A process for the preparation of 6-bromo-2-chloro-3-nitropyridine

Abstract

The application provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine and relates to the technical field of organic synthesis. 2-amino-3-nitro-6-chloropyridine is reacted with a hydrobromic acid acetic acid solution to obtain 2-amino-3-nitro-6-bromopyridine, which is diazotized to obtain 6-bromo-2-hydroxy-3-nitropyridine, and then the 6-bromo-2-hydroxy-3-nitropyridine is reacted with a chlorinating reagent to obtain 6-bromo-2-chloro-3-nitropyridine. The synthesis method of 6-bromo-2-chloro-3-nitropyridine has the advantages of easy availability of raw materials, low price, mild reaction condition, simple process, high economic benefit, suitability for large-scale production, and the like, can solve the current situation of high price of 6-bromo-2-chloro-3-nitropyridine, and can play a positive role in the promotion of downstream products of 6-bromo-2-chloro-3-nitropyridine.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 6-bromo-2-chloro-3-nitropyridine. BACKGROUND

[0002] 6-bromo-2-chloro-3-nitropyridine is widely used as a fine chemical raw material in pharmaceutical intermediates and the like. It is reported in patent WO2022042691A1 that 6-bromo-2-chloro-3-nitropyridine is a key intermediate for synthesizing GLP-1 agonists, and it is reported in patent CN109369641A that 6-bromo-2-chloro-3-nitropyridine is an important intermediate for synthesizing organic electroluminescent devices.

[0003] However, no synthesis method of 6-bromo-2-chloro-3-nitropyridine has been reported so far, resulting in a high price of 6-bromo-2-chloro-3-nitropyridine. At present, the price of 6-bromo-2-chloro-3-nitropyridine is high, which increases the cost burden for the promotion and application of downstream products thereof.

[0004] Therefore, there is an urgent need to develop a synthesis method of 6-bromo-2-chloro-3-nitropyridine with low price, mild reaction conditions, simple process, high economic benefit and suitability for large-scale production, so as to solve the current situation of high price of 6-bromo-2-chloro-3-nitropyridine and play a positive role in the promotion of downstream products thereof. SUMMARY

[0005] In view of the above problems, the application provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine. In the synthesis method, 2-amino-3-nitro-6-chloropyridine is reacted with a bromine acid-acetic acid solution to obtain 2-amino-3-nitro-6-bromopyridine, which is diazotized to obtain 6-bromo-2-hydroxy-3-nitropyridine, and then the 6-bromo-2-hydroxy-3-nitropyridine is reacted with a chlorinating reagent to obtain 6-bromo-2-chloro-3-nitropyridine. The synthesis method of 6-bromo-2-chloro-3-nitropyridine provided by the application has the advantages of easy availability and low price of raw materials, mild reaction conditions, simple process, high economic benefit and suitability for large-scale production, and can solve the current situation of high price of 6-bromo-2-chloro-3-nitropyridine and play a positive role in the promotion of downstream products thereof.

[0006] The technical scheme of the application comprises:

[0007] In one aspect, the application provides a synthesis method of 6-bromo-2-chloro-3-nitropyridine, and the technical route of the synthesis method is as follows:

[0008]

[0009] The synthesis method comprises the following steps:

[0010] (1) 2-amino-3-nitro-6-chloropyridine is reacted with hydrobromic acid acetic acid solution to obtain 2-amino-3-nitro-6-bromopyridine;

[0011] (2) 2-amino-3-nitro-6-bromopyridine is diazotized to obtain 6-bromo-2-hydroxy-3-nitropyridine;

[0012] (3) 6-bromo-2-hydroxy-3-nitropyridine is reacted with a chlorinating agent to obtain 6-bromo-2-chloro-3-nitropyridine.

[0013] Specifically, the step (1) is:

[0014] 2-amino-3-nitro-6-chloropyridine is added into hydrobromic acid acetic acid solution, and the temperature is raised to T1 to keep the reaction complete, the solution is evaporated under reduced pressure, the residue is poured into ice water, the pH is adjusted, the temperature is controlled at T2, a precipitate is formed, filtered, washed with water, and dried to obtain 2-amino-3-nitro-6-bromopyridine;

[0015] or 2-amino-3-nitro-6-chloropyridine is added into hydrobromic acid acetic acid solution, and the temperature is raised to T1 to keep the reaction complete, the solution is evaporated under reduced pressure, poured into ice water, the pH is adjusted, the temperature is controlled at T2, filtered, washed with water, and dried to obtain 2-amino-3-nitro-6-bromopyridine by recrystallization;

[0016] Further specifically, the hydrobromic acid acetic acid solution in the step (1) is 30% hydrobromic acid acetic acid solution.

[0017] Further specifically, the temperature T1 in the step (1) is 30-150°C.

[0018] Preferably, the temperature T1 in the step (1) is 90-120°C.

[0019] Further preferably, the temperature T1 in the step (1) is 90-100°C, 100-110°C, or 110-120°C.

[0020] Further specifically, the temperature T2 in the step (1) is 0-30°C.

[0021] Preferably, the temperature T2 in the step (1) is 5-15°C.

[0022] Further preferably, the temperature T2 in the step (1) is 5-10°C or 10-15°C.

[0023] Further specifically, the reaction complete in the step (1) is HPLC detection of reaction complete.

[0024] Further specifically, the pH adjusting agent used in the pH adjusting of step (1) includes ethylenediamine, ethanolamine, ammonia, sodium hydroxide, potassium hydroxide, and saturated aqueous sodium bicarbonate solution.

[0025] Preferably, the pH adjusting agent used in the pH adjusting of step (1) is ammonia.

[0026] Further specifically, the pH of step (1) is 7-9.

[0027] Preferably, the pH of step (1) is 8.

[0028] Further specifically, the drying of step (1) is vacuum drying at a temperature of 50-60℃.

[0029] Preferably, the vacuum drying temperature of step (1) is 55℃.

[0030] Specifically, step (2) is as follows: concentrated sulfuric acid is added to a reaction bottle, the temperature is lowered to 5℃, 2-amino-3-nitro-6-bromopyridine obtained in step (1) is added, the temperature is controlled to be no higher than 15℃, when the temperature is lowered to 0℃, aqueous sodium nitrite solution is added, the temperature is controlled to be within T3, after dropwise addition at room temperature, the mixture is stirred overnight, the reaction is complete, the reaction solution is poured into ice water, the temperature is controlled to be no higher than 30℃, solid is precipitated under stirring, the solid is filtered,

[0031] washed with water, and dried to obtain 6-bromo-2-hydroxy-3-nitropyridine.

[0032] Further specifically, the mass concentration of the concentrated sulfuric acid added in step (2) is 95%.

[0033] Further specifically, the temperature of T3 of step (2) is -10℃-40℃.

[0034] Preferably, the temperature of T3 of step (2) is 0℃-15℃.

[0035] Further preferably, the temperature of T3 of step (2) is 0℃-5℃, 5℃-10℃, or 10℃-15℃.

[0036] Further specifically, the molar ratio of 2-amino-3-nitro-6-bromopyridine to sodium nitrite of step (2) is 1:1-5.

[0037] Preferably, the molar ratio of 2-amino-3-nitro-6-bromopyridine to sodium nitrite of step (2) is 1:1-3.

[0038] Further preferably, the molar ratio of 2-amino-3-nitro-6-bromopyridine to sodium nitrite of step (2) is 1:1, 1:2, or 1:3.

[0039] Specifically, the step (3) is adding solvent into the reaction bottle, adding 6-bromo-2-hydroxy-3-nitropyridine obtained in step (2) under stirring, cooling to 0℃ in ice-salt bath, adding chlorinating reagent under stirring, controlling the temperature T4 in the range, keeping the reaction complete, pouring the reaction liquid into ice water, stirring, adjusting pH, extracting the combined organic phase, washing with water, drying, decolorizing, filtering, washing, concentrating the organic phase to small volume, adding petroleum ether, cooling to 0-5℃ under stirring, filtering, drying to obtain 6-bromo-2-chloro-3-nitropyridine.

[0040] Further specifically, the temperature T4 in step (3) is -10℃-40℃.

[0041] Preferably, the temperature T4 in step (3) is 0℃-5℃.

[0042] Further specifically, the solvent in step (3) includes ethyl acetate, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, toluene.

[0043] Preferably, the solvent in step (3) is acetonitrile, toluene.

[0044] Further specifically, the chlorinating reagent in step (3) includes phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, bis(trichloromethyl) carbonate, trichloromethyl chloroformate.

[0045] Preferably, the chlorinating reagent in step (3) is phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride.

[0046] Further specifically, the pH adjusting agent for adjusting pH in step (3) includes ethylenediamine, ethanolamine, ammonia, sodium hydroxide, potassium hydroxide, saturated aqueous sodium bicarbonate solution.

[0047] Preferably, the pH adjusting agent for adjusting pH in step (3) is saturated aqueous sodium bicarbonate solution.

[0048] Further specifically, the pH in step (3) is 6-9.

[0049] Preferably, the pH in step (3) is 7-8.

[0050] Further specifically, the reaction complete in step (3) is detected by TLC.

[0051] Further specifically, the solvent for extraction in step (2) is ethyl acetate.

[0052] Further specifically, the drying in step (3) is drying by adding anhydrous sodium sulfate.

[0053] Further specifically, the decolorization in step (3) is decolorization by adding activated carbon.

[0054] Further specifically, the elution in step (3) is elution by ethyl acetate.

[0055] In another aspect, the present application provides an application of the above-mentioned synthetic method, and the application comprises an application in the preparation of 6-bromo-2-chloro-3-nitropyridine or its analogues, and a pharmaceutically acceptable carrier and / or excipient.

[0056] Specifically, the analogues are derivatives of 6-bromo-2-chloro-3-nitropyridine, pharmaceutically acceptable salts thereof, tautomers thereof and / or stereoisomers thereof.

[0057] Technical effects achieved by the present application:

[0058] (1) The present application provides a synthetic method of 6-bromo-2-chloro-3-nitropyridine, which has easily available raw materials and low price, mild reaction conditions, simple process, high economic benefit and is suitable for large-scale production.

[0059] (2) The synthetic method of 6-bromo-2-chloro-3-nitropyridine provided by the present application can solve the current situation that the price of 6-bromo-2-chloro-3-nitropyridine is high, and can play a positive role in promoting the downstream products of 6-bromo-2-chloro-3-nitropyridine. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1 It is a nuclear magnetic resonance diagram of 2-amino-3-nitro-6-bromopyridine.

[0061] Figure 2 It is a nuclear magnetic resonance diagram of 6-bromo-2-chloro-3-nitropyridine. DETAILED DESCRIPTION

[0062] The present application will be described below in conjunction with specific examples, and the following examples are not used to limit the present application, but are used to illustrate the present application, so that the technical scheme of the present application is easier to understand and master. In the following examples, the experimental methods are conventional methods unless otherwise specified; and the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0063] Example 1

[0064] 1. Synthesis of 2-amino-3-nitro-6-bromopyridine

[0065] In a 2L autoclave, 1L of a 30% hydrobromic acid-acetic acid solution and 100g (0.58mol) of 2-amino-3-nitro-6-chloropyridine were added. The mixture was heated to 120℃ and reacted for 12 hours. HPLC analysis confirmed the reaction was complete. The acetic acid solution was evaporated under reduced pressure, and the residue was poured into 1kg of ice water. The pH was adjusted to 8 with concentrated ammonia, and the temperature was controlled at 5-15℃ to form a precipitate. The precipitate was filtered, washed with cold water, and dried under vacuum at 55℃ to obtain 123g of a yellow solid, 2-amino-3-nitro-6-bromopyridine, with a yield of 98%. The NMR spectrum is shown below. Figure 1 .

[0066] 1 H-NMR (400MHz, DMSO-d6); δ: 6.88 (1H, m, J = 7.2Hz), 8.24 (1H, d, J = 8.4Hz), 8.25 (2H, br s)

[0067] 2. Synthesis of 6-bromo-2-hydroxy-3-nitropyridine

[0068] In a 10L reactor, 5L of 95% sulfuric acid was added, and the mixture was cooled to approximately 5°C. Then, 1000g (4.59mol) of 2-amino-3-nitro-6-bromopyridine was slowly added, maintaining the temperature below 15°C. Once the temperature dropped to 0°C, 540g (7.83mol) of sodium nitrite (dissolved in 1.2L of water) was slowly added dropwise, maintaining the temperature between 0-15°C. After the addition was complete, the mixture was stirred overnight at room temperature. The next day, TLC showed the reaction was complete. The reaction solution was poured into 12kg of ice water, and the temperature was maintained below 30°C. A solid precipitated under stirring, was filtered, washed with cold water, and dried. 854g of a yellowish-green solid, 6-bromo-2-hydroxy-3-nitropyridine, was obtained, with a yield of Y = 85%.

[0069] 3. Synthesis of 6-bromo-2-chloro-3-nitropyridine

[0070] 1 L three-necked flask, mechanical stirring, oil bath, condenser. Into the flask was added 6-bromo-2-hydroxy-3-nitropyridine (50 g, 0.23 mol), acetonitrile (600 mL), and the mixture was cooled to 0 °C in an ice-salt bath. Phosphorus pentachloride (50 g, 0.24 mol) was added dropwise to the flask while stirring and the temperature was controlled to be no higher than 5 °C. After the addition was completed, the reaction was maintained at 0-5 °C. After 1.5 h, the reaction was sampled and TLC analysis showed that the reaction was complete. The reaction mixture was poured into 1.5 kg of ice water to quench the reaction. After stirring for 0.5 h, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (350 mL x 3), and the combined organic phase was washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate (100 g), decolorized with activated carbon (3 g), filtered, and eluted with ethyl acetate (100 mL). The organic phase was concentrated to a small volume, and a solid precipitated. The solid was dissolved in 1 L of petroleum ether, and more solid precipitated. The mixture was cooled to 0-5 °C and stirred for 0.5 h. The solid was filtered and dried to give 6-bromo-2-chloro-3-nitropyridine as a yellow solid (51 g, yield Y = 94%). The structure of the product was confirmed by1H NMR (see Figure 1). Figure 2 .

[0071] 1 H-NMR (400 MHz, CDC13-dl); δ: 7.64 (1H, dd, J = 4.4 Hz), 8.11 (1H, d, J = 8.4 Hz)

[0072] Example 2

[0073] 1. Synthesis of 2-amino-3-nitro-6-bromopyridine

[0074] Into a 1 L three-necked flask was added 30% hydrobromic acid in acetic acid (100 mL), and 2-amino-6-chloro-3-nitropyridine (10 g) was added slowly at room temperature. The reaction mixture was heated to 100 °C. After 24 h, 30% hydrogen bromide in acetic acid (100 mL) was added. After 48 h, the reaction mixture was cooled and concentrated. The residue was poured into 0.5 kg of ice water, and the pH was adjusted to 8 with concentrated aqueous ammonia while the temperature was controlled at 5-15 °C. A precipitate formed, which was filtered, washed with cold water, and dried in a vacuum oven at 55 °C. The product was recrystallized from isopropyl ether to give 2-amino-3-nitro-6-bromopyridine as a yellow solid (9 g, yield 72%).

[0075] 2. Synthesis of 6-bromo-2-hydroxy-3-nitropyridine

[0076] 10 L reactor was charged with 5 L of concentrated sulfuric acid and cooled to about 5 °C. 2-amino-3-nitro-6-bromopyridine (1000 g, 4.59 mol) was slowly added while maintaining the temperature below 15 °C. Once the temperature had dropped to 0 °C, sodium nitrite (700 g, 10.14 mol dissolved in 1.2 L of water) was slowly added dropwise while maintaining the temperature between 0 and 15 °C. The reaction was stirred overnight at room temperature. The next day, TLC showed that the reaction was complete. The reaction mixture was poured into 12 kg of ice water and the solid was precipitated while maintaining the temperature below 30 °C. The solid was filtered, washed with cold water and dried to obtain 834 g of 6-bromo-2-hydroxy-3-nitropyridine as a yellow-green solid in a yield of Y = 83%.

[0077] 3. Synthesis of 6-bromo-2-chloro-3-nitropyridine

[0078] A 1 L flask was charged with 6-bromo-2-hydroxy-3-nitropyridine (50 g, 0.23 mol), acetonitrile (600 mL) and cooled to 0 °C in an ice-salt bath. Phosphorus trichloride (33 g, 0.24 mol) was slowly added while maintaining the temperature below 5 °C. The reaction was maintained at 0-5 °C for 1.5 hours. The reaction mixture was poured into 1.2 kg of ice water and stirred for half an hour. The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The organic phase was extracted three times with ethyl acetate (350 mL*3), washed twice with saturated aqueous sodium chloride (500 mL*2), dried over anhydrous sodium sulfate (100 g), decolorized with activated carbon (3 g), filtered, rinsed with ethyl acetate (100 mL), and concentrated to a small volume. A solid was precipitated and more solid was precipitated upon the addition of 1 L of petroleum ether. The mixture was cooled to 0-5 °C and stirred for half an hour. The solid was filtered and dried to obtain 49 g of 6-bromo-2-chloro-3-nitropyridine as a yellow solid in a yield of Y = 90%.

[0079] Example 3

[0080] 1. Synthesis of 2-amino-3-nitro-6-bromopyridine

[0081] A 1 L flask was charged with 30% hydrobromic acid in acetic acid (100 mL) and 2-amino-6-chloro-3-nitropyridine (10 g) was slowly added at room temperature. The reaction mixture was heated to 90 °C. After 24 hours, 30% hydrogen bromide in acetic acid (100 mL) was added. After 48 hours, the reaction mixture was cooled and concentrated. The residue was poured into 0.5 kg of ice water and the pH was adjusted to 8 with concentrated aqueous ammonia while maintaining the temperature between 5 and 15 °C. A precipitate was formed, which was filtered and washed with cold water. The solid was dried under vacuum at 55 °C and recrystallized from isopropyl ether to obtain 8 g of 2-amino-3-nitro-6-bromopyridine as a yellow solid in a yield of 64%.

[0082] 2. Synthesis of 6-bromo-2-hydroxy-3-nitropyridine

[0083] 10 L reactor was charged with 5 L of concentrated sulfuric acid and cooled to about 5 °C. 2-amino-3-nitro-6-bromopyridine (1000 g, 4.59 mol) was slowly added while controlling the temperature to be no higher than 15 °C. When the temperature dropped to 0 °C, sodium nitrite (348 g, 5.04 mol dissolved in 1.2 L of water) was slowly added dropwise. The temperature was controlled to be between 0-15 °C. After the addition was completed, the reaction was stirred overnight at room temperature. The next day, TLC showed that the reaction was complete. The reaction solution was poured into 12 kg of ice water. The temperature was controlled to be no higher than 30 °C. The solid was precipitated while stirring. The solid was filtered, washed with cold water, and dried. Yellow-green solid 6-bromo-2-hydroxy-3-nitropyridine (804 g) was obtained with a yield of Y = 80%.

[0084] 3. Synthesis of 6-bromo-2-chloro-3-nitropyridine

[0085] 1 L three-necked flask was equipped with a mechanical stirrer and a condenser. The flask was charged with 6-bromo-2-hydroxy-3-nitropyridine (50 g, 0.23 mol), toluene (600 mL), and an ice-salt bath was used to cool the flask to 0 °C. Phosphorus oxychloride (37 g, 0.24 mol) was slowly added dropwise while stirring and controlling the temperature to be no higher than 5 °C. After the addition was completed, the reaction was incubated at 0-5 °C. After 1.5 hours, the reaction was sampled and TLC showed that the reaction was complete. The reaction solution was poured into 1.2 kg of ice water to quench the reaction. After stirring for half an hour, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (350 mL*3) three times. The organic phase was combined and washed with saturated brine (500 mL*2) twice. The organic phase was dried over anhydrous sodium sulfate (100 g), decolorized with activated carbon (3 g), filtered, and eluted with ethyl acetate (100 mL). The organic phase was concentrated to a small volume. Solid was precipitated. 1 L of petroleum ether was added. More solid was precipitated. The mixture was cooled to 0-5 °C and stirred for half an hour. The solid was filtered and dried. Yellow solid 6-bromo-2-chloro-3-nitropyridine (46 g) was obtained with a yield of Y = 85%.

[0086] The above detailed description is directed to one of the possible embodiments of the present application, which is not intended to limit the patent scope of the present application. It should be noted that any equivalent implementation or modification made without departing from the present application shall be included in the technical solution of the present application. Therefore, the patent protection scope of the present application shall be subject to the appended claims.

Claims

1. A process for the synthesis of 6-bromo-2-chloro-3-nitropyridine, characterized in that, The synthetic method comprises: (1) reacting 2-amino-3-nitro-6-chloropyridine with hydrobromic acid-acetic acid solution to obtain 2-amino-3-nitro-6-bromopyridine; (2) diazotizing 2-amino-3-nitro-6-bromopyridine to obtain 6-bromo-2-hydroxy-3-nitropyridine; (3) reacting 6-bromo-2-hydroxy-3-nitropyridine with a chlorinating reagent to obtain 6-bromo-2-chloro-3-nitropyridine; The step (1) is: 2-amino-3-nitro-6-chloropyridine is added into hydrobromic acid-acetic acid solution, heated to 120 DEG C, and reacted for 12 hours; after the reaction is completed, the solution is evaporated under reduced pressure, poured into ice water, and adjusted to a pH value; the temperature is controlled at T2; filtered, washed with water, and dried to obtain 2-amino-3-nitro-6-bromopyridine; The step (3) is: acetonitrile is added into a reaction bottle, 6-bromo-2-hydroxy-3-nitropyridine obtained in the step (2) is added under stirring, and the reaction bottle is cooled to 0 DEG C in an ice-salt bath; phosphorus pentachloride is added under stirring, and the temperature is controlled within T4; after the reaction is completed, the reaction liquid is poured into ice water, stirred, and adjusted to a pH value; the combined organic phase is extracted, washed with water, dried, decolorized, filtered, eluted, and concentrated to a small volume; solid is precipitated, petroleum ether is added, and the mixture is cooled to 0-5 DEG C under stirring; filtered, and dried to obtain 6-bromo-2-chloro-3-nitropyridine.

2. The method of synthesis of claim 1, wherein, The temperature T2 in the step (1) is 0 DEG C-30 DEG C.

3. The method of synthesis of claim 2, wherein, The temperature T2 in the step (1) is 5 DEG C-15 DEG C.

4. The method of synthesis of claim 1, wherein, The step (2) is: concentrated sulfuric acid is added into a reaction bottle, and the temperature is lowered to 5 DEG C; 2-amino-3-nitro-6-bromopyridine obtained in the step (1) is added, and the temperature is controlled to be not higher than 15 DEG C; after the temperature is lowered to 0 DEG C, sodium nitrite aqueous solution is added, and the temperature is controlled within T3; after dropwise addition is completed, the mixture is stirred overnight at room temperature; after the reaction is completed, the reaction liquid is poured into ice water, and the temperature is controlled to be not higher than 30 DEG C; solid is precipitated under stirring, filtered, washed with water, and dried to obtain 6-bromo-2-hydroxy-3-nitropyridine.

5. The method of synthesis of claim 4, wherein, The temperature T3 in the step (2) is -10 DEG C-40 DEG C.

6. The method of synthesis of claim 5, wherein, The temperature T3 in the step (2) is 0 DEG C-15 DEG C.

7. The method of synthesis of claim 4, wherein, The molar ratio of 2-amino-3-nitro-6-bromopyridine to sodium nitrite in the step (2) is 1:1-3.

8. The method of synthesis of claim 1, wherein, The temperature T4 in the step (3) is -10 DEG C-40 DEG C.

9. The method of synthesis of claim 8, wherein, The temperature T4 in the step (3) is 0 DEG C-5 DEG C.

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