A method for synthesizing quinolinic acid

Abstract

The application discloses a synthesis method of quinolinic acid, which comprises the following steps: (1) using a halogenated pyridine derivative as raw material, performing a Grignard reaction with a Grignard reagent solution to generate a first intermediate; (2) performing a carbonylation reaction on the first intermediate with carbon dioxide to obtain a second intermediate; and (3) performing an oxidation reaction on the second intermediate with an oxidizing agent to obtain a product quinolinic acid, and the specific reaction is shown in the following formula, wherein X is halogen, R is C 1‑3 alkyl or cyano, and R1 is C 2‑4 alkyl. The application provides a new method for preparing 2,3-pyridinedicarboxylic acid (quinolinic acid), which uses a halogenated and alkyl-substituted or cyano-substituted pyridine derivative as raw material, performs a Grignard reaction with a Grignard reagent, then performs a carbonylation reaction with carbon dioxide, and finally performs hydrolysis to obtain the product 2,3-pyridinedicarboxylic acid (quinolinic acid). The synthesis route has the advantages of mild reaction, easy operation, safety and environmental protection, and convenience for large-scale production.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceuticals, pesticides and dyes, and specifically to a method for synthesizing quinolinic acid (2,3-pyridinedicarboxylic acid). Background Technology

[0002] Quinolinic acid, also known as 2,3-pyridinedicarboxylic acid, is an important pharmaceutical, pesticide, and dye intermediate. In pharmaceuticals, it is used to synthesize a series of quinolone antibiotics. In pesticides, it is a raw material for the preparation of imidazolinone herbicides, thus possessing significant economic value. Its structure is shown below:

[0003]

[0004] The existing methods for preparing quinolinic acid mainly include the following:

[0005] 1. In earlier literature reports, quinolinic acid was prepared by oxidation of 8-hydroxyquinoline, which mainly involves oxidizing 8-hydroxyquinoline with concentrated nitric acid or hydrogen peroxide (e.g., patent DE3150005). However, this method has no practical production value because the raw material 8-hydroxyquinoline is expensive.

[0006]

[0007] 2. Quinoline-potassium permanganate oxidation method: This method involves a relatively vigorous reaction, produces a variety of products, and is difficult to separate. In addition, the reduction of potassium permanganate produces a large amount of manganese sludge solid waste, which is a byproduct of manganese dioxide, making post-treatment very difficult and posing significant environmental risks. Therefore, this method is generally not used in production at present.

[0008]

[0009] 3. Quinoline-hydrogen peroxide method and quinoline-hydrogen peroxide-sodium hypochlorite method, such as the preparation method disclosed by Karlheinz Giselbrecht in patent US20020062025 A1, although the purity of the 2,3-pyridinedicarboxylic acid product reaches 99.7%, the yield is low, only 71.14%. Furthermore, this preparation process involves two oxidation processes, making it relatively complex. Excess ozone is generated during the reaction, requiring post-treatment to remove it; otherwise, the ozone will irritate the human respiratory system, skin, and immune system to some extent.

[0010]

[0011] 4. Quinoline-sodium chlorate method: This is currently the mainstream production process. For example, the oxidation reaction catalyzed by copper ions disclosed in patent US4754039 by Michalowicz, William, et al. Its advantages include a mild reaction, inexpensive raw materials, and a relatively high yield. However, the conversion rate of sodium chlorate is very low in the initial stage, leading to raw material and heat accumulation. Sodium chlorate only reacts with the raw materials after an induction period, and the reaction needs to be carried out at 100℃ for about 17 hours, posing significant safety risks. Furthermore, it generates large quantities of high-salt, high-ammonia-nitrogen wastewater, resulting in serious environmental costs.

[0012]

[0013] In summary, quinoline acid, also known as 2,3-pyridine dicarboxylic acid, is an important fine chemical. However, the current preparation process for quinoline acid has serious problems and hidden dangers. Developing a new process for quinoline acid with industrial production value is an urgent issue that needs to be addressed. Summary of the Invention

[0014] Based on this, the present invention provides a method for synthesizing quinolinic acid, the method comprising the following steps:

[0015] (1) Using halopyridine derivatives as raw materials, Grignard reaction is carried out with Grignard reagent solution to generate the first intermediate;

[0016] (2) The first intermediate is subjected to a carbonylation reaction with carbon dioxide to obtain a second intermediate; and

[0017] (3) The second intermediate undergoes an oxidation reaction with an oxidant to yield the product quinolinic acid, as shown in the following reaction formula:

[0018]

[0019] Where X is a halogen and R is C 1-3 Alkyl or cyano, R1 is C 2-4 alkyl.

[0020] Furthermore, X is chlorine or bromine, R is methyl or cyano, and R1 is ethyl, C3 alkyl such as n-propyl, or C4 alkyl such as n-butyl or isobutyl.

[0021] Further, step (1) includes the following steps: weigh an appropriate amount of halopyridine derivative, add it to an appropriate solvent while stirring, maintain an appropriate system temperature, slowly add Grignard reagent solution, and keep it warm for a period of time after the addition is complete to obtain the first intermediate.

[0022] Furthermore, the halogenated pyridine derivative is 2-chloro-3-methylpyridine or 2-chloro-3-cyanopyridine.

[0023] Furthermore, the Grignard reagent is a solution of n-propyl magnesium halide tetrahydrofuran, ethyl magnesium halide tetrahydrofuran, n-butyl magnesium halide tetrahydrofuran, and / or isobutyl magnesium halide tetrahydrofuran.

[0024] Furthermore, the Grignard reagent is a solution of n-propyl magnesium bromide tetrahydrofuran, a solution of ethyl magnesium bromide tetrahydrofuran, a solution of n-butyl magnesium bromide tetrahydrofuran, and / or a solution of isobutyl magnesium bromide tetrahydrofuran.

[0025] Furthermore, the Grignard reagent solution is a tetrahydrofuran solution of n-propyl magnesium bromide, ethyl magnesium bromide, n-butyl magnesium bromide and / or isobutyl magnesium bromide at a concentration of 1.5M to 2.5M, for example, about 2M of n-propyl magnesium bromide tetrahydrofuran solution, about 2M of ethyl magnesium bromide tetrahydrofuran solution, about 2M of n-butyl magnesium bromide tetrahydrofuran solution, or about 2M of isobutyl magnesium bromide tetrahydrofuran solution.

[0026] Furthermore, the solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

[0027] Furthermore, the solvent is tetrahydrofuran.

[0028] Furthermore, the mass / volume ratio between the halopyridine derivative and the solvent is 0.2 to 0.3, for example 0.21 to 0.28, for example 0.212 to 0.277.

[0029] Furthermore, the mass / mass ratio between the Grignard reagent and the halopyridine derivative is 4 to 11, for example 4.47 to 10.83, for example 4.47 to 7.25.

[0030] Furthermore, the system temperature is -5℃ to 10℃, for example -5℃ to 0℃ or 0℃ to 10℃.

[0031] Furthermore, the heat preservation time is 0.5 hours to 4 hours, for example, 0.5 hours to 1 hour.

[0032] Furthermore, step (2) includes the following steps:

[0033] (2a) Introduce a suitable amount of CO2 gas, and optionally, after the gas is introduced, carry out a heat-preserving reaction; and

[0034] (2b) Pour the above reaction system into acid and stir. First heat and stir, then cool and stir. Filter to obtain filter cake. Wash the filter cake and dry to obtain the second intermediate.

[0035] Furthermore, the mass / mass ratio of the acid to the CO2 gas is 20 to 30, for example, about 24.

[0036] Furthermore, the heat preservation reaction time is 0.5 to 1.5 hours.

[0037] Furthermore, the acid is hydrochloric acid.

[0038] Furthermore, the temperature of the acid being stirred is approximately 0°C.

[0039] Furthermore, the acid comprises approximately 15% by volume.

[0040] Furthermore, the stirring time in the acid is 0.5 hours to 1 hour.

[0041] Furthermore, the temperature for heating and stirring is 25℃~30℃.

[0042] Furthermore, the heating and stirring time is approximately 0.5 hours.

[0043] Furthermore, the temperature for this cooling and stirring process is -5℃ to 0℃.

[0044] Furthermore, the cooling and stirring time is 6 to 8 hours.

[0045] Furthermore, the solvent used for washing is tetrahydrofuran.

[0046] Furthermore, step (3) includes the following steps:

[0047] (3a) The second intermediate was added to the acid, the oxidant was added at a certain system temperature, and the reaction was carried out for a period of time. The unreacted oxidant was removed by filtration, the acid was recovered, and the remaining solid was recrystallized with water to obtain the product quinoline acid.

[0048] Alternatively, (3b) the second intermediate is added to an alcohol, an oxidant is added at a certain system temperature and the reaction is carried out for a period of time, an appropriate amount of deodorant is added, the mixture is stirred, filtered, the alcohol is removed, and the remaining solid is recrystallized with water to obtain the product quinoline acid.

[0049] Alternatively, (3c) the second intermediate is added to water, glacial acetic acid is added, concentrated sulfuric acid is added dropwise at a certain temperature, after the addition is complete, the temperature is raised to a certain temperature for reflux reaction for a period of time, the mixture is kept warm and separated into layers, water is added again to the organic phase, liquid alkali is added dropwise at a certain temperature to adjust the pH to 8-9, activated carbon is added for decolorization, the mixture is filtered, acid is added dropwise to the filtrate to adjust the pH to 1-2, a solid is precipitated, the mixture is stirred and the temperature is lowered to a certain temperature, filtered, dried, and the product quinoline acid is obtained.

[0050] Furthermore, in step (3a), the acid is acetic acid.

[0051] Furthermore, the mass / volume ratio between the second intermediate and the acid is 0.2 to 0.3, for example, about 0.25.

[0052] Furthermore, the system temperature is 15℃~25℃, for example, about 20℃.

[0053] Furthermore, the oxidant is manganese dioxide and / or potassium permanganate.

[0054] Furthermore, the oxidant is added in the following order: first, manganese dioxide is added, and then potassium permanganate is added slowly in batches.

[0055] Furthermore, the mass / mass ratio of the oxidant to the second intermediate is 1.5 to 2.5, for example, about 1.85.

[0056] Furthermore, the mass / mass ratio of the potassium permanganate to the manganese dioxide is 100 to 250, preferably 135 to 230, for example about 210.

[0057] Furthermore, the reaction time is 1.5 to 2.5 hours, for example, about 2 hours.

[0058] Furthermore, the acid is recovered by vacuum distillation.

[0059] Furthermore, in step (3b), the alcohol is methanol.

[0060] Furthermore, the mass / volume ratio between the second intermediate and the alcohol is 0.15 to 0.25, for example, about 0.18.

[0061] Furthermore, the system temperature ranges from -15°C to -5°C, for example, approximately -10°C.

[0062] Furthermore, the oxidant is O3 and / or O2.

[0063] Furthermore, the reaction ends when the second intermediate becomes undetectable by thin-layer chromatography.

[0064] Furthermore, the deodorizing agent is sodium sulfite.

[0065] Furthermore, the mass / mass ratio of the deodorizing agent to the second intermediate is 0.5 to 1.0, for example, about 0.70.

[0066] Furthermore, the stirring time is 0.5 hours to 1.5 hours, for example, about 1 hour.

[0067] Furthermore, the method of alcohol removal is evaporation.

[0068] Further, in step (3c), the mass / volume ratio between the second intermediate and the water is 1.5 to 2.5, for example, about 1.9.

[0069] Furthermore, the mass / mass ratio of the second intermediate to the glacial acetic acid is 8 to 12, for example, about 10.

[0070] Furthermore, the temperature at which the concentrated sulfuric acid is added should not exceed 100°C.

[0071] Furthermore, the mass / mass ratio of the concentrated sulfuric acid to the second intermediate is 1.1 to 1.4, for example, about 1.25.

[0072] Furthermore, the temperature increase to a certain temperature is an increase to 100℃~110℃.

[0073] Furthermore, the reflux reaction time is 4 to 8 hours, for example, 5 to 6 hours.

[0074] Furthermore, the reflux reaction ends when the second intermediate is no longer detectable by thin-layer chromatography.

[0075] Furthermore, the temperature of this insulation layer is 40℃~60℃.

[0076] Furthermore, the volume / mass ratio of the water to the alkali solution added again is 2 to 3.5, for example, 2.4 to 3.1.

[0077] Furthermore, the temperature of the added alkali is 40°C to 60°C, for example, about 50°C.

[0078] Furthermore, the alkali is sodium hydroxide.

[0079] Furthermore, the decolorization time is 15 to 60 minutes, for example, about 30 minutes.

[0080] Furthermore, the acid used in adjusting the pH to 1-2 by adding acid is hydrochloric acid.

[0081] Furthermore, lowering the temperature to a certain temperature means lowering the temperature to 5℃~10℃.

[0082] Furthermore, the drying process is vacuum drying.

[0083] Furthermore, the drying temperature is 85°C to 95°C, for example, about 90°C.

[0084] The beneficial effects of this invention are:

[0085] This invention provides a novel method for preparing 2,3-pyridinedicarboxylic acid (quinolinic acid). The method uses halogenated and alkyl- or cyano-substituted pyridine derivatives as raw materials. First, a Grignard reaction is carried out with a Grignard agent, followed by carbonylation with carbon dioxide, and finally hydrolysis to obtain the product 2,3-pyridinedicarboxylic acid (quinolinic acid). This synthetic route has the advantages of mild reaction, ease of operation, safety, environmental friendliness, and suitability for large-scale production. Attached Figure Description

[0086] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without exceeding the scope of protection claimed by the present invention.

[0087] Figure 1 This is a schematic diagram of the H spectrum of quinolinic acid, the product obtained by the synthesis method of the present invention.

[0088] Figure 2 This is a schematic C-ray spectrum of quinolinic acid, the product obtained by the synthesis method of the present invention. Detailed Implementation

[0089] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0090] Unless otherwise stated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by one of ordinary skill in the field of this invention or the field of application of such terms. While any methods, conditions, substances, or materials similar to or equivalent to those disclosed herein may be used in the practice of this invention, preferred methods, conditions, substances, or materials are described herein.

[0091] This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances.

[0092] The singular forms “a,” “an,” and “the” used in the specification and appended claims include plural indicators unless the context clearly specifies otherwise.

[0093] In this invention, the term "comprising" and "including" are synonymous. The terms "comprising," "including," "having," "containing," or any other variations thereof as used herein are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0094] In this invention, when concentration, mass / volume ratio, mass / mass ratio, temperature, time, volume percentage, or other values ​​or parameters are expressed as ranges, preferred ranges, or a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value and any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range "4 to 11" is disclosed, the described range should be interpreted as including ranges "4 to 11", "5 to 11", "6 to 11", "7 to 11", "8 to 11", "9 to 11", "10 to 11", "4 to 10", "5 to 10", "6 to 10", "7 to 10", "8 to 10", "9 to 10", "4 to 9", "5 to 9", "6 to 9", "7 to 9", "8 to 9", "4 to 9", "5 to 9", "6 to 9", "7 to 9", "8 to 9", "4 to 8", "5 to 8", etc. When a range of values ​​is described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range, and the inventive objectives of the present invention can be achieved within the aforementioned range.

[0095] As described in the background section, existing methods for preparing quinolinic acid suffer from problems such as vigorous reactions, difficulty in operation, unsafe and environmentally unfriendly reactions, and inconvenience for large-scale production. To address these issues, this invention provides a method for synthesizing quinolinic acid, comprising the following steps:

[0096] (1) Using halopyridine derivatives as raw materials, Grignard reaction is carried out with Grignard reagent solution to generate the first intermediate;

[0097] (2) The first intermediate is subjected to a carbonylation reaction with carbon dioxide to obtain a second intermediate; and

[0098] (3) The second intermediate undergoes an oxidation reaction with an oxidant to yield the product quinolinic acid, as shown in the following reaction formula:

[0099]

[0100] Where X is a halogen and R is C 1-3 Alkyl or cyano, R1 is C 2-4 alkyl.

[0101] In a preferred embodiment, X is chlorine or bromine, R is methyl or cyano, and R1 is ethyl, C3 alkyl such as n-propyl, or C4 alkyl such as n-butyl or isobutyl.

[0102] In a preferred embodiment, step (1) includes the following steps: weigh an appropriate amount of halopyridine derivative, add it to an appropriate solvent while stirring, maintain an appropriate system temperature, slowly add Grignard reagent solution, and keep it warm for a period of time after the addition is complete to obtain the first intermediate.

[0103] In a preferred embodiment, the halogenated pyridine derivative is 2-chloro-3-methylpyridine or 2-chloro-3-cyanopyridine.

[0104] In a preferred embodiment, the Grignard reagent is a solution of n-propyl magnesium halide tetrahydrofuran, a solution of ethyl magnesium halide tetrahydrofuran, a solution of n-butyl magnesium halide tetrahydrofuran, and / or a solution of isobutyl magnesium halide tetrahydrofuran.

[0105] In a preferred embodiment, the Grignard reagent is a solution of n-propyl magnesium bromide tetrahydrofuran, a solution of ethyl magnesium bromide tetrahydrofuran, a solution of n-butyl magnesium bromide tetrahydrofuran, and / or a solution of isobutyl magnesium bromide tetrahydrofuran.

[0106] In a preferred embodiment, the Grignard reagent solution is a tetrahydrofuran solution of n-propyl magnesium bromide, ethyl magnesium bromide, n-butyl magnesium bromide and / or isobutyl magnesium bromide at a concentration of 1.5M to 2.5M, for example, about 2M of n-propyl magnesium bromide tetrahydrofuran solution, about 2M of ethyl magnesium bromide tetrahydrofuran solution, about 2M of n-butyl magnesium bromide tetrahydrofuran solution, or about 2M of isobutyl magnesium bromide tetrahydrofuran solution.

[0107] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 2" includes 2 ± 5%, or from 1.9 to 2.1.

[0108] In a preferred embodiment, the solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

[0109] In a preferred embodiment, the solvent is tetrahydrofuran.

[0110] In a preferred embodiment, the mass / volume ratio between the halopyridine derivative and the solvent is 0.2 to 0.3, for example 0.21 to 0.28, for example 0.212 to 0.277.

[0111] In a preferred embodiment, the mass / mass ratio between the Grignard reagent and the halopyridine derivative is 4 to 11, for example 4.47 to 10.83, for example 4.47 to 7.25.

[0112] In a preferred embodiment, the system temperature is -5°C to 10°C, for example -5°C to 0°C or 0°C to 10°C.

[0113] In a preferred embodiment, the heat preservation time is 0.5 hours to 4 hours, for example, 0.5 hours to 1 hour.

[0114] In a preferred embodiment, step (2) includes the following steps:

[0115] (2a) Introduce a suitable amount of CO2 gas, and optionally, after the gas is introduced, carry out a heat-preserving reaction; and

[0116] (2b) Pour the above reaction system into acid and stir. First heat and stir, then cool and stir. Filter to obtain filter cake. Wash the filter cake and dry to obtain the second intermediate.

[0117] In a preferred embodiment, the mass / mass ratio of the acid to the CO2 gas is 20 to 30, for example, about 24.

[0118] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 24" includes ±5% of 24, or from 22.8 to 25.2.

[0119] In a preferred embodiment, the heat preservation reaction takes 0.5 to 1.5 hours.

[0120] In a preferred embodiment, the acid is hydrochloric acid.

[0121] In a preferred embodiment, the temperature of the acid being stirred is about 0°C.

[0122] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0" includes ±5% of 0, or from -0.05 to 0.05.

[0123] In a preferred embodiment, the acid has a volume percentage of about 15%.

[0124] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 15" includes ±5% of 15, or from 14.25 to 15.75.

[0125] In a preferred embodiment, the stirring time in the acid is 0.5 hours to 1 hour.

[0126] In a preferred embodiment, the temperature of the heating and stirring is 25°C to 30°C.

[0127] In a preferred embodiment, the heating and stirring time is approximately 0.5 hours.

[0128] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.5" includes ±5% of 0.5, or from 0.475 to 0.525.

[0129] In a preferred embodiment, the temperature of the cooling stirring is -5°C to 0°C.

[0130] In a preferred embodiment, the cooling and stirring time is 6 to 8 hours.

[0131] In a preferred embodiment, the solvent for washing is tetrahydrofuran.

[0132] In a preferred embodiment, step (3) includes the following steps:

[0133] (3a) The second intermediate was added to the acid, the oxidant was added at a certain system temperature, and the reaction was carried out for a period of time. The unreacted oxidant was removed by filtration, the acid was recovered, and the remaining solid was recrystallized with water to obtain the product quinoline acid.

[0134] Alternatively, (3b) the second intermediate is added to an alcohol, an oxidant is added at a certain system temperature and the reaction is carried out for a period of time, an appropriate amount of deodorant is added, the mixture is stirred, filtered, the alcohol is removed, and the remaining solid is recrystallized with water to obtain the product quinoline acid.

[0135] Alternatively, (3c) the second intermediate is added to water, glacial acetic acid is added, concentrated sulfuric acid is added dropwise at a certain temperature, after the addition is complete, the temperature is raised to a certain temperature for reflux reaction for a period of time, the mixture is kept warm and separated into layers, water is added again to the organic phase, liquid alkali is added dropwise at a certain temperature to adjust the pH to 8-9, activated carbon is added for decolorization, the mixture is filtered, acid is added dropwise to the filtrate to adjust the pH to 1-2, a solid is precipitated, the mixture is stirred and the temperature is lowered to a certain temperature, filtered, dried, and the product quinoline acid is obtained.

[0136] In a preferred embodiment, in step (3a), the acid is acetic acid.

[0137] In a preferred embodiment, the mass / volume ratio of the second intermediate to the acid is 0.2 to 0.3, for example, about 0.25.

[0138] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 5" includes 5 ± 5%, or from 4.75 to 5.25.

[0139] In a preferred embodiment, the system temperature is 15°C to 25°C, for example, about 20°C.

[0140] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 20" includes ±5% of 20, or from 19 to 21.

[0141] In a preferred embodiment, the oxidant is manganese dioxide and / or potassium permanganate.

[0142] In a preferred embodiment, the oxidant is added in the following order: first, manganese dioxide is added, and then potassium permanganate is added slowly in batches.

[0143] In a preferred embodiment, the mass / mass ratio of the oxidant to the second intermediate is 1.5 to 2.5, for example, about 1.85.

[0144] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.85" includes ±5% of 1.85, or from 1.7575 to 1.9425.

[0145] In a preferred embodiment, the mass / mass ratio of the potassium permanganate to the manganese dioxide is 100 to 250, preferably 135 to 230, for example about 210.

[0146] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 210" includes ±5% of 210, or from 199.5 to 220.5.

[0147] In a preferred embodiment, the reaction time is 1.5 to 2.5 hours, for example, about 2 hours.

[0148] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 2" includes 2 ± 5%, or from 1.9 to 2.1.

[0149] In a preferred embodiment, the acid is recovered by vacuum distillation.

[0150] In a preferred embodiment, in step (3b), the alcohol is methanol.

[0151] In a preferred embodiment, the mass / volume ratio between the second intermediate and the alcohol is 0.15 to 0.25, for example, about 0.18.

[0152] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.18" includes ±5% of 0.18, or from 0.171 to 0.189.

[0153] In a preferred embodiment, the system temperature is -15°C to -5°C, for example, about -10°C.

[0154] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about -10" includes ±5% of -10, or from -10.5 to -9.5.

[0155] In a preferred embodiment, the oxidant is O3 and / or O2.

[0156] In a preferred embodiment, the reaction ends when the second intermediate can no longer be detected by thin-layer chromatography.

[0157] In a preferred embodiment, the deodorizing agent is sodium sulfite.

[0158] In a preferred embodiment, the mass / mass ratio of the deodorizing agent to the second intermediate is 0.5 to 1.0, for example, about 0.70.

[0159] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.7" includes ±5% of 0.7, or from 0.665 to 0.735.

[0160] In a preferred embodiment, the stirring time is 0.5 to 1.5 hours, for example, about 1 hour.

[0161] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1" includes ±5% of 1, or from 0.95 to 1.05.

[0162] In a preferred embodiment, the alcohol removal method is evaporation.

[0163] In a preferred embodiment, in step (3c), the mass / volume ratio between the second intermediate and the water is 1.5 to 2.5, for example, about 1.9.

[0164] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.9" includes ±5% of 1.9, or from 1.805 to 1.995.

[0165] In a preferred embodiment, the mass / mass ratio of the second intermediate to the glacial acetic acid is 8 to 12, for example, about 10.

[0166] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.9" includes ±5% of 1.9, or from 1.805 to 1.995.

[0167] In a preferred embodiment, the temperature at which the concentrated sulfuric acid is added is not higher than 100°C.

[0168] In a preferred embodiment, the mass / mass ratio of the concentrated sulfuric acid to the second intermediate is 1.1 to 1.4, for example, about 1.25.

[0169] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.25" includes ±5% of 1.25, or from 1.1875 to 1.3125.

[0170] In a preferred embodiment, the temperature increase to a certain temperature is an increase to 100°C to 110°C.

[0171] In a preferred embodiment, the reflux reaction takes 4 to 8 hours, for example 5 to 6 hours.

[0172] In a preferred embodiment, the reflux reaction ends when the second intermediate is no longer detectable by thin-layer chromatography.

[0173] In a preferred embodiment, the temperature of the insulation layer is 40°C to 60°C.

[0174] In a preferred embodiment, the volume / mass ratio of the water to the liquid alkali added in the water is 2 to 3.5, for example, 2.4 to 3.1.

[0175] In a preferred embodiment, the temperature of the added liquid alkali is 40°C to 60°C, for example, about 50°C.

[0176] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 50" includes 50 ± 5%, or from 47.5 to 52.5.

[0177] In a preferred embodiment, the alkali is sodium hydroxide.

[0178] In a preferred embodiment, the decolorization time is 15 min to 60 min, for example, about 30 min.

[0179] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 30" includes 30 ±5%, or from 28.5 to 31.5.

[0180] In a preferred embodiment, the acid used to adjust the pH to 1-2 is hydrochloric acid.

[0181] In a preferred embodiment, the temperature reduction to a certain temperature is to reduce the temperature to 5°C to 10°C.

[0182] In a preferred embodiment, the drying is vacuum drying.

[0183] In a preferred embodiment, the drying temperature is 85°C to 95°C, for example, about 90°C.

[0184] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 90" includes ±5% of 90, or from 85.5 to 94.5.

[0185] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0186] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0187] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this patent specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0188] Example

[0189] Preparation Example 1

[0190] The reaction formula for preparing Example 1 is shown below:

[0191]

[0192] Specific preparation method: 127.5 g (1.0 mol) of 2-chloro-3-methylpyridine was added to 600 ml of tetrahydrofuran under stirring. The system temperature was maintained at 0–10 °C. 920 g of 2M n-propylmagnesium bromide solution was slowly added dropwise, and the mixture was kept at this temperature for 1.0 h after the addition was complete. 50 g of CO2 gas was introduced, and the reaction was kept at this temperature for 1 h after the gas was completely introduced. The reaction mixture was then poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was then raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. After drying, 115 g of a grayish-white solid was obtained, which was intermediate 1-3, namely 2-carboxylic acid-3-methylpyridine, with a yield of 83.9%.

[0193] The solid obtained in the previous step was added to 450 ml of acetic acid. The system temperature was maintained at 20 °C. 1.0 g of manganese dioxide was added, followed by 210 g of potassium permanganate in slow batches. After the addition was complete, the temperature was maintained for 2 h. The mixture was filtered to remove unreacted potassium permanganate and manganese dioxide. Acetic acid was recovered by vacuum distillation and reused. The remaining solid was recrystallized with water to obtain products 1-4, namely 113.0 g of the target compound quinolinic acid. The yield of this step was 81%.

[0194] Preparation Example 2

[0195] The reaction formula for preparing Example 2 is shown below:

[0196]

[0197] Specific preparation method: 127.5 g (1.0 mol) of 2-chloro-3-methylpyridine was added to 600 ml of 2-methyltetrahydrofuran under stirring. The system temperature was maintained at 0–10 °C. 920 g of 2M n-propylmagnesium bromide solution was slowly added dropwise, and the mixture was kept at this temperature for 1.0 h after the addition was complete. 50 g of CO2 gas was introduced, and after the introduction was complete, the reaction system was poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was then raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. After drying, 96.0 g of a grayish-white solid was obtained, which was intermediate 1-3, namely 2-carboxylic acid-3-methylpyridine, with a yield of 70%.

[0198] The solid obtained in the previous step was added to 376 ml of acetic acid. The system temperature was maintained at 20 °C. 1.0 g of manganese dioxide was added, followed by 175.3 g of potassium permanganate in slow batches. After the addition was complete, the temperature was maintained for 2 h. The mixture was filtered to remove unreacted potassium permanganate and manganese dioxide. Acetic acid was recovered by vacuum distillation and reused. The remaining solid was recrystallized with water to obtain products 1-4, namely the target compound quinoline acid, in 87.8 g. The yield of this step was 75%.

[0199] Preparation Example 3

[0200] The reaction formula for preparing Example 3 is shown below:

[0201]

[0202] Specific preparation method: 127.5 g (1.0 mol) of 2-chloro-3-methylpyridine was added to 600 ml of toluene under stirring. The system temperature was maintained at 0–10 °C. 1380 g of 2M n-propylmagnesium bromide solution was slowly added dropwise. After the addition was complete, the temperature was raised to 60–70 °C and the reaction was maintained for 4.0 h. 50 g of CO2 gas was introduced, and the reaction was maintained for 1 h after the introduction was complete. The reaction system was poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. 75.3 g of a grayish-white solid was obtained by drying. This was intermediate 1-3, namely 2-carboxylic acid-3-methylpyridine, with a yield of 55.0%.

[0203] The solid obtained in the previous step was added to 295 ml of acetic acid. The system temperature was maintained at 20 °C. 1.0 g of manganese dioxide was added, followed by 137.5 g of potassium permanganate in slow batches. After the addition was complete, the temperature was maintained for 2 h. The mixture was filtered to remove unreacted potassium permanganate and manganese dioxide. Acetic acid was recovered by vacuum distillation and reused. The remaining solid was recrystallized with water to obtain products 1-4, i.e., 68.8 g of the target compound quinoline acid. The yield of this step was 75%.

[0204] Preparation Example 4

[0205] The reaction formula for preparing Example 4 is shown below:

[0206]

[0207] Specific preparation method: 127.5 g (1.0 mol) of 2-chloro-3-methylpyridine was added to 600 ml of tetrahydrofuran under stirring. The system temperature was maintained at 0–10 °C. 920 g of 2M n-propylmagnesium chloride solution was slowly added dropwise, and the mixture was kept at this temperature for 1.0 h after the addition was complete. 50 g of CO2 gas was introduced, and after the introduction was complete, the reaction system was poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was then raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. After drying, 27.8 g of a grayish-white solid was obtained, which was intermediate 1-3, i.e., 2-carboxylic acid-3-methylpyridine, with a yield of 20%.

[0208] Preparation Example 5

[0209] The reaction formula for preparing Example 5 is shown below:

[0210]

[0211] Specific preparation method: The preparation of 2-carboxylic acid-3-methylpyridine is the same as in Example 1.

[0212] Intermediates 1-3 obtained in the previous step were added to 650 ml of methanol. The system was cooled to -10°C, and ozone (O3 / O2) was slowly introduced while maintaining this temperature for the reaction. The reaction process was monitored by thin-layer chromatography. The reaction ended after the starting material disappeared. 80 g of sodium sulfite solid was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the methanol was evaporated for recycling. The remaining solid was recrystallized with water to obtain 118 g of the product. The yield was 70.8%.

[0213] Preparation Example 6

[0214] The reaction formula for preparing Example 6 is shown below:

[0215]

[0216] Specific preparation method: 138.5 g (1.0 mol) of 2-chloro-3-cyanopyridine was added to 500 ml of tetrahydrofuran under stirring. The system temperature was maintained at -5 to 0 °C. 620 g of 2M n-propylmagnesium bromide solution was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature for 0.5 h, and 50 g of CO2 gas was introduced. After the introduction was complete, the reaction mixture was poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 0.5 to 1 h. The temperature was then raised to 25-30 °C and stirred for another 0.5 h. The mixture was cooled to -5 to 0 °C and stirred at this temperature for 6-8 h. The mixture was then filtered. The filter cake was washed with a small amount of tetrahydrofuran and dried to obtain 124.7 g of a grayish-white solid, which was 2-carboxylic acid-3-cyanopyridine, with a yield of 84.2%.

[0217] Add the above product to 65g of water and 12.5g of glacial acetic acid. Add 156.0g of concentrated sulfuric acid dropwise while maintaining the temperature ≤100℃. After the addition is complete, raise the temperature to 100-110℃ and reflux for 5-6 hours. Detect the reaction process using thin-layer chromatography after the reaction is complete. After the starting material spot has essentially disappeared, maintain the temperature to allow the layers to separate.

[0218] Add 250 ml of water to the organic phase, maintain the temperature at approximately 50°C, and add 100.0 g of liquid alkali dropwise to adjust the pH to 8.0–9.0. Add activated carbon for decolorization for 30 min, filter, and add hydrochloric acid dropwise to adjust the pH to 1–2, precipitating a large amount of solid. Stir and cool to 5–10°C, filter, and dry under vacuum at 90°C to obtain 122.0 g of quinoline acid, with a yield of 86.7%.

[0219] Preparation Example 7

[0220] The reaction formula for preparing Example 7 is shown below:

[0221]

[0222] Specific preparation method: 138.5 g (1.0 mol) of 2-chloro-3-cyanopyridine was added to 500 ml of 2-methyltetrahydrofuran under stirring. The system temperature was maintained at -5 to 0 °C. 620 g of 2M n-propylmagnesium bromide solution was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature for 0.5 h, and 50 g of CO2 gas was introduced. After the introduction was complete, the reaction mixture was poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 0.5 to 1 h. The temperature was then raised to 25 to 30 °C and stirred for another 0.5 h. The mixture was cooled to -5 to 0 °C and stirred at this temperature for 6 to 8 h. The mixture was then filtered. The filter cake was washed with a small amount of tetrahydrofuran and dried to obtain 103.8 g of a grayish-white solid, which was 2-carboxylic acid-3-cyanopyridine, with a yield of 70.1%.

[0223] Add the above product to 52g of water and 10.0g of glacial acetic acid. Add 130.0g of concentrated sulfuric acid dropwise while maintaining the temperature ≤100℃. After the addition is complete, raise the temperature to 100-110℃ and reflux for 5-6 hours. Detect the reaction process using thin-layer chromatography after the reaction is complete. After the starting material spot has essentially disappeared, maintain the temperature to allow for layer separation.

[0224] Add 250 ml of water to the organic phase, maintain the temperature at approximately 50°C, and add 83.0 g of liquid alkali dropwise to adjust the pH to 8.0–9.0. Add activated carbon for decolorization for 30 min, filter, and add hydrochloric acid dropwise to adjust the pH to 1–2, precipitating a large amount of solid. Stir and cool to 5–10°C, filter, and dry under vacuum at 90°C to obtain 94.0 g of quinoline acid, with a yield of 80%.

[0225] Preparation Example 8

[0226] The reaction formula for preparing Example 8 is shown below:

[0227]

[0228] Specific preparation method: 138.5 g (1.0 mol) of 2-chloro-3-cyanopyridine was added to 600 ml of tetrahydrofuran under stirring. The system temperature was maintained at 0–10 °C. 920 g of 2M n-propylmagnesium chloride solution was slowly added dropwise, and the mixture was kept at this temperature for 1.0 h after the addition was complete. 50 g of CO2 gas was introduced, and after the introduction was complete, the reaction system was poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was then raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. After drying, 28.0 g of a grayish-white solid was obtained, which was intermediate 1-3, namely 2-carboxylic acid-3-methylpyridine, with a yield of 19%.

[0229] Preparation Example 9

[0230] The reaction formula for preparing Example 9 is shown below:

[0231]

[0232] Specific preparation method: 138.5 g (1.0 mol) of 2-chloro-3-cyanopyridine was added to 500 ml of toluene under stirring. The system temperature was maintained at -5 to 0 °C. 620 g of 2M n-propylmagnesium bromide solution was slowly added dropwise. After the addition was complete, the temperature was raised to 60 to 70 °C and the reaction was maintained for 4.0 h. 50 g of CO2 gas was introduced. After the introduction was complete, the reaction system was poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 0.5 to 1 h. The temperature was then raised to 25 to 30 °C and stirred for 0.5 h. The temperature was lowered to -5 to 0 °C and stirred at this temperature for 6 to 8 h. The mixture was then filtered. The filter cake was washed with a small amount of tetrahydrofuran and dried to obtain 77.0 g of a grayish-white solid, which was 2-carboxylic acid-3-cyanopyridine, with a yield of 52%.

[0233] Add the above product to 40g of water and 8.0g of glacial acetic acid. Add 96.3g of concentrated sulfuric acid dropwise while maintaining the temperature ≤100℃. After the addition is complete, raise the temperature to 100-110℃ and reflux for 5-6 hours. Detect the reaction process using thin-layer chromatography after the reaction is complete. After the starting material spot has essentially disappeared, maintain the temperature to allow for layer separation.

[0234] Add 150 ml of water to the organic phase, maintain the temperature at approximately 50°C, and add 62.0 g of liquid alkali dropwise to adjust the pH to 8.0–9.0. Add activated carbon for decolorization for 30 min, filter, and add hydrochloric acid dropwise to adjust the pH to 1–2, precipitating a large amount of solid. Stir and cool to 5–10°C, filter, and dry under vacuum at 90°C to obtain 66.2 g of quinoline acid, with a yield of 76.2%.

[0235] Preparation Example 10

[0236] The reaction formula for preparing Example 10 is shown below:

[0237]

[0238] Specific preparation method: 127.5 g (1.0 mol) of 2-chloro-3-methylpyridine was added to 600 ml of tetrahydrofuran under stirring. The system temperature was maintained at 0–10 °C. 887 g of 2M ethyl magnesium bromide solution was slowly added dropwise, and the mixture was kept at this temperature for 1.0 h after the addition was complete. 50 g of CO2 gas was introduced, and the reaction was kept at this temperature for 1 h after the gas was completely introduced. The reaction mixture was then poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was then raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. 110 g of a grayish-white solid was obtained by drying; this was intermediate 1-3, namely 2-carboxylic acid-3-methylpyridine, with a yield of 80.3%.

[0239] The solid obtained in the previous step was added to 450 ml of acetic acid. The system temperature was maintained at 20 °C. 1.0 g of manganese dioxide was added, followed by 210 g of potassium permanganate in slow batches. After the addition was complete, the temperature was maintained for 2 h. The mixture was filtered to remove unreacted potassium permanganate and manganese dioxide. Acetic acid was recovered by vacuum distillation and reused. The remaining solid was recrystallized with water to obtain product 1-4, i.e., 108.0 g of the target compound quinoline acid. The yield of this step was 80.6%.

[0240] Preparation Example 11

[0241] The reaction formula for preparing Example 11 is shown below:

[0242]

[0243] Specific preparation method: 127.5 g (1.0 mol) of 2-chloro-3-methylpyridine was added to 600 ml of tetrahydrofuran under stirring. The system temperature was maintained at 0–10 °C. 924 g of 2M isobutylmagnesium bromide solution was slowly added dropwise, and the mixture was kept at this temperature for 1.0 h after the addition was complete. 50 g of CO2 gas was introduced, and the reaction was kept at this temperature for 1 h after the gas was completely introduced. The reaction mixture was then poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was then raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. After drying, 108 g of a grayish-white solid was obtained, which was intermediate 1-3, namely 2-carboxylic acid-3-methylpyridine, with a yield of 78.8%.

[0244] The solid obtained in the previous step was added to 450 ml of acetic acid. The system temperature was maintained at 20 °C. 1.0 g of manganese dioxide was added, followed by 210 g of potassium permanganate in slow batches. After the addition was complete, the temperature was maintained for 2 h. The mixture was filtered to remove unreacted potassium permanganate and manganese dioxide. Acetic acid was recovered by vacuum distillation and reused. The remaining solid was recrystallized with water to obtain product 1-4, i.e., 106.5 g of the target compound quinoline acid. The yield of this step was 80.9%.

[0245] Preparation Example 12

[0246] The reaction formula for preparing Example 12 is shown below:

[0247]

[0248] Specific preparation method: 127.5 g (1.0 mol) of 2-chloro-3-methylpyridine was added to 600 ml of tetrahydrofuran under stirring. The system temperature was maintained at 0–10 °C. 924 g of 2M n-butylmagnesium bromide solution was slowly added dropwise, and the mixture was kept at this temperature for 1.0 h after the addition was complete. 50 g of CO2 gas was introduced, and the reaction was kept at this temperature for 1 h after the gas was completely introduced. The reaction mixture was then poured into 1200 g of 15% glacial hydrochloric acid at approximately 0 °C and stirred for 1.0 h. The temperature was then raised to 25–30 °C and stirred for 0.5 h. The temperature was lowered to -5–0 °C and stirred at this temperature for 6–8 h. The mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran. After drying, 113 g of a grayish-white solid was obtained, which was intermediate 1-3, namely 2-carboxylic acid-3-methylpyridine, with a yield of 82.4%.

[0249] The solid obtained in the previous step was added to 450 ml of acetic acid. The system temperature was maintained at 20 °C. 1.0 g of manganese dioxide was added, followed by 210 g of potassium permanganate in slow batches. After the addition was complete, the temperature was maintained for 2 h. The mixture was filtered to remove unreacted potassium permanganate and manganese dioxide. Acetic acid was recovered by vacuum distillation and reused. The remaining solid was recrystallized with water to obtain products 1-4, i.e., 111.7 g of the target compound quinoline acid. The yield of this step was 81.1%.

[0250] The structural identification spectrum of the product quinolinic acid (2,3-pyridinedicarboxylic acid) obtained by the synthesis method of the present invention is shown below. Figure 1 and Figure 2 As shown, the specific data is as follows:

[0251] 1 H-NMR (500MHz, DMSO) δ = 7.62 (dd, 1H), 8.24 (dd, 1H), 8.74 (dd, 1H), 13.53 (s, 2H); 13 C-NMR (100MHz, DMSO) δ=125.23, 125.99, 138.19, 151.96, 152.81, 168.25, 166.84.

[0252] The embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, any changes or modifications made by those skilled in the art based on the ideas of the present invention, its specific implementation methods, and its application scope, are all within the scope of protection of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A method for synthesizing quinolinic acid, characterized in that, The method includes the following steps: (1) Weigh an appropriate amount of halopyridine derivative, add it to an appropriate solvent while stirring, maintain an appropriate system temperature, and then slowly add Grignard reagent solution. After the addition is complete, keep it warm for a period of time to obtain the first intermediate. (2) The first intermediate is subjected to a carbonylation reaction with carbon dioxide to obtain a second intermediate; and (3) The second intermediate undergoes an oxidation reaction with an oxidant to obtain the product quinolinic acid, as shown in the following formula: In the halopyridine derivatives, X is chlorine and R is methyl or cyano; in the Grignard reagent, X is bromine and R1 is C. 2-4 Alkyl group; the solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

2. The method according to claim 1, characterized in that, R is methyl or cyano, and R1 is ethyl, C3 alkyl, or C4 alkyl.

3. The method according to claim 2, characterized in that, The C3 alkyl group is n-propyl.

4. The method according to claim 2, characterized in that, The C4 alkyl group is n-butyl or isobutyl.

5. The method according to claim 1, characterized in that, The Grignard reagent solution is n-propyl magnesium bromide tetrahydrofuran solution, ethyl magnesium bromide tetrahydrofuran solution, n-butyl magnesium bromide tetrahydrofuran solution and / or isobutyl magnesium bromide tetrahydrofuran solution.

6. The method according to claim 1, characterized in that, The Grignard reagent solution is a tetrahydrofuran solution with a concentration of 1.5M to 2.5M for n-propyl magnesium bromide, ethyl magnesium bromide, n-butyl magnesium bromide and / or isobutyl magnesium bromide.

7. The method according to claim 6, characterized in that, The Grignard reagent solution is a 1.9-2.1 M solution of n-propyl magnesium bromide tetrahydrofuran, a 1.9-2.1 M solution of ethyl magnesium bromide tetrahydrofuran, a 1.9-2.1 M solution of n-butyl magnesium bromide tetrahydrofuran, or a 1.9-2.1 M solution of isobutyl magnesium bromide tetrahydrofuran.

8. The method according to claim 1, characterized in that, The solvent is tetrahydrofuran.

9. The method according to claim 1, characterized in that, The mass / volume ratio between the halopyridine derivative and the solvent is 0.2 to 0.

3.

10. The method according to claim 9, characterized in that, The mass / volume ratio of the halopyridine derivative to the solvent is 0.21 to 0.

28.

11. The method according to claim 10, characterized in that, The mass / volume ratio between the halopyridine derivative and the solvent is 0.212 to 0.

277.

12. The method according to claim 1, characterized in that, The mass / mass ratio of the Grignard reagent to the halopyridine derivative is 4 to 11.

13. The method according to claim 12, characterized in that, The mass / mass ratio of the Grignard reagent to the halopyridine derivative is 4.47 to 10.

83.

14. The method according to claim 13, characterized in that, The mass / mass ratio of the Grignard reagent to the halopyridine derivative is 4.47 to 7.

25.

15. The method according to claim 1, characterized in that, The system temperature is -5℃ to 10℃.

16. The method according to claim 15, characterized in that, The system temperature is -5℃ to 0℃ or 0℃ to 10℃.

17. The method according to claim 1, characterized in that, The heat preservation time is 0.5 hours to 4 hours.

18. The method according to claim 17, characterized in that, The heat preservation time is 0.5 hours to 1 hour.

19. The method according to claim 1, characterized in that, Step (2) includes the following steps: (2a) A suitable amount of CO2 gas is introduced, and optionally, a heat preservation reaction is carried out after the gas is introduced; and (2b) Pour the above reaction system into acid and stir. First heat and stir, then cool and stir. Filter to obtain filter cake. Wash the filter cake and dry to obtain the second intermediate.

20. The method according to claim 19, characterized in that, The mass-to-mass ratio of the acid to the CO2 gas is 20 to 30.

21. The method according to claim 20, characterized in that, The mass ratio of the acid to the CO2 gas is 22.8 to 25.

2.

22. The method according to claim 19, characterized in that, The heat preservation reaction time is 0.5 to 1.5 hours.

23. The method according to claim 19, characterized in that, The acid is hydrochloric acid.

24. The method according to claim 19, characterized in that, The stirring temperature in the acid is -0.05~0.05℃.

25. The method according to claim 19, characterized in that, The acid has a volume percentage of 14.25% to 15.75%.

26. The method according to claim 19, characterized in that, The stirring time in the acid is 0.5 hours to 1 hour.

27. The method according to claim 19, characterized in that, The temperature for heating and stirring is 25℃~30℃.

28. The method according to claim 19, characterized in that, The heating and stirring time is 0.475~0.525 hours.

29. The method according to claim 19, characterized in that, The temperature for cooling and stirring is -5℃ to 0℃.

30. The method according to claim 19, characterized in that, The cooling and stirring time is 6 to 8 hours.

31. The method according to claim 19, characterized in that, The solvent used for washing is tetrahydrofuran.

32. The method according to claim 1, characterized in that, Step (3) includes the following steps: (3a) The second intermediate is added to acid, the oxidant is added at a certain system temperature, and the reaction is carried out for a period of time. The mixture is filtered to remove the unreacted oxidant, the acid is recovered, and the remaining solid is recrystallized with water to obtain the product quinoline acid. Alternatively, (3b) the second intermediate is added to an alcohol, an oxidant is added at a certain system temperature and the reaction is carried out for a period of time, an appropriate amount of deodorant is added, the mixture is stirred, filtered, the alcohol is removed, and the remaining solid is recrystallized with water to obtain the product quinoline acid; Alternatively, (3c) the second intermediate is added to water, glacial acetic acid is added, concentrated sulfuric acid is added dropwise at a certain temperature, after the addition is complete, the temperature is raised to a certain temperature for reflux reaction for a period of time, the mixture is kept warm and separated into layers, water is added again to the organic phase, liquid alkali is added dropwise at a certain temperature to adjust the pH to 8-9, activated carbon is added for decolorization, the mixture is filtered, acid is added dropwise to the filtrate to adjust the pH to 1-2, a solid is precipitated, the mixture is stirred and the temperature is lowered to a certain temperature, filtered, dried, and the product quinoline acid is obtained.

33. The method according to claim 32, characterized in that, In step (3a), the acid is acetic acid.

34. The method according to claim 33, characterized in that, The mass / volume ratio between the second intermediate and the acid is 0.2 to 0.

3.

35. The method according to claim 34, characterized in that, The mass / volume ratio of the second intermediate to the acid is 0.

25.

36. The method according to claim 32, characterized in that, In step (3a), the system temperature is 15℃~25℃.

37. The method according to claim 36, characterized in that, The system temperature is 19~21℃.

38. The method according to claim 32, characterized in that, In step (3a), the oxidant is manganese dioxide and / or potassium permanganate.

39. The method according to claim 38, characterized in that, In step (3a), the oxidant is added in the following order: first, manganese dioxide is added, and then potassium permanganate is added slowly in batches.

40. The method according to claim 32, characterized in that, In step (3a), the mass / mass ratio of the oxidant to the second intermediate is 1.5 to 2.

5.

41. The method according to claim 40, characterized in that, The mass ratio of the oxidant to the second intermediate is 1.7575 to 1.9425.

42. The method according to claim 38, characterized in that, The mass ratio of potassium permanganate to manganese dioxide is 100 to 250.

43. The method according to claim 42, characterized in that, The mass ratio of potassium permanganate to manganese dioxide is 135 to 230.

44. The method according to claim 43, characterized in that, The mass ratio of potassium permanganate to manganese dioxide is 199.5 to 220.

5.

45. The method according to claim 32, characterized in that, In step (3a), the reaction time is 1.5 hours to 2.5 hours.

46. ​​The method according to claim 45, characterized in that, The reaction time is 1.9 to 2.1 hours.

47. The method according to claim 32, characterized in that, The acid is recovered by vacuum distillation.

48. The method according to claim 32, characterized in that, In step (3b), the alcohol is methanol.

49. The method according to claim 32, characterized in that, In step (3b), the mass / volume ratio between the second intermediate and the alcohol is 0.15 to 0.

25.

50. The method according to claim 49, characterized in that, The mass / volume ratio between the second intermediate and the alcohol is 0.171 to 0.

189.

51. The method according to claim 32, characterized in that, In step (3b), the system temperature is -15℃ to -5℃.

52. The method according to claim 51, characterized in that, The system temperature ranges from -10.5℃ to -9.5℃.

53. The method according to claim 32, characterized in that, In step (3b), the oxidant is O3 and / or O2.

54. The method according to claim 32, characterized in that, In step (3b), the reaction ends when the second intermediate cannot be detected by thin-layer chromatography.

55. The method according to claim 32, characterized in that, The deodorizing agent is sodium sulfite.

56. The method according to claim 32, characterized in that, In step (3b), the mass / mass ratio of the deodorizing agent to the second intermediate is 0.5 to 1.

0.

57. The method according to claim 56, characterized in that, The mass ratio of the deodorizing agent to the second intermediate is 0.665 to 0.

735.

58. The method according to claim 32, characterized in that, In step (3b), the stirring time is 0.5 hours to 1.5 hours.

59. The method according to claim 58, characterized in that, The stirring time is 0.95 to 1.05 hours.

60. The method according to claim 32, characterized in that, The method for removing alcohol is evaporation.

61. The method according to claim 32, characterized in that, In step (3c), the mass / volume ratio between the second intermediate and the water is 1.5 to 2.

5.

62. The method according to claim 61, characterized in that, The mass / volume ratio of the second intermediate to the water is 1.805 to 1.

995.

63. The method according to claim 32, characterized in that, In step (3c), the mass / mass ratio between the second intermediate and the glacial acetic acid is 8 to 12.

64. The method according to claim 63, characterized in that, The mass ratio of the second intermediate to the glacial acetic acid is 10.

65. The method according to claim 32, characterized in that, The temperature at which concentrated sulfuric acid is added dropwise shall not exceed 100°C.

66. The method according to claim 32, characterized in that, In step (3c), the mass / mass ratio between the concentrated sulfuric acid and the second intermediate is 1.1 to 1.

4.

67. The method according to claim 66, characterized in that, The mass ratio of the concentrated sulfuric acid to the second intermediate is 1.1875 to 1.3125.

68. The method according to claim 32, characterized in that, The temperature increase to a certain temperature is to increase the temperature to 100℃~110℃.

69. The method according to claim 32, characterized in that, The reflux reaction time is 4 to 8 hours.

70. The method according to claim 69, characterized in that, The reflux reaction time is 5 to 6 hours.

71. The method according to claim 32, characterized in that, The reflux reaction ends when the second intermediate can no longer be detected by thin-layer chromatography.

72. The method according to claim 32, characterized in that, The temperature of the insulation layer is 40℃~60℃.

73. The method according to claim 32, characterized in that, The volume / mass ratio of the water to the liquid alkali added in the water is 2 to 3.

5.

74. The method according to claim 73, characterized in that, The volume-to-mass ratio of the water to the liquid alkali added in the water is 2.4 to 3.

1.

75. The method according to claim 32, characterized in that, The temperature of the added alkali is 40℃~60℃.

76. The method according to claim 75, characterized in that, The temperature of the added liquid alkali is 47.5~52.5℃.

77. The method according to claim 32, characterized in that, The alkali is sodium hydroxide.

78. The method according to claim 32, characterized in that, The decolorization time is 15 min to 60 min.

79. The method according to claim 78, characterized in that, The decolorization time is 28.5~31.5 min.

80. The method according to claim 32, characterized in that, The acid mentioned in the step of adjusting the pH to 1-2 by adding acid dropwise is hydrochloric acid.

81. The method according to claim 32, characterized in that, The temperature reduction to a certain temperature refers to reducing the temperature to 5℃~10℃.

82. The method according to claim 32, characterized in that, The drying process is vacuum drying.

83. The method according to claim 32, characterized in that, The drying temperature is 85℃~95℃.

84. The method according to claim 83, characterized in that, The drying temperature is 85.5~94.5℃.

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