Preparation method of abemaciclib intermediate 6-aminonicotinic acid

Abstract

The present invention relates to a preparation method of abemaciclib intermediate 6-aminonicotinic acid. Using 2-amino-5-methylpyridine as a raw material, through amino protection, oxidation with an oxidizing agent, and finally deprotection, the target product 6-aminonicotinic acid is obtained. The present invention uses 2-amino-5-methylpyridine as a raw material, and 6-aminonicotinic acid is obtained through amino protection, oxidative deprotection (one-pot method). It has a high yield, low cost, simple operation, low requirements for production equipment, and is suitable for industrial production; using a clean oxidizing agent for oxidation will not produce acid water containing heavy metals, has little corrosion to equipment, low cost, little environmental pollution, and is easy to industrialize production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 6-aminonicotinic acid, an intermediate of abemaciclib. Background Art

[0002] 6-aminonicotinic acid is the starting material for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine, a key intermediate of abemaciclib. The active pharmaceutical ingredient of Verzenios is abemaciclib, which is an oral targeted CDK4 / 6 inhibitor that can selectively inhibit cyclin-dependent kinases 4 / 6 (CDK4 / 6), restore cell cycle control, and block tumor cell proliferation. Dysregulation of the cell cycle is a hallmark of cancer, and CDK4 / 6 is overactive in many cancers, leading to uncontrolled cell proliferation. CDK4 / 6 is a key regulator of the cell cycle that triggers the transition of the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S1 phase). In estrogen receptor-positive (ER+) breast cancer, the overactivity of CDK4 / 6 is very frequent, and CDK4 / 6 is a key downstream target of the ER signal. Preclinical data show that dual inhibition of CDK4 / 6 and the ER signal has a synergistic effect and can inhibit the growth of G1-phase ER+ breast cancer cells.

[0003] Patent CN110156754 A reports a route for preparing 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine using 6-aminonicotinic acid as the starting material. This route is simple and has a high yield. The reaction formula is as follows:

[0004]

[0005] 6-aminonicotinic acid thus becomes a key raw material for the abemaciclib API.

[0006] In the prior art, the reported methods for preparing 6-aminonicotinic acid mainly include:

[0007] (1) Using 2-amino-5-chloropyridine as the starting material, the target product is obtained through an electrochemical reaction (Tetrahedron Letters (2003), 44(21), 4133-4135). The reaction formula is as follows:

[0008]

[0009] This method uses an electrochemical method, requires high equipment, uses heavy metal Pt, produces heavy metal wastewater, pollutes the environment, and is difficult to scale up for industrial production.

[0010] (2) Using 6-azido-3-pyridinecarboxylic acid as the starting material, the target product was obtained after reduction (ChemistrySelect (2018), 3(17), 4822-4826), and the reaction formula is as follows:

[0011]

[0012] The raw materials of this process route are flammable, explosive, and have poor safety. Moreover, they are not commercially produced and are not easy to purchase, so it is not suitable for industrial production.

[0013] (3) In Patent US 20200299282, using ethyl 6-aminonicotinate as the raw material, the target product was formed after hydrolysis with sodium hydroxide, and the reaction formula is as follows:

[0014]

[0015] The raw material ethyl 6-aminonicotinate of this method is relatively expensive, the yield is low, and the production cost is high, so it is not suitable for large-scale industrial production. Summary of the Invention

[0016] In order to overcome the deficiencies in the prior art, the present invention provides a preparation method of abemaciclib intermediate 6-aminonicotinic acid with simple operation, inexpensive raw materials, low environmental pollution, and high yield.

[0017] A preparation method of abemaciclib intermediate 6-aminonicotinic acid, using 2-amino-5-methylpyridine as the raw material, through amino protection, oxidation with an oxidant, and finally deprotection to obtain the target product 6-aminonicotinic acid.

[0018] Preferably, the preparation method of 6-aminonicotinic acid includes the following steps:

[0019] (1) Using 2-amino-5-methylpyridine as the raw material, through amino protection to obtain compound 1 with the structure shown in (I),

[0020]

[0021] (2) Compound 1 is obtained by one-pot oxidation and deprotection to obtain 6-aminonicotinic acid.

[0022] Preferably, the preparation method of 6-aminonicotinic acid includes the following steps:

[0023] (1) Using 2-amino-5-methylpyridine as the raw material, through amino protection to obtain compound 1 with the structure shown in (I),

[0024]

[0025] (2) Compound 1 is oxidized with an oxidant to obtain compound 2 with the structure shown in (II);

[0026] (3) Compound 2 is subjected to deprotection treatment to obtain 6-aminonicotinic acid.

[0027] Preferably, the preparation method of the 6-aminonicotinic acid specifically comprises the following steps:

[0028] (1) Add a solvent, 2-amino-5-methylpyridine, and an amino protecting agent into a reactor. After the feeding is completed, carry out a heat preservation reaction at 25°C to reflux for 2 to 5 hours, then cool down to 10 to 25°C, add water, stir for 0.5 to 1.0 hour, separate the layers, wash the organic layer with water, dry it with anhydrous ammonium sulfate, filter, and concentrate it under reduced pressure to dryness to obtain Compound 1;

[0029] (2) Add water and Compound 1 into a reactor. After the feeding, raise the temperature to 50 to 70°C, add an oxidizing agent in batches, and react at 80 to 90°C for 10 to 16 hours; when the TLC reaction is complete, filter off the salt while it is hot. Add a deprotecting agent to the filtrate and react at 80 to 90°C for 8 to 16 hours. When the TLC reaction is complete, cool down to 15 to 25°C, and perform post-treatment to obtain 6-aminonicotinic acid.

[0030] Preferably, the preparation method of the 6-aminonicotinic acid specifically comprises the following steps:

[0031] (1) Add a solvent, 2-amino-5-methylpyridine, and an amino protecting agent into a reactor. After the feeding is completed, carry out a heat preservation reaction at 25°C to reflux for 2 to 5 hours, then cool down to 10 to 25°C, add water, stir for 0.5 to 1.0 hour, separate the layers, wash the organic layer with water, dry it with anhydrous ammonium sulfate, filter, and concentrate it under reduced pressure to dryness to obtain Compound 1;

[0032] (2) Add Compound 1, an oxidizing agent, a surfactant, and a catalyst into a reactor, stir evenly, and then raise the temperature to 80 to 90°C and react for 10 to 16 hours; when the TLC reaction is complete, cool down to 15 to 25°C, add water, keep stirring, carry out suction filtration, wash the filter cake with water, and vacuum dry the filter cake to obtain Compound 2;

[0033] (3) Add Compound 2, a deprotecting agent, and water into a reactor, raise the temperature to 80 to 90°C, and react for 10 to 16 hours. When the TLC detection shows that the reaction is complete, cool down to 15 to 25°C, adjust the pH of the reaction solution to 2 to 3 with an acid, precipitate a solid, carry out suction filtration, wash the filter cake with water, and vacuum dry the filter cake to obtain white solid 6-aminonicotinic acid (Compound 3).

[0034] The specific reaction equation is as follows:

[0035]

[0036] Preferably, the solvent is dichloromethane or toluene; the amino protecting agent is one or any combination of two or more of acetyl chloride, acetic anhydride, benzoyl chloride, trimethylchlorosilane, triethylchlorosilane, di-tert-butyl dicarbonate, and benzyl chloroformate; the oxidizing agent is one or any combination of two or more of potassium manganate, sodium chlorite, sodium hypochlorite, hypobromous acid, oxygen, and hydrogen peroxide; the deprotecting agent is one or any combination of two or more of hydrochloric acid, sodium hydroxide, potassium hydroxide, hydrogen, and trifluoroacetic acid.

[0037] Preferably, the catalyst is one or any combination of two or more of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, and γ-aluminum oxide; the surfactant is stearic acid or sodium dodecylbenzenesulfonate.

[0038] Preferably, a base is further added in step (1), and the base is one or any combination of two or more of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and pyridine.

[0039] Preferably, the molar ratio of 2-amino-5-methylpyridine to the amino protecting agent is 1:1.0 - 2.5; the molar ratio of compound 1 to the deprotecting agent is 1:1 - 5.

[0040] Preferably, the mass ratio of compound 1, the catalyst, the surfactant, and the oxidizing agent is 1:0.03 - 0.1:0.001 - 0.02:3 - 7.

[0041] The beneficial effects of the present invention are as follows:

[0042] (1) The present invention uses 2-amino-5-methylpyridine as a raw material, and 6-aminonicotinic acid is prepared through amino protection and oxidative deprotection (stepwise or one-pot method), with high yield, low cost, simple operation, low requirements for production equipment, and is suitable for industrial production;

[0043] (2) The present invention uses a clean oxidizing agent for oxidation, does not produce acid water containing heavy metals, has little corrosion to equipment, low cost, little environmental pollution, and is easy for industrial production. Specific Embodiments

[0044] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto. Those of ordinary skill in the art can and should know that any simple change or substitution based on the essence of the present invention should fall within the protection scope required by the present invention.

[0045] The experimental methods described in the embodiments are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, can all be obtained from commercial channels.

[0046] Example 1

[0047] (1) Synthesis of 2-Acetamido-5-methylpyridine

[0048]

[0049] Add 662 g of dichloromethane, 50 g (0.46 mol) of 2-amino-5-methylpyridine, and 70.18 g (0.7 mol) of triethylamine into the reactor in sequence. The temperature of the reaction solution is T = 10 °C. Start to dropwise add 54.4 g (0.7 mol) of acetyl chloride, maintain the temperature at 30 °C. After the addition is completed, stir at the same temperature for 5 h. TLC detects that the reaction is complete, and then start to cool down. Cool down to T = 20 °C, add water, stir for 0.5 h, separate the layers. Wash the organic layer with water once, dry it with anhydrous ammonium sulfate, filter, and concentrate it under reduced pressure to dryness to obtain 62.5 g of the product, with a yield of 90%, EI-MS m / z: 151 [M+H] + 。

[0050] (2) Synthesis of 6-Acetamidonicotinic Acid

[0051]

[0052] Add 50 g (0.33 mol) of 2-acetamido-5-methylpyridine, 250 g of 30% hydrogen peroxide, 0.5 g of sodium dodecylbenzenesulfonate, and 2.5 g of γ-aluminum oxide into the reaction flask. After the addition is completed and stirred evenly, slowly heat up to 85 °C and keep the reaction for 16 h. TLC shows that the reaction is complete, cool down to 25 °C, add 200 g of water, keep stirring for 1 hour, filter by suction. Wash the filter cake with a small amount of water, and dry the filter cake under vacuum to obtain 54.6 g of a pale yellow to white solid, with a yield of 91%; EI-MS m / z: 181 [M+H] + 。

[0053] (3) Synthesis of 6-Aminonicotinic Acid

[0054]

[0055] Add 50 g (0.28 mol) of 6-acetamidonicotinic acid, 22.2 g (0.56 mol) of sodium hydroxide, and 200 g of water into the reaction flask, heat up to 80 °C, and react for 12 hours. TLC detects that the reaction is complete, cool down to 15 °C, adjust the pH of the reaction solution to 3 with 6M hydrochloric acid, and a large amount of solid precipitates. Filter by suction. Wash the filter cake with a small amount of water, and dry the filter cake under vacuum to obtain 35.3 g of white solid 6-aminonicotinic acid, with a yield of 92%.

[0056] Example 2

[0057] (1) Synthesis of 2-Acetamido-5-methylpyridine

[0058]

[0059] 662 g of dichloromethane was successively added to the reactor, followed by 50 g (0.46 mol) of 2-amino-5-methylpyridine and 49.13 g (0.49 mol) of triethylamine. The temperature of the reaction solution was T = 10 °C, and 36.3 g (0.46 mol) of acetyl chloride was added dropwise. The temperature was maintained at 35 °C. After the addition was complete, the mixture was stirred at the same temperature for 5 h. The reaction was detected to be complete by TLC, and then the temperature was lowered. When the temperature reached T = 20 °C, water was added, and the mixture was stirred for 0.5 h. After liquid separation, the organic layer was washed once with water, dried over anhydrous ammonium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 48.6 g of the product with a yield of 70%. EI-MS m / z: 151 [M+H] + 。

[0060] (2) Synthesis of 6-acetylaminonicotinic acid

[0061]

[0062] 50 g (0.33 mol) of 2-acetylamino-5-methylpyridine, 150 g of 30% hydrogen peroxide, 0.05 g of sodium dodecylbenzenesulfonate, and 1.5 g of γ-aluminum oxide were added to the reaction flask. After the addition was complete and the mixture was stirred evenly, the temperature was slowly raised to 90 °C and the reaction was carried out for 12 h while maintaining the temperature. The reaction was detected to be complete by TLC, and then the temperature was lowered to 25 °C. 200 g of water was added, and the mixture was stirred at a constant temperature for 1 h. Then, it was filtered by suction. The filter cake was rinsed with a small amount of water and dried in vacuo to obtain 39 g of a pale yellow to white solid with a yield of 65%. EI-MS m / z: 181 [M+H] + 。

[0063] (3) Synthesis of 6-aminonicotinic acid

[0064]

[0065] 50 g (0.28 mol) of 6-acetylaminonicotinic acid, 11.1 g (0.28 mol) of sodium hydroxide, and 200 g of water were added to the reaction flask. The temperature was raised to 90 °C and the reaction was carried out for 10 h. The reaction was detected to be complete by TLC, and then the temperature was lowered to 25 °C. The pH of the reaction solution was adjusted to 3 with 6M hydrochloric acid, and a large amount of solid precipitated. It was filtered by suction. The filter cake was rinsed with a small amount of water and dried in vacuo to obtain 30.7 g of white solid 6-aminonicotinic acid with a yield of 80%.

[0066] Example 3

[0067] (1) Synthesis of 2-acetylamino-5-methylpyridine

[0068]

[0069] 662 g of dichloromethane was successively added to the reactor, followed by 50 g (0.46 mol) of 2-amino-5-methylpyridine and 117 g (1.16 mol) of triethylamine. The temperature of the reaction solution was T = 10 °C, and 90.73 g (1.16 mol) of acetyl chloride was added dropwise. The temperature was maintained at 35 °C. After the addition was complete, the mixture was stirred at the same temperature for 3 h. The reaction was detected to be complete by TLC and then cooled. When the temperature dropped to T = 20 °C, water was added and the mixture was stirred for 0.5 h. After liquid separation, the organic layer was washed once with water, dried over anhydrous ammonium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 62.5 g of the product with a yield of 90%. EI-MS m / z: 151 [M+H] + 。

[0070] (2) Synthesis of 6-acetylaminonicotinic acid

[0071]

[0072] 50 g (0.33 mol) of 2-acetylamino-5-methylpyridine, 350 g of 30% hydrogen peroxide, 1.0 g of sodium dodecylbenzenesulfonate, and 5.0 g of γ-aluminum oxide were added to the reaction flask. After the addition was complete and the mixture was stirred evenly, the temperature was slowly raised to 90 °C and the reaction was carried out for 15 h while maintaining the temperature. The reaction was detected to be complete by TLC and then cooled to 25 °C. 200 g of water was added and the mixture was stirred at the same temperature for 1 h. Then, it was filtered by suction. The filter cake was rinsed with a small amount of water and dried in vacuo to obtain 51 g of a pale yellow to white solid with a yield of 85%. EI-MS m / z: 181 [M+H] + 。

[0073] (3) Synthesis of 6-aminonicotinic acid

[0074]

[0075] 50 g (0.28 mol) of 6-acetylaminonicotinic acid, 55.5 g (1.39 mol) of sodium hydroxide, and 200 g of water were added to the reaction flask. The temperature was raised to 85 °C and the reaction was carried out for 14 h. The reaction was detected to be complete by TLC and then cooled to 15 °C. The pH of the reaction solution was adjusted to 3 with 6 M hydrochloric acid, and a large amount of solid precipitated. It was filtered by suction. The filter cake was rinsed with a small amount of water and dried in vacuo to obtain 30.7 g of white solid 6-aminonicotinic acid with a yield of 80%.

[0076] Example 4

[0077] (1) Synthesis of 2-acetylamino-5-methylpyridine

[0078]

[0079] 662 g of dichloromethane was successively added to the reactor, followed by 50 g (0.46 mol) of 2-amino-5-methylpyridine and 70.18 g (0.7 mol) of triethylamine. The temperature of the reaction solution was T = 10 °C, and then 54.4 g (0.7 mol) of acetyl chloride was added dropwise. The temperature was maintained at 30 °C. After the addition was complete, the mixture was stirred at the same temperature for 5 h. The reaction was detected to be complete by TLC, and then the temperature was lowered. When the temperature reached T = 20 °C, water was added, and the mixture was stirred for 0.5 h. After liquid separation, the organic layer was washed with water once, dried over anhydrous ammonium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 62.5 g of the product with a yield of 90%. EI-MS m / z: 151 [M+H] + 。

[0080] (2) Synthesis of 6-acetylaminonicotinic acid

[0081]

[0082] 1000 g of water was added to the reaction flask. After stirring until clear, 50 g (0.33 mol) of 2-acetylamino-5-methylpyridine was added. After the addition was complete, the temperature was raised to 60 °C, and 157.8 g of potassium permanganate was added in batches. After the addition was completed, the temperature was slowly raised to 80 °C and the reaction was maintained for 16 h. The reaction was detected to be complete by TLC. The salt was filtered off while hot. 13.3 g of potassium hydroxide was added to the filtrate, and the reaction was carried out at 85 °C for 10 h. The reaction was detected to be complete by TLC. The temperature was lowered to 25 °C, and the pH of the reaction solution was adjusted to 3 with 6M hydrochloric acid. A large amount of solid precipitated out. The mixture was filtered by suction. The filter cake was rinsed with a small amount of water and dried in vacuo to obtain white solid 6-aminonicotinic acid with a yield of 95%.

[0083] EI-MS m / z: 139 [M+H] + , 1 HNMR(500 MHz, CDCl3): δ 8.79 (d, 1H, J = 2.1 Hz), 8.0 (dd, 1H, J = 8.3 Hz), 6.26 (d, 1H, J = 8.4 Hz), 7.36 (brs, 2H), 11.64 (brs, 1H).

[0084] Example 5

[0085] (1) Synthesis of 2-acetylamino-5-methylpyridine

[0086]

[0087] 430 g of toluene was successively added to a reactor, followed by 50 g (0.46 mol) of 2-amino-5-methylpyridine and 70.8 g (0.7 mol) of acetic anhydride. After the addition was complete, the mixture was refluxed and stirred for 5 h. The reaction was detected to be complete by TLC, and then the temperature was lowered. When the temperature dropped to T = 20 °C, water was added and the mixture was stirred for 0.5 h. After liquid separation, the organic layer was washed with water once, dried over anhydrous ammonium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 55.6 g of the product with a yield of 80%. EI-MS m / z: 151 [M+H] + 。

[0088] (2) Synthesis of 6-acetamido nicotinic acid

[0089]

[0090] 1000 g of water was added to a reaction flask. After stirring until clear, 50 g (0.33 mol) of 2-acetamido-5-methylpyridine was added. After the addition was complete, the temperature was raised to 60 °C, and 157.8 g of potassium permanganate was added in batches. After the addition was completed, the temperature was slowly raised to 90 °C and the reaction was maintained for 12 h. The reaction was detected to be complete by TLC. While it was still hot, the salts were filtered off. 16.5 g of sodium hydroxide was added to the filtrate and the reaction was carried out at 85 °C for 10 h. The reaction was detected to be complete by TLC, and the temperature was lowered to 25 °C. The pH of the reaction solution was adjusted to 3 with 6M hydrochloric acid, and a large amount of solid precipitated out. The mixture was suction filtered, the filter cake was rinsed with a small amount of water, and the filter cake was dried in vacuo to obtain white solid 6-aminonicotinic acid with a yield of 92%.

[0091] EI-MS m / z: 139 [M+H] + , 1 HNMR (500 MHz, CDCl3): δ 8.79 (d, 1H, J = 2.1 Hz), 8.0 (dd, 1H, J = 8.3 Hz), 6.26 (d, 1H, J = 8.4 Hz), 7.36 (brs, 2H), 11.64 (brs, 1H).

[0092] Example 6

[0093] (1) Synthesis of 2-acetamido-5-methylpyridine

[0094]

[0095] 662 g of dichloromethane was successively added to the reactor, followed by 50 g (0.46 mol) of 2-amino-5-methylpyridine and 70.18 g (0.7 mol) of triethylamine. The temperature of the reaction solution was T = 10 °C, and 54.4 g (0.7 mol) of acetyl chloride was added dropwise. The temperature was maintained at 30 °C. After the addition was complete, the mixture was stirred at the same temperature for 5 h. The reaction was detected to be complete by TLC, and then the temperature was lowered. When the temperature reached T = 20 °C, water was added, and the mixture was stirred for 0.5 h. After liquid separation, the organic layer was washed with water once, dried over anhydrous ammonium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 62.5 g of the product with a yield of 90%. EI-MS m / z: 151 [M+H] + 。

[0096] (2) Synthesis of 6-acetylaminonicotinic acid

[0097]

[0098] 1000 g of water was added to the reaction flask. After stirring until clear, 50 g (0.33 mol) of 2-acetylamino-5-methylpyridine was added. After the addition was complete, the temperature was raised to 60 °C, and 157.8 g of potassium permanganate was added in batches. After the addition was completed, the temperature was slowly raised to 85 °C, and the reaction was carried out under insulation for 14 h. The reaction was detected to be complete by TLC. The salt was filtered off while hot. 15 g of potassium carbonate was added to the filtrate, and the reaction was carried out at 85 °C for 12 h. The reaction was detected to be complete by TLC. The temperature was lowered to 25 °C, and the pH of the reaction solution was adjusted to 3 with 6M hydrochloric acid. A large amount of solid precipitated out. The mixture was filtered by suction. The filter cake was rinsed with a small amount of water and dried in vacuo to obtain white solid 6-aminonicotinic acid with a yield of 93%.

[0099] EI-MS m / z: 139 [M+H] + , 1 HNMR(500 MHz, CDCl3): δ 8.79 (d, 1H, J = 2.1 Hz), 8.0 (dd, 1H, J = 8.3 Hz), 6.26 (d, 1H, J = 8.4 Hz), 7.36 (brs, 2H), 11.64 (brs, 1H).

Claims

1. A preparation method of abemaciclib intermediate 6-aminonicotinic acid, characterized in that: Using 2-amino-5-methylpyridine as a raw material, the target product 6-aminonicotinic acid is prepared through amino protection, oxidation with an oxidizing agent, and finally deprotection; among them, oxidation and deprotection are achieved by a stepwise method or a one-pot method; When oxidation and deprotection are carried out by a stepwise method, it specifically includes the following steps: (1) Add a solvent, 2-amino-5-methylpyridine, and an amino protecting agent to a reactor. After the feeding is completed, keep the reaction at 25 °C to reflux for 2 to 5 hours, then cool down to 10 to 25 °C, add water, stir for 0.5 to 1.0 hour, separate the layers, wash the organic layer with water, dry it with anhydrous ammonium sulfate, filter, and concentrate under reduced pressure to dryness to obtain Compound 1; (2) Add Compound 1, an oxidizing agent, a surfactant, and a catalyst to a reactor. After stirring evenly, raise the temperature to 80 to 90 °C and react for 10 to 16 hours; when the TLC reaction is complete, cool down to 15 to 25 °C, add water, keep stirring, filter by suction, wash the filter cake with water, and dry the filter cake under vacuum to obtain Compound 2; (3) Add Compound 2, a deprotecting agent, and water to a reactor, raise the temperature to 80 to 90 °C, react for 10 to 16 hours, detect the reaction is complete by TLC, cool down to 15 to 25 °C, adjust the pH of the reaction solution to 2 to 3 with an acid, precipitate a solid, filter by suction, wash the filter cake with water, and dry the filter cake under vacuum to obtain white solid 6-aminonicotinic acid; In the stepwise method, the oxidizing agent is hydrogen peroxide, the surfactant is sodium dodecylbenzenesulfonate, and the catalyst is γ-aluminum oxide; When oxidation and deprotection are carried out by a one-pot method, it specifically includes the following steps: (1) Add a solvent, 2-amino-5-methylpyridine, and an amino protecting agent to a reactor. After the feeding is completed, keep the reaction at 25 °C to reflux for 2 to 5 hours, then cool down to 10 to 25 °C, add water, stir for 0.5 to 1.0 hour, separate the layers, wash the organic layer with water, dry it with anhydrous ammonium sulfate, filter, and concentrate under reduced pressure to dryness to obtain Compound 1; (2) Add water and Compound 1 to a reactor. After feeding, raise the temperature to 50 to 70 °C, add the oxidizing agent in batches, and react at 80 to 90 °C for 10 to 16 hours after adding; when the TLC reaction is complete, filter off the salt while it is hot, add a deprotecting agent to the filtrate, react at 80 to 90 °C for 8 to 16 hours, when the TLC reaction is complete, cool down to 15 to 25 °C, and perform post-treatment to obtain 6-aminonicotinic acid; In the one-pot method, the oxidizing agent is potassium permanganate.

2. The preparation method of abemaciclib intermediate 6-aminonicotinic acid according to claim 1, wherein: The solvent is dichloromethane or toluene; the amino protecting agent is one or any combination of two or more of acetyl chloride, acetic anhydride, benzoyl chloride, trimethylchlorosilane, triethylchlorosilane, di-tert-butyl dicarbonate, benzyl chloroformate; the deprotecting agent is one or any combination of two or more of hydrochloric acid, sodium hydroxide, potassium hydroxide, hydrogen, trifluoroacetic acid.

3. The preparation method of abemaciclib intermediate 6-aminonicotinic acid according to claim 2, wherein: In step (1), a base is also added, and the base is one or any combination of two or more of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine.

4. The preparation method of abemaciclib intermediate 6-aminonicotinic acid according to claim 1, wherein: The molar ratio of 2-amino-5-methylpyridine to the amino protecting agent is 1:1.0 to 2.5; the molar ratio of Compound 1 to the deprotecting agent is 1:1 to 5.

5. The preparation method of abemaciclib intermediate 6-aminonicotinic acid according to claim 1, characterized in that: The mass ratio of Compound 1, catalyst, surfactant, and oxidant is 1: 0.03 - 0.1: 0.001 - 0.02: 3 - 7.

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