Method for continuously preparing 2-amino-3, 5-dibromopyrazine

Abstract

The invention belongs to the technical field of synthesis of 2-amino-3, 5-dibromopyrazine, and discloses a method for continuously preparing 2-amino-3, 5-dibromopyrazine, which comprises the following steps: reacting 2-cyanopyrazine, sodium hypochlorite and inorganic alkali in a mixed aqueous solution to obtain an aqueous solution of 2-aminopyrazine; the method comprises the following steps: adding a hydrobromic acid solution into an aqueous solution of 2-aminopyrazine, carrying out online acidification, then adding hydrogen peroxide, and carrying out a reaction at 5-10 DEG C for 5-20 min; after the reaction is finished, quenching, neutralizing, extracting and purifying the reaction to obtain 2-amino-3, 5-dibromopyrazine; the reaction is continuously carried out in a tubular reactor. According to the present invention, the bromine active reagent is generated in situ by using the hydrobromic acid and hydrogen peroxide system to bromate the 2-aminopyrazine, such that the atom economy is good, the cost is low, the continuous flow production is convenient, the automatic production requirement is met, and the industrial application value is provided.

Description

Technical Field

[0001] This invention belongs to the field of 2-amino-3,5-dibromopyrazine synthesis technology, specifically relating to a method for the continuous preparation of 2-amino-3,5-dibromopyrazine. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] 2-Amino-3,5-dibromopyrazine is an important intermediate for imidazopyrazine drugs, which inhibits the proliferation of cancer cells to varying degrees and is widely used in the pharmaceutical and chemical industries.

[0004] Currently, the mainstream synthetic methods for this compound all use 2-cyanopyrazine and sodium hypochlorite as raw materials to prepare 2-aminopyrazine in aqueous solution. After purification, the 2-aminopyrazine is reacted with a brominating reagent in an organic solvent system to obtain 2-amino-3,5-dibromopyrazine. The brominating reagent can be phosphorus tribromooxy, dibromohydantoin, or N-bromosuccinimide (NBS), etc.

[0005] Since step one is carried out in an aqueous solution and step two is carried out in an organic solution, the reaction systems, reagent properties and reaction conditions of the two steps are different. As a result, it is difficult to prepare 2-amino-3,5-dibromopyrazine using a continuous method. This leads to problems such as poor atom economy, cumbersome post-processing and low yield in the existing preparation methods. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a method for the continuous preparation of 2-amino-3,5-dibromopyrazine. The intermediate 2-aminopyrazine is not separated from the system and is directly subjected to continuous bromination.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention provides a method for the continuous preparation of 2-amino-3,5-dibromopyrazine, comprising the following steps: A mixed aqueous solution of 2-cyanopyrazine, sodium hypochlorite, and an inorganic base was reacted to obtain an aqueous solution of 2-aminopyrazine. Add hydrobromic acid solution to an aqueous solution of 2-aminopyrazine for online acidification, then add hydrogen peroxide and react at 5-10℃ for 5-20 min. After the reaction was completed, the reaction was quenched and neutralized, and the product was extracted and purified to obtain 2-amino-3,5-dibromopyrazine. The above reactions are carried out continuously in a tubular reactor.

[0008] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows: First, compared with the reported synthesis process, the present invention uses a continuous flow reverse reactor for production, and the intermediate 2-aminopyrazine can be directly brominated without leaving the system; second, the present invention uses a hydrobromic acid and hydrogen peroxide system to generate a bromine-active reagent in situ to brominate 2-aminopyrazine, which has good atom economy, low cost, and is easy to produce using a continuous flow reverse reactor, meeting the requirements of automated production and having greater value for industrial application. Attached Figure Description

[0009] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0010] Figure 1 This is a schematic diagram of the system structure for the continuous preparation of 2-amino-3,5-dibromopyrazine according to an embodiment of the present invention; Figure 2 This is the 1H NMR spectrum of 2-amino-3,5-dibromopyrazine prepared in Example 1 of this invention.

[0011] The components include: 1. Sodium hydroxide storage tank; 2. Pump; 3. 2-Cyanopyrazine storage tank; 4. First reaction tube; 5. Hydrobromic acid storage tank; 6. Online acidification reactor; 7. Second reaction tube; 8. Post-treatment reactor; 9. Hydrogen peroxide storage tank; 10. Mixer; and 11. Sodium hypochlorite storage tank. Detailed Implementation

[0012] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0013] The mainstream synthetic methods for 2-amino-3,5-dibromopyrazine all use 2-cyanopyrazine and sodium hypochlorite as raw materials to prepare 2-aminopyrazine in aqueous solution. After purifying 2-aminopyrazine, it is reacted with a brominating reagent in an organic solvent system to obtain 2-amino-3,5-dibromopyrazine.

[0014] Step one requires the reaction to be carried out in an inorganic alkaline aqueous solution, using sodium hypochlorite as a reagent. After the reaction, 2-aminopyrazine needs to be separated by vacuum distillation. This indicates that step one is an aqueous-phase reaction involving a strong oxidizing agent (sodium hypochlorite) and alkaline conditions. Step two requires the reaction to be carried out in an organic solvent, using phosphorus oxybromide, dibromohydantoin, or N-bromosuccinimide as the brominating agent. This is an organic-phase reaction, requiring anhydrous or low-aqueous conditions to ensure efficient bromination.

[0015] If a continuous preparation is attempted, the aqueous reaction mixture from step one (containing water, inorganic salts, residual sodium hypochlorite, etc.) will be directly introduced into step two. Water and organic solvents may form a two-phase system, leading to an uneven reaction; more importantly, water can cause the brominating reagent to hydrolyze and become ineffective, generating hydrogen bromide or other byproducts, thereby reducing the bromination yield.

[0016] The sodium hypochlorite residue from step one is a strong oxidizing agent. If it proceeds directly to step two, it may undergo a redox reaction with the brominating reagent, leading to its decomposition. The inorganic base (such as sodium hydroxide) in step one may make the bromination reaction conditions in step two too alkaline, causing the brominating reagent to become unstable or hydrolyze.

[0017] This invention provides a method for the continuous preparation of 2-amino-3,5-dibromopyrazine, comprising the following steps: A mixed aqueous solution of 2-cyanopyrazine, sodium hypochlorite, and an inorganic base was reacted to obtain an aqueous solution of 2-aminopyrazine. Hydrobromic acid solution was added to an aqueous solution of 2-aminopyrazine for online acidification, followed by the addition of hydrogen peroxide. The reaction was carried out at -5 to 20°C for 5-30 minutes. After the reaction was completed, the reaction was quenched and neutralized, and the product was extracted and purified to obtain 2-amino-3,5-dibromopyrazine. The above reactions are carried out continuously in a tubular reactor.

[0018] 2-Cyanopyrazine (with -CN attached to the 2-position of the pyrazine ring) is converted to 2-aminopyrazine (with -NH2 substituted -CN) under the action of inorganic bases (such as NaOH) and sodium hypochlorite (NaClO). The specific process is as follows: The cyano group (-CN) first hydrolyzes to an amide group (-CONH2) in an alkaline aqueous solution; Sodium hypochlorite reacts with sodium hypochlorite under alkaline conditions to form hypochlorite ions (ClO). - The amide group attacks the carbonyl carbon, forming an N-chloroamide intermediate; this intermediate undergoes dechlorination under alkaline conditions. - This generates an isocyanate intermediate (-N=C=O); the isocyanate further hydrolyzes, releasing CO3. 2- And an amino group (-NH2) is generated, finally yielding an aqueous solution of 2-aminopyrazine.

[0019] Aqueous solutions of 2-aminopyrazine are acidified with hydrobromic acid (HBr), and then hydrogen peroxide (H2O2) is added, resulting in a dibromination reaction at low temperature. Hydrobromic acid provides Br - Hydrogen peroxide acts as an oxidizing agent under acidic conditions, turning Br₂ into Br₂. - Oxidized to elemental bromine; In 2-aminopyrazine, the amino group (-NH2) is a strong electron-donating group, which activates the ortho and para positions of the pyrazine ring through a conjugation effect (the ortho position of -NH2 at position 2 of the pyrazine ring is at positions 3 and 5, and the para position is at position 6). The generated Br2 acts as an electrophile, preferentially attacking the 3 and 5 positions with the highest electron cloud density, resulting in an amphiphilic substitution reaction to generate 2-amino-3,5-dibromopyrazine.

[0020] Both reactions are carried out continuously in an aqueous system. The intermediate 2-aminopyrazine does not need to be separated and purified. The pH is directly adjusted by online acidification, which avoids the hydrolysis problem of brominating reagent caused by switching between organic and aqueous phases in traditional processes, and achieves continuous flow high-efficiency conversion.

[0021] Sodium hypochlorite can reduce Br - Oxidation to higher oxidation states of bromate (such as BrO3) - Excess sodium hypochlorite may oxidize the amino group (-NH2) of 2-aminopyrazine, generating nitroso or nitro byproducts, thus affecting the purity of the target product. Inorganic bases (such as sodium hydroxide) can make the reaction system strongly alkaline, which adversely affects the bromination reaction.

[0022] In this invention, hydrobromic acid solution is added to the aqueous solution of 2-aminopyrazine to perform online acidification. Hydrobromic acid (HBr) reacts with residual inorganic base (such as NaOH) to generate sodium bromide (NaBr) and water, thereby adjusting the pH of the system to acidic and meeting the acidic environment required for the bromination reaction.

[0023] Under acidic conditions, sodium hypochlorite can react with HBr (NaClO + 2HBr → NaCl + Br2 + H2O), converting potential oxidizing impurities into Br2 required for bromination, thus eliminating interference and improving atom economy.

[0024] In the second step of the bromination reaction, hydrogen peroxide is used as the oxidant instead of sodium hypochlorite because: The second step, bromination, needs to be carried out in an acidic system (after acidification with hydrobromic acid). Hydrogen peroxide can stably bromine under acidic conditions. - Oxidation to Br2 (reaction formula: H2O2 + 2H+) + + 2Br - → Br₂ + 2H₂O), while sodium hypochlorite readily decomposes into Cl₂ under acidic conditions and competes with Br⁻ for oxidation (ClO). - + 2Br - + 2H + → Cl - + Br2+ H2O), which leads to a decrease in the utilization rate of brominating reagents and the introduction of chlorine-containing byproducts.

[0025] Sodium hypochlorite has a stronger oxidizing power than hydrogen peroxide. If used in the bromination step, it may directly oxidize the -NH2 group of 2-aminopyrazine to form nitroso or nitro impurities, while hydrogen peroxide selectively oxidizes Br under acidic conditions at low temperatures (5-10℃). - The risk of oxidation of amino groups is extremely low.

[0026] Hydrogen peroxide's reduction product is water, which does not introduce new salts or organic impurities. It is compatible with aqueous systems, ensuring continuous conversion of the intermediate without separation. Sodium hypochlorite, on the other hand, leaves residual Cl-. - It may react with subsequent reagents or affect the purity of the product.

[0027] In some embodiments, the molar ratio of 2-cyanopyrazine, sodium hypochlorite, and inorganic base is 1:1.1-1.3:2-3. Sodium hypochlorite and inorganic base are used in slightly excess amounts to ensure complete reaction of the 2-cyanopyrazine.

[0028] In some embodiments, the inorganic base is sodium hydroxide.

[0029] In some embodiments, the reaction temperature during the preparation of 2-aminopyrazine is 40-70°C and the residence time is 5-15 min.

[0030] Preferably, the reaction temperature in the preparation of 2-aminopyrazine is 50-60℃ and the residence time is 7-12 min.

[0031] In some embodiments, the molar ratio of 2-cyanopyrazine, hydrobromic acid, and hydrogen peroxide is 0.8-0.2:5-7:2-3. A slight excess of hydrobromic acid and hydrogen peroxide ensures complete reaction of the 2-cyanopyrazine.

[0032] Preferably, the dwell time for online acidification is 3-10 minutes, and more preferably 5 minutes.

[0033] In some embodiments, hydrogen peroxide is added and the reaction is carried out at 5-10°C for 5-20 minutes.

[0034] Preferably, hydrogen peroxide is added and the reaction is carried out at 7-10°C for 5-15 minutes.

[0035] A further preferred method involves adding hydrogen peroxide and reacting at 7-10°C for 7-12 minutes.

[0036] In some embodiments, the reaction is quenched by adding a saturated sodium sulfite solution to the reaction system.

[0037] In some embodiments, the extraction reagent added in the extraction step is dichloromethane, chloroform, ethyl acetate, butyl acetate, or toluene; preferably ethyl acetate.

[0038] In some embodiments, the purification step includes decolorizing the obtained crude product with activated carbon and then crystallizing it.

[0039] The present invention will be further described below with reference to the embodiments.

[0040] Example 1 The preparation method of 2-amino-3,5-dibromopyrazine includes the following steps: ; like Figure 1 As shown, in the tubular reactor, a 10% (% is a mass percentage) sodium hypochlorite solution is pumped from the sodium hypochlorite storage tank 11 into the mixer 10, and a 20% sodium hydroxide solution is pumped from the sodium hydroxide storage tank 1 into the mixer 10 using pump 2. The flow rate of the sodium hypochlorite solution is 14 g / min, the flow rate of the sodium hydroxide solution is 5 g / min, and the mixer temperature is set to 5℃. 2-Cyanopyrazine is pumped from 2-cyanopyrazine storage tank 3 through another pipeline at a flow rate of 2 g / min to the first reaction tube 4. The oil bath temperature of the first reaction tube 4 is set to 55°C and the residence time is 10 min. After the reaction is complete, the solution flows into the online acidification reactor 6. Hydrobromic acid is pumped from the hydrobromic acid storage tank 5 into the online acidification reactor 6. Online acidification is carried out using 40% hydrobromic acid at a flow rate of 5 g / min. After acidification, the flow rate of the liquid is 25 g / min, and then it is reacted with 20% hydrogen peroxide (the hydrogen peroxide is stored in the hydrogen peroxide storage tank 9) in the second reaction tube 7. The flow rate of hydrogen peroxide is 10 g / min, the oil bath temperature of the second reaction tube 7 is set to 8℃, and the residence time is 10 min. After the reaction was completed, the product flowed into post-treatment vessel 8, where saturated sodium sulfite solution was added for quenching and neutralization. Ethyl acetate was then added for extraction, and the organic phase was concentrated to obtain a crude product. The crude product was then decolorized and crystallized on activated carbon to obtain 233 g of pure product, with a yield of 81% (yield obtained by combining the reaction solutions after 1 hour of stable operation). The 1H NMR spectrum of the prepared 2-amino-3,5-dibromopyrazine is shown below. Figure 2 As shown.

[0041] Example 2 The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 47°C, and the oil bath temperature of the second reaction tube 7 is -3°C; all other aspects are the same as in Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 70%.

[0042] Example 3 The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 55°C, and the oil bath temperature of the second reaction tube 7 is -3°C; all other aspects are the same as in Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 72%.

[0043] Example 4 The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 55°C, and the oil bath temperature of the second reaction tube 7 is 3°C; all other aspects are the same as in Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 75%.

[0044] Example 5 The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 55°C, and the oil bath temperature of the second reaction tube 7 is 15°C; all other aspects are the same as in Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 69%.

[0045] Example 6 The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 65°C, and the oil bath temperature of the second reaction tube 7 is 7°C; all other aspects are the same as in Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 51%.

[0046] Example 7 The difference from Example 1 is that the residence time in the first reaction tube is 20 min and the residence time in the second reaction tube is 10 min, and the yield of 2-amino-3,5-dibromopyrazine prepared is 77%.

[0047] Example 8 The difference from Example 1 is that the residence time in the first reaction tube is 15 min and the residence time in the second reaction tube is 10 min, and the yield of 2-amino-3,5-dibromopyrazine prepared is 74%.

[0048] Example 9 The difference from Example 1 is that the residence time in the first reaction tube is 5 min and the residence time in the second reaction tube is 10 min, and the yield of 2-amino-3,5-dibromopyrazine prepared is 66%.

[0049] Example 10 The difference from Example 1 is that the residence time in the first reaction tube is 10 min and the residence time in the second reaction tube is 5 min, and the yield of 2-amino-3,5-dibromopyrazine prepared is 73%.

[0050] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for the continuous preparation of 2-amino-3,5-dibromopyrazine, characterized in that: Includes the following steps: A mixed aqueous solution of 2-cyanopyrazine, sodium hypochlorite, and an inorganic base in a molar ratio of 1:1.1-1.3:2-3 was reacted to obtain an aqueous solution of 2-aminopyrazine. Hydrobromic acid solution was added to an aqueous solution of 2-aminopyrazine for online acidification, followed by the addition of hydrogen peroxide. The molar ratio of 2-cyanopyrazine, hydrobromic acid, and hydrogen peroxide was 0.8-0.2:5-7:2-3. The reaction was carried out at -5 to 20°C for 5-30 minutes. After the reaction was completed, the reaction was quenched and neutralized, and the product was extracted and purified to obtain 2-amino-3,5-dibromopyrazine. The above reactions are carried out continuously in a tubular reactor.

2. The method for continuous preparation of 2-amino-3,5-dibromopyrazine according to claim 1, characterized in that: The inorganic base is sodium hydroxide.

3. The method for continuous preparation of 2-amino-3,5-dibromopyrazine according to claim 1, characterized in that: The reaction temperature in the preparation of 2-aminopyrazine is 40-70℃, and the residence time is 5-15 min.

4. The method for continuous preparation of 2-amino-3,5-dibromopyrazine according to claim 3, characterized in that: The reaction temperature in the preparation of 2-aminopyrazine is 50-60℃, and the residence time is 7-12 min.

5. The method for continuous preparation of 2-amino-3,5-dibromopyrazine according to claim 1, characterized in that: Add hydrogen peroxide to it and react at 5-10℃ for 5-15 minutes.

6. The method for continuous preparation of 2-amino-3,5-dibromopyrazine according to claim 1, characterized in that: The reaction is quenched by adding a saturated sodium sulfite solution to the reaction system.

7. The method for continuous preparation of 2-amino-3,5-dibromopyrazine according to claim 1, characterized in that: In the extraction step, the extraction reagent added is dichloromethane, chloroform, ethyl acetate, butyl acetate, or toluene.

8. The method for continuous preparation of 2-amino-3,5-dibromopyrazine according to claim 7, characterized in that: The purification step includes decolorizing the obtained crude product with activated carbon and then crystallizing it.

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