced pressure until the volume is reduced to 1 / 5, cool to 25° C., precipitate a solid, centrifuge and filter, recrystallize the solid using ethyl acetate, wash the solid three times with an appropriate amount of saturated NaCl solution, and dry the light yellow crystalline solid obtained after filtration at 40° C. for 2-3 hours to obtain 2-amino-3,5-dibromopyrazine with a content higher than 99.5%; 3) The 2-amino-3,5-dibromopyrazine obtained in step 2) is dissolved in an appropriate amount of N,N-dimethylformamide, and then 4-aminobenzoic acid is added in a molar ratio of 1: (1.1-1.8) to 2-amino-3,5-dibromopyrazine. After complete dissolution, K2CO3 is added in a molar ratio of 1:2 to 2-amino-3,5-dibromopyrazine. After reacting at 100° C. for 6 hours under N2 protection, the mixture is cooled to 25° C. and filtered. The filtrate is concentrated under reduced pressure until the volume is reduced to 1 / 5, cooled to 25° C., a solid is precipitated, and centrifuged. The obtained solid is dissolved in an appropriate amount of boiling water, filtered while hot, and the obtained solid is washed 3 times with an appropriate amount of saturated NaCl solution. The solid obtained after filtration is dried at 60° C. for 2-3 hours to obtain a pharmaceutical intermediate M. 。

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