A method for synthesizing 2,3-diamino-4-bromopyridine

Abstract

The invention discloses a method for synthesizing 2,3-diamino-4-bromopyridine. The method is characterized by comprising the steps of reacting N-BOC-2-amino-4-chloropyridine with a halogenating reagent to obtain N-Boc-2-amino-4-chloro-5-halopyridine, and then removing Boc to obtain 2-amino-4-chloro-5-halopyridine; nitrating 2-amino-4-chloro-5-halopyridine with a mixed acid to obtain 4-chloro-5-halo-3-nitropyridine-2-amine, and then reacting the 2-amino-4-chloro-5-halopyridine with sodium methoxide to obtain 5-halo-4-methoxy-3-nitropyridine-2-amine; reacting 5-halo-4-methoxy-3-nitropyridine-2-amine with a reducing reagent to obtain 4-methoxy-pyridine-2,3-diamine; and reacting 4-methoxy-pyridine-2,3-diamine with a brominating reagent to obtain a 2,3-diamino-4-bromopyridine product. The method has the advantages of mild reaction conditions, low production cost and high yield.

Description

Technical Field

[0001] The present invention relates to the field of synthesis of pharmaceutical and pesticide intermediates, and in particular to a method for synthesizing 2,3-diamino-4-bromopyridine. Background Art

[0002] Pyridopyrazines have been synthesized as novel p38a MAP kinase inhibitors for the treatment of cytokine-driven diseases such as inflammatory bowel disease and rheumatoid arthritis. New pyrido[2,3-b]pyrazine derivatives have been described as kinase inhibitors for the treatment of malignancies and other diseases based on pathological cell proliferation. Pyrido[2,3-b]pyrazines have also been reported as useful angiostatics for the treatment of various diseases, including myocardial infarction, ischemia-reperfusion injury, and autoimmune rheumatoid arthritis. The antimicrobial activity of pyridopyrazines has been demonstrated by inhibition of FtsZ polymerization. Furthermore, pyrido[2,3-b]pyrazines exhibit bactericidal activity.

[0003] 2,3-Diamino-4-bromopyridine is a key intermediate in the synthesis of pyrido[2,3-b]pyrazines. The existing synthesis method of 2,3-diamino-4-bromopyridine is to use 2-amino-4-bromopyridine as the starting material, and obtain a mixture of 2-amino-4-bromo-5-nitropyridine and 2-amino-4-bromo-3-nitropyridine through nitration and nitro transposition. Due to the similar physicochemical properties of the two mixtures, the separation and purification efficiency is low. The literature shows that the yield of 2-amino-4-bromo-3-nitropyridine obtained by column purification is only 20% (J.Med.Chem.2020,63,13013-13030); then, the nitro group is reduced to obtain 2,3-diamino-4-bromopyridine, and the yield in the literature is 37% (CN103435561). The starting materials of this process are expensive; the separation of the isomers produced by the nitration product is difficult and the yield is low. At the same time, the yield of nitro reduction is also low, resulting in an overall yield of less than 8%; this process is complex to operate, has high production costs, low overall yield, poor social and economic benefits, and is not suitable for large-scale production.

[0004] Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for synthesizing 2,3-diamino-4-bromopyridine with a simple process route, mild reaction conditions, low production cost, high yield and suitability for large-scale production.

[0006] The technical solution adopted by the present invention to solve the above technical problems is: a method for synthesizing 2,3-diamino-4-bromopyridine, comprising the following steps:

[0007] (1) reacting N-BOC-2-amino-4-chloropyridine with a halogenating agent to obtain N-Boc-2-amino-4-chloro-5-halopyridine;

[0008] (2) reacting N-Boc-2-amino-4-chloro-5-halopyridine with dilute acid to remove Boc to obtain 2-amino-4-chloro-5-halopyridine;

[0009] (3) nitrating 2-amino-4-chloro-5-halopyridine with a mixed acid to obtain 4-chloro-5-halo-3-nitropyridine-2-amine;

[0010] (4) reacting 4-chloro-5-halogeno-3-nitropyridine-2-amine with sodium methoxide to obtain 5-halogeno-4-methoxy-3-nitropyridine-2-amine;

[0011] (5) 5-halogenated-4-methoxy-3-nitropyridine-2-amine is reacted with a reducing agent to obtain 4-methoxy-pyridine

[0012] -2,3-diamine;

[0013] (6) 4-Methoxy-pyridine-2,3-diamine is reacted with a bromination reagent to obtain 2,3-diamino-4-bromopyridine.

[0014] Furthermore, the specific process of step (1) is as follows: dissolving N-BOC-2-amino-4-chloropyridine in a solvent, then adding a halogenating agent, heating to T1, keeping the temperature at T1 for reaction until the reaction is complete, evaporating the solvent under reduced pressure, pouring into cold water, stirring, extracting with ethyl acetate, separating the ethyl acetate phase, washing twice with a saturated sodium bicarbonate aqueous solution, and concentrating the organic phase to dryness to obtain solid N-Boc-2-amino-4-chloro-5-halogenopyridine, wherein the controlled temperature of T1 is 10°C ≤ T1 ≤ 150°C.

[0015] Furthermore, the solvent is acetonitrile, 1,4-dioxane, methanol, ethanol, isopropanol or dichloroethane; and the halogenation reagent is a chlorination reagent, a bromination reagent or an iodination reagent.

[0016] Furthermore, the molar ratio of the N-BOC-2-amino-4-chloropyridine to the halogenating agent is 1:(1-5).

[0017] Furthermore, the specific process of step (2) is as follows: adding N-Boc-2-amino-4-chloro-5-halopyridine to dilute acid at room temperature, then heating to T2, keeping warm at T2 until the reaction is complete, pouring the reaction solution into crushed ice, adjusting the pH to 8-9 with 50wt% sodium hydroxide aqueous solution, controlling the temperature not higher than 30°C, a large amount of solid precipitated, extracting the solid product twice with ethyl acetate, washing the organic phase twice with saturated brine, drying with anhydrous sodium sulfate, decolorizing with activated carbon, filtering, rinsing with ethyl acetate, concentrating the organic phase to dryness, adding petroleum ether, precipitating solids, filtering, rinsing the filter cake with petroleum ether, and drying to obtain an off-white solid 2-amino-4-chloro-5-halopyridine, wherein the temperature of T2 is controlled to be -10°C≤T2≤150°C, and the dilute acid is dilute sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid or hydrochloric acid.

[0018] Further, the specific process of step (3) is as follows: slowly add 2-amino-4-chloro-5-halogenopyridine to the concentrated sulfuric acid solution under an ice-water bath, control the temperature not higher than T3, continue cooling in an ice-water bath, and when the temperature drops to T4, slowly add the nitrating reagent dropwise, control the temperature not higher than T5, and stir at room temperature overnight; the next day, slowly raise the temperature to T6, keep the temperature for reaction for 3 hours, cool the reaction mixture to room temperature, then pour into ice water, neutralize with ammonia water, extract with ethyl acetate, wash the organic phase with saturated brine, and add anhydrous sulfuric acid. The reaction mixture is dried with sodium sulfate and desolventized to obtain a yellow solid 4-chloro-5-halogenated-3-nitropyridine-2-amine, wherein the controlled temperature of T3 is -5°C ≤ T3 ≤ 50°C; the controlled temperature of T4 is -5°C ≤ T4 ≤ 30°C; the controlled temperature of T5 is 5°C ≤ T5 ≤ 40°C, and the controlled temperature of T6 is 25°C ≤ T6 ≤ 150°C; the nitrating agent is concentrated nitric acid, fuming nitric acid, potassium nitrate or sodium nitrate; and the molar ratio of the 2-amino-4-chloro-5-halogenated pyridine to the nitrating agent is 1:(1-3).

[0019] Furthermore, the specific process of step (4) is: slowly adding 4-chloro-5-halogenated-3-nitropyridine-2-amine to a sodium methoxide solution at room temperature, keeping warm at temperature T7 until the reaction is complete, pouring the reaction mixture into cold water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, and desolventizing to obtain a yellow solid 5-halogenated-4-methoxy-3-nitropyridine-2-amine, wherein the control temperature of T7 is 15°C ≤ T7 ≤ 150°C; the molar ratio of the 4-chloro-5-halogenated-3-nitropyridine-2-amine to the sodium methoxide is 1: (1 to 3).

[0020] Furthermore, the specific process of step (5) is as follows: after adding methanol and 5-halogenated-4-methoxy-3-nitropyridine-2-amine to the autoclave, a palladium-carbon catalyst and an acid binding agent are added, stirring is started, the air in the autoclave is replaced with nitrogen three times, and then hydrogen is introduced to maintain the internal pressure at 0.01MPa≤P≤1MPa and the temperature T8 for complete reaction, the reaction mixture is filtered, the catalyst is removed, the filtrate is poured into cold water, extracted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, desolventized, and recrystallized from ethyl acetate to obtain 4-methoxy-pyridine-2,3-diamine, wherein the control temperature of T8 is 10°C≤T8≤120°C, and the mass fraction of palladium in the palladium-carbon catalyst is 10wt%;

[0021] Furthermore, the specific process of step (6) is as follows: 4-methoxy-pyridine-2,3-diamine is slowly added to the solvent at room temperature, stirring is started, and then a bromination reagent is added, the temperature is raised to T9 for reaction, and the temperature is kept at T9 until the reaction is complete, the reaction solution is poured into ice water, the pH is adjusted to 10 with an aqueous sodium hydroxide solution, and then extracted three times with ethyl acetate, the organic phase obtained by extraction is washed twice with a saturated aqueous sodium bicarbonate solution, the organic phase is concentrated to dryness, and then dichloromethane is added. After the solid is precipitated, it is placed in a refrigerator and frozen for two hours, filtered, and the filter cake is rinsed with dichloromethane to obtain a brown-gray solid 2,3-diamino-4-bromopyridine, wherein the control temperature of T9 is 40°C≤T9≤150°C, and the bromination reagent is phosphorus oxybromide or phosphorus tribromide.

[0022] Furthermore, the molar ratio of the 4-methoxy-pyridine-2,3-diamine to the bromination reagent is 1:(1-5).

[0023] Compared with the prior art, the present invention has the advantages of: disclosing a method for synthesizing 2,3-diamino-4-bromopyridine; the synthetic route uses 2-chloro-4-amino-5-methylpyridine as a raw material, and comprises six steps: synthesis of N-Boc-2-amino-4,5-dichloropyridine, synthesis of 4,5-dichloro-2-aminopyridine, synthesis of 4,5-dichloro-3-nitropyridine-2-amine, synthesis of 5-chloro-4-methoxy-3-nitropyridine-2-amine, synthesis of 4-methoxy-pyridine-2,3-diamine, and synthesis of 2,3-diamino-4-bromopyridine; the synthetic method for 2,3-diamino-4-bromopyridine uses N-BOC-2-amino-4-chloropyridine, which is mass-produced and inexpensive by our company, as a starting raw material; the synthetic process is simple, the reaction conditions are mild, the yield is high, the production cost is low, and the industrial applicability value is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The nuclear magnetic resonance spectrum of 2,3-diamino-4-bromopyridine prepared in Example 1 of the present invention

[0025] Figure 2 The nuclear magnetic resonance spectrum of 2,3-diamino-6-bromopyridine prepared in Example 1 of the present invention DETAILED DESCRIPTION

[0026] The present invention will be described in further detail below with reference to the accompanying drawings and embodiments. Specific embodiments

[0028] A method for synthesizing 2,3-diamino-4-bromopyridine comprises the following steps:

[0029] (1) reacting N-BOC-2-amino-4-chloropyridine with a halogenating agent to obtain N-Boc-2-amino-4-chloro-5-halopyridine;

[0030] (2) reacting N-Boc-2-amino-4-chloro-5-halopyridine with dilute acid to remove Boc to obtain 2-amino-4-chloro-5-halopyridine;

[0031] (3) nitrating 2-amino-4-chloro-5-halopyridine with a mixed acid to obtain 4-chloro-5-halo-3-nitropyridine-2-amine;

[0032] (4) reacting 4-chloro-5-halogeno-3-nitropyridine-2-amine with sodium methoxide to obtain 5-halogeno-4-methoxy-3-nitropyridine-2-amine;

[0033] (5) reacting 5-halogenated-4-methoxy-3-nitropyridine-2-amine with a reducing agent to obtain 4-methoxy-pyridine-2,3-diamine;

[0034] (6) 4-methoxy-pyridine-2,3-diamine is reacted with a bromination reagent to obtain 2,3-diamino-4-bromopyridine. The synthetic route is as follows:

[0035]

[0036] The specific process of the above step (1) is as follows: dissolving N-BOC-2-amino-4-chloropyridine in a solvent, then adding a halogenating agent, heating to T1, keeping the temperature at T1 for reaction until the reaction is complete, evaporating the solvent under reduced pressure, pouring into cold water, stirring, extracting with ethyl acetate, separating the ethyl acetate phase, washing twice with a saturated sodium bicarbonate aqueous solution, and concentrating the organic phase to dryness to obtain solid N-Boc-2-amino-4-chloro-5-halogenopyridine, wherein the controlled temperature of T1 is 10°C≤T1≤150°C, wherein the solvent is acetonitrile, 1,4-dioxane, methanol, ethanol, isopropanol or dichloroethane; the halogenating agent is a chlorinating agent, a brominating agent or an iodinating agent; and the molar ratio of N-BOC-2-amino-4-chloropyridine to the halogenating agent is 1:(1-5).

[0037] The specific process of the above step (2) is as follows: N-Boc-2-amino-4-chloro-5-halopyridine is added to dilute acid at room temperature, then the temperature is raised to T2, and the temperature is kept at T2 until the reaction is complete, the reaction solution is poured into crushed ice, the pH is adjusted to 8-9 with 50wt% sodium hydroxide aqueous solution, the temperature is controlled not higher than 30°C, a large amount of solid is precipitated, the solid product is extracted twice with ethyl acetate, the organic phase is washed twice with saturated brine, dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, rinsed with ethyl acetate, the organic phase is concentrated to dryness, petroleum ether is added, solid is precipitated, filtered, the filter cake is rinsed with petroleum ether, and dried to obtain an off-white solid 2-amino-4-chloro-5-halopyridine, wherein the temperature T2 is controlled to be -10°C≤T2≤150°C, and the dilute acid is dilute sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid or hydrochloric acid.

[0038] The specific process of the above step (3) is as follows: slowly add 2-amino-4-chloro-5-halopyridine to the concentrated sulfuric acid solution under an ice-water bath, control the temperature not to be higher than T3, continue cooling in an ice-water bath, and when the temperature drops to T4, slowly add the nitrating reagent dropwise, control the temperature not to be higher than T5, and stir at room temperature overnight; the next day, slowly raise the temperature to T6, keep the temperature for reaction for 3 hours, cool the reaction mixture to room temperature, then pour into ice water, neutralize with ammonia water, extract with ethyl acetate, wash the organic phase with saturated brine, and remove the residue. The reaction mixture was dried with sodium sulfate and desolventized to obtain a yellow solid 4-chloro-5-halogenated-3-nitropyridine-2-amine, wherein the controlled temperature of T3 was -5°C ≤ T3 ≤ 50°C; the controlled temperature of T4 was -5°C ≤ T4 ≤ 30°C; the controlled temperature of T5 was 5°C ≤ T5 ≤ 40°C; and the controlled temperature of T6 was 25°C ≤ T6 ≤ 150°C. The nitrating agent was concentrated nitric acid, fuming nitric acid, potassium nitrate or sodium nitrate; and the molar ratio of 2-amino-4-chloro-5-halogenated pyridine to the nitrating agent was 1:(1-3).

[0039] The specific process of the above step (4) is as follows: 4-chloro-5-halogenated-3-nitropyridine-2-amine is slowly added to a sodium methoxide solution at room temperature, and the temperature is kept at T7 until the reaction is complete. The reaction mixture is poured into cold water, extracted with ethyl acetate, and the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and desolventized to obtain a yellow solid 5-halogenated-4-methoxy-3-nitropyridine-2-amine, wherein the control temperature of T7 is 15°C ≤ T7 ≤ 150°C; the molar ratio of the 4-chloro-5-halogenated-3-nitropyridine-2-amine to the sodium methoxide is 1: (1 to 3).

[0040] The specific process of the above step (5) is as follows: after adding methanol and 5-halogenated-4-methoxy-3-nitropyridine-2-amine to the autoclave, a palladium-carbon catalyst and an acid binding agent are added, stirring is started, the air in the autoclave is replaced with nitrogen three times, and then hydrogen is introduced to maintain the internal pressure at 0.01MPa≤P≤1MPa and the temperature T8 for complete reaction, the reaction mixture is filtered, the catalyst is removed, the filtrate is poured into cold water, extracted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, desolventized, and recrystallized from ethyl acetate to obtain 4-methoxy-pyridine-2,3-diamine, wherein the control temperature of T8 is 10°C≤T8≤120°C, and the mass fraction of palladium in the palladium-carbon catalyst is 10wt%.

[0041] The specific process of the above step (6) is as follows: 4-methoxy-pyridine-2,3-diamine is slowly added to the solvent at room temperature, stirring is started, then a bromination reagent is added, the temperature is raised to T9 for reaction, and the temperature is kept at T9 until the reaction is complete, the reaction solution is poured into ice water, the pH is adjusted to 10 with a sodium hydroxide aqueous solution, and then extracted with ethyl acetate three times, the organic phase obtained by extraction is washed twice with a saturated sodium bicarbonate aqueous solution, the organic phase is concentrated to dryness, and then dichloromethane is added. After the solid is precipitated, it is placed in a refrigerator and frozen for two hours, filtered, and the filter cake is rinsed with dichloromethane to obtain a brown-gray solid 2,3-diamino-4-bromopyridine, wherein the control temperature of T9 is 40°C≤T9≤150°C, the bromination reagent is phosphorus oxybromide or phosphorus tribromide, and the molar ratio of 4-methoxy-pyridine-2,3-diamine to the bromination reagent is 1:(1-5).

[0042] Example 1

[0043] A method for synthesizing 2,3-diamino-4-bromopyridine comprises the following steps:

[0044] 1. Synthesis of N-Boc-2-amino-4,5-dichloropyridine

[0045] Prepare a 10L three-necked flask, mechanically stir, and reflux condenser; first add 5L acetonitrile to the reaction flask, then add N-BOC-2-amino-4-chloropyridine (825g, 3.9mol), start stirring, add NCS (587.4g, 4.4mol), heat to 80℃ and reflux reaction, the system changes from turbid to clear; TLC (EA:PE=1:5, UV) is taken after three hours, showing that the reaction is complete; the reaction solution is concentrated to dryness, solid precipitates, 6L water is added to disperse, the solid is insoluble, and 8L ethyl acetate is added and stirred for half an hour, the solid is dissolved in ethyl acetate, the ethyl acetate phase is separated, and washed twice with saturated sodium bicarbonate aqueous solution (3L×2), the organic phase is concentrated to almost dryness, solid precipitates, 500ml petroleum ether is added, more solid precipitates, and the refrigerator is frozen for two hours, filtered, and the filter cake is rinsed with 500ml petroleum ether to obtain 671g of off-white solid, with a yield of 70%.

[0046] Synthesis of 2,4,5-dichloro-2-aminopyridine

[0047] Prepare a 5L three-necked flask with a mechanical stirrer, a thermometer, and a reflux condenser. First, add 1.8L of water to the reaction flask and stir. Then, add 1.8L of concentrated hydrochloric acid, and finally, add N-Boc-2-amino-4,5-dichloropyridine (500g, 2.02mol). Set the temperature to 100°C and maintain overnight. The next day, take a sample by TLC (EA:PE = 1:1, UV). If the reaction is complete, turn off the heat, remove the oil bath, and stir to room temperature. Solids will precipitate. Pour the reaction solution into 6kg of crushed ice and adjust the pH to 8-9 with 50wt% sodium hydroxide solution. Keep the temperature below 20°C. Add more ice to cool if the temperature rises. A large amount of solid will precipitate after adjustment. The product was extracted with ethyl acetate twice (5 L × 2), the organic phase was washed twice with saturated brine (3 L × 2), dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, rinsed with ethyl acetate, and the organic phase was concentrated to a small volume. Solid precipitated. 1 L of petroleum ether was added, more solid precipitated, filtered, rinsed with 500 ml of petroleum ether, and dried to obtain 285 g of an off-white solid with a yield of 86%.

[0048] Synthesis of 3,4,5-dichloro-3-nitropyridin-2-amine

[0049] Prepare a 3L three-necked flask, mechanically stir, and reflux condenser. First, add 1L of 98% concentrated sulfuric acid to the reaction flask, start stirring, and slowly add 4,5-dichloro-3-nitropyridine-2-amine (200g, 1.2mol) in an ice-water bath. Control the temperature not to exceed 40°C. When the temperature drops to about 5°C, slowly add 90% fuming nitric acid (120g, 1.7mol) dropwise. Control the temperature not to exceed 20°C. After the drop is complete, stir at room temperature overnight. The next day, slowly heat to 75°C and keep warm for 3 hours. Cool to room temperature, then pour into ice water, neutralize with ammonia water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and desolventize to obtain 230g of yellow solid with a yield of 90%.

[0050] 4. Synthesis of 5-chloro-4-methoxy-3-nitropyridin-2-amine

[0051] Prepare a 3L three-necked flask, mechanical stirring, and a reflux condenser. First, add 1L of anhydrous DMF to the reaction flask, start stirring, add 4,5-dichloro-3-nitropyridine-2-amine (208g, 1.0mol) at room temperature, then add sodium methoxide (62g, 1.15mol) and stir at room temperature overnight. The next day, the reaction mixture was poured into 3L of cold water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and desolventized to obtain 183g of a yellow solid with a yield of 90%.

[0052] 5. Synthesis of 4-methoxy-pyridine-2,3-diamine

[0053] In a 2L autoclave, 1L of methanol and 5-chloro-4-methoxy-3-nitropyridine-2-amine (100g, 0.50mol) were added, and finally 3g of a palladium-carbon catalyst having a mass fraction of 10wt% of palladium and 150mL of a 6N aqueous sodium hydroxide solution were added. Stirring was started, and the air in the kettle was replaced with nitrogen three times. Then, hydrogen was introduced to maintain an internal pressure of 0.5MPa, and the reaction was carried out at room temperature for 8 hours. The reaction was complete, the reaction mixture was filtered, the catalyst was removed, and the filtrate was poured into 2L of cold water and extracted with ethyl acetate. The organic phase was washed with saturated common salt water, dried over anhydrous sodium sulfate, and desolventized. Recrystallization from ethyl acetate gave 58g of a gray solid in a yield of 85%.

[0054] 6. Synthesis of 2,3-diamino-4-bromopyridine

[0055] Prepare a 2L three-necked flask with mechanical stirring and a reflux condenser. First, add 1L of acetonitrile to the reaction flask and stir. Then, add 4-methoxy-pyridine-2,3-diamine (100g, 0.72mol) and phosphorus oxybromide (240g, 0.84mol). Heat to 80°C and reflux until the reaction turns from turbid to clear. After 6 hours, a TLC sample (EA:PE = 1:1, UV) indicates completion of the reaction. Pour the reaction solution into 2kg of ice water and adjust the pH to 10 with 6N sodium hydroxide solution. Extract the mixture three times with ethyl acetate. Separate the organic phase and wash it twice with saturated sodium bicarbonate solution (500mL x 2). Concentrate the organic phase to near dryness. Solid precipitates. Add 500ml of dichloromethane to precipitate more solid. Chill the mixture for two hours. Filter the filter cake and rinse it with 500ml of dichloromethane to obtain 122g of a brownish-gray solid, a 90% yield. The NMR spectrum of the product 2,3-diamino-4-bromopyridine is as follows Figure 1 As stated.

[0056] Example 2

[0057] 1. Synthesis of N-Boc-2-amino-4,5-dichloropyridine

[0058] Prepare a 10L three-necked flask, mechanically stir, and reflux condenser; first add 5L of 1,4-dioxane to the reaction flask, then add N-BOC-2-amino-4-chloropyridine (825g, 3.9mol), start stirring, add NCS (587.4g, 4.4mol), heat to 90℃ for reaction, and the system changes from turbid to clear; take a sample TLC (EA:PE=1:5, UV) after three hours, showing that the reaction is complete; concentrate the reaction solution to dryness, solid precipitates, add 6L of water to disperse, the solid is insoluble, then add 8L of ethyl acetate and stir for half an hour, the solid dissolves in ethyl acetate, separate the ethyl acetate phase, wash twice with saturated sodium bicarbonate aqueous solution (3L×2), concentrate the organic phase to almost dryness, solid precipitates, add 500ml of petroleum ether, precipitate more solid, put it in the refrigerator and freeze for two hours, filter, and rinse the filter cake with 500ml of petroleum ether to obtain 633g of off-white solid, with a yield of 66%.

[0059] Synthesis of 2,4,5-dichloro-2-aminopyridine

[0060] Prepare a 5L three-necked flask with a mechanical stirrer, a thermometer, and a reflux condenser. First, add 1.8L of water to the reaction flask and stir. Then, add 1L of 48% hydrobromic acid. Finally, add N-Boc-2-amino-4,5-dichloropyridine (500g, 2.02mol). Set the temperature to 100°C and maintain overnight. The next day, take a sample by TLC (EA:PE = 1:1, UV). If the reaction is complete, turn off the heat, remove the oil bath, and stir to room temperature. Solids will precipitate. Pour the reaction solution into 6kg of crushed ice and adjust the pH to 8-9 with 50wt% sodium hydroxide solution. Keep the temperature below 20°C. Add more ice to cool if the temperature rises. A large amount of solid will precipitate after adjustment. The product was extracted with ethyl acetate twice (5 L × 2), and the organic phase was washed twice with saturated brine (3 L × 2), dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, rinsed with ethyl acetate, and the organic phase was concentrated to a small volume. Solid precipitated, 1 L of petroleum ether was added, more solid precipitated, filtered, rinsed with 500 ml of petroleum ether, and dried to obtain 278 g of an off-white solid with a yield of 84%.

[0061] Synthesis of 3,4,5-dichloro-3-nitropyridin-2-amine

[0062] Prepare a 3L three-necked flask, mechanically stir, and reflux condenser. First, add 1L of 98% concentrated sulfuric acid to the reaction flask, start stirring, and slowly add 4,5-dichloro-3-nitropyridine-2-amine (200g, 1.2mol) in an ice-water bath. Control the temperature not to exceed 40°C. When the temperature drops to about 5°C, slowly add 90% fuming nitric acid (92g, 1.3mol) dropwise. Control the temperature not to exceed 20°C. After the drop is complete, stir at room temperature overnight. The next day, slowly heat to 75°C and keep warm for 3 hours. Cool to room temperature, then pour into ice water, neutralize with ammonia water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and desolventize to obtain 223g of yellow solid with a yield of 87%.

[0063] 4. Synthesis of 5-chloro-4-methoxy-3-nitropyridin-2-amine

[0064] Prepare a 3L three-necked flask, mechanically stir, and reflux condenser. First, add 1L of anhydrous DMF to the reaction flask, start stirring, add 4,5-dichloro-3-nitropyridine-2-amine (208g, 1.0mol) at room temperature, then add sodium methoxide (62g, 1.15mol), stir at room temperature for 30 minutes, then heat to 60°C and react overnight. The next day, pour the reaction mixture into 3L of cold water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and desolventize to obtain 175g of yellow solid with a yield of 86%.

[0065] 5. Synthesis of 4-methoxy-pyridine-2,3-diamine

[0066] In a 2L autoclave, 1L methanol and 5-chloro-4-methoxy-3-nitropyridine-2-amine (100g, 0.50mol) were added, and finally 3g of palladium-carbon catalyst and 150mL of triethylamine with a mass fraction of palladium being 10wt% were added. Stirring was started, and the air in the kettle was replaced with nitrogen 3 times. Then, hydrogen was introduced to maintain an internal pressure of 0.5MPa, and the reaction was carried out at room temperature for 8 hours. The reaction was complete, and the reaction mixture was filtered to remove the catalyst. The filtrate was poured into 2L cold water and extracted with ethyl acetate. The organic phase was washed with saturated common salt water, dried over anhydrous sodium sulfate, and desolventized. Recrystallization from ethyl acetate gave 55g of a gray solid in an 80% yield.

[0067] 6. Synthesis of 2,3-diamino-4-bromopyridine

[0068] Prepare a 2L three-necked flask with mechanical stirring and a reflux condenser. First, add 1L of toluene to the reaction flask and stir. Then, add 4-methoxy-pyridine-2,3-diamine (100g, 0.72mol) and phosphorus oxybromide (240g, 0.84mol). Heat to 110°C and reflux until the reaction is complete, turning the turbidity clear. After 5 hours, a TLC sample (EA:PE = 1:1, UV) indicates completion of the reaction. Pour the reaction solution into 2kg of ice water and adjust the pH to 10 with 6N sodium hydroxide solution. Extract the mixture three times with ethyl acetate, separate the organic phase, and wash it twice with saturated sodium bicarbonate solution (500mL x 2). Concentrate the organic phase to near dryness, and solid precipitate. Add 500ml of dichloromethane to precipitate more solid. Chill the mixture for two hours. Filter the filter cake and rinse it with 500ml of dichloromethane to obtain 119g of a brownish-gray solid, yielding 88%.

[0069] Example 3

[0070] 1. Synthesis of N-Boc-2-amino-4,5-dichloropyridine

[0071] Prepare a 1L three-necked flask, mechanically stir, and reflux condenser; first add 500mL of acetonitrile to the reaction flask, then add N-BOC-2-amino-4-chloropyridine (82.5g, 0.39mol), start stirring, add NCS (52g, 0.39mol), heat to 80℃ and reflux reaction, the system changes from turbid to clear; TLC (EA:PE=1:5, UV) is taken after three hours, showing that there are still raw materials that have not reacted completely; the reaction solution is concentrated to dryness, solid precipitates, 600mL of water is added to disperse, the solid is insoluble, and 800mL of ethyl acetate is added and stirred for half an hour, the solid is dissolved in ethyl acetate, the ethyl acetate phase is separated, and washed twice with saturated sodium bicarbonate aqueous solution (300mL×2), the organic phase is concentrated to dryness, solid precipitates, 50ml of petroleum ether is added, more solid precipitates, and the refrigerator is frozen for two hours, filtered, and the filter cake is rinsed with 50ml of petroleum ether to obtain 60g of off-white solid, with a yield of 63%.

[0072] Synthesis of 2,4,5-dichloro-2-aminopyridine

[0073] Prepare a 1L three-necked flask with a mechanical stirrer, a thermometer, and a reflux condenser. First, add 200mL of water to the reaction flask and stir. Then, add 25mL of 68% concentrated nitric acid. Finally, add N-Boc-2-amino-4,5-dichloropyridine (50g, 0.2mol). Set the temperature to 100°C and maintain overnight. The next day, take a sample by TLC (EA:PE = 1:1, UV). If the reaction is complete, turn off the heat, remove the oil bath, and stir to room temperature. Solids will precipitate. Pour the reaction solution into 600g of crushed ice and adjust the pH to 8-9 with 50wt% sodium hydroxide solution. Keep the temperature below 20°C. Add more ice to cool if the temperature rises. A large amount of solid will precipitate after adjustment. The product was extracted twice with ethyl acetate (500 mL × 2), and the organic phase was washed twice with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, rinsed with ethyl acetate, and the organic phase was concentrated to a small volume. Solid precipitated, 100 mL of petroleum ether was added, more solid precipitated, filtered, rinsed with 50 ml of petroleum ether, and dried to obtain 26.5 g of an off-white solid with a yield of 80%.

[0074] Synthesis of 3,4,5-dichloro-3-nitropyridin-2-amine

[0075] Prepare a 3L three-necked flask, mechanically stir, and reflux condenser. First, add 1L of 98% concentrated sulfuric acid to the reaction flask, start stirring, and slowly add 4,5-dichloro-3-nitropyridine-2-amine (200g, 1.2mol) in an ice-water bath. Control the temperature not to exceed 40°C. When the temperature drops to about 5°C, slowly add concentrated nitric acid (158g, 1.7mol) with a mass concentration of 68%. Control the temperature not to exceed 20°C. After the drop is complete, stir at room temperature overnight. The next day, slowly heat to 75°C and keep warm for 3 hours. Cool to room temperature, then pour into ice water, neutralize with ammonia water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and desolventize to obtain 222g of yellow solid with a yield of 87%.

[0076] 4. Synthesis of 5-chloro-4-methoxy-3-nitropyridin-2-amine

[0077] Prepare a 3L three-necked flask, mechanically stir, and reflux condenser. First, add 500mL of anhydrous methanol to the reaction flask, start stirring, add 4,5-dichloro-3-nitropyridine-2-amine (100g, 0.48mol) at room temperature, then add sodium methoxide (30g, 0.55mol), stir at room temperature for 30 minutes, then heat to 60°C and react overnight. The next day, pour the reaction mixture into 1.5kg of ice water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and desolventize to obtain 81g of yellow solid with a yield of 83%.

[0078] 5. Synthesis of 4-methoxy-pyridine-2,3-diamine

[0079] In a 2L autoclave, 1L of methanol and 5-chloro-4-methoxy-3-nitropyridine-2-amine (100g, 0.50mol) were added, followed by 3g of a palladium-carbon catalyst containing 10wt% palladium and 150mL of a 6N aqueous sodium hydroxide solution. Stirring was initiated, and the air in the autoclave was replaced with nitrogen three times. Hydrogen was then introduced to maintain an internal pressure of 0.1MPa, and the reaction was carried out at 40°C for 8 hours. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the mother liquor was poured into 2L of cold water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, desolvated, and recrystallized from ethyl acetate to obtain 53g of a gray solid in a yield of 78%.

[0080] 6. Synthesis of 2,3-diamino-4-bromopyridine

[0081] Prepare a 2L three-necked flask with mechanical stirring and a reflux condenser. First, add 1L of acetonitrile to the reaction flask and stir. Then, add 4-methoxy-pyridine-2,3-diamine (100g, 0.72mol) and phosphorus oxybromide (240g, 0.84mol). Heat to 60°C for reaction, and the system will turn from turbid to clear. After 15 hours, a TLC sample (EA:PE = 1:1, UV) indicates completion of the reaction. Pour the reaction solution into 2kg of ice water and adjust the pH to 10 with 6N sodium hydroxide solution. Extract three times with ethyl acetate. Separate the organic phase and wash twice with saturated sodium bicarbonate solution (500mL x 2). Concentrate the organic phase to near dryness, and solid precipitate. Add 500mL of dichloromethane to precipitate more solid. Refrigerate for two hours. Filter and rinse the filter cake with 500mL of dichloromethane to obtain 111g of a brown-gray solid, with a yield of 82%.

[0082] The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Any changes, modifications, additions or substitutions made by persons of ordinary skill in the art within the spirit and scope of the present invention shall also fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 2,3-diamino-4-bromopyridine, characterized in that The following steps are involved: (1) reacting N-BOC-2-amino-4-chloropyridine with a halogenating agent to obtain N-Boc-2-amino-4-chloro-5-halopyridine; (2) Removing Boc from N-Boc-2-amino-4-chloro-5-halopyridine with dilute acid to obtain 2-amino-4-chloro-5-halopyridine; (3) Nitrate 2-amino-4-chloro-5-halopyridine with mixed acid to obtain 4-chloro-5-halo-3-nitropyridine-2-amine; (4) reacting 4-chloro-5-halogeno-3-nitropyridine-2-amine with sodium methoxide to obtain 5-halogeno-4-methoxy-3-nitropyridine-2-amine; (5) reacting 5-halogenated-4-methoxy-3-nitropyridine-2-amine with a reducing agent to obtain 4-methoxy-pyridine-2,3-diamine; (6) 4-Methoxy-pyridine-2,3-diamine is reacted with a bromination reagent to obtain 2,3-diamino-4-bromopyridine.

2. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 1, characterized in that The specific process of step (1) is as follows: dissolving N-BOC-2-amino-4-chloropyridine in a solvent, then adding a halogenating agent, heating to T1, keeping the temperature at T1 for reaction until the reaction is complete, evaporating the solvent under reduced pressure, pouring into cold water, stirring, extracting with ethyl acetate, separating the ethyl acetate phase, washing twice with a saturated sodium bicarbonate aqueous solution, and concentrating the organic phase to dryness to obtain solid N-Boc-2-amino-4-chloro-5-halogenopyridine, wherein the controlled temperature of T1 is 10°C≤T1≤150°C.

3. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 2, characterized in that: The solvent is acetonitrile, 1,4-dioxane, methanol, ethanol, isopropanol or dichloroethane; the halogenation reagent is a chlorination reagent, a bromination reagent or an iodination reagent.

4. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 2, characterized in that: The molar ratio of the N-BOC-2-amino-4-chloropyridine to the halogenating agent is 1:(1-5).

5. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 1, characterized in that The specific process of step (2) is as follows: N-Boc-2-amino-4-chloro-5-halopyridine is added to dilute acid at room temperature, and then the temperature is raised to T2, and the temperature is kept at T2 until the reaction is complete, the reaction solution is poured into crushed ice, and the pH is adjusted to 8-9 with 50wt% sodium hydroxide aqueous solution, and the temperature is controlled not to be higher than 30°C. A large amount of solid is precipitated, and the solid product is extracted twice with ethyl acetate. The organic phase is washed twice with saturated brine, dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, rinsed with ethyl acetate, and the organic phase is concentrated to dryness. Petroleum ether is then added to precipitate solids, filtered, and the filter cake is rinsed with petroleum ether and dried to obtain an off-white solid 2-amino-4-chloro-5-halopyridine, wherein the temperature of T2 is controlled to be -10°C≤T2≤150°C, and the dilute acid is dilute sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid or hydrochloric acid.

6. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 1, characterized in that The specific process of step (3) is as follows: slowly add 2-amino-4-chloro-5-halogenopyridine to the concentrated sulfuric acid solution in an ice-water bath, control the temperature not higher than T3, continue cooling in an ice-water bath, and when the temperature drops to T4, slowly add the nitrating reagent dropwise, control the temperature not higher than T5, and stir at room temperature overnight; the next day, slowly increase the temperature to T6, keep the temperature for reaction for 3 hours, cool the reaction mixture to room temperature, then pour it into ice water, neutralize it with ammonia water, extract with ethyl acetate, wash the organic phase with saturated brine, and remove the residue. The mixture is dried with sodium sulfate and desolventized to obtain a yellow solid 4-chloro-5-halogenated-3-nitropyridine-2-amine, wherein the controlled temperature of T3 is -5°C ≤ T3 ≤ 50°C; the controlled temperature of T4 is -5°C ≤ T4 ≤ 30°C; the controlled temperature of T5 is 5°C ≤ T5 ≤ 40°C; and the controlled temperature of T6 is 25°C ≤ T6 ≤ 150°C. The nitrating agent is concentrated nitric acid or fuming nitric acid; and the molar ratio of the 2-amino-4-chloro-5-halogenated pyridine to the nitrating agent is 1:(1-3).

7. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 1, characterized in that The specific process of step (4) is as follows: 4-chloro-5-halogenated-3-nitropyridine-2-amine is slowly added to a sodium methoxide solution at room temperature, and the temperature is kept at T7 until the reaction is complete. The reaction mixture is poured into cold water, extracted with ethyl acetate, and the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and desolventized to obtain a yellow solid 5-halogenated-4-methoxy-3-nitropyridine-2-amine, wherein the control temperature of T7 is 15°C ≤ T7 ≤ 150°C; the molar ratio of the 4-chloro-5-halogenated-3-nitropyridine-2-amine to the sodium methoxide is 1: (1~3).

8. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 1, characterized in that The specific process of step (5) is as follows: after adding methanol and 5-halogenated-4-methoxy-3-nitropyridine-2-amine into the autoclave, palladium-carbon catalyst and acid binding agent are added, stirring is started, the air in the autoclave is replaced with nitrogen three times, and then hydrogen is introduced to maintain the internal pressure at 0.01MPa≤P≤1MPa and temperature T8 for complete reaction, the reaction mixture is filtered to remove the catalyst, the filtrate is poured into cold water, extracted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, desolvated, and recrystallized from ethyl acetate to obtain 4-methoxy-pyridine-2,3-diamine, wherein the control temperature of T8 is 10°C≤T8≤120°C, and the mass fraction of palladium in the palladium-carbon catalyst is 10wt%.

9. A method for synthesizing 2,3-diamino-4-bromopyridine according to claim 1, characterized in that The specific process of step (6) is as follows: 4-methoxy-pyridine-2,3-diamine is slowly added to the solvent at room temperature, stirring is started, and then a bromination reagent is added, the temperature is raised to T9 for reaction, and the temperature is kept at T9 until the reaction is complete, the reaction solution is poured into ice water, the pH is adjusted to 10 with sodium hydroxide aqueous solution, and then extracted three times with ethyl acetate, the organic phase obtained by extraction is washed twice with a saturated sodium bicarbonate aqueous solution, the organic phase is concentrated to dryness and then dichloromethane is added. After the solid is precipitated, it is placed in a refrigerator and frozen for two hours, filtered, and the filter cake is rinsed with dichloromethane to obtain a brown-gray solid 2,3-diamino-4-bromopyridine, wherein the control temperature of T9 is 40°C≤T9≤150°C, and the bromination reagent is phosphorus oxybromide or phosphorus tribromide.

10. The method for synthesizing 2,3-diamino-4-bromopyridine according to claim 9, wherein: The molar ratio of the 4-methoxy-pyridine-2,3-diamine to the bromination reagent is 1:(1-5).

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