A process for the preparation of 2-methyl-3-nitro-4-hydroxypyridine

Abstract

The application discloses a preparation method of 2-methyl-3-nitro-4-hydroxypyridine, which comprises the following steps: taking 2-chloro-4-amino pyridine as raw material, and first reacting with mixed acid to obtain an intermediate 2-chloro-3-nitro-4-amino pyridine; the obtained intermediate is first reacted with dimethyl / ethyl malonate to obtain dimethyl / ethyl 2-(4-amino-3-nitro pyridine-2-yl) malonate, and then the dimethyl / ethyl 2-(4-amino-3-nitro pyridine-2-yl) malonate is subjected to a hydrolysis reaction to obtain an intermediate 2-methyl-3-nitro-4-amino pyridine; and the intermediate 2-methyl-3-nitro-4-amino pyridine is subjected to diazotization and hydrolysis reactions to obtain 2-methyl-3-nitro-4-hydroxypyridine. The target product is obtained by adopting a three-step method, raw materials are cheap and easy to obtain, the process is simple and easy to operate, the cost is low, the product has high yield and purity, the method is suitable for large-scale production, and has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, specifically to a method for preparing 2-methyl-3-nitro-4-hydroxypyridine. Background Technology

[0002] 2-Methyl-3-nitro-4-hydroxypyridine has wide applications as a fine chemical raw material and pharmaceutical intermediate. For example, patent WO2018037223A1 reports that it can be used to synthesize novel antibiotic compounds for treating infections and diseases caused by Gram-positive and / or Gram-negative bacteria, particularly gonococcal infections and their associated diseases. Patent WO2011146287A1 also reports that it is an important intermediate in the synthesis of ALK5 inhibitors. The literature *Journal of Organic Chemistry*, 2017, vol. 82, #8, pp. 4328–4335 reports a compound I (structural formula shown below) with anti-HIV and antibacterial properties, and 2-methyl-3-nitro-4-hydroxypyridine is a key intermediate in the synthesis of compound I.

[0003]

[0004] Regarding the preparation methods of 2-methyl-3-nitro-4-hydroxypyridine, two methods have been publicly reported. The first process uses 2-methylpyridine oxide as the starting material, which is nitrated to obtain 2-methyl-4-nitropyridine oxide. The 2-methyl-4-nitropyridine oxide reacts with potassium tert-butoxide and methanol to obtain 2-methyl-4-methoxypyridine oxide. The 2-methyl-4-methoxypyridine oxide undergoes a reduction reaction with iron powder to obtain 2-methyl-4-methoxypyridine. The 2-methyl-4-methoxypyridine reacts with mixed acids to obtain 2-methyl- A mixture of 3-nitro-4-methoxypyridine and 2-methyl-5-nitro-4-methoxypyridine was reacted with hydrobromic acid to yield a mixture of 2-methyl-3-nitro-4-hydroxypyridine and 2-methyl-5-nitro-4-hydroxypyridine in a 3:1 ratio. Because the physicochemical properties of 2-methyl-3-nitro-4-hydroxypyridine and 2-methyl-5-nitro-4-hydroxypyridine are similar, no literature has been published on the separation and purification of pure 2-methyl-3-nitro-4-hydroxypyridine (WO2018037223A1, its synthetic route is shown below). This synthetic route is too long, involving a total of 5 steps, with a very low overall yield of only 4.3%, failing to yield a high-purity 2-methyl-3-nitro-4-hydroxypyridine product. Furthermore, this process is complex, has very high industrial production costs, poor socioeconomic benefits, and is unsuitable for large-scale production.

[0005]

[0006] Another process uses 2-methyl-4-aminopyridine as a starting material, which undergoes an aminodiazotization reaction followed by hydrolysis to obtain 2-methyl-4-hydroxypyridine. Then, it is nitrated with mixed acids to yield an inseparable mixture of 2-methyl-3-nitro-4-hydroxypyridine and 2-methyl-5-nitro-4-hydroxypyridine in a 3:1 ratio. This process also fails to address the product purification issue. It requires a subsequent step where a small amount of pure 2-methyl-3-nitro-4-bromopyridine is obtained using HPLC separation (Journal of Organic Chemistry, 2017, vol. 82, #8, pp. 4328–4335, the synthetic route is shown below). This process is only suitable for laboratory research and development and is not suitable for large-scale production.

[0007] Summary of the Invention

[0008] In view of the above-mentioned problems in the prior art, the purpose of this invention is to provide a method for preparing 2-methyl-3-nitro-4-hydroxypyridine with a simple process, mild reaction conditions, low production cost, high product purity, and suitability for large-scale production.

[0009] This invention discloses a method for preparing 2-methyl-3-nitro-4-hydroxypyridine, using 2-chloro-4-aminopyridine as a raw material. First, it reacts with mixed acids to obtain the intermediate 2-chloro-3-nitro-4-aminopyridine. The obtained intermediate is then reacted with dimethyl / ethyl malonate to obtain dimethyl / ethyl 2-(4-amino-3-nitropyridin-2-yl)malonate, followed by hydrolysis to obtain the intermediate 2-methyl-3-nitro-4-aminopyridine. The intermediate 2-methyl-3-nitro-4-aminopyridine is then subjected to diazotization and hydrolysis to obtain 2-methyl-3-nitro-4-hydroxypyridine.

[0010] Its synthetic route is as follows:

[0011]

[0012] Furthermore, the present invention also specifies a specific method for preparing 2-methyl-3-nitro-4-hydroxypyridine, which specifically includes the following steps:

[0013] 1) Under an ice-salt bath, the raw material 2-chloro-4-aminopyridine was slowly added to concentrated sulfuric acid and stirred until homogeneous. Then, nitric acid was slowly added dropwise while maintaining the temperature below 20°C. After the addition was complete, the mixture was stirred overnight at room temperature and then heated to T1 to carry out the reaction. The reaction solution was post-treated to obtain a yellow solid 2-chloro-3-nitro-4-aminopyridine.

[0014] 2) In the presence of a solvent, dimethyl / ethyl malonate and an alkaline substance were stirred at room temperature to obtain a mixture. The mixture was then reacted with 2-chloro-3-nitro-4-aminopyridine obtained in step 1) at T2. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature and hydrobromic acid was added. After stirring evenly, the mixture was heated to T3 and kept at that temperature. After the reaction was completed, the mixture was post-treated to obtain a yellow solid 2-methyl-3-nitro-4-aminopyridine.

[0015] 3) Slowly add the 2-methyl-3-nitro-4-aminopyridine from step 2) to dilute acid and stir until dissolved. Slowly add sodium nitrite solution dropwise under ice-salt bath temperature control. After the addition is complete, raise the temperature to 10-25℃ and continue the reaction. After the reaction is complete as detected by TLC, pour the reaction solution into ice water, adjust the pH to weakly acidic with ammonia water, precipitate out, filter, wash the filter cake with water until neutral, dry, and recrystallize with methanol to obtain a light yellow solid 2-methyl-3-nitro-4-hydroxypyridine.

[0016] Furthermore, the present invention also specifies that T1 in step 1) is 50-150°C; and the molar ratio of 2-chloro-4-aminopyridine, sulfuric acid, and nitric acid is 1:2-30:1-3.

[0017] Furthermore, the present invention further specifies the post-processing procedure in step 1) as follows: after the reaction solution is cooled to room temperature, it is poured into ice water, the pH is adjusted to 3 with ammonia water, the temperature is controlled not to exceed 20°C, a precipitate is generated, the filter cake is washed with water until neutral, dried, and recrystallized with methanol to obtain a yellow solid 2-chloro-3-nitro-4-aminopyridine.

[0018] Furthermore, the present invention also specifies that T2 in step 2) is 10-150℃ and T3 is 50-130℃.

[0019] Furthermore, the present invention further specifies that the solvent in step 2) is one or any combination of acetonitrile, 1,4-dioxane, tetrahydrofuran, DMF, and DMSO.

[0020] Furthermore, the present invention further specifies that the alkaline substance is one of sodium hydride, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0021] Furthermore, the present invention also specifies that the molar ratio of 2-chloro-3-nitro-4-aminopyridine, dimethyl / ethyl malonate and alkaline substance in step 2) is 1:1 to 4:1 to 4.

[0022] Furthermore, the present invention further specifies that the dilute acid in step 3) is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid, dilute hydrochloric acid, or dilute phosphoric acid.

[0023] Furthermore, the present invention also specifies that the molar ratio of 2-methyl-3-nitro-4-aminopyridine and sodium nitrite in step 3) is 1:1 to 3.

[0024] By adopting the above-mentioned technology, compared with the prior art, the beneficial effects of the present invention are as follows: The present invention uses 2-chloro-4-aminopyridine as raw material, and generates the target product 2-methyl-3-nitro-4-hydroxypyridine by nitration, substitution, hydrolysis, diazotization and hydrolysis in sequence. The raw materials are cheap and readily available, the process is simple and easy to operate, the cost is low, and the product has a high yield and purity, which is suitable for large-scale production and has broad application prospects. Attached Figure Description

[0025] Figure 1 The nuclear magnetic resonance spectrum of 2-chloro-3-nitro-4-aminopyridine prepared in Example 1 of this invention;

[0026] Figure 2 The nuclear magnetic resonance spectrum of 2-methyl-3-nitro-4-hydroxypyridine prepared in Example 1 of this invention. Detailed Implementation

[0027] The present invention will be further described below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention is not limited thereto.

[0028] Example 1

[0029] Synthesis of 1,2-chloro-3-nitro-4-aminopyridine

[0030] In a 3L reaction flask, 1.1L of 98% concentrated sulfuric acid was added. The mixture was cooled to 0°C in an ice-salt bath. 2-chloro-4-aminopyridine (170g, 1.32mol) was slowly added with stirring, maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Then, 98% fuming nitric acid (85g, 1.32mol) was slowly added dropwise, maintaining a temperature not exceeding 20°C. After the addition was complete, the mixture was stirred at room temperature overnight. The next day, the temperature was slowly raised to 75°C and maintained for 3 hours. After cooling to room temperature, the mixture was poured into 3.5kg of ice water. The pH was adjusted to 3 with ammonia water, and the temperature was maintained not exceeding 20°C. A precipitate formed. The precipitate was filtered, washed with water until neutral, dried, and recrystallized from methanol to obtain 145g of a yellow solid, 2-chloro-3-nitro-4-aminopyridine, with a yield of 63%. Its structure was confirmed by 1H NMR spectroscopy, and its NMR spectrum is shown below. Figure 1 As shown, 1 HNMR (400MHz, DMSO) δppm 6.81-6.82 (1H, d, J = 4.8Hz.) 7.36 (2H, br.s.) 7.89-7.90 (1H, d, J = 5.2Hz).

[0031] 2. Synthesis of 2-methyl-3-nitro-4-aminopyridine

[0032] In a 3L reaction flask, 1L of N,N-dimethylformamide and diethyl malonate (369g, 2.3mol) were added and stirred. Under nitrogen protection, 60% sodium hydroxide (92g, 2.3mol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Then, 2-chloro-3-nitro-4-aminopyridine (200g, 1.15mol) was added. After the addition was complete, the temperature was slowly raised to 70°C and maintained for 2 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature. Then, 1L of 48% hydrobromic acid was carefully added. After stirring at room temperature for 15 minutes, the temperature was slowly raised to 100°C and maintained for 4 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature and then poured into 3 kg of ice water. The pH was adjusted to 8 with ammonia water, and the temperature was controlled not to exceed 20°C to form a precipitate. The precipitate was filtered, the filter cake was washed with water until neutral, and dried to obtain 157 g of yellow solid 2-methyl-3-nitro-4-aminopyridine, with a yield of 89%.

[0033] 3. Synthesis of 2-methyl-3-nitro-4-hydroxypyridine

[0034] Add 1.8L of 18% dilute sulfuric acid aqueous solution to a 5L three-necked flask. Slowly add 200g of 2-methyl-3-nitro-4-aminopyridine (1.3mol) while stirring. After stirring until dissolved at room temperature, cool to 0°C in an ice-salt bath. Then, slowly add sodium nitrite aqueous solution (108g of 1.56mol of sodium nitrite dissolved in 300g of water) dropwise, controlling the temperature not to exceed 10°C. After the addition is complete, continue the reaction at 10-15°C for 1 hour. Then, stir at room temperature and let the reaction proceed overnight. The following day, after TLC detection showed the reaction was complete, the reaction solution was poured into 2 kg of ice water, the pH was adjusted to 5 with ammonia, and the temperature was controlled to not exceed 20℃ to form a precipitate. The precipitate was filtered, the filter cake was washed with water until neutral, dried, and recrystallized from methanol to obtain 181 g of a pale yellow solid, 2-methyl-3-nitro-4-hydroxypyridine, with a yield of 90% and an HPLC purity of 98.9% (214 nm). Its structure was confirmed by 1H NMR, and its NMR spectrum is shown below. Figure 2 As shown, 1 HNMR (400MHz, DMSO) δppm2.26 (3H, br.s.) 6.27-6.29 (1H, d, J = 7.2Hz) 7.67-7.69 (1H, d, J = 7.2Hz).

[0035] Example 2

[0036] Synthesis of 1,2-chloro-3-nitro-4-aminopyridine

[0037] In a 3L reaction flask, 1.1L of 98% concentrated sulfuric acid was added. The mixture was cooled to 0°C in an ice-salt bath. 2-Chloro-4-aminopyridine (170g, 1.32mol) was slowly added with stirring, maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Then, 98% fuming nitric acid (102g, 1.58mol) was slowly added dropwise, maintaining a temperature not exceeding 20°C. After the addition was complete, the mixture was stirred at room temperature overnight. The next day, the temperature was slowly raised to 75°C and maintained for 3 hours. After cooling to room temperature, the mixture was poured into 3.5kg of ice water. The pH was adjusted to 3 with ammonia, and the temperature was maintained not exceeding 20°C. A precipitate formed. The precipitate was filtered, washed with water until neutral, dried, and recrystallized from methanol to obtain 110g of a yellow solid, with a yield of 48%.

[0038] 2. Synthesis of 2-methyl-3-nitro-4-aminopyridine

[0039] In a 3L reaction flask, 1L of N,N-dimethylformamide and dimethyl malonate (229g, 1.73mol) were added and stirred. Under nitrogen protection, 60% sodium hydroxide (69g, 1.73mol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Then, 2-chloro-3-nitro-4-aminopyridine (200g, 1.15mol) was added. After the addition was complete, the temperature was slowly raised to 70℃ and maintained for 2 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature. Then, 1L of 48% hydrobromic acid was carefully added. After stirring at room temperature for 15 minutes, the temperature was slowly raised to 100℃ and maintained for 4 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature. Then, it was poured into 3kg of ice water, and the pH was adjusted to 8 with ammonia water. The temperature was controlled not to exceed 20℃ to form a precipitate. The precipitate was filtered, the filter cake was washed with water until neutral, and dried to obtain 138g of yellow solid, with a yield of 78%.

[0040] 3. Synthesis of 2-methyl-3-nitro-4-hydroxypyridine

[0041] In a 5L three-necked flask, 1.8L of 18% dilute sulfuric acid aqueous solution was added. 200g of 2-methyl-3-nitro-4-aminopyridine (1.3mol) was slowly added with stirring. After dissolving completely at room temperature, the solution was cooled to 0°C in an ice-salt bath. Then, 108g of sodium nitrite aqueous solution (1.3mol sodium nitrite dissolved in 300g water) was slowly added dropwise, controlling the temperature not to exceed 10°C. After the addition was complete, the reaction was continued at 10–15°C for 1 hour, followed by stirring at room temperature overnight. The next day, after TLC detection showed complete reaction, the reaction solution was poured into 2kg of ice water. The pH was adjusted to 5 with ammonia, and the temperature was controlled not to exceed 20°C, allowing a precipitate to form. The precipitate was filtered, washed with water until neutral, dried, and recrystallized from methanol to obtain 164g of a pale yellow solid, 2-methyl-3-nitro-4-hydroxypyridine, with a yield of 82% and an HPLC purity of 98.9% (214nm).

[0042] Example 3

[0043] Synthesis of 1,2-chloro-3-nitro-4-aminopyridine

[0044] In a 3L reaction flask, 1.1L of 98% concentrated sulfuric acid was added. The mixture was cooled to 0°C in an ice-salt bath. 2-chloro-4-aminopyridine (170g, 1.32mol) was slowly added with stirring, maintaining a temperature not exceeding 30°C. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Then, 65% concentrated nitric acid (128g, 1.32mol) was slowly added dropwise, maintaining a temperature not exceeding 20°C. After the addition was complete, the mixture was stirred at room temperature overnight. The next day, the temperature was slowly raised to 75°C and maintained for 3 hours. After cooling to room temperature, the mixture was poured into 3.5kg of ice water. The pH was adjusted to 3 with ammonia water, and the temperature was maintained not exceeding 20°C. A precipitate formed. The precipitate was filtered, washed with water until neutral, dried, and recrystallized from methanol to obtain 138g of a yellow solid, with a yield of 60%.

[0045] 2. Synthesis of 2-methyl-3-nitro-4-aminopyridine

[0046] In a 3L reaction flask, 1L of N,N-dimethylformamide and diethyl malonate (369g, 2.3mol) were added and stirred. Sodium hydroxide (92g, 2.3mol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Then, 2-chloro-3-nitro-4-aminopyridine (200g, 1.15mol) was added. After the addition was complete, the temperature was slowly raised to 70℃ and maintained for 2 hours. After TLC confirmation of complete reaction, the reaction mixture was cooled to room temperature. Then, 1L of 48% hydrobromic acid was carefully added. After stirring at room temperature for 15 minutes, the temperature was slowly raised to 100℃ and maintained for 4 hours. After TLC confirmation of complete reaction, the reaction mixture was cooled to room temperature. Then, it was poured into 3kg of ice water, and the pH was adjusted to 8 with ammonia water. The temperature was controlled not to exceed 20℃ to form a precipitate. The precipitate was filtered, the filter cake was washed with water until neutral, and dried to obtain 150g of a yellow solid, with a yield of 85%.

[0047] 3. Synthesis of 2-methyl-3-nitro-4-hydroxypyridine

[0048] In a 3L three-necked flask, 1L of a 12% (w / w) dilute sulfuric acid aqueous solution was added. 100g of 2-methyl-3-nitro-4-aminopyridine (0.65mol) was slowly added with stirring. After dissolving completely at room temperature, the solution was cooled to 0°C in an ice-salt bath. Then, 54g of sodium nitrite aqueous solution (0.78mol sodium nitrite dissolved in 150g water) was slowly added dropwise, controlling the temperature not to exceed 10°C. After the addition was complete, the reaction was continued at 10–15°C for 1 hour, followed by stirring at room temperature overnight. The next day, after TLC analysis confirmed the reaction was complete, the reaction solution was poured into 2kg of ice water. The pH was adjusted to 5 with ammonia, and the temperature was controlled not to exceed 20°C, allowing a precipitate to form. The precipitate was filtered, washed with water until neutral, dried, and recrystallized from methanol to obtain 82g of a pale yellow solid, 2-methyl-3-nitro-4-hydroxypyridine, with a yield of 81% and an HPLC purity of 98.9% (214nm).

Claims

1. A method for preparing 2-methyl-3-nitro-4-hydroxypyridine, characterized in that... Using 2-chloro-4-aminopyridine as a raw material, it is first reacted with mixed acid to obtain the intermediate 2-chloro-3-nitro-4-aminopyridine. The obtained intermediate is first reacted with dimethyl / ethyl malonate to obtain dimethyl / ethyl 2-(4-amino-3-nitropyridin-2-yl)malonate, and then hydrolyzed to obtain the intermediate 2-methyl-3-nitro-4-aminopyridine. The intermediate 2-methyl-3-nitro-4-aminopyridine is then subjected to diazotization and hydrolysis to obtain 2-methyl-3-nitro-4-hydroxypyridine. Its synthetic route is as follows: Specifically, the steps include the following: 1) Under an ice-salt bath, the raw material 2-chloro-4-aminopyridine was slowly added to concentrated sulfuric acid and stirred until homogeneous. Then, nitric acid was slowly added dropwise while maintaining the temperature below 20°C. After the addition was complete, the mixture was stirred overnight at room temperature and then heated to T1 to carry out the reaction. The reaction solution was post-treated to obtain a yellow solid 2-chloro-3-nitro-4-aminopyridine. 2) In the presence of a solvent, dimethyl / ethyl malonate and an alkaline substance were stirred at room temperature to obtain a mixture. The mixture was then reacted with 2-chloro-3-nitro-4-aminopyridine obtained in step 1) at T2. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature and hydrobromic acid was added. After stirring evenly, the mixture was heated to T3 and kept at that temperature. After the reaction was completed, the mixture was post-treated to obtain a yellow solid 2-methyl-3-nitro-4-aminopyridine. 3) Slowly add the 2-methyl-3-nitro-4-aminopyridine from step 2) to dilute acid and stir until dissolved. Slowly add sodium nitrite aqueous solution dropwise under the temperature control of ice-salt bath. After the addition is complete, raise the temperature to 10-25℃ and continue the reaction. After the reaction is complete as detected by TLC, pour the reaction solution into ice water, adjust the pH to weakly acidic with ammonia water, precipitate out, filter, wash the filter cake with water until neutral, dry it, and then recrystallize it with methanol to obtain a light yellow solid 2-methyl-3-nitro-4-hydroxypyridine. In step 1), T1 is 50-150℃; the molar ratio of 2-chloro-4-aminopyridine, sulfuric acid, and nitric acid is 1:2-30:1-3. The post-treatment process in step 1) is as follows: After the reaction solution is cooled to room temperature, it is poured into ice water, the pH is adjusted to 3 with ammonia water, the temperature is controlled not to exceed 20℃, a precipitate is generated, the filter cake is washed with water until neutral, dried, and recrystallized with methanol to obtain a yellow solid 2-chloro-3-nitro-4-aminopyridine. In step 2), T2 is 10-150℃ and T3 is 50-130℃; The solvent in step 2) is one or any combination of acetonitrile, 1,4-dioxane, tetrahydrofuran, DMF, and DMSO; the alkaline substance is one of sodium hydride, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide. In step 2), the molar ratio of 2-chloro-3-nitro-4-aminopyridine, dimethyl / ethyl malonate, and the alkaline substance is 1:1 to 4:1 to 4. The dilute acid in step 3) is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid, dilute hydrochloric acid, or dilute phosphoric acid; In step 3), the molar ratio of 2-methyl-3-nitro-4-aminopyridine to sodium nitrite is 1:1 to 3.

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