A process for the synthesis of 2-chloronicotinic acid

Abstract

This application relates to the technical field of organic synthesis, specifically disclosing a synthesis process for 2-chloronicotinic acid. The synthesis process for 2-chloronicotinic acid includes the following steps: S1: Water, concentrated sulfuric acid, 3-cyanopyridine, and a composite catalyst are mixed, pre-reacted, and then hydrogen peroxide is added. After oxidation, the pH is adjusted, solid-liquid separation is performed, and the mixture is washed to obtain an oxide intermediate; S2: Under an inert atmosphere, phosphorus oxychloride is added to a reactor, along with the oxide intermediate and triethylamine, to perform a chlorination reaction. After the reaction, phosphorus oxychloride is recovered, and the remaining material is hydrolyzed, followed by solid-liquid separation and washing to obtain a chloride; S3: The chloride is subjected to alkali dissolution, neutralization, decolorization, and acid precipitation, followed by solid-liquid separation and washing. This is repeated with a second alkali dissolution, neutralization, second decolorization, addition of a complexing agent, and second acid precipitation, followed by solid-liquid separation, washing, drying, and pulverization to obtain 2-chloronicotinic acid. The 2-chloronicotinic acid obtained in this application has high purity and yield.

Description

Technical Field

[0001] This application relates to the field of organic synthesis, and more specifically, to a process for synthesizing 2-chloronicotinic acid. Background Technology

[0002] Currently, in the fields of pharmaceutical and pesticide chemistry, 2-chloronicotinic acid, as a key intermediate in the synthesis of various important active molecules, is experiencing continuous market demand growth. It is not only a core component in the preparation of broad-spectrum herbicides such as nicosulfuron and pyraclostrobin, but also a key starting material for the synthesis of anti-AIDS drugs such as nevirapine. However, the industrial synthesis of this compound has long faced challenges stemming from the interplay of yield, purity, and production cost, becoming a technological bottleneck restricting the improvement of quality and efficiency in related industrial chains.

[0003] Existing technologies mainly focus on the oxidation-chlorination route of 3-cyanopyridine, but each route has significant shortcomings. Patent application CN101117332A discloses a method for preparing 2-chloronicotinic acid, the steps of which are as follows: 3-cyanopyridine is reacted with water as a solvent in the presence of a highly efficient oxidizing catalyst, molybdenum acetylacetonate, and 20%~30% H2O2 is added dropwise. After the addition is complete, the mixture is kept at a constant temperature to ensure complete oxidation. Then, some water is recovered, followed by cooling, standing, filtration, and drying to obtain nicotinamide N-oxide. Under an anhydrous reaction environment and nitrogen positive pressure protection, nicotinamide N-oxide is cooled to between -10 and 10°C, diluted with a haloalkane solvent, and then an organic base acting as an acid-binding agent is added dropwise between -10 and 10°C. The mixture reacts with a chlorinating agent in the presence of a phosphonodichloride catalyst. The solvent and chlorinating agent are then recovered, followed by hydrolysis. The solution is adjusted to neutral with an alkali, filtered, and dried to obtain 2-chloro-3-cyanopyridine. 2-chloro-3-cyanopyridine is then hydrolyzed with a strong alkali aqueous solution, filtered, and dried to obtain 2-chloronicotinic acid.

[0004] In this technical solution, the homogeneous molybdenum catalyst used in the oxidation step is difficult to completely separate after the reaction, which easily leads to metal ions remaining in the intermediates and final products, affecting the purity of the product. In addition, the chlorination step is maintained at a low temperature throughout to ensure selectivity, resulting in slow reaction kinetics and incomplete conversion of the key chlorination reaction. This not only limits the improvement of yield, but the incompletely converted intermediates also easily affect the purity of the final product. Summary of the Invention

[0005] To further improve the purity and yield of 2-chloronicotinic acid, this application provides a synthesis process for 2-chloronicotinic acid.

[0006] This application provides a synthesis process for 2-chloronicotinic acid, employing the following technical solution:

[0007] A process for synthesizing 2-chloronicotinic acid includes the following steps:

[0008] S1: Oxidation:

[0009] After mixing water, concentrated sulfuric acid, 3-cyanopyridine and the composite catalyst, a pre-reaction was performed, followed by the addition of hydrogen peroxide. After oxidation, the pH was adjusted to 4.5-5.0, and the solid and liquid phases were separated and washed to obtain an oxide intermediate. The composite catalyst was prepared by amylating silica gel, modifying it with niobium salt, and then loading it with phosphotungstic acid.

[0010] S2: Chlorination and hydrolysis:

[0011] Phosphorus oxychloride was added to the reactor under an inert atmosphere, along with an oxide intermediate and triethylamine, to carry out a chlorination reaction. The chlorination reaction was controlled by a programmed temperature rise. After the reaction was completed, phosphorus oxychloride was recovered, and the remaining material was hydrolyzed, followed by solid-liquid separation, washing, and the chloride was obtained.

[0012] S3: Deamination and purification: The chloride is subjected to alkaline dissolution deamination reaction at a temperature of 90~98℃ for 2.5~3.5h. After neutralization, decolorization, and acid precipitation, the solid and liquid are separated and washed to obtain crude 2-chloronicotinic acid.

[0013] The crude product was subjected to a second alkaline dissolution at a temperature of 45-55℃, followed by neutralization, a second decolorization, the addition of a complexing agent, and a second acid precipitation. After solid-liquid separation, washing, drying, and pulverization, 2-chloronicotinic acid was obtained.

[0014] In this technical solution, aminated silica gel provides stable binding sites for niobium salt and phosphotungstic acid. Niobium salt and phosphotungstic acid form a synergistic catalytic system, enhancing the selective oxidation of 3-cyanopyridine by hydrogen peroxide to generate a high-purity oxide intermediate. The chlorination step precisely matches the chlorination reaction kinetics through programmed temperature rise, avoiding excessive local reactions that lead to polychlorinated byproducts. The purification step first uses high-temperature strong alkali dissolution to simultaneously complete the complete hydrolysis and deammoniation of chloride and crude impurity removal. Then, a low-temperature mild secondary alkali dissolution at 45~55℃ completely dissolves the crude product. The pH value of the system is precisely controlled by neutralization to optimize the impurity removal environment, deeply removing residual organic pigments and trace organic impurities through adsorption. A complexing agent is added to chelate and remove metal ion impurities in the system. Finally, the precipitation process of the target product is precisely controlled through secondary acid precipitation to further remove residual trace impurities, achieving deep purification of 2-chloronicotinic acid and obtaining a high-purity finished product.

[0015] Preferably, the mass ratio of water, concentrated sulfuric acid, 3-cyanopyridine, composite catalyst and hydrogen peroxide is (18~22):(2.8~3.2):100:(0.6~0.8):(95~100).

[0016] Preferably, the hydrogen peroxide has a mass fraction of 30% to 35%.

[0017] Preferably, the mass ratio of phosphorus oxychloride, oxide intermediate and triethylamine is (110~130):20:(11~13).

[0018] Preferably, the preparation method of the composite catalyst includes the following steps:

[0019] S11: After calcining the silicone, it is amination to obtain amination silicone;

[0020] S12: Mix aminated silica gel with an oxalic acid aqueous solution of niobium salt at a solid-liquid ratio of 1g:(0.5~0.6)mL, let stand, dry, calcine, then impregnate in phosphotungstic acid solution, mix at 40~50℃ for 6~8h, separate solid and liquid, wash, dry, and obtain composite catalyst.

[0021] In this technical solution, silica gel is first calcined to remove surface adsorbed water and impurities, and the surface silanol groups are activated to provide reaction sites for subsequent amination. After amination, the amino groups introduced on the silica gel surface can combine with the oxalic acid complex anions of niobium through electrostatic interaction to achieve stable loading of niobium salt, while providing anchoring sites for the immobilization of phosphotungstic acid. After modification, the niobium salt is calcined to form stable niobium oxide active sites, which form a synergistic catalytic system with the subsequently impregnated phosphotungstic acid to improve the activity and selectivity of the oxidation reaction.

[0022] Preferably, the amination specifically involves: calcining silica gel, uniformly dispersing it in an ethanol-water solution containing 3% to 5% aminosilane by mass, adjusting the pH to 4.0 to 4.5, heating to 55 to 65°C, reacting for 3 to 5 hours, cooling, centrifuging, drying, and storing for later use.

[0023] Preferably, in the oxalic acid aqueous solution of the niobium salt, the mass fraction of the niobium salt is 5% to 7%, and the mass fraction of the oxalic acid is 1% to 1.5%.

[0024] Preferably, the phosphotungstic acid solution has a mass fraction of 10% to 12%.

[0025] Preferably, in step S12, the roasting temperature is 450~500℃ and the time is 2~3h.

[0026] Preferably, in step S1, the pre-reaction conditions are: heating to 55~65℃ and reacting for 50~70 minutes.

[0027] Preferably, in step S1, the oxidation reaction conditions are: heating to 60~70℃ and reacting for 12~14 hours.

[0028] Preferably, in step S2, when adding the oxide intermediate and triethylamine, the temperature inside the reactor is controlled to be no higher than 25°C.

[0029] More preferably, in step S2, when the oxide intermediate and triethylamine are added, the temperature inside the reactor is controlled to be 8~10°C.

[0030] In this technical solution, the low-temperature environment can significantly reduce the complexation reaction rate of triethylamine and phosphorus oxychloride, allowing the active chlorinating agent to be generated slowly and ensuring the orderly progress of the main reaction. Simultaneously, it can effectively inhibit the formation of polychlorinated byproducts and improve the selectivity of the chlorination reaction.

[0031] Preferably, in step S2, the chlorination reaction is controlled by programmed temperature rise as follows: first, at 20~25℃, hold for 30~35 min, then rise to 50℃~60℃, hold for 4~6 h, then continue to rise to 70~80℃, hold for 50~70 min, then rise to 90~98℃, hold for 3~5 h.

[0032] In this technical solution, the low-temperature stage safely initiates the reaction and controls the exothermic reaction, the intermediate-temperature stage ensures the main reaction proceeds fully, and the final high-temperature stage ensures the complete reaction and prepares for subsequent steps. This programmed temperature rise system systematically manages the reaction kinetics and thermal effects, which is a key process guarantee for obtaining high chlorination rates and high product purity.

[0033] Preferably, in step S2, the hydrolysis temperature is 45~55℃, and the hydrolysis time is 1~2 hours.

[0034] Preferably, in step S3, both the alkali dissolution and the secondary alkali dissolution use liquid alkali with a mass fraction of 28% to 30%.

[0035] Preferably, in step S3, the mass ratio of water to liquid alkali in the alkali dissolution is 20:(6~6.5).

[0036] Preferably, in step S3, during the secondary alkaline dissolution, liquid alkali is used to adjust the pH of the system to 7.5~8.0.

[0037] Preferably, in step S3, activated carbon is used in both the decolorization and the secondary decolorization.

[0038] Preferably, in step S3, the temperature is set to 85~95℃ during the decolorization and secondary decolorization.

[0039] Preferably, in step S3, the mass ratio of activated carbon to chloride in both the decolorization and secondary decolorization is (0.11~0.13):1.

[0040] Preferably, in step S3, the complexing agent is disodium ethylenediaminetetraacetate, and the mass ratio of disodium ethylenediaminetetraacetate to chloride is (0.003~0.005):1.

[0041] In this technical solution, disodium ethylenediaminetetraacetate is added after the secondary decolorization. The mechanism is that disodium ethylenediaminetetraacetate reacts with the trace metal ions remaining in the solution to generate a stable water-soluble complex, which further reduces the content of metal impurities in the finished product and improves the chemical purity, long-term stability and appearance quality of 2-chloronicotinic acid.

[0042] Preferably, in step S3, both the acid precipitation and the secondary acid precipitation use hydrochloric acid with a mass fraction of 35% to 37% to adjust the pH of the system to 1.5 to 2.0.

[0043] This technical solution utilizes the characteristic that the target product 2-chloronicotinic acid has the lowest solubility near its isoelectric point, enabling it to crystallize efficiently while retaining most water-soluble impurities in the mother liquor, thus improving the purity and yield of the final product.

[0044] Preferably, in step S2, after phosphorus oxychloride, the step of adding N,N-dimethylformamide is also included.

[0045] Preferably, in step S2, the mass ratio of N,N-dimethylformamide to the oxide intermediate is (0.05~0.1):1.

[0046] In this technical solution, the highly active chlorinated imine salt intermediate generated by combining N,N-dimethylformamide and phosphorus oxychloride significantly improves the chlorination efficiency and selectivity.

[0047] Preferably, in step S2, after phosphorus oxychloride, the step of adding phenylphosphonic dichloride is also included.

[0048] Preferably, in step S2, the mass ratio of phenylphosphonic dichloride to the oxide intermediate is (0.05~0.1):1.

[0049] In this technical solution, the phosphoryl group in the phenylphosphonic dichloride molecule can form a synergistic effect with phosphorus oxychloride to enhance the chlorination activity of the system. At the same time, the steric hindrance effect of phenylphosphonic dichloride can further suppress polychlorination side reactions.

[0050] In summary, this application has the following beneficial effects:

[0051] In the oxidation stage, this application employs a composite catalyst, which reduces the risk of metal residue and significantly improves the selectivity and conversion rate of 3-cyanopyridine oxidation, providing a high-purity intermediate for subsequent steps. In the chlorination and hydrolysis stages, programmed temperature control significantly improves the rate and conversion rate of the chlorination reaction while maintaining good selectivity, thereby increasing the yield. In the purification stage, a series of purification processes, supplemented by disodium ethylenediaminetetraacetate complexation for impurity removal, can progressively and thoroughly remove various impurities such as organic pigments, isomers, and trace metal ions. Attached Figure Description

[0052] Figure 1 This is a high-performance liquid chromatogram of 2-chloronicotinic acid prepared in Example 1 of this application;

[0053] Figure 2 This is a high-performance liquid chromatogram of 2-chloronicotinic acid prepared in Example 4 of this application;

[0054] Figure 3 This is a high-performance liquid chromatogram of 2-chloronicotinic acid prepared in Example 5 of this application;

[0055] Figure 4 The high-performance liquid chromatogram of 2-chloronicotinic acid standard. Detailed Implementation

[0056] The present application will be further described in detail below with reference to the embodiments.

[0057] Unless otherwise specified, the raw materials used in the embodiments and comparative examples of this application are all commercially available.

[0058] Special note: In the following examples, when using phosphorus oxychloride, it is necessary to ensure that the entire process is carried out in an anhydrous environment.

[0059] Preparation of composite catalysts in Examples 1-2

[0060] Preparation Example 1

[0061] The preparation method of the composite catalyst in this example includes the following steps:

[0062] S11: Place the silica gel in a sintering apparatus, heat it to 500℃ at a rate of 5℃ / min, keep it at that temperature for 4 hours, cool it naturally to room temperature, add 3% (w / w) of an ethanol aqueous solution of 3-aminopropyltriethoxysilane, ultrasonically disperse it for 30 minutes (300W / 40kHz), adjust the pH to 4.5, heat it to 55℃, react for 5 hours, cool it to room temperature, filter it, wash it three times with anhydrous ethanol, and vacuum dry it at 110℃ and -0.09MPa to constant weight to obtain amino-modified silica gel.

[0063] S12: Aminated silica gel was mixed evenly with a 5% (w / w) aqueous solution of niobium oxalate in oxalic acid at a solid-liquid ratio of 1g:0.5mL. After standing at 25℃ for 2h, it was dried at 120℃ for 4h. The temperature was then increased to 450℃ at a rate of 3℃ / min and calcined for 3h. After cooling to room temperature, it was impregnated in a 10% (w / w) phosphotungstic acid solution at a solid-liquid ratio of 1g:5mL. The temperature was increased to 50℃ and stirred for 6h. After filtration, it was washed twice with a small amount of deionized water and dried at 100℃ for 6h to obtain the composite catalyst.

[0064] The silica gel has a particle size distribution of 200-300 mesh and a specific surface area of ​​300-500 m².2 / g; In the ethanol-water solution, the volume ratio of ethanol to water is 95:5; The mass fraction of oxalic acid in the aqueous solution is 1%.

[0065] Preparation Example 2

[0066] The preparation method of the composite catalyst in this example includes the following steps:

[0067] The silica gel was placed in a sintering apparatus and heated to 500°C at a rate of 5°C / min. It was then calcined at this temperature for 4 hours and allowed to cool naturally to room temperature. A 5% (w / w) aqueous solution of 3-aminopropyltriethoxysilane in ethanol was added, and the mixture was ultrasonically dispersed for 30 minutes (300W / 40kHz). The pH was adjusted to 4.0, and the temperature was raised to 65°C. The reaction was carried out for 3 hours. After cooling to room temperature, the mixture was filtered, washed three times with anhydrous ethanol, and vacuum dried at 110°C and -0.09MPa to constant weight to obtain amino-modified silica gel.

[0068] Aminated silica gel was mixed evenly with a 7% (w / w) aqueous solution of niobium oxalate in oxalic acid at a solid-liquid ratio of 1 g: 0.5 mL. After standing at 30 °C for 1.5 h, it was dried at 120 °C for 4 h, heated to 500 °C at a rate of 3 °C / min, calcined for 2 h, cooled to room temperature, and then impregnated in a 12% (w / w) phosphotungstic acid solution at a solid-liquid ratio of 1 g: 5 mL. The mixture was heated to 40 °C and stirred for 8 h. After filtration, it was washed twice with a small amount of deionized water and dried at 100 °C for 6 h to obtain the composite catalyst.

[0069] The silica gel has a particle size distribution of 200-300 mesh and a specific surface area of ​​300-500 m². 2 / g; In the ethanol-water solution, the volume ratio of ethanol to water is 95:5; The mass fraction of oxalic acid in the aqueous solution is 1.5%.

[0070] Example 1

[0071] The synthesis process of 2-chloronicotinic acid in this embodiment includes the following steps:

[0072] S1: Add 200 kg of water, 30 kg of 98% concentrated sulfuric acid, 1000 kg of 3-cyanopyridine, and 7.0 kg of the composite catalyst from Preparation Example 1 to an oxidation reactor. Stir and slowly heat to 60°C, maintain the temperature for 60 min, add 960 kg of 35% hydrogen peroxide dropwise in two batches, heat to 65°C, maintain the temperature for 13 h, cool to 20°C, adjust the pH to 4.5 with 52.5% potassium carbonate solution, filter, centrifuge, wash with water, and vacuum dry to obtain the oxide intermediate.

[0073] S2: Under a nitrogen atmosphere, 1200 kg of phosphorus oxychloride was vacuum-pumped into a reactor. The reactor temperature was controlled at 9±1℃ using a jacketed chilled brine solution. Then, 200 kg of oxide intermediate was added, followed by the slow addition of 120 kg of triethylamine, maintaining the system temperature at 10℃. After the addition was complete, the mixture was kept at 25℃ for 30 minutes and then transferred by gravity to a chlorination reactor. The tail gas absorption device was activated, and the mixture was heated for approximately 2 minutes. Once the material began to react, the steam temperature was controlled at 55℃ for 5 hours, then at 75℃ for 60 minutes, and at 95℃ for 4 hours. After the reaction was complete, the vacuum was slowly opened, and phosphorus oxychloride was recovered by vacuum distillation. After recovery, the remaining material was transferred to a water washing vessel by gravity while still hot. Water, twice the volume of the material, was added at once for hydrolysis at approximately 50℃ for 1.5 hours. The mixture was then cooled to 15℃, centrifuged, and washed twice with water to obtain chloride.

[0074] S3: Add 2000 kg of water to the alkali dissolving kettle, then slowly add 620 kg of 30% liquid alkali. After mixing evenly, add 162 kg of chloride, start stirring, heat to 95℃, keep warm for 3 hours, cool down to 90℃, then adjust the pH to 7.5 with 37% hydrochloric acid, add 20 kg of activated carbon, stir and mix for 15 minutes, let stand for 30 minutes, filter, transfer the filter residue to the activated carbon washing kettle for washing and recovery, transfer the filtrate to the acid precipitation kettle, cool down to 70℃, adjust the pH to 1.5 with 37% hydrochloric acid, cool down to 30℃, retest the pH. If the pH is higher than 1.5, continue to add 37% hydrochloric acid until the pH is 1.5, centrifuge, wash with water, and obtain the crude product.

[0075] Add 2000 kg of water to the alkali dissolution vessel, then add the crude product. Heat to 50°C, slowly add 30% (w / w) liquid alkali, adjust to pH 7.5, continue heating to 90°C, add 20 kg of activated carbon, maintain the temperature for decolorization for 15 min, let stand for 30 min, filter, transfer the filter residue to the activated carbon washing vessel for washing and recovery, add 0.65 kg of disodium ethylenediaminetetraacetate to the filtrate, stir and mix for 10 min, transfer the filtrate to the acid precipitation vessel, cool to 70°C, adjust the pH to 1.5 with 37% (w / w) hydrochloric acid, cool to 30°C, retest the pH. If the pH is higher than 1.5, continue adding 37% (w / w) hydrochloric acid until the pH is 1.5, centrifuge, wash with water, and dry to obtain 2-chloronicotinic acid.

[0076] Tests showed that 2-chloronicotinic acid appeared as a white crystalline powder with a purity of 99.895%, a yield of 96.1%, a melting point of 178℃, and a 6-chloronicotinic acid content of ≤0.20%.

[0077] Example 2

[0078] The synthesis process of 2-chloronicotinic acid in this embodiment includes the following steps:

[0079] S1: 180 kg of water, 28 kg of 98% concentrated sulfuric acid, 1000 kg of 3-cyanopyridine, and 6.0 kg of the composite catalyst from Preparation Example 2 were added to an oxidation reactor. The mixture was stirred and slowly heated to 55°C and kept at that temperature for 70 min. 950 kg of 35% hydrogen peroxide was added dropwise in three portions. The temperature was raised to 60°C and kept at that temperature for 14 h. The temperature was then lowered to 20°C. The pH was adjusted to 5.0 using a 52.5% potassium carbonate solution. After filtration, the mixture was centrifuged, washed with water, and vacuum dried to obtain the oxide intermediate.

[0080] S2: Under a nitrogen atmosphere, 1100 kg of phosphorus oxychloride was vacuum-pumped into a reactor. When the reactor temperature was controlled at 9±1℃ using a jacketed chilled brine, 200 kg of oxide intermediate was added, followed by the slow addition of 110 kg of triethylamine. During this process, the system temperature was controlled at 10℃. After the addition was completed, the mixture was kept at 20℃ for 35 min and then transferred to a chlorination reactor by gravity. After the tail gas absorption device was turned on, the mixture was heated for about 2 min. After the material started to react, the steam temperature was controlled at 50℃ and kept at that temperature for 6 h. Then, the steam temperature was controlled at 70℃ and kept at that temperature for 70 min. Finally, the steam temperature was controlled at 90℃ and kept at that temperature for 5 h. After the reaction was completed, the vacuum was slowly turned on, and the mixture was distilled under reduced pressure to recover phosphorus oxychloride. After the recovery was completed, the remaining material was transferred to a water washing vessel while still hot by gravity flow. Water with a volume twice that of the material was added at once for hydrolysis. The hydrolysis temperature was about 45℃ and the hydrolysis was carried out for 2 h. The mixture was then cooled to 15℃, centrifuged, and washed twice with water to obtain chloride.

[0081] S3: Add 2000 kg of water to the alkali dissolving kettle, then slowly add 600 kg of 30% liquid alkali. After mixing evenly, add 160 kg of chloride, start stirring, heat to 90℃, keep at that temperature for 3.5 h, cool down to 85℃, then adjust the pH to 7.5 using 35% hydrochloric acid, add 18 kg of activated carbon, stir and mix for 15 min, let stand for 30 min, filter, transfer the filter residue to the activated carbon washing kettle for washing and recovery, transfer the filtrate to the acid precipitation kettle, cool down to 70℃, adjust the pH to 2.0 using 35% hydrochloric acid, cool down to 30℃, retest the pH. If the pH is higher than 2.0, continue to add 35% hydrochloric acid until the pH is 2.0, centrifuge, wash with water, and obtain the crude product.

[0082] Add 2000 kg of water to the alkali dissolution vessel, then add the crude product. Heat to 45°C, slowly add 30% (w / w) liquid alkali, adjust to pH 7.5, continue heating to 85°C, add 18 kg of activated carbon, maintain the temperature for decolorization for 15 min, let stand for 30 min, filter, transfer the filter residue to the activated carbon washing vessel for washing and recovery, add 0.5 kg of disodium ethylenediaminetetraacetate to the filtrate, stir and mix for 10 min, transfer the filtrate to the acid precipitation vessel, cool to 70°C, adjust the pH to 2.0 with 35% (w / w) hydrochloric acid, cool to 30°C, retest the pH. If the pH is higher than 2.0, continue adding 35% (w / w) hydrochloric acid until the pH is 2.0, centrifuge, wash with water, and dry to obtain 2-chloronicotinic acid.

[0083] Testing revealed that 2-chloronicotinic acid appears as a white crystalline powder with a purity of 99.872%, a yield of 95.8%, a melting point of 176℃, and a 6-chloronicotinic acid content of ≤0.20%.

[0084] Example 3

[0085] The synthesis process of 2-chloronicotinic acid in this embodiment includes the following steps:

[0086] S1: 220 kg of water, 32 kg of 98% concentrated sulfuric acid, 1000 kg of 3-cyanopyridine, and 8.0 kg of the composite catalyst from Preparation Example 2 were added to an oxidation reactor. The mixture was stirred and slowly heated to 65°C and kept at that temperature for 50 min. 1000 kg of 30% hydrogen peroxide was added dropwise in three portions. The temperature was raised to 70°C and kept at that temperature for 12 h. The temperature was then lowered to 20°C. The pH was adjusted to 4.5 using a 52.5% potassium carbonate solution. After filtration, the mixture was centrifuged, washed with water, and vacuum dried to obtain the oxide intermediate.

[0087] S2: Under a nitrogen atmosphere, 1300 kg of phosphorus oxychloride was vacuum-pumped into a reactor. When the reactor temperature was controlled at 9±1℃ using a jacketed chilled brine, 200 kg of oxide intermediate was added, followed by the slow addition of 130 kg of triethylamine. During this process, the system temperature was controlled at 10℃. After the addition was completed, the mixture was kept at 25℃ for 35 min and then transferred to a chlorination reactor by gravity. After the tail gas absorption device was turned on, the mixture was heated for about 2 min. After the material began to react, the steam temperature was controlled at 60℃ and kept at 4 h. Then, the steam temperature was controlled at 80℃ and kept at 50 min. Finally, the steam temperature was controlled at 98℃ and kept at 3 h. After the reaction was completed, the vacuum was slowly turned on, and phosphorus oxychloride was recovered by vacuum distillation. After the recovery was completed, the remaining material was put into a water washing vessel while still hot by gravity flow. Water with a volume twice that of the material was added at once for hydrolysis. The hydrolysis temperature was about 55℃ and the hydrolysis was carried out for 1 h. The mixture was then cooled to 15℃, centrifuged, and washed twice with water to obtain chloride.

[0088] S3: Add 2000 kg of water to the alkali dissolving kettle, then slowly add 650 kg of 28% liquid alkali. After mixing evenly, add 163 kg of chloride, start stirring, heat to 98℃, keep at that temperature for 2.5 h, cool to 95℃, then adjust the pH to 7.5 using 37% hydrochloric acid. Add 21 kg of activated carbon, stir and mix for 15 min, let stand for 30 min, filter, transfer the filter residue to the activated carbon washing kettle for washing and recovery, transfer the filtrate to the acid precipitation kettle, cool to 70℃, adjust the pH to 1.5 using 37% hydrochloric acid, cool to 30℃, retest the pH. If the pH is higher than 1.5, continue to add 37% hydrochloric acid until the pH is 1.5, centrifuge, wash with water, and obtain the crude product.

[0089] Add 2000 kg of water to the alkali dissolution vessel, then add the crude product. Heat to 45°C, slowly add 30% (w / w) liquid alkali, adjust to pH 8.0, continue heating to 95°C, add 21 kg of activated carbon, maintain the temperature for decolorization for 15 min, let stand for 30 min, filter, transfer the filter residue to the activated carbon washing vessel for washing and recovery, add 0.8 kg of disodium ethylenediaminetetraacetate to the filtrate, stir and mix for 10 min, transfer the filtrate to the acid precipitation vessel, cool to 70°C, adjust the pH to 1.5 with 37% (w / w) hydrochloric acid, cool to 30°C, retest the pH. If the pH is higher than 1.5, continue adding 37% (w / w) hydrochloric acid until the pH is 1.5, centrifuge, wash with water, and dry to obtain 2-chloronicotinic acid.

[0090] Testing revealed that 2-chloronicotinic acid appears as a white crystalline powder with a purity of 99.880%, a yield of 95.9%, a melting point of 177℃, and a 6-chloronicotinic acid content of ≤0.20%.

[0091] Example 4

[0092] The difference between this embodiment and Embodiment 1 is that:

[0093] S2: Under a nitrogen atmosphere, 1200 kg of phosphorus oxychloride was vacuum-pumped into a reactor. The reactor temperature was controlled at 9±1℃ using a jacketed chilled brine solution. Then, 10 kg of N,N-dimethylformamide and 200 kg of oxide intermediate were added, followed by the slow addition of 120 kg of triethylamine, maintaining the system temperature at 10℃. After the addition was complete, the mixture was kept at 25℃ for 30 minutes and then transferred by gravity to a chlorination reactor. The tail gas absorption device was activated, and the mixture was heated for approximately 2 minutes. Once the reaction began, the steam temperature was controlled at 55℃ for 5 hours, then at 75℃ for 60 minutes, and at 95℃ for 4 hours. After the reaction was complete, the vacuum was slowly opened, and phosphorus oxychloride was recovered by vacuum distillation. After recovery, the remaining material was transferred to a water washing vessel by gravity while still hot. Water, twice the volume of the material, was added at once for hydrolysis at approximately 50℃ for 1.5 hours. The mixture was then cooled to 15℃, centrifuged, and washed twice to obtain chloride.

[0094] Everything else is the same as in Example 1.

[0095] Testing revealed that 2-chloronicotinic acid appears as a white crystalline powder with a purity of 99.916%, a yield of 96.3%, a melting point of 178℃, and a 6-chloronicotinic acid content of ≤0.18%.

[0096] Example 5

[0097] The difference between this embodiment and Embodiment 1 is that:

[0098] S2: Under a nitrogen atmosphere, 1200 kg of phosphorus oxychloride was vacuum-pumped into the reactor. Using a jacketed chilled brine system to control the reactor temperature at 9±1℃, 10 kg of phenylphosphonic dichloride, 10 kg of N,N-dimethylformamide, and 200 kg of oxide intermediate were added. Then, 120 kg of triethylamine was slowly added dropwise, maintaining the system temperature at 10℃ throughout. After the addition was complete, the mixture was kept at 25℃ for 30 minutes. The mixture was then transferred by gravity to a chlorination reactor. The tail gas absorption device was then activated, and the mixture was heated for approximately [time missing]. After 2 minutes, once the material begins to react, the steam temperature is controlled at 55℃ and maintained for 5 hours. Then, the steam temperature is controlled at 75℃ and maintained for 60 minutes. Finally, the steam temperature is controlled at 95℃ and maintained for 4 hours. After the reaction is complete, the vacuum is slowly opened, and the material is distilled under reduced pressure to recover phosphorus oxychloride. After recovery, the remaining material is transferred to a water washing vessel by gravity while still hot. Water with a volume twice that of the material is added at once for hydrolysis. The hydrolysis temperature is approximately 50℃, and the hydrolysis lasts for 1.5 hours. The temperature is then lowered to 15℃, and the material is centrifuged and washed twice with water to obtain chloride.

[0099] Everything else is the same as in Example 1.

[0100] Testing revealed that 2-chloronicotinic acid appears as a white crystalline powder with a purity of 99.919%, a yield of 96.4%, a melting point of 178℃, and a 6-chloronicotinic acid content of ≤0.15%.

[0101] Example 6

[0102] The difference between this embodiment and Embodiment 1 is that:

[0103] S2: Under a nitrogen atmosphere, 1200 kg of phosphorus oxychloride was vacuum-pumped into the reactor. Using a jacketed chilled brine system to control the reactor temperature at 9±1℃, 20 kg of phenylphosphonic dichloride, 20 kg of N,N-dimethylformamide, and 200 kg of oxide intermediate were added. Then, 120 kg of triethylamine was slowly added dropwise, maintaining the system temperature at 10℃ throughout. After the addition was complete, the mixture was kept at 25℃ for 30 minutes. The mixture was then transferred by gravity to a chlorination reactor. The tail gas absorption device was then activated, and the mixture was heated for approximately [time missing]. After 2 minutes, once the material begins to react, the steam temperature is controlled at 55℃ and maintained for 5 hours. Then, the steam temperature is controlled at 75℃ and maintained for 60 minutes. Finally, the steam temperature is controlled at 95℃ and maintained for 4 hours. After the reaction is complete, the vacuum is slowly opened, and the material is distilled under reduced pressure to recover phosphorus oxychloride. After recovery, the remaining material is transferred to a water washing vessel by gravity while still hot. Water with a volume twice that of the material is added at once for hydrolysis. The hydrolysis temperature is approximately 50℃, and the hydrolysis lasts for 1.5 hours. The temperature is then lowered to 15℃, and the material is centrifuged and washed twice with water to obtain chloride.

[0104] Everything else is the same as in Example 1.

[0105] Tests showed that 2-chloronicotinic acid appeared as a white crystalline powder with a purity of 99.925%, a yield of 97.0%, a melting point of 178℃, and a 6-chloronicotinic acid content of ≤0.15%.

[0106] Table 1. Peaks corresponding to the high-performance liquid chromatograms of 2-chloronicotinic acid prepared in Example 1

[0107]

[0108] Table 2. Peaks corresponding to the high-performance liquid chromatograms of 2-chloronicotinic acid prepared in Example 5.

[0109]

[0110] Table 3. Peaks corresponding to the high performance liquid chromatograms of 2-chloronicotinic acid standards.

[0111]

[0112] Combine Tables 1 to 3, Figures 1-4The test data from Examples 1-6 show that this process achieves a dual improvement in the quality and yield of 2-chloronicotinic acid. By fine-tuning the composite catalyst and process parameters in each step of oxidation, chlorination, and purification, key indicators such as product purity, yield, and melting point are stabilized at excellent levels, laying a solid foundation for the process. The introduction of a single auxiliary agent, N,N-dimethylformamide, in the chlorination step improves product purity, reduces major impurities, and initially improves the yield. Furthermore, the combined use of phenylphosphonic dichloride and N,N-dimethylformamide leverages their synergistic effect. Based on this optimization, the overall effect of the chlorination reaction is enhanced, product purity and yield are continuously optimized, and impurities are further suppressed. By optimizing the dosage of the composite auxiliary agent, the yield is significantly improved, purity is maintained at a higher level, the content of major impurities is reduced to a lower range, and the product melting point remains stable.

[0113] Among them, reference Figure 4 The high-performance liquid chromatography (HPLC) chromatogram of the 2-chloronicotinic acid standard is shown below. Figures 1-3 The retention time of the main peak of the 2-chloronicotinic acid sample prepared in the corresponding examples was basically the same as that of the standard sample, with no obvious impurity peaks. Combined with the main peak area ratio in Tables 1 and 2, it was confirmed that the high-purity target product 2-chloronicotinic acid was successfully obtained in each example.

[0114] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A process for the synthesis of 2-chloronicotinic acid, characterized in that, Includes the following steps: S1: Oxidation: Water, concentrated sulfuric acid, 3-cyanopyridine, and the composite catalyst are mixed and pre-reacted. Hydrogen peroxide is added, and after oxidation, the pH is adjusted to 4.5-5.

0. Solid-liquid separation and washing are performed to obtain the oxide intermediate. The composite catalyst is prepared by amylating silica gel, modifying it with niobium salt, and then loading it with phosphotungstic acid. The pre-reaction conditions are: heating to 55-65℃ and reacting for 50-70 min; the oxidation reaction conditions are: heating to 60-70℃ and reacting for 12-14 h. The preparation method of the composite catalyst includes the following steps: S11: After calcining silica gel, amination is performed to obtain amination silica gel; the amination is specifically performed by calcining silica gel, uniformly dispersing it in an ethanol aqueous solution with a mass fraction of 3%~5% aminosilane, adjusting the pH to 4.0~4.5, heating to 55~65℃, reacting for 3~5h, cooling, centrifuging, drying, and setting aside; S12: Mixing the amination silica gel with an oxalic acid aqueous solution of niobium salt at a solid-liquid ratio of 1g:(0.5~0.6)mL, allowing it to stand, drying, calcining, and then impregnating it in a phosphotungstic acid solution, mixing at 40~50℃ for 6~8h, separating the solid and liquid, washing, and drying to obtain the composite catalyst; in the oxalic acid aqueous solution of niobium salt, the mass fraction of niobium salt is 5%~7%, and the mass fraction of oxalic acid is 1%~1.5%; S2: Chlorination and hydrolysis: Under an inert atmosphere, phosphorus oxychloride is added to the reactor, along with an oxide intermediate and triethylamine, to carry out a chlorination reaction. The chlorination reaction is controlled by programmed temperature rise. After the reaction is completed, phosphorus oxychloride is recovered, and the remaining material is hydrolyzed, followed by solid-liquid separation, washing, and the chloride is obtained. The chlorination reaction is controlled by a programmed temperature rise as follows: first, hold at 20~25℃ for 30~35 min, then raise the temperature to 50℃~60℃ and hold for 4~6 h, then continue to raise the temperature to 70~80℃ and hold for 50~70 min, then raise the temperature to 90~98℃ and hold for 3~5 h. S3: Deamination and purification: The chloride is subjected to alkaline dissolution deamination reaction at a temperature of 90~98℃ for 2.5~3.5h. After neutralization, decolorization, and acid precipitation, the solid and liquid are separated and washed to obtain crude 2-chloronicotinic acid. The crude product was subjected to a second alkaline dissolution at a temperature of 45-55℃, followed by neutralization, a second decolorization, the addition of a complexing agent, and a second acid precipitation. After solid-liquid separation, washing, drying, and pulverization, 2-chloronicotinic acid was obtained.

2. The synthesis process of 2-chloronicotinic acid according to claim 1, characterized in that, The mass ratio of water, concentrated sulfuric acid, 3-cyanopyridine, composite catalyst and hydrogen peroxide is (18~22):(2.8~3.2):100:(0.6~0.8):(95~100).

3. The synthesis process of 2-chloronicotinic acid according to claim 1, characterized in that, The mass ratio of phosphorus oxychloride, oxide intermediate and triethylamine is (110~130):20:(11~13).

4. The synthesis process of 2-chloronicotinic acid according to claim 1, characterized in that, In step S2, when adding the oxide intermediate and triethylamine, the temperature inside the reactor is controlled to be no higher than 25°C.

5. The synthesis process of 2-chloronicotinic acid according to claim 1, characterized in that, In step S3, the complexing agent is disodium ethylenediaminetetraacetate, and the mass ratio of disodium ethylenediaminetetraacetate to chloride is (0.003~0.005):

1.

6. The synthesis process of 2-chloronicotinic acid according to claim 1, characterized in that, In step S2, after phosphorus oxychloride, there is also a step of adding N,N-dimethylformamide.

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