A process for the preparation of 4-aminonicotinic acid

Abstract

The application provides a preparation method of 4-aminonicotinic acid and belongs to the technical field of organic synthesis. The preparation method of 4-aminonicotinic acid provided by the application takes 4,6-dichloronicotinic acid ester as a raw material, carries out 4-position amination and reduction to obtain 4-aminonicotinic acid ester, and finally, carries out alkaline hydrolysis to obtain 4-aminonicotinic acid. The process route selected by the application is simple, the reaction condition is mild and safe, the raw material source is wide, the method is suitable for industrial mass production, and has a wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 4-aminonicotinic acid. Background Technology

[0002] 4-Aminonicotinic acid exists in the structures of many natural products and is an important pharmaceutical intermediate. It can be used to synthesize poly(ADP-ribose) polymerase inhibitors (WO2018125961A1) and 4-aminopyridine derivatives with anti-amnesia activity for the treatment of Alzheimer's disease. [1] New MtbTMPK inhibitors can be synthesized. [2] It can synthesize sulfonamide derivatives for use as NAMPT inhibitors in antitumor drugs (CN107987060); it can also synthesize drugs for the treatment of cardiovascular and cerebrovascular diseases, whose derivatives are analogs of coenzyme nicotinamide purine nucleotides, playing an important role in cell metabolism. [3] Therefore, 4-aminonicotinic acid is a widely used pharmaceutical intermediate.

[0003] Existing research has yielded numerous literature reports on the synthesis routes of 4-aminonicotinic acid, mainly including the following routes:

[0004] 1. Starting with 3-methylpyridine, it is first oxidized with hydrogen peroxide to produce 3-methylpyridine oxide, and then synthesized into 4-aminonicotinic acid through a four-step reaction of nitration, oxidation, and reduction. [4] The synthetic route is as follows:

[0005]

[0006] The key intermediate 3-methyl-4-nitropyridine nitroxide in this process is explosive and unsafe to operate; the nitration and oxidation reactions also produce a large amount of waste sulfuric acid, putting great pressure on the treatment of waste; in addition, the post-treatment of the nitro iron powder reduction reaction is complicated and produces a large amount of waste iron sludge; the overall yield is also low, less than 8%; therefore, this process has poor socio-economic benefits and is not suitable for large-scale industrial production.

[0007] 2. Starting with isoquinoline, 3,4-pyridinedicarboxylic acid was obtained through oxidative ring-opening. This was followed by intramolecular dehydration under acetic anhydride to give 3,4-pyridinedicarboxylic anhydride, which was then subjected to regioselective ammonolysis to generate 4-amidopyridine-3-carboxylic acid. Finally, the target product, 4-aminonicotinic acid, was obtained through a Hofmann degradation reaction. [5] Its synthesis route is as follows:

[0008]

[0009] This process is cumbersome, generates large volumes of waste acid and wastewater, and produces a large number of byproducts during regional selective ammonolysis, making post-processing of the final product difficult and resulting in the inability to obtain pure 4-aminonicotinic acid. Therefore, this process is not suitable for large-scale industrial production.

[0010] 3. Using 4-chloronicotinic acid as a raw material, 4-aminonicotinic acid (WO2015103355A1) was obtained by reacting it with ammonia water under high temperature and pressure. The synthetic route is as follows:

[0011]

[0012] This process involves high reaction temperatures and pressures, has poor operational safety, and the raw materials are expensive, resulting in poor socio-economic benefits and making it unsuitable for large-scale industrial production.

[0013] 4. Starting with 3-methylpyridine, the reaction was first oxidized with hydrogen peroxide to generate 3-methylpyridine oxide, then nitrated to obtain 3-methyl-4-nitropyridine oxide, which was then reduced to 4-amino-3-methylpyridine. Following amino protection, potassium permanganate oxidation of the methyl group, and deprotection, a six-step reaction was performed to obtain the target product, 4-aminonicotinic acid, with an overall yield of 21.7%. [6] The synthetic route is as follows:

[0014]

[0015] This process is cumbersome, generates a large amount of waste acid and wastewater, and produces a large amount of solid waste from the reduction of nitro groups by iron powder and the oxidation of methyl groups by potassium permanganate. Similarly, 3-methyl-4-nitropyridine nitrogen oxides are explosive and unsafe to operate. With its long steps and low overall yield, this process is not suitable for large-scale industrial production.

[0016] 5. Starting with 1-benzyl-4-piperidinone-3-carboxylic acid ester, piperidin-4-one-3-carboxylate is obtained via hydrogenolysis. Then, the piperidin-4-one-3-carboxylate reacts with a halogenating agent to give the corresponding dihalogenated or trihalogenated product, wherein the halogenating agent is bromine, chlorine, or hydrogen halide + hydrogen peroxide. Finally, elimination followed by ammonia addition yields 4-aminonicotinic acid (CN110483388A). The synthetic route is as follows:

[0017]

[0018] The hydrogenation and halogenation reactions in this process are both high-risk reactions, requiring highly skilled operators and sophisticated equipment, and the raw materials are also expensive. Therefore, this process is not suitable for large-scale industrial production.

[0019] [1]Andreani A, Leoni A, Locatelli A, et al. 4-Aminopyridine derivatives with antiamnesic activity[J]. Eur J Med Chem. 2000Jan; 35(1):77-82.

[0020] [2]Jian Y, Forbes HE, Hulpia F, et al. 2-((3,5-Dinitrobenzyl)thio)quinazolinones:Potent Antimycobacterial Agents Activated by Deazaflavin(F420)-Dependent Nitroreductase(Ddn)[J]. J Med Chem. 2021 Jan 14;64(1):440-457.

[0021] [3]Nishiwaki N,Azuma M,Tamura M,et al.Facile synthesis of functionalized 4-aminopyridines[J].Chem Commun(Camb).2002 Sep 21;(18):2170-1.

[0022] [4] Zhou ZL, Navratil JM, Cai SX, et al.Synthesis and SAR of 5-,6-,7-and8-aza analogues of 3-aryl-4-hydroxyquinolin-2(1H)-one as NMDA / glycine siteantagonists[J]. Bioorg Med Chem. 2001 Aug; 9(8):2061-71.

[0023] [5] Su Ce, He Junhua. Synthesis of 4-aminonicotinic acid [J]. Journal of Chemical Engineering of Chinese Universities, 2010, 24(05):907-910.

[0024] [6]ECTAYLOR JR.and ALDO J.CROVETTI.PYRIDINE-1-OXIDES.I.SYNTHESIS OFSOME NICOTINIC ACID DERIVATIVES[J].The Journal of Organic Chemistry.1954 19(10),1633-1640. Summary of the Invention

[0025] To address the aforementioned shortcomings, this invention provides a method for preparing 4-aminonicotinic acid. The method uses 4,6-dichloronicotinic acid ester as a raw material, undergoing a two-step reaction of 4-position amination and reduction to obtain 4-aminonicotinic acid ester. Finally, 4-aminonicotinic acid is obtained through alkaline hydrolysis. The process route chosen in this invention is simple, the reaction conditions are mild and safe, and the raw materials are widely available, making it suitable for large-scale industrial production and possessing broad application prospects.

[0026] The technical solution of the present invention includes:

[0027] On the one hand, the present invention provides a method for preparing 4-aminonicotinic acid, the synthetic route of which is as follows:

[0028]

[0029] (1) Compound I was amination at the 4-position of compound II to obtain compound III;

[0030] (2) Compound III was deprotected by amino groups to give compound IV;

[0031] (3) Compound IV was hydrolyzed to give compound V;

[0032] R1 is a straight-chain or branched C1-C6 saturated or unsaturated alkyl group or a C1-C6 saturated or unsaturated cycloalkyl group.

[0033] R2 is a substituted or unsubstituted phenyl or pyridyl group.

[0034] Specifically, R1 is a straight-chain C1-C6 saturated alkyl group.

[0035] Preferably, the R1 structure is CH3.

[0036] Specifically, R2 is a substituted or unsubstituted phenyl group.

[0037] Preferably, the R2 structure is as follows:

[0038]

[0039] Specifically, step (1) involves adding compound I to a solvent (1) containing triethylamine, dissolving it, cooling it to 10°C in an ice-water bath, adding compound II, stirring the mixture at 10°C for 1 hour, removing the ice-water bath, raising the temperature to T1, and distilling it under reduced pressure after the reaction is complete. The solution is then poured into cold water, extracted, combined with the organic phases, washed, dried, dissolved, and recrystallized to obtain compound III.

[0040] More specifically, the solvent (1) mentioned in step (1) is one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, and acetone.

[0041] Preferably, the solvent (1) mentioned in step (1) is acetonitrile or N,N-dimethylformamide.

[0042] More specifically, the temperature of T1 mentioned in step (1) is 10-120℃.

[0043] Preferably, the temperature of T1 in step (1) is 10℃-20℃, 20℃-30℃, 30℃-40℃, 40℃-50℃, 50℃-60℃, 60℃-70℃, 70℃-80℃, 80℃-90℃, 90℃-100℃, 100℃-110℃, or 110℃-120℃.

[0044] More preferably, the temperature of T1 in step (1) is 20℃-30℃, 30℃-40℃, or 40℃-50℃.

[0045] More specifically, the molar ratio of compound I, compound II and triethylamine in step (1) is 1:1-2:1-3.

[0046] Preferably, the molar ratio of compound I, compound II and triethylamine in step (1) is 1:1:1, 1:1:2, 1:1:3, 1:2:1, 1:2:2, or 1:2:3.

[0047] Preferably, the solvent used for extraction in step (1) is ethyl acetate.

[0048] Preferably, the solvent used for cleaning in step (1) is saturated saline solution.

[0049] Preferably, the substance used for drying in step (1) is anhydrous sodium sulfate.

[0050] Preferably, the substance used for recrystallization in step (1) is methyl tert-butyl ether.

[0051] Preferably, the complete reaction in step (1) is determined by TLC detection.

[0052] Specifically, step (2) involves adding compound III obtained in step (1) to an acidic solvent (2), heating it to T2 with stirring, adding a reducing agent, and controlling the temperature not to exceed T3; then, keeping the reaction at T3 until the reaction is complete, cooling it to T4, filtering it, evaporating the filtrate under reduced pressure, pouring it into ice water, adjusting the pH, and controlling the temperature not to exceed 20°C; then, extracting and combining the organic phases, washing, drying, and desolventizing to obtain compound IV.

[0053] More specifically, the solvent (2) mentioned in step (2) is one or more of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, and acetone.

[0054] Preferably, the solvent (2) mentioned in step (2) is methanol.

[0055] More specifically, the temperature of T2 mentioned in step (2) is 10℃-80℃.

[0056] Preferably, the temperature of T2 in step (2) is 10℃-20℃, 20℃-30℃, 30℃-40℃, 40℃-50℃, 50℃-60℃, 60℃-70℃, or 70℃-80℃.

[0057] More preferably, the temperature of T2 in step (2) is 50°C.

[0058] More specifically, the temperature of T3 mentioned in step (2) is 20℃-100℃.

[0059] Preferably, the temperature of T3 in step (2) is 20℃-30℃, 30℃-40℃, 40℃-50℃, 50℃-60℃, 60℃-70℃, 70℃-80℃, 80℃-90℃, or 90℃-100℃.

[0060] More preferably, the temperature of T3 in step (2) is 60°C.

[0061] More specifically, the temperature of T4 in step (2) is -10℃ to 60℃.

[0062] Preferably, the temperature of T4 in step (2) is -10℃-0℃, 0℃-10℃, 10℃-20℃, 20℃-30℃, 30℃-40℃, 40℃-50℃, or 50℃-60℃.

[0063] More preferably, the temperature of T4 in step (2) is 30°C.

[0064] More specifically, the reducing agent mentioned in step (2) is one or more of hydrogen, zinc powder, and iron powder.

[0065] More specifically, the temperature of the ice water mentioned in step (2) is 0-10℃.

[0066] More specifically, the pH mentioned in step (2) is 6-9.

[0067] Preferably, the pH in step (2) is 7-8.

[0068] More specifically, the pH adjuster mentioned in step (2) is one of sodium hydroxide, potassium hydroxide, ammonia, and sodium bicarbonate.

[0069] Preferably, the pH adjuster mentioned in step (2) is sodium hydroxide.

[0070] More preferably, the pH adjuster mentioned in step (2) is 10% sodium hydroxide.

[0071] More specifically, the solvent used for extraction in step (2) is ethyl acetate.

[0072] More specifically, the solvent used for cleaning in step (2) is saturated saline solution.

[0073] More specifically, the substance used for drying in step (2) is anhydrous sodium sulfate.

[0074] More specifically, the complete reaction described in step (2) refers to the complete reaction as detected by TLC.

[0075] Specifically, step (3) involves adding the compound IV obtained in step (2) into an alkaline solution at a temperature of T5. After the addition is complete, the reaction is maintained at a temperature of T6. After the reaction is complete, the pH is adjusted, the mixture is cooled to 5°C in an ice-water bath, stirred for 1 hour, a precipitate is formed, filtered, and dried to obtain compound V.

[0076] More specifically, the temperature of T5 in step (3) is 0℃-50℃.

[0077] Preferably, the temperature of T5 in step (3) is 0℃-10℃, 10℃-20℃, 20℃-30℃, 30℃-40℃, or 40℃-50℃.

[0078] More preferably, the temperature of T5 in step (3) is 20°C.

[0079] More specifically, the temperature of T6 in step (3) is 10℃-100℃.

[0080] Preferably, the temperature of T6 in step (3) is 20℃-50℃.

[0081] More preferably, the temperature of T6 in step (2) is 20℃-30℃, 30℃-40℃, or 40℃-50℃.

[0082] More specifically, the alkaline solution mentioned in step (3) is one or more of sodium hydroxide solution, potassium hydroxide solution, and lithium hydroxide solution.

[0083] Preferably, the alkaline solution in step (3) is a sodium hydroxide solution or a lithium hydroxide solution.

[0084] More specifically, the molar ratio of compound IV to alkaline solution in step (3) is 1:1-5.

[0085] Preferably, the molar ratio of compound IV to alkaline solution in step (3) is 1:1-5, 1:1-4, 1:1-3, 1:1-2, 1:2-5, 1:2-4, 1:2-3, 1:3-5, or 1:3-4.

[0086] More preferably, the molar ratio of compound IV to alkaline solution in step (3) is 1:1, 1:2, 1:3, 1:4, or 1:5.

[0087] More specifically, the pH mentioned in step (3) is 3-5.

[0088] Preferably, the pH in step (3) is 4.

[0089] More specifically, the pH adjuster mentioned in step (3) is one of hydrochloric acid, sulfuric acid, acetic acid, malic acid, phosphoric acid, tartaric acid, and maleic acid.

[0090] Preferably, the pH adjuster mentioned in step (3) is hydrochloric acid.

[0091] More preferably, the pH adjuster in step (3) is 6N hydrochloric acid.

[0092] More specifically, the complete reaction described in step (3) refers to the complete reaction as detected by TLC.

[0093] On the other hand, the present invention provides applications of the above-described preparation method, characterized in that the applications include applications in the preparation of 4-aminonicotinic acid or its analogues, and pharmaceutically acceptable carriers and / or excipients.

[0094] Specifically, the analogues are derivatives of 4-aminonicotinic acid, pharmaceutically acceptable salts thereof, tautomers thereof, and / or stereoisomers thereof.

[0095] The technical effects achieved by this invention are as follows:

[0096] (1) The present invention provides a method for preparing 4-aminonicotinic acid. The method uses 4,6-dichloronicotinic acid ester as raw material, and obtains 4-aminonicotinic acid ester through two-step reactions of 4-position amination and reduction. Finally, 4-aminonicotinic acid is obtained by alkaline hydrolysis.

[0097] (2) The preparation method of 4-aminonicotinic acid provided by the present invention has a simple process route, mild and safe reaction conditions, and a wide range of raw material sources. It is suitable for large-scale industrial production and has broad application prospects. Attached Figure Description

[0098] Figure 1 The image shows the nuclear magnetic resonance (NMR) image of 4-aminonicotinic acid. Detailed Implementation

[0099] The present invention will be described below with reference to specific embodiments. These embodiments are not intended to limit the present invention, but only to illustrate the present invention and make the technical solution of the present invention easier to understand and master. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0100] Example 1

[0101] 1. Synthesis of methyl 6-chloro-4-(4-methoxybenzylamino)nicotinic acid

[0102] In a 1L four-necked flask, 250mL of acetonitrile and 70g (692mmol) of triethylamine were added. Then, 100g (485mmol) of methyl 4,6-dichloronicotinic acid was added with stirring at room temperature. After stirring until dissolved, the mixture was cooled to 10°C in an ice-water bath. Next, 93g (679mmol) of 4-methoxybenzylamine was slowly added. The mixture was stirred at 10°C for 1 hour, then the ice-water bath was removed, and the mixture was allowed to warm naturally to room temperature overnight. The next day, TLC analysis showed that the reaction proceeded completely. The reaction mixture was distilled under reduced pressure, and the residue was poured into 1kg of cold water and extracted three times with ethyl acetate (600mL x 3). The organic phases were combined, washed with saturated brine (500mL x 1), dried over anhydrous sodium sulfate (100g), and dissolved. The solution was removed, and the mixture was recrystallized from methyl tert-butyl ether to give 113g of a white solid, methyl 6-chloro-4-(4-methoxybenzylamino)nicotinic acid, with a yield of 89%.

[0103] Synthesis of 2,4-aminonicotinic acid methyl ester

[0104] In a 10L reaction flask, 3L of methanol and 2L of trifluoroacetic acid were added. Then, 1000g (3260mmol) of methyl 6-chloro-4-(4-methoxybenzylamino)nicotinic acid prepared in step 1 was added with stirring. The temperature was then slowly raised to 50℃, and 530g (8154mmol) of zinc powder was added in batches, controlling the temperature not to exceed 60℃. After the addition was complete, the reaction was maintained at 60℃ overnight. The next day, TLC confirmed that the reaction was complete. The reaction mixture was cooled to 30℃, filtered to remove insoluble matter, and the filtrate was evaporated to dryness under reduced pressure. The residue was poured into 4kg of ice water, and the pH was adjusted to 7-8 with a 10% sodium hydroxide aqueous solution, controlling the temperature not to exceed 20℃. The mixture was then extracted three times with ethyl acetate (2L*3), the organic phases were combined, washed with saturated brine (1L*1), dried over anhydrous sodium sulfate (300g), and solvent was removed to obtain 426g of pale yellow solid methyl 4-aminonicotinic acid, with a yield of 86%.

[0105] Synthesis of 3,4-aminonicotinic acid

[0106] In a 1L four-necked flask, 300mL of cold water was added, followed by the addition of 32g (800mmol) of sodium hydroxide while stirring. The flask was cooled to 20°C in an ice-water bath. Then, 100g (657mmol) of methyl 4-aminonicotinic acid prepared in step 2 was slowly added. After the addition was complete, the mixture was kept at 20°C overnight. The next day, TLC analysis showed that the reaction of the starting material was complete. The pH was adjusted to 4 with 6N hydrochloric acid, and the mixture was cooled to 5°C in an ice-water bath and stirred for 1 hour to form a precipitate. The precipitate was filtered, dried, and 87g of pale yellow solid 4-aminonicotinic acid was obtained, with a yield of 96%. The NMR spectrum is shown below. Figure 1 . 1 HNMR (DMSO-d6) δ6.93 (s, 1H), δ7.95 (d J=1.0Hz, 1H), δ8.55 (dd J=3.5Hz, 1H)

[0107] Example 2

[0108] 1. Synthesis of methyl 6-chloro-4-(4-methoxybenzylamino)nicotinic acid

[0109] Add 100 mL of N,N-dimethylformamide and 67.5 g of triethylamine to a 250 mL four-necked flask.

[0110] (667 mmol) methyl 4,6-dichloronicotinic acid ester 46 g (223 mmol) was added under stirring at room temperature. After stirring until dissolved, the mixture was cooled to 10°C in an ice-water bath. Then, 26.3 g (246 mmol) benzylamine was slowly added. The mixture was stirred at 10°C for 1 hour, then the ice-water bath was removed, and the mixture was allowed to warm to room temperature overnight. The next day, TLC showed that the reaction was complete. The reaction mixture was distilled under reduced pressure, and the residue was poured into 0.5 kg of cold water and extracted three times with ethyl acetate (300 mL * 3). The organic phases were combined, washed with saturated brine (400 mL * 1), dried over anhydrous sodium sulfate (100 g), dissolved, and recrystallized from methyl tert-butyl ether to give 54 g of off-white solid methyl 6-chloro-4-(4-methoxybenzylamino)nicotinic acid ester, yield 87%.

[0111] Synthesis of 2,4-aminonicotinic acid methyl ester

[0112] In a 1L reaction flask, 300mL of methanol and 250mL of trifluoroacetic acid were added. 100g (361mmol) of 4-(benzylamino)-6-chloronicotinic acid methyl ester prepared in step 1 was added with stirring. The temperature was then slowly raised to 50℃, and 59g (908mmol) of zinc powder was added in portions, maintaining the temperature below 60℃. After the addition was complete, the reaction was maintained at 60℃ overnight. The next day, TLC analysis showed complete reaction of the raw materials. The reaction mixture was cooled to 30℃, filtered to remove insoluble matter, and the filtrate was evaporated to dryness under reduced pressure. The residue was poured into 0.5kg of ice water, and the pH was adjusted to 7-8 with a 10% sodium hydroxide aqueous solution, maintaining the temperature below 20℃. The mixture was then extracted three times with ethyl acetate (300mL x 3), and the organic phases were combined, washed with saturated brine (400mL x 1), dried over anhydrous sodium sulfate (100g), and dissolved to obtain 45g of pale yellow solid 4-aminonicotinic acid methyl ester, with a yield of 82%.

[0113] Synthesis of 3,4-aminonicotinic acid

[0114] Add 400 mL of cold water to a 1 L four-necked flask, and add 40 g (1000 mmol) of sodium hydroxide while stirring. Cool to 20 °C in an ice-water bath. Then, slowly add 100 g (657 mmol) of methyl 4-aminonicotinic acid prepared in step 2. After the addition is complete, keep the mixture at 40 °C overnight. The next day, TLC showed that the reaction of the starting material was complete. Adjust the pH to 4 with 6 N hydrochloric acid, cool to 5 °C in an ice-water bath, and stir for 1 hour to form a precipitate. Filter and dry to obtain 82 g of pale yellow solid 4-aminonicotinic acid, with a yield of 90%.

[0115] Example 3

[0116] 1. Synthesis of methyl 6-chloro-4-(4-methoxybenzylamino)nicotinic acid

[0117] In a 1L four-necked flask, 250mL of acetonitrile and 70g (692mmol) of triethylamine were added. Then, 100g (485mmol) of methyl 4,6-dichloronicotinic acid was added with stirring at room temperature. After stirring until dissolved, the mixture was cooled to 10°C in an ice-water bath. Next, 93g (679mmol) of 4-methoxybenzylamine was slowly added. The mixture was stirred at 10°C for 1 hour, then the ice-water bath was removed, and the temperature was raised to 50°C and reacted overnight. The next day, TLC confirmed complete reaction of the starting material. The reaction mixture was distilled under reduced pressure, and the residue was poured into 0.5kg of cold water and extracted three times with ethyl acetate (300mL each). The organic phases were combined, washed with saturated brine (400mL each), dried over anhydrous sodium sulfate (100g), and dissolved. The solution was removed, and the mixture was recrystallized from methyl tert-butyl ether to give 95g of a white solid, methyl 6-chloro-4-(4-methoxybenzylamino)nicotinic acid, with a yield of 78%.

[0118] Synthesis of 2,4-aminonicotinic acid methyl ester

[0119] In a 1L reaction flask, 300mL of methanol and 150mL of trifluoroacetic acid were added. While stirring, 100g (326mmol) of 4-(benzylamino)-6-chloronicotinic acid methyl ester prepared in step 1 was added. The mixture was then slowly heated to 50℃, and 53g (815mmol) of zinc powder was added in portions, maintaining the temperature below 60℃. After the addition was complete, the mixture was kept at 60℃ overnight. The next day, TLC analysis confirmed complete reaction of the starting materials. The reaction mixture was cooled to 30℃, filtered to remove insoluble matter, and the filtrate was evaporated to dryness under reduced pressure. The residue was poured into 0.5kg of ice water, and the pH was adjusted to 7-8 with a 10% sodium hydroxide aqueous solution, maintaining the temperature below 20℃. The mixture was then extracted three times with ethyl acetate (300mL x 3), and the organic phases were combined, washed with saturated brine (400mL x 1), dried over anhydrous sodium sulfate (100g), and solvent removed to obtain 41g of pale yellow solid 4-aminonicotinic acid methyl ester, with a yield of 75%.

[0120] Synthesis of 3,4-aminonicotinic acid

[0121] In a 1L four-necked flask, 300mL of cold water was added, and 33g (786mmol) of lithium hydroxide hydrate was added with stirring. The flask was cooled to 20°C in an ice-water bath. Then, 100g (657mmol) of 4-aminonicotinic acid methyl ester prepared in step 2 was slowly added. After the addition was complete, the flask was kept at 50°C overnight. The next day, TLC was used to check that the reaction of the starting material was complete. The pH was adjusted to 4 with 6N hydrochloric acid, and the flask was cooled to 5°C in an ice-water bath with stirring for 1 hour to form a precipitate. The precipitate was filtered and dried to obtain 76g of a pale yellow solid, with a yield of 83%.

[0122] The above detailed description is a specific illustration of one feasible embodiment of the present invention, and this embodiment is not intended to limit the patent scope of the present invention. It should be noted that all equivalent implementations or modifications made without departing from the present invention should be included within the scope of the technical solution of the present invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims

1. A method for preparing 4-aminonicotinic acid, characterized in that, The synthetic route of the preparation method is as follows: (1) Compound I was amination at the 4-position by compound II to obtain compound III; (2) Compound III was deprotected by amino groups to give compound IV; (3) Compound IV was hydrolyzed to give compound V; R1 is a straight-chain or branched C1-C6 saturated alkyl group or a C1-C6 saturated cycloalkyl group; R2 is a substituted or unsubstituted phenyl or pyridyl group; Step (3) involves adding the compound IV obtained in step (2) to a sodium hydroxide solution at a temperature of T5. After the addition is complete, the mixture is kept at 20°C for reaction. After the reaction is complete, the pH is adjusted, and the mixture is cooled to 5°C in an ice-water bath and stirred for 1 hour to form a precipitate. The precipitate is then filtered, dried, and compound V is obtained.

2. The preparation method according to claim 1, characterized in that, Step (1) involves adding compound I to a solvent (1) containing triethylamine, dissolving it, cooling it to 10°C in an ice-water bath, adding compound II, stirring the mixture at 10°C for 1 hour, removing the ice-water bath, raising the temperature to T1, and distilling it under reduced pressure after the reaction is complete. The solution is then poured into cold water, extracted, combined with the organic phases, washed, dried, dissolved, and recrystallized to obtain compound III.

3. The preparation method according to claim 2, characterized in that, The solvent (1) mentioned in step (1) is one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, and acetone.

4. The preparation method according to claim 2, characterized in that, The temperature of T1 mentioned in step (1) is 10℃-120℃.

5. The preparation method according to claim 2, characterized in that, The molar ratio of compound I, compound II and triethylamine in step (1) is 1:1-2:1-3.

6. The preparation method according to claim 1, characterized in that, Step (2) involves adding compound III obtained in step (1) to an acidic solvent (2), heating it to T2 with stirring, adding a reducing agent, and controlling the temperature not to exceed T3; then, keeping the reaction at T3 until the reaction is complete, cooling it to T4, filtering it, evaporating the filtrate under reduced pressure, pouring it into ice water, adjusting the pH to 7-8, and controlling the temperature not to exceed 20℃; then, extracting and combining the organic phases, washing, drying, and desolventizing to obtain compound IV.

7. The preparation method according to claim 6, characterized in that, The solvent (2) mentioned in step (2) is one or more of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, and acetone.

8. The preparation method according to claim 6, characterized in that, The temperature of T2 in step (2) is 10℃-80℃; the temperature of T3 is 20℃-100℃; and the temperature of T4 is -10℃-60℃.

9. The preparation method according to claim 6, characterized in that, The reducing agent mentioned in step (2) is one or both of zinc powder and iron powder.

10. The preparation method according to claim 1, characterized in that, The temperature of T5 mentioned in step (3) is 0℃-50℃.

11. The preparation method according to claim 1, characterized in that, The molar ratio of compound IV to sodium hydroxide solution in step (3) is 1:1-5.

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