A process for the preparation of 3-amino-pyridine-2-carboxylic acid methyl ester

Abstract

The application discloses a preparation method of 3-aminopyridine-2-carboxylic acid methyl ester and belongs to the technical field of fine chemical industry. The 3-aminopyridine-2-carboxylic acid methyl ester is prepared from 2-carboxylic acid pyridine as raw material, reaction of the 2-carboxylic acid pyridine with LDA and borate to obtain 2-carboxylic acid pyridine-3-boronic acid, esterification reaction of the 2-carboxylic acid pyridine-3-boronic acid with methanol to obtain 2-methoxycarbonyl pyridine-3-boronic acid, and reaction of the 2-methoxycarbonyl pyridine-3-boronic acid with ammonia water under the action of cuprous oxide. The preparation method is simple in reaction steps, easy to control, avoids application of an easy-to-explosive reagent, is safer in process, and improves market competitiveness of the product.

Description

Technical Field

[0001] This invention relates to a method for preparing methyl 3-aminopyridine-2-carboxylic acid, belonging to the field of fine chemical technology. Background Technology

[0002] 3-Aminopyridine-2-carboxylic acid methyl ester is an important pharmaceutical and pesticide intermediate with a wide range of applications. It is a key raw material for the synthesis of 3-mercaptopyridine-2-carboxylic acid, a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor. This compound inhibits glucose synthesis through specific inhibition of PEPCK in the gluconeogenesis pathway, effectively lowering blood glucose levels. Furthermore, studies have shown that compounds with an α-pyridine carboxylic acid structure exhibit excellent gluconeogenesis inhibitory effects. This property can be used to synthesize various inhibitors for the treatment of various diseases, including cancer and toxoplasmosis. The amino group in 3-aminopyridine-2-carboxylic acid methyl ester can promote electrophilic substitution reactions, allowing for the conversion and addition of functional groups to the amino group.

[0003] There are two main methods for preparing methyl 3-aminopyridine-2-carboxylic acid in existing literature:

[0004] The first method, described in the literature [Bioorganic and Medicinal Chemistry, 2001, vol. 9, #8, pp. 2061-2071], uses 2,3-pyridinedicarboxylic acid as a starting material. It reacts with acetic anhydride at 120°C to dehydrate and form anhydride, which then reacts with acetamide to give 2,3-pyridinediimide. Subsequently, it undergoes a rearrangement reaction with sodium hypobromite and sodium hydroxide to give 3-aminopyridine-2-carboxylic acid, and finally reacts with diazomethane to give methyl 3-aminopyridine-2-carboxylic acid. This method has the following drawbacks:

[0005] A. The total yield is 3%, which is relatively low.

[0006] B. The use of diazomethane, a reagent that is prone to explosives, is costly and not conducive to large-scale production.

[0007] The reaction route is shown below:

[0008]

[0009] The second method, as described in the literature [Journal of Medicinal Chemistry, 2009, vol. 52, #9, pp. 2754-2761], uses 2,3-pyridinedicarboxylic acid as a starting material. It is dehydrated by reacting with acetic anhydride at 120°C, followed by reaction with methanol to obtain 2-methoxycarbonyl-3-pyridinecarboxylic acid. Subsequently, it reacts with diphenyl azidophosphate and triethylamine in tert-butanol to obtain N-BOC-3-aminopyridine-2-carboxylic acid methyl ester. Finally, it undergoes deprotection with trifluoroacetic acid, and the alkalinity is adjusted to obtain 3-aminopyridine-2-carboxylic acid methyl ester. This method has the following drawbacks:

[0010] A. After 2,3-pyridinedicarboxylic acid is dehydrated with acetic anhydride, it reacts with methanol to produce the isomer 3-methoxycarbonyl-2-pyridinecarboxylic acid. The isomer is not easy to remove, resulting in a low yield.

[0011] B. The use of diphenyl azidophosphate, a readily explosive reagent, results in high costs and hinders large-scale production.

[0012] The reaction route is shown below:

[0013]

[0014] To overcome the shortcomings of existing synthetic methods, it is necessary to improve the preparation method of methyl 3-aminopyridine-2-carboxylic acid ester and develop a synthetic route with higher yield, no isomers, and more suitable for industrial production. Summary of the Invention

[0015] To better address the aforementioned problems, this invention discloses a method for preparing methyl 3-aminopyridine-2-carboxylic acid. The invention uses pyridine 2-carboxylate as a raw material, reacting it with LDA and a borate ester to obtain pyridine-2-carboxylic acid 3-boronic acid; subsequently, it undergoes esterification with methanol to obtain 2-methoxycarbonylpyridine-3-boronic acid; finally, it reacts with ammonia in the presence of cuprous oxide to obtain methyl 3-aminopyridine-2-carboxylic acid. The preparation method provided by this invention features simple reaction steps, is easy to control, avoids the use of easily explosive reagents, is safer than other methods, and also enhances the market competitiveness of the product.

[0016] To achieve the above objectives, the preparation process of methyl 3-aminopyridine-2-carboxylate of the present invention includes the following steps: using pyridine 2-carboxylate as a raw material, reacting it with LDA and borate ester to obtain pyridine 2-carboxylate-3-boronic acid; subsequently reacting it with methanol to obtain 2-methoxycarbonylpyridine-3-boronic acid; and finally reacting it with ammonia water under the action of cuprous oxide to obtain methyl 3-aminopyridine-2-carboxylate.

[0017] Furthermore, in the above technical solution, the preparation method is represented by the following reaction equation:

[0018]

[0019] The specific steps are as follows:

[0020] 1) Mix 2-carboxylic acid pyridine and tetrahydrofuran, cool to an ultra-low temperature state, add LDA and borate ester in sequence, quench with glacial acetic acid, extract with dichloromethane, and purify with organic phase to obtain 2-carboxylic acid pyridine-3-boronic acid;

[0021] 2) Mix 2-carboxylic acid pyridine-3-boronic acid with methanol, add thionyl chloride, heat to react, concentrate under reduced pressure, cool and add water to precipitate, and filter to obtain 2-methoxycarbonylpyridine-3-boronic acid;

[0022] 3) Mix 2-methoxycarbonylpyridine-3-boronic acid, cuprous oxide and methanol, add ammonia water and react at room temperature to obtain methyl 3-aminopyridine-2-carboxylic acid.

[0023] Further, in step 1), the borate ester is selected from trimethyl borate or triisopropyl borate; the ultra-low temperature is -80℃ to -60℃.

[0024] Further, in step 1), the molar ratio of 2-carboxylic acid pyridine, LDA and borate ester is 1:2.1-2.2:1.3-1.4.

[0025] Further, in step 2), the molar ratio of 2-carboxylic acid pyridine-3-boronic acid to thionyl chloride is 1:1.2-1.8; the heating reaction is at 55-65℃.

[0026] Further, in step 3), the molar ratio of 2-methoxycarbonylpyridine-3-boronic acid, cuprous oxide and ammonia is 1:0.1-0.2:5-6.

[0027] Beneficial effects of the invention

[0028] Compared with the prior art, the method for preparing methyl 3-aminopyridine-2-carboxylic acid provided by this invention has the following advantages: no isomers are generated in the reaction, the yield and purity are greatly improved, and the use of easily explosive reagents is avoided. Detailed Implementation

[0029] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0030] Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0031] Example 1: Synthesis of pyridine-2-carboxylic acid 3-boronate

[0032]

[0033] 61.6 g of 2-carboxylic acid pyridine and 600 mL of tetrahydrofuran were added to a reaction flask at room temperature. The mixture was cooled to -85 °C, and 550 mL of LDA (2.0 M) was added dropwise. Then, 122.2 g of triisopropyl borate was added dropwise. The reaction was carried out at -75 to -70 °C for 2 hours. The temperature was slowly raised to 10 °C, then lowered to -5 °C. Glacial acetic acid and water were added to quench the reaction. The mixture was allowed to stand and separate into layers. The upper organic phase was concentrated under reduced pressure to remove tetrahydrofuran. The lower aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine, and concentrated under reduced pressure to remove dichloromethane. The mixture was then recrystallized from 75% methanol to obtain 61 g of 3-boronic acid pyridine-2-carboxylic acid, with a yield of 73.1% and an HPLC resolution of 99.3%. 1 H-NMR (400MHz, DMSO-d6) δ: 12.72 (s, 1H), 8.20-8.18 (m, 1H), 7.89-7.87 (m, 1H), 6.97-6.95 (m, 1H), 5.68 (s, 2H).

[0034] Example 2

[0035]

[0036] At room temperature, 61.6 g of pyridine 2-carboxylate and 600 mL of tetrahydrofuran were added to a reaction flask. The mixture was cooled to -85 °C, and 550 mL of LDA (2.0 M) was added dropwise. Then, 72.7 g of trimethyl borate was added dropwise. The reaction was carried out at -75 to -70 °C for 2 hours. The temperature was slowly raised to 10 °C, then lowered to -5 °C. Glacial acetic acid and water were added to quench the reaction. The mixture was allowed to stand and separate into layers. The upper organic phase was concentrated under reduced pressure to remove tetrahydrofuran, and the lower aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine, and the dichloromethane was concentrated under reduced pressure. The mixture was then recrystallized from 75% methanol to obtain 54.8 g of pyridine-2-carboxylic acid 3-borate, with a yield of 65.7% and an HPLC resolution of 98.7%.

[0037] Example 3: Synthesis of 2-methoxycarbonylpyridine-3-boronic acid

[0038]

[0039] 50.1 g of pyridine-2-carboxylic acid 3-borate and 750 mL of methanol were added to a reaction flask at room temperature. The mixture was cooled to 35 °C, and 46.4 g of thionyl chloride was added dropwise. The reaction was carried out at 60 °C for 6 hours. No raw material was found in the HPLC. The methanol was concentrated under reduced pressure, and the mixture was cooled to 10-15 °C. 350 g of water was added, and the mixture was slurried, filtered, and dried to obtain 51.2 g of 2-methoxycarbonylpyridine-3-boronic acid, with a yield of 94.3% and an HPLC yield of 99.4%. 1H-NMR (400MHz, DMSO-d6)δ:8.19-8.17(m,1H),7.83-7.81(m,1H),6.99-6.97(m,1H),5.06(s,2H),3.81(s,3H).

[0040] Example 4: Synthesis of methyl 3-aminopyridine-2-carboxylate

[0041]

[0042] 45.2 g of 2-methoxycarbonylpyridine-3-boronic acid, 8.6 g of cuprous oxide, and 260 mL of methanol were added to a reaction flask at room temperature. The mixture was cooled to 15 °C, and 102 g of 25% ammonia was added dropwise. The reaction was carried out at room temperature for 16 hours. No raw material remained on HPLC. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove methanol. 300 mL of methyl tert-butyl ether was added, and the pH was adjusted to 1.5-2.0 with 2N hydrochloric acid. The product was in the aqueous phase. The mixture was allowed to stand and separate into layers. The lower aqueous phase was retained. The aqueous phase was adjusted to pH 9.0-9.5 with potassium carbonate aqueous solution. The mixture was extracted with dichloromethane, and the organic phase was washed with water and brine. 1 g of activated carbon was added, and the mixture was heated and stirred for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove dichloromethane. n-Butyl acetate and n-heptane were added and the mixture was hot-mixed. The mixture was cooled, filtered, and dried to obtain 32.2 g of methyl 3-aminopyridine-2-carboxylic acid, with a yield of 84.7% and an HPLC yield of 99.6%. 1 H NMR (400MHz, CDCl3) δ: 8.08-8.06 (m, 1H), 7.24-7.20 (m, 1H), 7.06-7.01 (m, 1H), 5.75 (s, 1H), 3.97 (s, 3H).

[0043] The embodiments described above provide a detailed explanation of the implementation of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered to fall within the protection scope of the present invention.

Claims

1. A method for preparing methyl 3-aminopyridine-2-carboxylate, characterized in that, The process includes the following steps: using 2-carboxylic acid pyridine as a raw material, reacting it with LDA and a borate ester to obtain 2-carboxylic acid pyridine-3-boronic acid; subsequently mixing it with methanol, adding thionyl chloride, and esterifying it at elevated temperature to obtain 2-methoxycarbonylpyridine-3-boronic acid; finally reacting it with ammonia in the presence of cuprous oxide to obtain methyl 3-aminopyridine-2-carboxylic acid; wherein the borate ester is selected from trimethyl borate or triisopropyl borate.

2. The method for preparing methyl 3-aminopyridine-2-carboxylate according to claim 1, characterized in that, The specific steps are as follows: ； 1) Mix 2-carboxylic acid pyridine and tetrahydrofuran, cool to an ultra-low temperature, add LDA and borate ester sequentially, quench with glacial acetic acid, extract with dichloromethane, and purify with organic phase to obtain 2-carboxylic acid pyridine-3-boronic acid; the ultra-low temperature is -80℃ to -60℃; 2) Mix 2-carboxylic acid pyridine-3-boronic acid with methanol, add thionyl chloride, heat to react, concentrate under reduced pressure, cool and add water to precipitate, and filter to obtain 2-methoxycarbonylpyridine-3-boronic acid; 3) Mix 2-methoxycarbonylpyridine-3-boronic acid, cuprous oxide and methanol, add ammonia water and react at room temperature to obtain methyl 3-aminopyridine-2-carboxylic acid.

3. The method for preparing methyl 3-aminopyridine-2-carboxylate according to claim 2, characterized in that: In step 1), the molar ratio of 2-carboxylic acid pyridine, LDA and borate ester is 1: 2.1-2.2: 1.3-1.

4.

4. The method for preparing methyl 3-aminopyridine-2-carboxylate according to claim 2, characterized in that: In step 2), the molar ratio of 2-carboxylic acid pyridine-3-boronic acid to thionyl chloride is 1:1.2-1.

8.

5. The method for preparing methyl 3-aminopyridine-2-carboxylate according to claim 2, characterized in that: In step 3), the molar ratio of 2-methoxycarbonylpyridine-3-boronic acid, cuprous oxide and ammonia is 1: 0.1-0.2: 5-6.

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