A method for preparing a non-fenretinide key intermediate

Abstract

The present application relates to a kind of preparation method of non-nalidixic acid key intermediate, comprising the following steps: (1) with 2-chloro-4-amino-5-methyl pyridine as raw material, reaction is carried out using potassium alcoholate, join catalyst La2O3-KOH / ZrO2 / γ-Al2O3 catalysis, obtain the compound of structural formula as shown in II;(2) the compound obtained in step (1) is hydrolyzed in hydrogen bromide solution to obtain 2-hydroxy-4-amino-5-methyl pyridine.The preparation condition of the present application is mild, two steps can be carried out in conventional reaction kettle, not only good safety, but also can effectively reduce coupling impurity;Overall two-step molar yield can reach more than 90%, not only can reduce cost, but also short reaction time can improve production efficiency, efficiently synthesize non-nalidixic acid key intermediate.

Description

Technical Field

[0001] This invention belongs to the field of intermediate preparation technology, specifically relating to a method for preparing a key intermediate of phenelzine. Background Technology

[0002] Finerenone (BAY 94-8862) is a nonsteroidal selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the harmful effects of excessive mineralocorticoid receptor activation. In diabetic patients, excessive mineralocorticoid receptor activation is thought to contribute to the progression of chronic kidney disease and cardiovascular damage, which may be driven by metabolic, hemodynamic, or inflammatory and fibrotic factors.

[0003] In July 2021, based on the positive results of 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. Currently, finerenone has submitted marketing applications in China and many other countries and regions around the world and is under review.

[0004] In December 2021, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended approval for the marketing application of the nonsteroidal selective mineralocorticoid receptor antagonist fenelone. Fennellone (10 mg or 20 mg) is recommended for the treatment of adult patients with chronic kidney disease (stages 3 and 4 with albuminuria) and type 2 diabetes. If approved, fenelone will become the first nonsteroidal selective mineralocorticoid receptor antagonist for improving renal outcomes in adult patients with chronic kidney disease and type 2 diabetes.

[0005] The chemical structure of fenelone is shown below:

[0006] 2-Hydroxy-4-amino-5-methylpyridine is a key intermediate in the synthesis of phenelzine. Currently, the preparation methods for 2-hydroxy-4-amino-5-methylpyridine generally employ high-temperature and high-pressure reactions, and also suffer from low yields. Its synthetic route is as follows:

[0007] The current process has the following main problems: (1) Due to the use of high temperature and high pressure, the safety is poor and the equipment requirements are high; (2) There are many high temperature side reactions and the yield is low. The molar yield in the literature is 70-80%; (3) The reaction time is 18-24 hours and the production efficiency is low. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, this invention provides a method for preparing 2-hydroxy-4-amino-5-methylpyridine, a key intermediate in phenelzine. This invention employs a two-step method to synthesize 2-hydroxy-4-amino-5-methylpyridine, first preparing an ether followed by hydrolysis; both steps can be carried out in conventional reactors, offering both safety and high efficiency.

[0009] The technical solution adopted in this invention is as follows: A method for preparing a key intermediate of phenelzine includes the following steps: (1) Using 2-chloro-4-amino-5-methylpyridine as a raw material, potassium alkoxide was used for the reaction, and La2O3-KOH / ZrO2 / γ-Al2O3 catalyst was added to catalyze the reaction, and the compound with the following structural formula was obtained;

[0010] Wherein, R is one of methyl, ethyl, butyl, tert-butyl, and benzyl; (2) The compound obtained in step (1) was hydrolyzed in hydrogen bromide solution to give 2-hydroxy-4-amino-5-methylpyridine.

[0011] The synthetic route of this invention is as follows:

[0012] Preferably, the catalyst La2O3-KOH / ZrO2 / γ-Al2O3 is prepared by the following method: zirconium oxychloride and La(NO3)3 are dissolved in deionized water to form a solution. Ammonia is added dropwise under uniform stirring until a white precipitate Zr(OH)4 is formed. The precipitate is then allowed to stand and age. The solution is then vacuum filtered and washed with deionized water until no Cl is detected. - The catalyst was dried in an infrared rapid dryer until it was completely dried; γ-Al2O3 was added, mixed evenly, ground and sieved; aged under reflux with KOH, filtered; and calcined under N2 atmosphere to obtain the catalyst.

[0013] The catalyst of this invention is a composite oxide. A solid superbase, La₂O₃-KOH / ZrO₂ / γ-Al₂O₃ (catalyst KZA-650), was obtained through alkali metal compound modification. A high-thermal-stability, large-specific-surface-area aluminum-zirconium composite oxide support was prepared by reflux aging with alkaline solution, and then modified with 30% KOH. After calcination under N₂ atmosphere, the solid superbase was obtained. Zr(OH)₄ / γ-Al₂O₃ reacts with potassium hydroxide to form sodium aluminate with a bound structure. The addition of potassium hydroxide causes electron transfer, increasing the negative charge density on the oxygen anions, thus forming high-base centers on the surface of the solid superbase. Rare earth metal La can increase the stability of the tetragonal ZrO₂ crystal form, and the tetragonal crystal form exhibits the best catalytic effect.

[0014] As a preferred option, step (1) is as follows: take 2-chloro-4-amino-5-methylpyridine, add it to a four-necked flask, then add toluene, potassium methoxide or n-butanol, potassium hydroxide, and then add the catalyst La2O3-KOH / ZrO2 / γ-Al2O3. Control the temperature to 60~100℃ and react for 5~8h. After the reaction is completed, a white solid product is obtained after post-treatment.

[0015] Preferably, the molar ratio of 2-chloro-4-amino-5-methylpyridine to potassium alkoxide is 1:1.1~2, and the mass ratio of 2-chloro-4-amino-5-methylpyridine to catalyst La2O3-KOH / ZrO2 / γ-Al2O3 is 1:0.005~0.009.

[0016] As a preferred option, step (2) is as follows: the white solid obtained in step (1) is added to a four-necked flask, and then a solvent and a 48% HBr aqueous solution are added. The mixture is reacted at 100°C for 4 to 8 hours. After the reaction is complete, 2-hydroxy-4-amino-5-methylpyridine is obtained through post-treatment.

[0017] As a preferred embodiment, when R is methyl, weigh 13.82 g of the white solid obtained in step (1), add it to a 250 ml four-necked flask, add 40 mL of acetic acid and 33.71 g of 48% HBr aqueous solution, react at 100 °C for 4-6 hours until the reaction is complete, cool down, remove acetic acid by vacuum distillation, add 20 mL of water, adjust the pH to 7-8 with ammonia, extract four times with butanol, combine the organic layers, evaporate to dryness to obtain a white solid, and slurry it once with 2-3 times the amount of water, filter and dry to obtain 11.90 g of white solid, with a molar yield of 95.89%, a purity of 99.92%, and a maximum single impurity of 0.02%.

[0018] As a preferred option, when R is butyl, weigh 18.01 g of the white solid obtained in step (1), add it to a 250 ml four-necked flask, add 54 mL of acetic acid and 33.71 g of 48% HBr aqueous solution, react at 100 °C for 5-8 hours until the reaction is complete, cool down, remove acetic acid by vacuum distillation, add 20 mL of water, adjust the pH to 7-8 with ammonia, extract four times with butanol, combine the organic layers, evaporate to dryness to obtain a white solid, and slurry it once with 2-3 times the amount of water, filter and dry to obtain 11.80 g of white solid, with a molar yield of 95.08%, a purity of 99.94%, and a maximum single impurity of 0.02%.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The preparation conditions of this invention are mild, and both steps can be carried out in a conventional reactor, which not only ensures good safety but also effectively reduces coupling impurities; 2. The overall two-step molar yield can reach over 90%, which is higher than existing technologies. This not only reduces costs but also improves production efficiency due to the shorter reaction time, enabling the efficient synthesis of key intermediates for fenelone. Attached Figure Description

[0020] Figure 1 This is the XRD pattern of the catalyst; Figure 2 This is the TG-DTA diagram of the catalyst precursor; Figure 3 These are XRD patterns at different activation temperatures; Figure 4 This is the 1H NMR spectrum of 2-hydroxy-4-amino-5-methylpyridine. Detailed Implementation

[0021] The invention will be further described below with reference to specific embodiments, but the scope of protection of the invention is not limited thereto. Those skilled in the art will and should recognize that any simple changes or substitutions based on the essential spirit of the invention should fall within the scope of protection claimed by the invention.

[0022] Unless otherwise specified, all raw materials mentioned in this article were purchased from the market, and percentages mentioned in this article are percentages by weight unless otherwise specified.

[0023] Preparation of catalyst KZA-650 Take 20g of zirconium oxychloride octahydrate and La(NO3)3, add 200ml of deionized water to prepare a 10% (w / w) solution. While stirring at a constant speed, slowly add ammonia water dropwise until the pH reaches approximately 10. Stop adding ammonia water at this point; a white precipitate Zr(OH)4 will form. Let the precipitate stand for 24 hours; filter under vacuum and wash with deionized water until no Cl- is visible. - The catalyst was dried in an infrared rapid dryer; ground, 12.54 g of γ-Al2O3 was added, mixed evenly, and ground through a 100-mesh sieve; aged under reflux with 30% KOH for 12 hours, and filtered; calcined and activated at 650℃ in a N2 atmosphere for 6 hours, and cooled to room temperature in a dryer to obtain catalyst KZA-650. Figure 1 The image shows the XRD pattern of the catalyst. At 2θ = 30 degrees, the characteristic peak of the tetragonal zirconia crystal form appears. Figure 2 The image shows the TG-DTA curve of the catalyst precursor, indicating that its calcination activation temperature range is 500~650℃. Figure 3 The XRD patterns at different activation temperatures show that the characteristic peak M of the monoclinic crystal form is relatively small at 650℃, while the characteristic peak M of the tetragonal crystal form is high. Therefore, the activation temperature of 650℃ can be selected.

[0024] Example 1 Synthesis of compound IIa

[0025] Weigh 14.26 g of compound I and add it to a 250 mL four-necked flask. Add 0.14 g of catalyst KZA-650, 140 mL of toluene, 8.41 g of potassium methoxide, and 1.2 equivalents. Heat to 60 °C and maintain the temperature for 6 h. After the reaction is complete, cool down and add 50 mL of water to adjust the pH to 7. Remove toluene and water by vacuum distillation to obtain a solid. Pulverize with ethyl acetate, filter, and evaporate the filtrate to dryness to obtain a white solid. Pulverize the solid with n-heptane and ethyl acetate to obtain 13.21 g of a white solid (compound IIa), with a yield of 97.58% and a chemical purity of 99.52%.

[0026] Synthesis of Compound III

[0027] 13.82 g of compound IIa was weighed and added to a 250 mL four-necked flask, followed by 40 mL of acetic acid and 33.71 g of 48% HBr aqueous solution. The reaction was carried out at 100 °C for 4–6 hours until complete. The mixture was then cooled, and the acetic acid was removed by vacuum distillation. 20 mL of water was added, and the pH was adjusted to 7–8 with ammonia. The mixture was extracted four times with butanol, and the organic layers were combined and evaporated to dryness to obtain a white solid. The solid was then slurried once with 2–3 times its volume of water, filtered, and dried to obtain 11.90 g of a white solid. The 1H NMR spectrum of the prepared 2-hydroxy-4-amino-5-methylpyridine is shown below. Figure 4 As shown, the molar yield was 95.89%, the purity was 99.92%, and the maximum single impurity was 0.02%.

[0028] Example 2 Synthesis of compound IIb

[0029] Weigh 14.26 g of compound I and add it to a 250 ml four-necked flask. Then add 100 g of n-butanol, 11.22 g of potassium hydroxide, and 0.1 g of catalyst KZA-650. Heat to 70 °C and keep warm for 7 h. After the reaction is complete, remove n-butanol and water by vacuum distillation to obtain a solid. Add 50 ml of water and 100 ml of ethyl acetate, and separate the layers. Then extract twice with ethyl acetate, combine the organic layers, wash once with a small amount of water, and evaporate to dryness to obtain a white solid. The solid is slurried with n-heptane and ethyl acetate to obtain 17.80 g of white solid (compound IIb), with a yield of 98.72% and a chemical purity of 99.50%.

[0030] Synthesis of Compound III

[0031] Weigh 18.01 g of compound IIb and add it to a 250 mL four-necked flask. Then add 54 mL of acetic acid and 33.71 g of 48% HBr aqueous solution. React at 100 °C for 5-8 hours until the reaction is complete. Cool down and remove acetic acid under reduced pressure. Add 20 mL of water and adjust the pH to 7-8 with ammonia. Extract four times with butanol. Combine the organic layers and evaporate to dryness to obtain a white solid. Pulverize with 2-3 times the amount of water once. Filter and dry to obtain 11.80 g of white solid. The molar yield is 95.08%, the purity is 99.94%, and the maximum single impurity is 0.02%.

[0032] Example 3 Catalyst recycling Following the method for synthesizing compound IIa in Example 1, a catalyst recycling experiment was conducted. The catalyst of the present invention was recycled, and the results are shown in Table 1: Table 1

[0033] As shown in Table 1, without catalyst, the coupling impurities reached 1.2%, and the yield was only 90.77%. With catalyst, the coupling impurities decreased significantly, and the yield increased significantly. After six catalyst reuses, the coupling impurities increased slightly, but the yield remained basically unchanged, indicating that the catalyst has good reusability.

[0034] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of phenelzine, characterized in that... Includes the following steps: (1) Using 2-chloro-4-amino-5-methylpyridine as a raw material, potassium alkoxide was used for the reaction, and La2O3-KOH / ZrO2 / γ-Al2O3 catalyst was added to catalyze the reaction, and the following compound was obtained; ； Wherein, R is one of methyl, ethyl, butyl, tert-butyl, and benzyl; (2) The compound obtained in step (1) was hydrolyzed in hydrogen bromide solution to give 2-hydroxy-4-amino-5-methylpyridine; The catalyst La2O3-KOH / ZrO2 / γ-Al2O3 was prepared by the following method: zirconium oxychloride and La(NO3)3 were dissolved in deionized water to form a solution. Ammonia was added dropwise under uniform stirring until a white precipitate Zr(OH)4 was formed. The precipitate was allowed to stand and age. It was then vacuum filtered and washed with deionized water until no Cl- was detected. - The catalyst was dried in an infrared rapid dryer until it was completely dried; γ-Al2O3 was added, mixed evenly, ground and sieved; aged by reflux with KOH, filtered; and calcined at 650℃ under N2 atmosphere to obtain the catalyst.

2. A method for preparing a key intermediate of phenelzine, characterized in that... Includes the following steps: (1) Using 2-chloro-4-amino-5-methylpyridine as raw material, n-butanol and potassium hydroxide were used for reaction, and La2O3-KOH / ZrO2 / γ-Al2O3 catalyst was added to catalyze the reaction, and the following compound was obtained; ； Wherein, R is one of methyl, ethyl, butyl, tert-butyl, and benzyl; (2) The compound obtained in step (1) was hydrolyzed in hydrogen bromide solution to give 2-hydroxy-4-amino-5-methylpyridine; The catalyst La2O3-KOH / ZrO2 / γ-Al2O3 was prepared by the following method: zirconium oxychloride and La(NO3)3 were dissolved in deionized water to form a solution. Ammonia was added dropwise under uniform stirring until a white precipitate Zr(OH)4 was formed. The precipitate was allowed to stand and age. It was then vacuum filtered and washed with deionized water until no Cl- was detected. - The catalyst was dried in an infrared rapid dryer until it was completely dried; γ-Al2O3 was added, mixed evenly, ground and sieved; aged by reflux with KOH, filtered; and calcined at 650℃ under N2 atmosphere to obtain the catalyst.

3. The method for preparing the phenelzine key intermediate according to claim 1 or 2, characterized in that... Step (1) is as follows: Take 2-chloro-4-amino-5-methylpyridine, add it to a four-necked flask, then add toluene, potassium methoxide or n-butanol, potassium hydroxide, and then add the catalyst La2O3-KOH / ZrO2 / γ-Al2O3. Control the temperature at 60~100℃ and react for 5~8h. After the reaction is completed, a white solid product is obtained after post-treatment.

4. The method for preparing the key intermediate of phenelzine according to claim 3, characterized in that: The molar ratio of 2-chloro-4-amino-5-methylpyridine to potassium alkoxide is 1:1.1~2, and the mass ratio of 2-chloro-4-amino-5-methylpyridine to catalyst La2O3-KOH / ZrO2 / γ-Al2O3 is 1:0.005~0.

009.

5. The method for preparing the phenelzine key intermediate according to claim 3, characterized in that... Step (2) is as follows: The white solid obtained in step (1) is added to a four-necked flask, and then a solvent and a 48% HBr aqueous solution are added. The mixture is reacted at 100°C for 4-8 hours. After the reaction is complete, 2-hydroxy-4-amino-5-methylpyridine is obtained through post-treatment.

6. The method for preparing the key intermediate of phenelzine according to claim 5, characterized in that: When R is methyl, weigh 13.82 g of the white solid obtained in step (1), add it to a 250 ml four-necked flask, add 40 mL of acetic acid and 33.71 g of 48% HBr aqueous solution, react at 100 °C for 4-6 hours until the reaction is complete, cool down, remove acetic acid by vacuum distillation, add 20 mL of water, adjust the pH to 7-8 with ammonia, extract four times with butanol, combine the organic layers, evaporate to dryness to obtain a white solid, and slurry once with 2-3 times the amount of water, filter and dry to obtain 11.90 g of white solid, with a molar yield of 95.89%, a purity of 99.92%, and a maximum single impurity of 0.02%.

7. The method for preparing the key intermediate of phenelzine according to claim 5, characterized in that: When R is butyl, weigh 18.01 g of the white solid obtained in step (1), add it to a 250 ml four-necked flask, add 54 mL of acetic acid and 33.71 g of 48% HBr aqueous solution, react at 100 °C for 5-8 hours until the reaction is complete, cool down, remove acetic acid by vacuum distillation, add 20 mL of water, and adjust the pH to 7-8 with ammonia water, extract four times with butanol, combine the organic layers, evaporate to dryness to obtain a white solid, and slurry it once with 2-3 times the amount of water, filter and dry to obtain 11.80 g of white solid, with a molar yield of 95.08%, a purity of 99.94%, and a maximum single impurity of 0.02%.

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