A process for the continuous production of 2-amino-3,5-dibromopyrazine

Abstract

The application belongs to the technical field of 2-amino-3,5-dibromopyrazine synthesis, and discloses a method for continuously preparing 2-amino-3,5-dibromopyrazine, which comprises the following steps: reacting a mixed aqueous solution of 2-cyanopyrazine, sodium hypochlorite and an inorganic base to obtain an aqueous solution of 2-aminopyrazine; adding a hydrobromic acid solution to the aqueous solution of 2-aminopyrazine for online acidification, then adding hydrogen peroxide thereto, and reacting at 5-10 DEG C for 5-20 min; after the reaction is completed, the reaction is quenched, neutralized, extracted, purified, and 2-amino-3,5-dibromopyrazine is obtained; and the above reaction is continuously carried out in a tubular reactor. The bromination of 2-aminopyrazine is carried out by using a hydrogen bromide and hydrogen peroxide system to generate a bromine active reagent in situ, which is good in atomic economy, low in cost, convenient for continuous flow production, meets the requirements of automatic production, and has more industrial application value.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of 2-amino-3,5-dibromopyrazine synthesis, and particularly relates to a method for continuously preparing 2-amino-3,5-dibromopyrazine. BACKGROUND

[0002] The statements herein are provided only to enhance understanding of the present application and are not necessarily intended to constitute the prior art.

[0003] 2-amino-3,5-dibromopyrazine is an important intermediate of imidazopyrazine new drugs, which inhibits the proliferation of cancer cells to different extents and is widely used in the field of pharmaceutical and chemical industry.

[0004] At present, the mainstream synthesis method of the compound is to use 2-cyanopyrazine and sodium hypochlorite as raw materials to prepare 2-amino-pyrazine in an aqueous solution, purify the 2-amino-pyrazine, and then react with a brominating reagent in an organic solvent system to obtain 2-amino-3,5-dibromopyrazine. The brominating reagent can be phosphorus tribromide, dibromohydantoin or N-bromosuccinimide (NBS) and the like.

[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, which further leads to the difficulty in continuously preparing 2-amino-3,5-dibromopyrazine, and the existing preparation method has the problems of poor atom economy, complicated post-treatment and low yield. SUMMARY

[0006] In view of the deficiencies of the prior art, the purpose of the present application is to provide a method for continuously preparing 2-amino-3,5-dibromopyrazine. The intermediate 2-amino-pyrazine is not taken out of the system and is directly subjected to continuous bromination.

[0007] In order to achieve the above-mentioned purpose, the present application is realized by the following technical scheme:

[0008] The present application provides a method for continuously preparing 2-amino-3,5-dibromopyrazine, comprising the following steps:

[0009] A mixed aqueous solution of 2-cyanopyrazine, sodium hypochlorite and inorganic base is reacted to obtain an aqueous solution of 2-amino-pyrazine;

[0010] Hydrobromic acid solution is added to the aqueous solution of 2-amino-pyrazine for online acidification, then hydrogen peroxide is added thereto, and the reaction is carried out at 5-10℃ for 5-20min;

[0011] After the reaction is completed, the reaction is quenched and neutralized, the product is extracted and purified to obtain 2-amino-3,5-dibromopyrazine;

[0012] The above reaction is continuously carried out in a tubular reactor.

[0013] The beneficial effects achieved by one or more embodiments of the present application are as follows:

[0014] Firstly, compared with the reported synthesis process, the present application uses continuous flow tube reaction for production, and the intermediate 2-amino-pyrazine can be brominated directly without being taken out of the system; secondly, the present application uses hydrobromic acid and hydrogen peroxide system to generate bromine active reagent in situ for bromination of 2-amino-pyrazine, which is good in atomic economy, low in cost, and convenient for continuous flow tube reaction for production, meets the requirements of automatic production, and has more industrial application value. BRIEF DESCRIPTION OF DRAWINGS

[0015] The drawings accompanying the specification of this application form a part thereof, serve to provide further understanding of the application, and together with the description of the exemplary embodiments of the application and explanations thereof serve to explain the application, and do not constitute an improper limitation of the application.

[0016] Figure 1 is a schematic structural diagram of a system for continuously preparing 2-amino-3,5-dibromopyrazine according to an embodiment of the present application;

[0017] Figure 2 is a nuclear magnetic hydrogen spectrum of 2-amino-3,5-dibromopyrazine prepared in Embodiment 1 of the present application.

[0018] In the figure, 1 is a sodium hydroxide storage tank, 2 is a pump, 3 is a 2-cyanopyrazine storage tank, 4 is a first reaction tube, 5 is a hydrobromic acid storage tank, 6 is an online acidification kettle, 7 is a second reaction tube, 8 is a post-treatment kettle, 9 is a hydrogen peroxide storage tank, 10 is a mixer, and 11 is a sodium hypochlorite storage tank. DETAILED DESCRIPTION

[0019] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used in the present application have the same meaning as generally understood by those skilled in the art to which the present application belongs.

[0020] The main synthesis method of 2-amino-3,5-dibromopyrazine uses 2-cyanopyrazine and sodium hypochlorite as raw materials to prepare 2-amino-pyrazine in an aqueous solution, purifies the 2-amino-pyrazine, and then reacts with a bromination reagent in an organic solvent system to obtain 2-amino-3,5-dibromopyrazine.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] This invention provides a method for the continuous preparation of 2-amino-3,5-dibromopyrazine, comprising the following steps:

[0025] A mixed aqueous solution of 2-cyanopyrazine, sodium hypochlorite, and an inorganic base was reacted to obtain an aqueous solution of 2-aminopyrazine.

[0026] 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.

[0027] 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.

[0028] The above reactions are carried out continuously in a tubular reactor.

[0029] 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:

[0030] The cyano group (-CN) first hydrolyzes to an amide group (-CONH2) in an alkaline aqueous solution;

[0031] 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. -, generating isocyanate intermediate (-N=C=O); isocyanate is further hydrolyzed to release CO3 2- and generate amino (-NH2), finally obtaining 2-amino pyrazine aqueous solution.

[0032] After the 2-amino pyrazine aqueous solution is acidified by hydrobromic acid (HBr), hydrogen peroxide (H2O2) is added, and a double bromination reaction occurs at low temperature:

[0033] Hydrobromic acid provides Br - Hydrogen peroxide acts as an oxidizing agent under acidic conditions to oxidize Br - to elemental bromine;

[0034] In 2-amino pyrazine, the amino group (-NH2) is a strong electron-donating group, which activates the ortho positions of the pyrazine ring (the ortho positions of the 2-amino pyrazine ring are 3 and 5, and the para position is 6) through conjugation effect. The generated Br2 acts as an electrophile and preferentially attacks the 3 and 5 positions with the highest electron cloud density, resulting in a double electrophilic substitution reaction to generate 2-amino-3,5-dibromopyrazine.

[0035] Both reactions are continuously carried out in an aqueous system, and the intermediate 2-amino pyrazine does not need to be separated and purified. By adjusting the pH through online acidification, the problem of hydrolysis of bromination reagents caused by organic phase / water phase switching in traditional processes is avoided, realizing continuous flow high-efficiency conversion.

[0036] Sodium hypochlorite can oxidize Br - to higher valence bromate (such as BrO3 - ), or directly oxidize Br2 to generate bromoxides, resulting in the failure of bromination reagents and reducing the bromination efficiency; excessive sodium hypochlorite may oxidize the amino group (-NH2) of 2-amino pyrazine to generate nitroso or nitro byproducts, affecting the purity of the target product. Inorganic bases such as sodium hydroxide can cause the reaction system to be strongly basic, which is not conducive to the bromination reaction.

[0037] In the present invention, by adding hydrobromic acid solution to the aqueous solution of 2-amino pyrazine, online acidification is carried out, and hydrobromic acid (HBr) reacts with residual inorganic bases (such as NaOH) to generate sodium bromide (NaBr) and water, adjusting the pH of the system to acidic, meeting the demand of bromination reaction for acidic environment.

[0038] Under acidic conditions, sodium hypochlorite can react with HBr (NaClO + 2HBr → NaCl + Br2+ H2O), converting potential oxidizing impurities into Br2 required for bromination, eliminating interference and improving atomic economy.

[0039] In the second step of bromination reaction, hydrogen peroxide is used as an oxidizing agent instead of sodium hypochlorite, the reason is:

[0040] The second step of bromination needs to be carried out in an acidic system (acidified by hydrobromic acid). Hydrogen peroxide is stable in an acidic condition and can oxidize Br - to Br2(reaction formula: H2O2+ 2H + + 2Br - → Br2+ 2H2O), while sodium hypochlorite is easy to decompose into Cl2in an acidic condition and can compete with Br⁻for oxidation (ClO - + 2Br - + 2H + → Cl - + Br2+ H2O), which leads to a decrease in the utilization rate of the bromination reagent and the introduction of chlorine-containing byproducts.

[0041] Sodium hypochlorite is more oxidizing than hydrogen peroxide. If used in the bromination step, it can directly oxidize the -NH2of 2-aminopyrazine to generate nitroso or nitro impurities, while hydrogen peroxide selectively oxidizes Br - in an acidic condition at low temperature (5-10℃) with very low risk of oxidation of the amino group.

[0042] The reduction product of hydrogen peroxide is water, which does not introduce new salts or organic impurities and is compatible with aqueous systems, ensuring that the intermediates can be continuously converted without the need for separation; while sodium hypochlorite can leave Cl - , which can react with subsequent reagents or affect the purity of the product.

[0043] In some embodiments, the molar ratio of 2-cyanopyrazine, sodium hypochlorite, and inorganic base is 1:1.1-1.3:2-3. The amount of sodium hypochlorite and inorganic base is slightly excessive to ensure complete reaction of 2-cyanopyrazine.

[0044] In some embodiments, the inorganic base is sodium hydroxide.

[0045] In some embodiments, the reaction temperature during the preparation of 2-aminopyrazine is 40-70℃, and the residence time is 5-15 min.

[0046] Preferably, the reaction temperature during the preparation of 2-aminopyrazine is 50-60℃, and the residence time is 7-12 min.

[0047] In some embodiments, the molar ratio of 2-cyanopyrazine, hydrobromic acid, and hydrogen peroxide is 0.8-0.2:5-7:2-3. Hydrobromic acid and hydrogen peroxide are slightly excessive to ensure complete reaction of 2-cyanopyrazine.

[0048] Preferably, the residence time of the online acidification is 3-10 min, preferably 5 min.

[0049] In some embodiments, hydrogen peroxide is added thereto, and the reaction is carried out at 5-10℃ for 5-20 min.

[0050] Preferably, hydrogen peroxide is added and the reaction is carried out at 7-10°C for 5-15 minutes.

[0051] A further preferred method involves adding hydrogen peroxide and reacting at 7-10°C for 7-12 minutes.

[0052] In some embodiments, the reaction is quenched by adding a saturated sodium sulfite solution to the reaction system.

[0053] In some embodiments, the extraction reagent added in the extraction step is dichloromethane, chloroform, ethyl acetate, butyl acetate, or toluene; preferably ethyl acetate.

[0054] In some embodiments, the purification step includes decolorizing the obtained crude product with activated carbon and then crystallizing it.

[0055] The present invention will be further described below with reference to the embodiments.

[0056] Example 1

[0057] The preparation method of 2-amino-3,5-dibromopyrazine includes the following steps:

[0058] ;

[0059] 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℃.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] After the reaction, the reaction solution was flowed into the post-treatment kettle 8, saturated sodium sulfite solution was added for quenching and neutralization, and then ethyl acetate was added for extraction. The organic phase was concentrated to obtain a crude product. The crude product was decolorized and crystallized by activated carbon to obtain a pure product 233 g, with a yield of 81% (the yield was obtained by combining and processing the reaction liquid for 1 hour). The nuclear magnetic resonance spectrum of the prepared 2-amino-3,5-dibromopyrazine is shown in Figure 2 .

[0064] Example 2

[0065] The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 47°C, the oil bath temperature of the second reaction tube 7 is -3°C, and the others are the same as Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 70%.

[0066] Example 3

[0067] The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 55°C, the oil bath temperature of the second reaction tube 7 is -3°C, and the others are the same as Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 72%.

[0068] Example 4

[0069] The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 55°C, the oil bath temperature of the second reaction tube 7 is 3°C, and the others are the same as Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 75%.

[0070] Example 5

[0071] The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 55°C, the oil bath temperature of the second reaction tube 7 is 15°C, and the others are the same as Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 69%.

[0072] Example 6

[0073] The difference from Example 1 is that the oil bath temperature of the first reaction tube 4 is 65°C, the oil bath temperature of the second reaction tube 7 is 7°C, and the others are the same as Example 1. The yield of the prepared 2-amino-3,5-dibromopyrazine is 51%.

[0074] Example 7

[0075] 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. The yield of the prepared 2-amino-3,5-dibromopyrazine is 77%.

[0076] Example 8

[0077] The difference from Example 1 is that the residence time in the first reactor tube is 15 min and the residence time in the second reactor tube is 10 min, and the yield of 2-amino-3,5-dibromopyrazine produced is 74%.

[0078] Example 9

[0079] The difference from Example 1 is that the residence time in the first reactor tube is 5 min and the residence time in the second reactor tube is 10 min, and the yield of 2-amino-3,5-dibromopyrazine produced is 66%.

[0080] Example 10

[0081] The difference from Example 1 is that the residence time in the first reactor tube is 10 min and the residence time in the second reactor tube is 5 min, and the yield of 2-amino-3,5-dibromopyrazine produced is 73%.

[0082] The above only describes preferred embodiments of the present application and is not intended to limit the present application. The present application can have various modifications and changes for those skilled in the art. Any modification, equivalent replacement, improvement, etc. within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for the continuous preparation of 2-amino-3,5-dibromopyrazine, characterized in that: Includes the following steps: In a tubular reactor, a 10% sodium hypochlorite solution by mass is pumped from a sodium hypochlorite storage tank into a mixer, and a 20% sodium hydroxide solution is pumped from a sodium hydroxide storage tank into the mixer. 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 was pumped from the 2-cyanopyrazine storage tank through another pipeline at a flow rate of 2 g / min to the first reaction tube. The oil bath temperature of the first reaction tube was set to 55°C and the residence time was 10 min. After the reaction is complete, the solution flows into the online acidification reactor. Hydrobromic acid is pumped from the hydrobromic acid storage tank into the online acidification reactor. Online acidification is performed 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, which is stored in a hydrogen peroxide storage tank, in the second reaction tube. The flow rate of the hydrogen peroxide is 10 g / min, the oil bath temperature of the second reaction tube is set to 8°C, and the residence time is 10 min. After the reaction was completed, the product flowed into a post-processing vessel, where saturated sodium sulfite solution was added for quenching and neutralization. Then, ethyl acetate was added for extraction. The organic phase was concentrated to obtain a crude product. The crude product was decolorized and crystallized with activated carbon to obtain 233g of pure product, with a yield of 81%.

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