Process for the synthesis of 4-amino-5-methyl-2-hydroxypyridine

Abstract

The application discloses a synthesis method of 4-amino-5-methyl-2-hydroxypyridine, which has the following steps: ① taking 5-methyl-4-nitro-2-pyridinamine as a starting material, performing a diazotization reaction with sodium nitrite, and then hydrolyzing to obtain 5-methyl-4-nitropyridin-2(1H)-one; and ② performing catalytic hydrogenation on the 5-methyl-4-nitropyridin-2(1H)-one to obtain 4-amino-5-methyl-2-hydroxypyridine. The synthesis method is simple in operation, high in safety, low in production cost, simple in post-treatment, small in environmental pollution, low in side reaction, high in reaction yield, good in product quality, high in purity and suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical technology, specifically relating to a method for synthesizing 4-amino-5-methyl-2-hydroxypyridine. Background Technology

[0002] 4-Amino-5-methyl-2-hydroxypyridine (also known as 4-amino-5-methyl-2-pyridone), CAS number 95306-64-2, molecular formula C6H8ON2, molecular weight 124.14, structural formula as follows: .

[0003] 4-Amino-5-methyl-2-hydroxypyridine is an important component in drug design, and its derivatives possess high biological activity, finding wide applications in chemistry, chemical engineering, and pharmaceuticals. For example, it is a crucial intermediate in the synthesis of phenelzine. Phenelzine is a novel nonsteroidal mineralocorticoid receptor antagonist (MRA) primarily used to treat type 2 diabetes-related chronic kidney disease (CKD) and heart failure. It works by inhibiting excessive activation of mineralocorticoid receptors, reducing inflammation and fibrosis, protecting cardiac and renal function, and lowering the risk of cardiovascular events.

[0004] In July 2021, based on positive results from the FIDELIO-DKD Phase III clinical trial in adult patients with chronic kidney disease and type 2 diabetes, the U.S. FDA approved finerenone (Kerendia®) for marketing. In December 2021, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended approval of the marketing application for the nonsteroidal selective mineralocorticoid receptor antagonist finerenone, recommending finerenone (10 mg or 20 mg) for the treatment of adult patients with chronic kidney disease (stages 3 and 4 with albuminuria) and type 2 diabetes. Marketing applications for finerenone have been submitted in China and several other countries and regions worldwide and are currently under review.

[0005] The existing methods for synthesizing 4-amino-5-methyl-2-hydroxypyridine generally use 2-chloro-5-methylpyridine as the starting material. First, oxidize it to obtain 2-chloro-5-methylpyridine nitrate, then nitrate it to obtain 2-chloro-4-nitro-5-methylpyridine nitrate, then reduce it to obtain 2-chloro-4-amino-5-methylpyridine, and finally hydrolyze it to obtain 4-amino-5-methyl-2-hydroxypyridine [see Chinese patent documents CN103193704A, CN115340492A, CN119320348A, etc.].

[0006] The synthesis route is as follows: .

[0007] The shortcomings of this method are: (1) The second step of nitration is a high-risk reaction with low safety and very unstable yield.

[0008] (2) The third step of the reduction reaction is prone to dechlorination side reaction, which affects the purity of the product and the reaction yield. Moreover, the metal reduction method is not environmentally friendly.

[0009] (3) The fourth step of hydrolysis requires high temperature and high pressure, which not only consumes a lot of energy and has high requirements for equipment and low safety, but also has a lot of high-temperature side reactions. The impurities generated will lead to a decrease in the total yield during subsequent purification.

[0010] To address the problem of the fourth step hydrolysis reaction in the above synthetic route, Chinese patent document CN114656400A discloses a two-step method. First, 2-chloro-4-amino-5-methylpyridine is reacted with potassium alkoxide in the presence of a self-made catalyst to obtain 2-alkoxy-4-amino-5-methylpyridine, and then hydrolyzed in hydrogen bromide solution to obtain 4-amino-5-methyl-2-hydroxypyridine.

[0011] The synthesis route is as follows: .

[0012] While this two-step method solves the problem of high temperature and high pressure, it requires the self-made expensive precious metal catalyst, resulting in high raw material costs and making it unsuitable for large-scale industrial production.

[0013] To address the problems in the third and fourth steps of the above synthetic route, Chinese patent document CN117024335A discloses a method of first hydrolyzing and then reducing.

[0014] The synthesis route is as follows: .

[0015] Although the hydrolysis reaction conditions are mild and the reduction reaction does not have the problem of dechlorination, the hydrolysis reaction yield is very low, only 40%, resulting in an overall yield of less than 20%, which makes it even less suitable for large-scale industrial production. Summary of the Invention

[0016] The purpose of this invention is to solve the above-mentioned problems and provide a method for synthesizing 4-amino-5-methyl-2-hydroxypyridine that has low production cost, high safety, high reaction yield and product purity, and is suitable for large-scale industrial production.

[0017] The technical solution to achieve the objective of this invention is: a method for synthesizing 4-amino-5-methyl-2-hydroxypyridine, comprising the following steps: ① Using 5-methyl-4-nitro-2-pyridinamine [CAS No. 895520-03-3] as the starting material, it is first diazotized with sodium nitrite, and then hydrolyzed to obtain 5-methyl-4-nitropyridin-2(1H)-one; ②The 5-methyl-4-nitropyridine-2(1H)-one was catalytically hydrogenated to obtain 4-amino-5-methyl-2-hydroxypyridine.

[0018] The synthesis route is as follows: .

[0019] The diazotization reaction in step ① above is carried out in the presence of an acidic catalyst; the acidic catalyst is one or more of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and trifluoroacetic acid; preferably sulfuric acid or hydrochloric acid.

[0020] The diazotization reaction temperature in step ① above is -20 to 50°C, preferably 0 to 5°C.

[0021] The catalyst used in step ② above for catalytic hydrogenation is one or more of palladium on carbon, ruthenium on carbon, platinum on carbon, and Raney nickel; preferably palladium on carbon or Raney nickel.

[0022] The catalytic hydrogenation in step ② above is carried out in the presence of an organic solvent; the organic solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dimethylformamide (DMF), dimethylacetamide (DMAc), N-methylpyrrolidone, ethyl acetate, benzene, toluene, and xylene; preferably methanol or ethanol.

[0023] The catalytic hydrogenation reaction temperature in step ② above is -10 to 120°C, preferably 20 to 50°C.

[0024] The catalytic hydrogenation reaction pressure in step ② above is 0.1–10 MPa, preferably 0.6–0.9 MPa.

[0025] The positive effects of this invention are: the synthesis method of this invention is simple to operate, has high safety, low production cost, simple post-processing, less environmental pollution, fewer side reactions, high reaction yield, good product quality, and high purity, making it suitable for large-scale industrial production. Attached Figure Description

[0026] Figure 1 The image shows the LC-MS spectrum of the intermediate obtained in step ① of Example 1.

[0027] Figure 2 The image shows the LC-MS spectrum of the final product obtained in step ② of Example 1.

[0028] Figure 3The image shows the DSC spectrum of the final product obtained in step ② of Example 1. Detailed Implementation

[0029] (Example 1) The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine in this embodiment includes the following steps: ① Slowly add 36 mL of concentrated sulfuric acid (0.676 mol) to 300 mL of water and cool to room temperature. Then add 30 g of 5-methyl-4-nitro-2-pyridinamine (0.196 mol) in portions and cool in an ice-water bath to 0-5°C. While stirring, slowly add 30 mL of sodium nitrite aqueous solution (containing 15 g of sodium nitrite, 0.217 mmol). After the addition is complete, remove the ice-water bath and slowly heat the reaction solution to room temperature. Then add 150 mL of sodium hydroxide aqueous solution (containing 46 g of sodium hydroxide, 1.15 mol) dropwise and keep the temperature below 20°C until the reaction is complete.

[0030] After the reaction was completed, the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was first extracted three times with dichloromethane (200 mL × 3), then washed with water and brine. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain 28.3 g of 5-methyl-4-nitropyridine-2(1H)-one, with a yield of 93.7%.

[0031] The LC-MS spectrum of the intermediate is shown below. Figure 1 ,Depend on Figure 1 It can be seen that its molecular weight is 154.0 (MS: M+H), which is basically consistent with 5-methyl-4-nitropyridine-2(1H)-one.

[0032] ② Dissolve 28.3g of 5-methyl-4-nitropyridine-2(1H)-one obtained in step ① in 200g of methanol, then add it to a high-pressure hydrogenation reactor, and then add 1.5g of 5wt% wet palladium on carbon. Seal the high-pressure hydrogenation reactor, replace the air with nitrogen three times, replace the nitrogen with hydrogen three times, and then stir the reaction until complete at a pressure of 0.6MPa and a temperature of 30℃.

[0033] After the reaction was completed, the catalyst was recovered by filtration (which can be reused), and the solvent was removed from the filtrate by evaporation to obtain the crude product. The crude product was then recrystallized from toluene to obtain 21.8 g of 4-amino-5-methyl-2-hydroxypyridine, with a yield of 95.7% and an HPLC purity of 99.57%.

[0034] The LC-MS spectrum of the final product is shown below. Figure 2 ,Depend on Figure 2 It can be seen that its molecular weight is 124.1 (MS: M+H), which is basically the same as that of 4-amino-5-methyl-2-hydroxypyridine.

[0035] The DSC spectrum of the final product is shown below. Figure 3 .

[0036] (Example 2) The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine in this embodiment includes the following steps: ① Slowly add 20 mL of concentrated hydrochloric acid (0.652 mol) to 300 mL of water and cool to room temperature. Then add 30 g of 5-methyl-4-nitro-2-pyridinamine (0.196 mol) in portions. Cool the mixture in an ice-water bath to 0–5 °C. While stirring, slowly add 30 mL of sodium nitrite aqueous solution (containing 15 g of sodium nitrite, 0.217 mmol). After the addition is complete, remove the ice-water bath and slowly heat the reaction solution to room temperature. Then add 150 mL of sodium hydroxide aqueous solution (containing 46 g of sodium hydroxide, 1.15 mol) dropwise, keeping the temperature below 20 °C, until the reaction is complete.

[0037] After the reaction was completed, the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was first extracted three times with dichloromethane (200 mL × 3), then washed with water and brine. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain 28.7 g of 5-methyl-4-nitropyridine-2(1H)-one, with a yield of 95.0%.

[0038] ② Dissolve 28.7g of 5-methyl-4-nitropyridine-2(1H)-one obtained in step ① in 200g of methanol, then add it to a high-pressure hydrogenation reactor, add 3g of Raney nickel, seal the high-pressure hydrogenation reactor, replace the air with nitrogen three times, replace the nitrogen with hydrogen three times, and then stir the reaction until complete at a pressure of 0.6MPa and a temperature of 30℃.

[0039] After the reaction was completed, the catalyst was recovered by filtration (which can be reused), and the solvent was removed from the filtrate by evaporation to obtain the crude product. The crude product was then recrystallized from toluene to obtain 22.2 g of 4-amino-5-methyl-2-hydroxypyridine, with a yield of 96.1% and an HPLC purity of 99.64%.

Claims

1. A method for synthesizing 4-amino-5-methyl-2-hydroxypyridine, comprising the following steps: ① Using 5-methyl-4-nitro-2-pyridineamine as the starting material, it is first diazotized with sodium nitrite, and then hydrolyzed to obtain 5-methyl-4-nitropyridine-2(1H)-one; ②The 5-methyl-4-nitropyridine-2(1H)-one was catalytically hydrogenated to obtain 4-amino-5-methyl-2-hydroxypyridine.

2. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 1, characterized in that: The diazotization reaction in step ① above is carried out in the presence of an acidic catalyst; the acidic catalyst is one or more of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and trifluoroacetic acid.

3. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 2, characterized in that: The acidic catalyst is sulfuric acid or hydrochloric acid.

4. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 1, characterized in that: The diazotization reaction temperature in step ① above is -20 to 50℃.

5. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 4, characterized in that: The diazotization reaction temperature in step ① above is 0–5℃.

6. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 1, characterized in that: The catalyst used in step ② above for catalytic hydrogenation is one or more of palladium on carbon, ruthenium on carbon, platinum on carbon, and Raney nickel.

7. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 1, characterized in that: The catalytic hydrogenation in step ② above is carried out in the presence of an organic solvent; the organic solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, ethyl acetate, benzene, toluene, and xylene.

8. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 1, characterized in that: The catalytic hydrogenation reaction temperature in step ② above is -10 to 120°C, and the catalytic hydrogenation reaction pressure is 0.1 to 10 MPa.

9. The method for synthesizing 4-amino-5-methyl-2-hydroxypyridine according to claim 8, characterized in that: The catalytic hydrogenation reaction temperature in step ② above is 20–50°C, and the catalytic hydrogenation reaction pressure is 0.6–0.9 MPa.

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