A method for synthesizing 3-amino-2-pyridine carboxylic acid

Abstract

The application belongs to the field of medicine and pesticide intermediate synthesis, and particularly relates to a synthesis method of 3-amino-2-pyridine carboxylic acid. The method comprises the following steps: S1, reacting diethyl malonate and sodium hydride to obtain a sodium salt, and then reacting the sodium salt with 2,6-dichloro-3-nitropyridine to obtain 2-(6-chloro-3-nitropyridine-2-yl) malonic acid 1,3-diethyl ester; S2, reacting 2-(6-chloro-3-nitropyridine-2-yl) malonic acid 1,3-diethyl ester in the presence of a solvent and an oxidizing agent to obtain 6-chloro-3-nitro-2-pyridine carboxylic acid; and S3, hydrogen reduction of 6-chloro-3-nitro-2-pyridine carboxylic acid to obtain 3-amino-2-pyridine carboxylic acid. The process route is simple, easy to control, the raw materials are widely available, the yield is high, the cost is low, and the method is suitable for large-scale production, and has a good application prospect in the pharmaceutical industry, synthetic chemistry and medicinal chemistry.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and pesticide intermediate synthesis, specifically relating to a method for synthesizing 3-amino-2-pyridinecarboxylic acid. Background Technology

[0002] 3-Amino-2-pyridinecarboxylic acid is an important pharmaceutical and pesticide intermediate with wide applications in medicinal chemistry. It can be used to synthesize PDE9 inhibitors (CN111471059, 2020, A), as well as antibacterial borate pyridinecarboxylate esters, which can treat atopic dermatitis (AD) or eczema (Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, #23, p. 5963-5967). It can also be used to synthesize new antidiabetic drugs (Journal of Medicinal Chemistry, 2008, vol. 51, #7, p. 2196-2207). The literature [Journal of Organic Chemistry, 2004, vol. 69, #1, p. 54-61] reported I and II (as shown below) as a new peptide coupling additive, in which 3-amino-2-pyridinecarboxylic acid is the key intermediate in its synthesis.

[0003]

[0004] The traditional synthesis of 3-amino-2-pyridinecarboxylic acid uses pyridine-2,3-dicarboxylic acid as a starting material. It first reacts with acetic anhydride to obtain the corresponding lactam, and then reacts with acetamide to obtain the corresponding lactam. The two-step yield is 56%. The lactam undergoes Hofmann degradation with sodium hypobromite, yielding a mixture of 3-amino-2-pyridinecarboxylic acid and 2-amino-3-pyridinecarboxylic acid, which is difficult to separate and purify. Zhang-Lin Zhou et al. reported in Bioorganic & Medicinal Chemistry 9 (2001) 2061-2071 that copper ions can form a chelate with 3-amino-2-pyridinecarboxylic acid, while 2-amino-3-pyridinecarboxylic acid cannot form a chelate with copper ions, thus achieving separation. The formed chelate is dissolved in water by introducing hydrogen sulfide gas, forming copper sulfide precipitate. 3-amino-2-pyridinecarboxylic acid dissolves in water, and after filtration and evaporation of the solvent water, 3-amino-2-pyridinecarboxylic acid is obtained as a single 3-amino-2-pyridinecarboxylic acid. This process involves a long number of steps (five in total), is complex to operate, and has a low overall yield (less than 10%), resulting in extremely high production costs. Moreover, the reaction process uses highly toxic compounds such as bromine and hydrogen sulfide, making it unsuitable for large-scale production.

[0005]

[0006] US2005182045A1 reports the use of 3-nitro-2-pyridinecarboxylic acid as a raw material, with palladium-catalyzed hydrogenation reduction to obtain 3-amino-2-pyridinecarboxylic acid in a yield of 67%. This process uses expensive raw materials, has high production costs, and poor socioeconomic benefits; it is only suitable for laboratory synthesis for research purposes and not for large-scale production.

[0007]

[0008] The traditional synthesis process of 3-amino-2-pyridinecarboxylic acid is complex, difficult to purify, has an extremely low overall yield, and high production costs, resulting in a persistently high price for 3-amino-2-pyridinecarboxylic acid, which increases the cost burden on the promotion and application of its downstream products. Summary of the Invention

[0009] Terminology and Declarations of this Invention:

[0010] 1. Articles “a,” “a kind,” and “the”: These include plural objects unless otherwise explicitly specified as a single (kind) object.

[0011] 2. Numerical Range: Unless otherwise expressly stated, all ranges or ratios disclosed herein shall be understood to include any and all subranges or subratios contained herein. For example, a stated range or ratio of 1 to 30 shall be considered to be included between the minimum value of 1 and the maximum value of 30, and includes any subranges or subratios, integers, decimals, or subranges or subratios consisting of integers or decimals, including the endpoints.

[0012] In view of the technical problems of high starting material prices and complex process operation in existing technologies, which lead to high industrialization costs and complex processes, the purpose of this invention is to provide a method for synthesizing 3-amino-2-pyridinecarboxylic acid.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] A method for synthesizing 3-amino-2-pyridinecarboxylic acid includes the following steps:

[0015] S1, diethyl malonate and sodium hydride react to give sodium salt, sodium salt then reacts with 2,6-dichloro-3-nitropyridine. After the reaction is complete, post-treatment gives the compound shown in Formula I, namely 1,3-diethyl 2-(6-chloro-3-nitropyridine-2-yl)malonic acid.

[0016] S2. An oxidant is added to the 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid described in step S1 in the presence of a solvent, and the reaction is carried out until the reaction is complete. After post-treatment, 6-chloro-3-nitro-2-pyridinic acid is obtained.

[0017] S3. The 6-chloro-3-nitro-2-pyridinecarboxylic acid obtained in step S2 is subjected to hydrogenation reduction under catalytic conditions, followed by post-treatment to obtain 3-amino-2-pyridinecarboxylic acid;

[0018] The compound represented by Formula I has the following structural formula:

[0019]

[0020] Furthermore, R1 and R2 in the formula are independently selected from C1-C6 alkyl groups.

[0021] The synthesis route is as follows:

[0022]

[0023] Further, in step S1, the molar ratio of 2,6-dichloro-3-nitropyridine, diethyl malonate and sodium hydride is 1:(1-5):(1-5).

[0024] Further, the diethyl malonate mentioned in step S1 is dissolved in an organic solvent, wherein the organic solvent is at least one selected from acetonitrile, 1,4-dioxane, N,N-dimethylformamide, ethylene glycol dimethyl ether, dichloroethane, dimethyl sulfoxide, and tetrahydrofuran.

[0025] Furthermore, in step S1, the reaction time of diethyl malonate with sodium hydride is 0.5h-2h, and the reaction temperature is 10-30℃.

[0026] Further, the 2,6-dichloro-3-nitropyridine described in step S1 is dissolved in an organic solvent, wherein the organic solvent is at least one selected from acetonitrile, 1,4-dioxane, N,N-dimethylformamide, ethylene glycol dimethyl ether, dichloroethane, dimethyl sulfoxide, and tetrahydrofuran.

[0027] Furthermore, the temperature at which the sodium salt of 2,6-dichloro-3-nitropyridine is added in step S1 is controlled between -35°C and 50°C.

[0028] Preferably, the 2,6-dichloro-3-nitropyridine in step S1 is added slowly dropwise.

[0029] Furthermore, in step S1, the reaction temperature of the sodium salt with 2,6-dichloro-3-nitropyridine is -35℃ to 50℃, and the reaction time is 1-12h.

[0030] Preferably, the reaction time of the sodium salt with 2,6-dichloro-3-nitropyridine in step S1 is 1-6 hours.

[0031] Further, in step S1, the post-processing includes the following steps: carefully pouring the reaction mixture into ice water, then adjusting the pH to 4 with 6 mol / L hydrochloric acid, extracting three times with methyl tert-butyl ether, combining the organic phases, washing the organic phase once with saturated sodium bicarbonate aqueous solution, washing the organic phase once with saturated brine, decolorizing with activated carbon, drying with anhydrous sodium sulfate, filtering, combining the organic phases, and concentrating to dryness; then, evaporating diethyl malonate at 65°C using a vacuum oil pump (10 mmHg) to obtain a yellow oily substance, 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid.

[0032] Further, the molar ratio of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid to the oxidant in step S2 is 1:(2-50).

[0033] Furthermore, the temperature at which the oxidant is added in step S2 is controlled between 20°C and 100°C.

[0034] Furthermore, the reaction temperature in step S2 is controlled between 40°C and 150°C.

[0035] Further, in step S2, the oxidant is at least one of sodium dichromate, potassium dichromate, hydrogen peroxide, potassium permanganate, or nitric acid.

[0036] Furthermore, the solvent is selected according to different oxidants: if the oxidant is potassium permanganate, water is selected as its solvent; if the oxidant is nitric acid, nitric acid is selected as its solvent; if the oxidant is hydrogen peroxide, N,N-dimethylformamide is selected as its solvent; if the oxidant is sodium dichromate or potassium dichromate, sulfuric acid is selected as its solvent.

[0037] Further, the post-processing described in step S2 includes the following steps: filtering the reaction mixture, evaporating the filtrate to dryness, pouring the residue into cold water, adjusting the pH to 3 with 6 mol / L hydrochloric acid to form a precipitate, filtering, and drying to obtain 6-chloro-3-nitro-2-pyridinecarboxylic acid.

[0038] Furthermore, the catalyst described in step S3 is a 10% palladium-on-carbon catalyst.

[0039] Further, in step S3, the ratio of 6-chloro-3-nitro-2-pyridinecarboxylic acid to 10% palladium on carbon catalyst is 1 mol: (5-12) g.

[0040] Furthermore, in the hydrogenation reduction reaction described in step S3, the internal pressure of hydrogenation is controlled at 0.01 MPa-1 MPa, the reaction temperature is controlled at 0℃-100℃, and the reaction time is 1-15 h.

[0041] Further, the post-processing described in step S3 includes the following steps: filtering the reaction mixture to remove the catalyst, adjusting the pH of the filtrate to 4 with 6 mol / L hydrochloric acid, filtering to remove solid impurities, evaporating the filtrate under reduced pressure to dryness, adding 90% ethanol to the residue, heating to reflux and stirring for 1 hour, then cooling to 45°C, filtering, and drying to obtain a pale yellow solid 3-amino-2-pyridinecarboxylic acid.

[0042] Compared with the prior art, the method for synthesizing 3-amino-2-pyridinecarboxylic acid according to the above-described technical solution of the present invention has the following advantages:

[0043] This invention uses 2,6-dichloro-3-nitropyridine as the starting material. The experimental steps are simple and easy to operate, the experimental conditions are simple, the starting material is widely available, the cost is low, the yield is high, and it is suitable for large-scale production. It has good application prospects in pharmaceutical synthesis, pharmaceutical industry and materials science. Attached Figure Description

[0044] Figure 1 The image shows the 1H NMR spectrum of 3-amino-2-pyridinecarboxylic acid synthesized in Example 1. Detailed Implementation

[0045] The present invention will be further described below with reference to the embodiments.

[0046] Example

[0047] Example 1

[0048]

[0049] 1. Synthesis of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid

[0050] In a 1L reaction flask, 300mL of tetrahydrofuran and diethyl malonate (167g, 1.04mol) were added at room temperature. Sodium hydride (60%, w / w, 42g, 1.04mol) was slowly added while stirring. After the addition was complete, the mixture was stirred at room temperature for 40 minutes, then cooled to -20°C. 2,6-Dichloro-3-nitropyridine (100g, 0.52mol) was dissolved in 150mL of tetrahydrofuran and slowly added dropwise to the reaction flask while maintaining the -20°C internal temperature. The addition was completed over approximately 30 minutes. After the addition was complete, the mixture was kept at -20°C for 3 hours. TLC analysis was performed, and after the reaction was complete, the reaction mixture was carefully poured into 1kg of ice water. The pH was then adjusted to 4 with 6mol / L hydrochloric acid. The mixture was extracted three times (700mL × 3) with methyl tert-butyl ether. The organic phases were combined and saturated with... The organic phase was washed once with sodium bicarbonate aqueous solution (600 mL × 1), once with saturated brine (1 L × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with methyl tert-butyl ether (100 mL × 2). The organic phases were combined and concentrated to dryness. Then, diethyl malonate was evaporated at 65 °C using a vacuum oil pump (10 mmHg) to obtain 160 g of crude 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, which could be used directly in the next step of the reaction without purification.

[0051] 2. Synthesis of 6-chloro-3-nitro-2-pyridinecarboxylic acid

[0052] In a 2L reaction flask, 1L of 70% concentrated nitric acid was added at room temperature. While stirring, 160g of the yellow oily substance obtained in the previous step, 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, was slowly added. The mixture was then slowly heated to 83℃ and maintained at this temperature for 16 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure. The residue was poured into 1L of ice water and stirred for 30 minutes to form a precipitate. This precipitate was filtered, dried, and yielded 83g of a gray solid, 6-chloro-3-nitro-2-pyridinic acid. The overall yield of the two steps was 79%.

[0053] 3. Synthesis of 3-amino-2-pyridinecarboxylic acid

[0054] In a 2L autoclave, 500mL of methanol and 100g (0.49mol) of 6-chloro-3-nitro-2-pyridinecarboxylic acid were added. Finally, 5g of 10% palladium on carbon catalyst and 500mL of 1mol / L sodium hydroxide aqueous solution were added. The mixture was stirred, and the air inside the autoclave was purged with nitrogen three times. Then, hydrogen was introduced to maintain an internal pressure of 0.5MPa, and the reaction was carried out at room temperature for 8 hours. After the reaction was complete, the reaction mixture was filtered to remove the catalyst. The pH of the filtrate was adjusted to 4 with 6mol / L hydrochloric acid, filtered again to remove solid impurities, and the filtrate was evaporated to dryness under reduced pressure. The residue was added to 2L of 90% ethanol, and the mixture was heated to reflux and stirred for 1 hour. Then, it was cooled to 45℃, filtered, and dried to obtain 53g of pale yellow solid 3-amino-2-pyridinecarboxylic acid with an HPLC purity greater than 99% and a yield of 78%. The 1H NMR spectrum is shown below. Figure 1 .

[0055] 1 H NMR (DMSO-d6) δ7.30 (dd J=5.6Hz, 1H), δ7.36 (dd J1=3.6, J2=5.6Hz, 1H), δ7.85 (dd J=5.2Hz, 1H)

[0056] Example 2

[0057] 1. Synthesis of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid

[0058] In a 1L reaction flask, 300mL of tetrahydrofuran and diethyl malonate (167g, 1.04mol) were added at room temperature. Sodium hydride (60%, w / w, 42g, 1.04mol) was slowly added while stirring. After the addition was complete, the mixture was stirred at room temperature for 40 minutes, then cooled to -20°C. 2,6-Dichloro-3-nitropyridine (100g, 0.52mol) was dissolved in 150mL of tetrahydrofuran and slowly added dropwise to the reaction flask while maintaining the -20°C internal temperature. The addition was completed over approximately 30 minutes. After the addition was complete, the mixture was kept at -20°C for 3 hours. TLC analysis was performed, and after the reaction was complete, the reaction mixture was carefully poured into 1kg of ice water. The pH was then adjusted to 4 with 6mol / L hydrochloric acid. The mixture was extracted three times (700mL × 3) with methyl tert-butyl ether. The organic phases were combined and saturated with... The organic phase was washed once with sodium bicarbonate aqueous solution (600 mL × 1), once with saturated brine (1 L × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with methyl tert-butyl ether (100 mL × 2). The organic phases were combined and concentrated to dryness. Then, diethyl malonate was evaporated at 65 °C using a vacuum oil pump (10 mmHg) to obtain 160 g of crude 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, which could be used directly in the next step of the reaction without purification.

[0059] 2. Synthesis of 6-chloro-3-nitro-2-pyridinecarboxylic acid

[0060] In a 2L reaction flask, 1L of DMF and 55g of NaOH were added at room temperature. While stirring, 160g of the yellow oily substance obtained in the previous step, 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, was slowly added. The temperature was then raised to 80℃, and 185g of 30% hydrogen peroxide was slowly added dropwise. After the addition was complete, the reaction was maintained at 80-90℃ for 3 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure. The residue was poured into 1L of ice water, and the pH was adjusted to 3 with 6mol / L hydrochloric acid while stirring, forming a precipitate. The precipitate was filtered, washed with water, and dried to obtain 78g of 6-chloro-3-nitro-2-pyridinic acid. The overall yield of the two steps was 74%.

[0061] 3. Synthesis of 3-amino-2-pyridinecarboxylic acid

[0062] In a 2L autoclave, 500mL of methanol and 100g (0.49mol) of 6-chloro-3-nitro-2-pyridinecarboxylic acid were added. Finally, 5g of 10% palladium on carbon catalyst and 500mL of 1mol / L sodium hydroxide aqueous solution were added. Stirring was started, and the air inside the autoclave was purged with nitrogen three times. Then, hydrogen was introduced to maintain an internal pressure of 0.5MPa, and the reaction was carried out at 50℃ for 8 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered to remove the catalyst, and the pH of the filtrate was adjusted to 4 with 6mol / L hydrochloric acid. Filtering was continued to remove solid impurities, and the filtrate was evaporated to dryness under reduced pressure. The residue was added to 2L of 90% ethanol, and the mixture was heated to reflux and stirred for 1 hour. Then, the mixture was cooled to 45℃, filtered, and dried to obtain 48g of a pale yellow solid, 3-amino-2-pyridinecarboxylic acid, with a yield of 70%.

[0063] Example 3

[0064] 1. Synthesis of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid

[0065] In a 1L reaction flask, 300mL of tetrahydrofuran and diethyl malonate (167g, 1.04mol) were added at room temperature. Sodium hydride (60%, w / w, 42g, 1.04mol) was slowly added while stirring. After the addition was complete, the mixture was stirred at room temperature for 40 minutes, then cooled to -20°C. 2,6-Dichloro-3-nitropyridine (100g, 0.52mol) was dissolved in 150mL of tetrahydrofuran and slowly added dropwise to the reaction flask while maintaining the -20°C internal temperature. The addition was completed over approximately 30 minutes. After the addition was complete, the mixture was kept at -20°C for 3 hours. TLC analysis was performed, and after the reaction was complete, the reaction mixture was carefully poured into 1kg of ice water. The pH was then adjusted to 4 with 6mol / L hydrochloric acid. The mixture was extracted three times (700mL × 3) with methyl tert-butyl ether. The organic phases were combined and saturated with... The organic phase was washed once with sodium bicarbonate aqueous solution (600 mL × 1), once with saturated brine (1 L × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with methyl tert-butyl ether (100 mL × 2). The organic phases were combined and concentrated to dryness. Then, diethyl malonate was evaporated at 65 °C using a vacuum oil pump (10 mmHg) to obtain 160 g of crude 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, which could be used directly in the next step of the reaction without purification.

[0066] 2. Synthesis of 6-chloro-3-nitro-2-pyridinecarboxylic acid

[0067] In a 2L reaction flask, 1.3L of 0.5mol / L NaOH was added at room temperature. While stirring, 160g of the yellow oily substance obtained in the previous step, 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, was slowly added. Then, the temperature was raised to 70℃, and 550g of potassium permanganate was slowly added, controlling the temperature not to exceed 95℃. After the addition was complete, the reaction was maintained at 95℃ for 3 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with hot water (100mL × 2). The filtrate was cooled to 10℃ with ice, and the pH was adjusted to 3 with 6mol / L hydrochloric acid while stirring, forming a precipitate. This precipitate was filtered, washed with water, and dried to obtain 71g of 6-chloro-3-nitro-2-pyridinic acid. The overall yield of the two steps was 67%.

[0068] 3. Synthesis of 3-amino-2-pyridinecarboxylic acid

[0069] In a 2L autoclave, 500mL of methanol and 100g (0.49mol) of 6-chloro-3-nitro-2-pyridinecarboxylic acid were added. Finally, 5g of 10% palladium on carbon catalyst and 500mL of 1mol / L sodium hydroxide aqueous solution were added. The mixture was stirred, and the air inside the autoclave was purged with nitrogen three times. Then, hydrogen was introduced to maintain an internal pressure of 0.5MPa, and the reaction was carried out at 70℃ for 8 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered to remove the catalyst, and the pH of the filtrate was adjusted to 4 with 6mol / L hydrochloric acid. The mixture was filtered again to remove solid impurities, and the filtrate was evaporated to dryness under reduced pressure. The residue was added to 2L of 90% ethanol, and the mixture was heated to reflux and stirred for 1 hour. Then, it was cooled to 45℃, filtered, and dried to obtain 45g of a pale yellow solid, 3-amino-2-pyridinecarboxylic acid, with a yield of 66%.

[0070] Example 4

[0071] The difference between this embodiment and Example 1 is that in the synthesis step of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, the molar ratio of 2,6-dichloro-3-nitropyridinium, diethyl malonate and sodium hydride is 1:5:5.

[0072] 1. Synthesis of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid

[0073] In a 1L reaction flask, 300mL of tetrahydrofuran and diethyl malonate (417.5g, 2.6mol) were added at room temperature. Sodium hydride (60%, w / w, 105g, 2.6mol) was slowly added with stirring. After the addition was complete, the mixture was stirred at room temperature for 40 minutes, then cooled to -20°C. 2,6-Dichloro-3-nitropyridine (100g, 0.52mol) was dissolved in 150mL of tetrahydrofuran and slowly added dropwise to the reaction flask while maintaining the -20°C internal temperature. The addition was completed over approximately 30 minutes. After the addition was complete, the mixture was kept at -20°C for 3 hours. TLC analysis was performed. After the reaction was complete, the reaction mixture was carefully poured into 1kg of ice water. The pH was then adjusted to 4 with 6mol / L hydrochloric acid. The mixture was extracted three times (700mL × 3) with methyl tert-butyl ether. The organic phases were combined and saturated with... The organic phase was washed once with sodium bicarbonate aqueous solution (600 mL × 1), once with saturated brine (1 L × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with methyl tert-butyl ether (100 mL × 2). The organic phases were combined and concentrated to dryness. Then, diethyl malonate was evaporated at 65 °C using a vacuum oil pump (10 mmHg) to obtain 180 g of crude 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, which could be used directly in the next step of the reaction without further purification.

[0074] 2. Synthesis of 6-chloro-3-nitro-2-pyridinecarboxylic acid

[0075] In a 2L reaction flask, 1L of 70% concentrated nitric acid was added at room temperature. While stirring, 180g of the yellow oily substance obtained in the previous step, 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, was slowly added. The mixture was then slowly heated to 83℃ and maintained at this temperature for 16 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure. The residue was poured into 1L of ice water and stirred for 30 minutes to form a precipitate. This precipitate was filtered, dried, and yielded 85g of a gray solid, 6-chloro-3-nitro-2-pyridinic acid. The overall yield of the two steps was 81%.

[0076] 3. Synthesis of 3-amino-2-pyridinecarboxylic acid

[0077] In a 2L autoclave, 500mL of methanol and 100g (0.49mol) of 6-chloro-3-nitro-2-pyridinecarboxylic acid were added. Finally, 5g of 10% palladium on carbon catalyst and 500mL of 1mol / L sodium hydroxide aqueous solution were added. The mixture was stirred, and the air inside the autoclave was purged with nitrogen three times. Then, hydrogen was introduced to maintain an internal pressure of 0.5MPa, and the reaction was carried out at room temperature for 8 hours. After the reaction was complete, the reaction mixture was filtered to remove the catalyst. The pH of the filtrate was adjusted to 4 with 6mol / L hydrochloric acid, filtered again to remove solid impurities, and the filtrate was evaporated to dryness under reduced pressure. The residue was added to 2L of 90% ethanol, and the mixture was heated to reflux and stirred for 1 hour. Then, it was cooled to 45°C, filtered, and dried to obtain 51g of a pale yellow solid, 3-amino-2-pyridinecarboxylic acid, with an HPLC purity of 98% and a yield of 75%.

[0078] Example 5

[0079] The difference between this embodiment and Example 1 is that in the synthesis step of 6-chloro-3-nitro-2-pyridinecarboxylic acid, the molar ratio of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid to the oxidant is 1:50.

[0080] 1. Synthesis of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid

[0081] In a 1L reaction flask, 300mL of tetrahydrofuran and diethyl malonate (167g, 1.04mol) were added at room temperature. Sodium hydride (60%, w / w, 42g, 1.04mol) was slowly added while stirring. After the addition was complete, the mixture was stirred at room temperature for 40 minutes, then cooled to -20°C. 2,6-Dichloro-3-nitropyridine (100g, 0.52mol) was dissolved in 150mL of tetrahydrofuran and slowly added dropwise to the reaction flask while maintaining the -20°C internal temperature. The addition was completed over approximately 30 minutes. After the addition was complete, the mixture was kept at -20°C for 3 hours. TLC analysis was performed, and after the reaction was complete, the reaction mixture was carefully poured into 1kg of ice water. The pH was then adjusted to 4 with 6mol / L hydrochloric acid. The mixture was extracted three times (700mL × 3) with methyl tert-butyl ether. The organic phases were combined and saturated with... The organic phase was washed once with sodium bicarbonate aqueous solution (600 mL × 1), once with saturated brine (1 L × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with methyl tert-butyl ether (100 mL × 2). The organic phases were combined and concentrated to dryness. Then, diethyl malonate was evaporated at 65 °C using a vacuum oil pump (10 mmHg) to obtain 160 g of crude 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, which could be used directly in the next step of the reaction without purification.

[0082] 2. Synthesis of 6-chloro-3-nitro-2-pyridinecarboxylic acid

[0083] In a 5L reaction flask, 1.5L of 70% concentrated nitric acid was added at room temperature. While stirring, 160g of the yellow oily substance obtained in the previous step, 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid, was slowly added. The mixture was then slowly heated to 83℃ and maintained at this temperature for 16 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure. The residue was poured into 1L of ice water and stirred for 30 minutes to form a precipitate. This precipitate was filtered, dried, and yielded 72g of a gray solid, 6-chloro-3-nitro-2-pyridinic acid. The overall yield of the two steps was 69%.

[0084] 3. Synthesis of 3-amino-2-pyridinecarboxylic acid

[0085] In a 2L autoclave, 500mL of methanol and 100g (0.49mol) of 6-chloro-3-nitro-2-pyridinecarboxylic acid were added. Finally, 5g of 10% palladium on carbon catalyst and 500mL of 1mol / L sodium hydroxide aqueous solution were added. The mixture was stirred, and the air inside the autoclave was purged with nitrogen three times. Then, hydrogen was introduced to maintain an internal pressure of 0.5MPa, and the reaction was carried out at room temperature for 8 hours. After the reaction was complete, the reaction mixture was filtered to remove the catalyst. The pH of the filtrate was adjusted to 4 with 6mol / L hydrochloric acid, filtered again to remove solid impurities, and the filtrate was evaporated to dryness under reduced pressure. The residue was added to 2L of 90% ethanol, and the mixture was heated to reflux and stirred for 1 hour. Then, it was cooled to 45℃, filtered, and dried to obtain 49g of a pale yellow solid, 3-amino-2-pyridinecarboxylic acid, with an HPLC purity greater than 99% and a yield of 72%.

[0086] Comparative Example 1

[0087] Step (2) in Example 268 of US2005182045A1.

[0088] Comparative Example 2

[0089] Scheme 2 in Zhang-Lin Zhou et al. Bioorganic & Medicinal Chemistry, 2001, 9, 2061-2071.

[0090] Cost evaluation

[0091] Select Examples 1-3, Comparative Examples 1 and 2, and calculate the cost required to produce 100g of 3-amino-2-pyridinecarboxylic acid. The costs are shown in Table 1.

[0092] Table 1

[0093]

[0094]

[0095]

[0096] Table 2

[0097]

[0098] As shown in Table 2, the cost of preparing 100g of 3-amino-2-pyridinecarboxylic acid in Examples 1-3 is only RMB 901.51-1443.27, while Comparative Example 1 costs RMB 78074.67 and Comparative Example 2 costs RMB 2352.44.

[0099] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing 3-amino-2-pyridinecarboxylic acid, characterized in that, Includes the following steps: S1, diethyl malonate and sodium hydride react to give sodium salt, sodium salt then reacts with 2,6-dichloro-3-nitropyridine until the reaction is complete, and after post-treatment, 1,3-diethyl 2-(6-chloro-3-nitropyridine-2-yl)malonic acid is given; S2. An oxidant is added to the 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid described in step S1 in the presence of a solvent, and the reaction is carried out until the reaction is complete. After post-treatment, 6-chloro-3-nitro-2-pyridinic acid is obtained. S3. The 6-chloro-3-nitro-2-pyridinecarboxylic acid obtained in step S2 is subjected to hydrogenation reduction under catalytic conditions, followed by post-treatment to obtain 3-amino-2-pyridinecarboxylic acid; The molar ratio of 2,6-dichloro-3-nitropyridine, diethyl malonate and sodium hydride in step S1 is 1:(1-5):(1-5).

2. The synthesis method according to claim 1, characterized in that, In step S1, both diethyl malonate and 2,6-dichloro-3-nitropyridine are dissolved in an organic solvent, which is at least one of acetonitrile, 1,4-dioxane, N,N-dimethylformamide, ethylene glycol dimethyl ether, dichloroethane, dimethyl sulfoxide, and tetrahydrofuran.

3. The synthesis method according to claim 1, characterized in that, The reaction time of diethyl malonate with sodium hydride in step S1 is 0.5 h-2 h, and the reaction temperature is 10-30℃. In step S1, the temperature at which 2,6-dichloro-3-nitropyridine is added to the sodium salt is controlled between -35 ℃ and 50 ℃. The addition of 2,6-dichloro-3-nitropyridine in step S1 is by slow dropwise addition; The reaction temperature of the sodium salt with 2,6-dichloro-3-nitropyridine in step S1 is -35 ℃ to 50 ℃, and the reaction time is 1-12 h. The post-processing described in step S1 The process includes the following steps: the reaction mixture is carefully poured into ice water, then the pH is adjusted to 4 with 6 mol / L hydrochloric acid, extracted three times with methyl tert-butyl ether, the organic phases are combined, the organic phase is washed once with saturated sodium bicarbonate aqueous solution and once with saturated brine, decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, the organic phases are combined, and concentrated to dryness; then, diethyl malonate is evaporated at 65 °C using a vacuum oil pump at 10 mmHg to obtain a yellow oily substance, 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid.

4. The synthesis method according to claim 3, characterized in that, The reaction time of the sodium salt with 2,6-dichloro-3-nitropyridine in step S1 is 1-6 h.

5. The synthesis method according to claim 1, characterized in that: The molar ratio of 1,3-diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonic acid to the oxidant in step S2 is 1:(2-50).

6. The synthesis method according to claim 1, characterized in that, The temperature at which the oxidant is added in step S2 is controlled between 20 ℃ and 100 ℃; The reaction temperature in step S2 is controlled between 40 ℃ and 150 ℃; The post-processing described in step S2 includes the following steps: filtering the reaction mixture, evaporating the filtrate to dryness, pouring the residue into cold water, adjusting the pH to 3 with 6 mol / L hydrochloric acid to form a precipitate, filtering, and drying to obtain 6-chloro-3-nitro-2-pyridinecarboxylic acid.

7. The synthesis method according to claim 1, characterized in that, The oxidant in step S2 is at least one of sodium dichromate, potassium dichromate, hydrogen peroxide, potassium permanganate, and nitric acid. The solvent used in step S2 is selected according to different oxidants: if the oxidant is potassium permanganate, water is selected as its solvent; if the oxidant is nitric acid, nitric acid is selected as its solvent; if the oxidant is hydrogen peroxide, N,N-dimethylformamide is selected as its solvent; if the oxidant is sodium dichromate or potassium dichromate, sulfuric acid is selected as its solvent.

8. The synthesis method according to claim 1, characterized in that, The catalyst in step S3 is a 10% palladium on carbon catalyst.

9. The synthesis method according to claim 8, characterized in that, The ratio of 6-chloro-3-nitro-2-pyridinecarboxylic acid to 10% palladium on carbon catalyst in step S3 is 1 mol: (5-12) g.

10. The synthesis method according to claim 1, characterized in that, In step S3, the internal pressure of hydrogenation during hydrogenation reduction is controlled at 0.01 MPa-1 MPa, the reaction temperature is controlled at 0 ℃-100 ℃, and the reaction time is 1-15 h.

11. The synthesis method according to claim 1, characterized in that, The post-processing described in step S3 includes the following steps: filtering the reaction mixture to remove the catalyst, adjusting the pH of the filtrate to 4 with 6 mol / L hydrochloric acid, filtering to remove solid impurities, evaporating the filtrate under reduced pressure to dryness, adding 90% ethanol to the residue, heating to reflux and stirring for 1 hour, then cooling to 45°C, filtering, and drying to obtain a pale yellow solid, namely 3-amino-2-pyridinecarboxylic acid.

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