Process for synthesizing high-efficiency catalytic nicosulfuron nicotinamide intermediate

Abstract

This invention discloses a highly efficient catalytic synthesis process for nicotinamide intermediates using the field of organic synthesis technology. The process includes: adding appropriate amounts of dichloronicotinic acid, organic solvent, lanthanum-doped composite metal fluoride-diatomaceous earth supported catalyst, and encapsulated 4A molecular sieve to a reaction vessel under nitrogen protection; purging with nitrogen, heating, and stirring; introducing anhydrous dimethylamine gas, controlling the pressure, and continuing stirring; after the reaction is complete, washing with sodium bicarbonate aqueous solution, washing with deionized water, drying, concentrating, and recrystallizing to obtain the target product. The lanthanum-doped composite metal fluoride-diatomaceous earth supported catalyst prepared by this invention is recyclable, has mild reaction conditions, high product yield, is environmentally friendly, and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates. Background Technology

[0002] Nicosulfuron is a highly selective systemic herbicide belonging to the sulfonylurea class. It primarily controls annual and perennial grasses and some broadleaf weeds in cornfields by inhibiting acetolactate enzymes, and is currently one of the most important post-emergence herbicides for cornfields worldwide. Dichloro-N,N-dimethylnicotinamide is a key intermediate in the synthesis of nicosulfuron. Currently reported synthetic routes for dichloro-N,N-dimethylnicotinamide mainly include the following: Starting with tricyanopyridine as the starting material, the target product is obtained through multiple steps including oxidation, chlorination, hydrolysis, acylation, and amination. This route is lengthy and generates significant amounts of waste. Another route involves the direct reaction of dichloro-trichloromethylpyridine with an aqueous solution of dimethylamine, but the source of the raw material is limited, the cost is high, and the pH control requirements are stringent, resulting in significant wastewater generation. A third route involves the condensation reaction of aminopropenal and cyanoacetamide under the catalysis of piperidine and acetic acid, followed by cyclization with hydrogen chloride to obtain the target product. A fourth route uses propynyl alcohol as the starting material, involving oxidative addition, transesterification, condensation, and cyclization, but the yield of the condensation reaction is low. These synthetic routes generally involve the use of acylation reagents such as thionyl chloride and phosphorus oxychloride, generating large amounts of acidic and phosphorus-containing wastewater, causing serious environmental pollution; the steps are lengthy, and the overall yield is low; some routes use highly toxic raw materials, posing serious safety hazards.

[0003] In recent years, significant progress has been made in the direct catalytic synthesis of amide bonds. Heterogeneous catalysts have attracted widespread attention in the direct amidation reaction of carboxylic acids and amines due to their advantages of easy separation, recovery, and recycling. Existing technologies have reported the use of metal oxides and metal-organic frameworks as catalysts for the direct amidation reaction of carboxylic acids and amines. However, these catalyst systems still have shortcomings when applied to the amidation reaction of dichloronicotinic acid and dimethylamine: some catalysts have low Lewis acid site density on their surface, resulting in insufficient catalytic activity; the metal-organic framework structure of some catalysts lacks stability under alkaline conditions; some catalysts involve noble metals or complex organic ligands, leading to high preparation costs; and some catalysts are easily deactivated by moisture in the reaction system. Furthermore, most existing amidation reactions are reversible, and the water generated in the closed system cannot be removed, resulting in limited reaction equilibrium and difficulty in improving conversion rates. Therefore, developing a novel inorganic catalyst with inexpensive and readily available raw materials, controllable preparation process, high catalytic activity, good stability, and recyclability, and combining it with an effective in-situ dehydration strategy for the efficient synthesis of dichloro-N,N-dimethylnicotinamide, has significant industrial application value and environmental significance. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates.

[0005] In a first aspect, the present invention provides a highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates, comprising the following steps:

[0006] S1. By weight, under nitrogen protection, add 100-200 parts of 2-chloronicotinic acid, 500-2000 parts of organic solvent, 2.5-10 parts of lanthanum-doped composite metal fluoride-diatomite supported catalyst and 20-50 parts of encapsulated 4A molecular sieve to the reactor.

[0007] S2. Purge with nitrogen gas, heat to 80-110℃, and stir.

[0008] S3. Then introduce 50-120 parts of anhydrous dimethylamine gas and stir. After the anhydrous dimethylamine gas has been introduced, continue stirring the reaction at 80-110℃.

[0009] S4. After the reaction is complete, the mixture is allowed to cool naturally to room temperature. The encapsulated 4A molecular sieve is removed and filtered to obtain a lanthanum-doped composite metal fluoride-diatomaceous earth supported catalyst and filtrate. The filtrate is transferred to a separatory funnel, washed with sodium bicarbonate aqueous solution and then with deionized water to separate the organic phase. The organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product is recrystallized with a mixed solvent of ethyl acetate and n-hexane, filtered, and dried.

[0010] In this invention, a highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates exhibits a precise thermodynamic driving and kinetic control mechanism. The core mechanism of the reaction lies in the amidation dehydration condensation between o-chloronicotinic acid and dimethylamine. In the liquid-phase environment provided by the organic solvent, the multi-metallic active centers on the surface of the supported catalyst act as strong electron acceptors, polarizing the carbonyl carbon-oxygen double bond of the o-chloronicotinic acid molecule through coordination, significantly enhancing the electrophilicity of the carbonyl carbon atom, thereby lowering the energy barrier of the reaction. At this time, under the controlled environment provided by the pressure vessel, excess anhydrous dimethylamine molecules act as strong nucleophiles, efficiently attacking the activated carbonyl sites, forming a tetrahedral intermediate, and subsequently undergoing proton transfer and leaving group removal to transform into the target amide molecule. During this process, the quadrangular molecular sieve encapsulated in the system plays a crucial in-situ dehydration function. Utilizing its specific pore size, it selectively captures trace amounts of water molecules generated in the reaction, forcibly breaking the reversible equilibrium of the amidation reaction, inducing the chemical reaction to continuously shift towards product formation, and ensuring a high conversion rate of the raw materials. The nitrogen protective atmosphere effectively prevents the oxidation and passivation of catalyst active sites by oxygen in the air and the interference of moisture on reaction equilibrium. The purification process after the reaction, based on the difference in acid-base chemical properties, uses a weak alkaline solution of sodium bicarbonate to wash the organic phase, precisely converting unreacted residual acidic raw materials into water-soluble sodium salts and removing them, fundamentally eliminating the influence of impurities on the chromatographic purity of the product. Subsequent anhydrous drying and vacuum concentration processes further remove trace amounts of moisture and solvent from the system, creating a highly supersaturated environment for final crystallization. In the mixed system of ethyl acetate and n-hexane, the solubility variation with temperature guides the target molecules to arrange and grow orderly on the surface of the crystal nuclei. Finally, precise temperature control and cooling yield a crystallized product with a perfect lattice and extremely high purity. This entire process, through the organic combination of heterogeneous catalysis and physicochemical separation, achieves the precise transformation from basic pesticide raw materials to high-value-added fine chemicals.

[0011] According to a preferred embodiment of the present invention, in step S1, the organic solvent is toluene or xylene.

[0012] According to a preferred embodiment of the present invention, in step S2, the stirring time is 30-60 min.

[0013] According to a preferred embodiment of the present invention, in step S3, the stirring reaction is continued at 80-110°C for 4-8 hours.

[0014] According to a preferred embodiment of the present invention, in step S4, the vacuum degree under reduced pressure conditions is 0.08-0.1 MPa.

[0015] According to a preferred embodiment of the present invention, the preparation steps of the lanthanum-doped composite metal fluoride-diatomite supported catalyst include:

[0016] A1. By weight, 100-150 parts of sodium hexafluoroaluminate, 30-45 parts of potassium hexafluorozirconate, 20-30 parts of potassium hexafluorotitanate and 10-15 parts of anhydrous lanthanum fluoride are added to a ball mill, zirconium oxide grinding balls are added, the mixture is ball-milled at room temperature, sieved, and the mixed powder is collected. The mixed powder is transferred to a tube furnace and calcined at 445-455℃ under nitrogen protection, and then cooled naturally to room temperature to obtain the precursor powder.

[0017] A2. Mix 160-240 parts of precursor powder with 40-60 parts of diatomaceous earth, add 600-900 parts of anhydrous ethanol, and shear and disperse to obtain a mixed slurry; place the mixed slurry in a rotary evaporator and evaporate it in a water bath at 48-52℃ to obtain a dry supported composite powder; transfer the dry supported composite powder to a muffle furnace and calcine it at 348-352℃ to obtain a supported composite metal fluoride intermediate;

[0018] A3. Disperse 200-300 parts of the supported composite metal fluoride intermediate in 3000-4500 parts of anhydrous toluene and sonicate; add 50-75 parts of 3-aminopropyltrimethoxysilane and 1-1.5 parts of glacial acetic acid; under nitrogen protection, heat to 108-112℃ and reflux; after the reaction is complete, filter and collect the solid; wash the solid with toluene, anhydrous ethanol and deionized water respectively, and dry in a vacuum drying oven at 78-82℃ to obtain the amino-modified supported catalyst;

[0019] A4. Disperse 200-300 parts of amino-modified supported catalyst in 2400-3600 parts of N,N-dimethylformamide and sonicate to obtain a dispersion. Under nitrogen protection, add 60-90 parts of trimethyl phosphate dropwise to the dispersion, heat to 128-132℃ and stir to obtain a mixture. Add 40-60 parts of dehydrated 2-phosphonobutane-1,2,4-tricarboxylic acid and 1000-1500 parts of N,N-dimethylformamide to the mixture and continue stirring at 128-132℃. Cool to 78-82℃ and add ammonia to adjust the pH to 6.5-7.0. Aged at 78-82℃ with stirring. Filter and collect the solid. Wash the solid sequentially with N,N-dimethylformamide, anhydrous ethanol and deionized water, transfer to a vacuum drying oven and dry and activate at 100-120℃.

[0020] In this invention, the construction mechanism of the lanthanum-doped composite metal fluoride-diatomite supported catalyst is rooted in the deep coupling of solid-phase chemistry and interfacial functionalization modification. First, during the catalyst framework construction stage, high-energy mechanical ball milling causes sodium hexafluoroaluminate, potassium hexafluorozirconate, potassium hexafluorotitanate, and anhydrous lanthanum fluoride to undergo intense collisions, shearing, and compression at the microscopic level. During this process, mechanical energy is converted into lattice distortion energy, leading to the breakage and recombination of the original crystal forms of various fluoride salts, forming a highly active amorphous or microcrystalline mixture. The subsequent high-temperature calcination process is crucial for lattice reconstruction. The rare-earth element lanthanum, with its large ionic radius and unique electronic orbital structure, is in-situ doped into the lattice of the multi-metal fluoride, causing non-uniform charge distribution and forming numerous unsaturated metal centers on the solid surface. These centers constitute highly efficient Lewis acid active sites. To further increase the exposure frequency of active sites and enhance mechanical strength, diatomite with abundant hierarchical pore structures and a high specific surface area is selected as the support carrier. During ethanol dispersion and high-temperature calcination, the composite metal fluoride precursor is firmly anchored to the silanol groups on the diatomaceous earth surface through physical adsorption and chemical bonding. Subsequently, an organic-inorganic hybrid modification stage is performed, utilizing the covalent grafting of aminopropyltrimethoxysilane in an anhydrous system to introduce active amino groups onto the support surface via silicon-oxygen bonds. This amino layer not only alters the surface's hydrophilicity and hydrophobicity but also serves as a molecular framework guiding subsequent functionalization. Through the continuous intervention of trimethyl phosphate and phosphonobutanetricarboxylic acid, a complex three-dimensional organic functional network is woven on the catalyst surface. Phosphonic acid groups and carboxyl groups bind to the metal center through multidentate coordination, forming a synergistic catalytic environment possessing both Lewis and Brønsted acidity. Final ammonia conditioning and medium-temperature vacuum activation eliminate residual solvent molecules within the pores, inducing spatial rearrangement of organic segments, ultimately constructing a composite catalytic system with molecular recognition capabilities and highly efficient electron transport channels.

[0021] According to a preferred embodiment of the present invention, in step A1, the calcination time at 445-455°C is 6-8 hours.

[0022] According to a preferred embodiment of the present invention, in step A2, the calcination time at 348-352°C is 4-6 hours.

[0023] According to a preferred embodiment of the present invention, in step A3, the reflux reaction at 108-112°C is carried out for 24-30 hours.

[0024] According to a preferred embodiment of the present invention, in step A4, the stirring and aging time at 78-82°C is 8-10 hours.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] (1) The lanthanum-doped composite metal fluoride-diatomite supported catalyst used in this invention has a unique structure and excellent catalytic performance. The catalyst forms a stable lattice framework through high-temperature calcination of the composite metal fluoride precursor. The uniform doping of rare earth element lanthanum effectively regulates the acid strength and acid site distribution on the catalyst surface, enhancing the catalyst's Lewis acid activation ability for carboxyl carbonyl groups. The introduction of diatomite support provides abundant microporous and mesoporous structures, which is beneficial for the diffusion of substrate molecules and the exposure of active sites. Through aminosilane grafting, trimethyl phosphate modification, and phosphonate butane tricarboxylic acid crosslinking modification, a three-dimensional organic-inorganic hybrid network is constructed on the catalyst surface. The phosphate and carboxylic acid groups in the network can preferentially anchor the carboxyl group of dichloronicotinic acid through hydrogen bonding and coordination, thereby effectively inhibiting the nucleophilic substitution side reaction of dimethylamine on the chlorine atom at the second position of the pyridine ring and significantly improving the selectivity of the amidation reaction. Meanwhile, the catalyst is a stable heterogeneous system, which can be separated and recovered by simple filtration after reaction without complicated regeneration treatment. It can be recycled multiple times while maintaining high catalytic activity, which greatly reduces the consumption cost of catalyst and the amount of solid waste generated.

[0027] (2) This invention employs a synthesis process combining in-situ dehydration of 4A molecular sieves with pressurized excess dimethylamine gas, effectively overcoming the thermodynamic equilibrium limitations and kinetic obstacles of direct amidation reactions. In a closed reaction system, if the water generated by the condensation reaction of carboxylic acids and amines is not removed in time, it will rapidly cause the reaction to reach equilibrium and lead to poisoning and deactivation of the catalyst active sites. This invention directly adds the encapsulated 4A molecular sieve to the reaction system, utilizing its regular pore structure to selectively adsorb water molecules while excluding larger dimethylamine and solvent molecules, achieving in-situ continuous removal of the water generated in the reaction, continuously disrupting the reaction equilibrium, and driving the reaction toward the product. At the same time, this invention uses pressurized excess anhydrous dimethylamine gas to compensate for the concentration loss caused by the gas phase distribution of low-boiling-point dimethylamine under high-temperature reaction conditions, ensuring that dimethylamine is always in excess in the reaction system, providing sufficient stoichiometric driving force for the complete conversion of dichloronicotinic acid. The above synergistic strategy enables the reaction to proceed efficiently under mild temperature conditions, avoiding the safety risks and increased side reactions caused by high temperature and high pressure, and ensuring high yield and high purity of the target product.

[0028] (3) The process route of this invention is simple, environmentally friendly, safe to operate, and suitable for large-scale industrial production. This invention uses a one-step direct amidation reaction to replace the traditional multi-step synthesis route, eliminating the use of highly toxic acyl chloride reagents such as thionyl chloride and phosphorus oxychloride, thus avoiding the generation of acidic wastewater and phosphorus-containing wastewater from the source. The only byproduct of the reaction is water, resulting in high atom economy and meeting the requirements of green chemistry and clean production. In the post-treatment process, sodium bicarbonate aqueous solution is used for washing, which effectively removes unreacted dichloronicotinic acid. High-purity products can be obtained by simple recrystallization without the need for cumbersome column chromatography or multiple crystallizations. The ball milling, calcination, shear dispersion, rotary evaporation, and ultrasonic dispersion involved in the catalyst preparation process are all mature chemical unit operations with strong equipment versatility and easy scale-up production. Detailed Implementation

[0029] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0030] Example 1

[0031] This embodiment provides a highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates, including the following steps:

[0032] S1. Under nitrogen protection, 150g of 2-chloronicotinic acid, 1250g of toluene, 6.25g of lanthanum-doped composite metal fluoride-diatomite supported catalyst, and 35g of encapsulated 4A molecular sieve are sequentially added to a pressure reactor equipped with a mechanical stirrer, reflux condenser, thermometer, and pressure control device. The aforementioned 4A molecular sieve is pre-activated in a muffle furnace at 350℃ for 4 hours, and then placed in a specially made stainless steel mesh bag and sealed. The mesh bag pore size is smaller than the molecular sieve particle diameter to ensure that the molecular sieve does not leak.

[0033] S2. Start stirring and purge the reaction system with nitrogen three times. Each time, first evacuate to -0.08MPa and then purge with nitrogen to atmospheric pressure. Under nitrogen protection, heat the reaction system to 95°C and stir at this temperature for 45 minutes at a stirring speed of 400 rpm.

[0034] S3. Control the pressure of the reactor to 0.35 MPa, and introduce 85 g of anhydrous dimethylamine gas into the reactor at a controlled rate for 1.5 h. During the introduction process, maintain a stirring speed of 400 rpm to ensure uniform distribution and complete dissolution of dimethylamine in the reaction system. After the anhydrous dimethylamine gas is introduced, continue stirring the reaction at 95 °C for 6 h at a stirring speed of 400 rpm. During the reaction, take samples every 1 h to monitor the reaction progress using high performance liquid chromatography (HPLC). Use a C18 column, with the mobile phase being acetonitrile:water = 60:40 (volume ratio), a flow rate of 1.0 mL / min, and a detection wavelength of 254 nm, until the conversion rate of 2-chloronicotinic acid no longer increases.

[0035] S4. After the reaction is complete, the reaction system is naturally cooled to room temperature. After removing the encapsulated 4A molecular sieve, the lanthanum-doped composite metal fluoride-diatomite supported catalyst is separated and recovered by vacuum filtration (using an organic filter membrane with a pore size of 0.45 μm during vacuum filtration), yielding the lanthanum-doped composite metal fluoride-diatomite supported catalyst and filtrate. The filtrate is transferred to a separatory funnel, washed once with 400 g of 5% sodium bicarbonate aqueous solution, shaken for 5 min, and allowed to stand for separation. The aqueous phase is discarded, and then washed twice with 750 g of deionized water, shaking for 5 min each time, and allowed to stand for separation. The aqueous phase is discarded, and the organic phase is separated. The phase was transferred to an Erlenmeyer flask, 20 g of anhydrous sodium sulfate was added, and the mixture was shaken for 10 min and then allowed to stand for 30 min to dry. The dried organic phase was concentrated under reduced pressure (vacuum degree 0.09 MPa, water bath temperature not exceeding 60℃) and concentrated using a rotary evaporator until no liquid evaporated, yielding a light yellow crude product. The crude product was dissolved in a mixed solvent of 450 g of ethyl acetate and n-hexane (volume ratio 1:3) in a water bath at 60℃, then naturally cooled to room temperature and placed in a refrigerator at 0-5℃ for crystallization for 2 h. The crystals were separated by filtration and dried in a vacuum drying oven at 50℃ for 8 h to obtain 2-chloro-N,N-dimethylnicotinamide.

[0036] Preparation of lanthanum-doped composite metal fluoride-diatomite supported catalysts:

[0037] A1. 125g sodium hexafluoroaluminate, 37.5g potassium hexafluorozirconate, 25g potassium hexafluorotitanate, and 12.5g anhydrous lanthanum fluoride were added to a planetary ball mill, along with 1600g of zirconia grinding balls (with a mass ratio of 5mm and 10mm diameter grinding balls of 1:1). The mill was then operated at 400rpm for 4 hours at room temperature, with a 5min cooling interval every 1 hour to prevent local overheating. After milling, the mixture was passed through a 200-mesh sieve and the mixed powder was collected. The resulting mixed powder was transferred to a tube furnace and heated from room temperature to 450℃ at a rate of 5℃ / min under nitrogen protection (nitrogen flow rate of 100mL / min). The mixture was then calcined at this temperature for 7 hours and allowed to cool naturally to room temperature before being removed to obtain the precursor powder.

[0038] A2. Mix 200g of precursor powder with 50g of diatomaceous earth, add 750g of anhydrous ethanol as a dispersion medium, and disperse the mixture using a high-speed shear disperser at 10000rpm for 30min to obtain a mixed slurry. Place the mixed slurry in a rotary evaporator and evaporate the anhydrous ethanol in a 50℃ water bath under a vacuum of 0.09MPa. The rotary evaporator speed is 60rpm. After evaporation until no liquid is distilled off, continue to hold the temperature for 30min to obtain a dry supported composite powder. Transfer the powder to a muffle furnace and heat it to 350℃ at a heating rate of 2℃ / min. Calcinate at this temperature for 5h and allow it to cool naturally to room temperature to obtain a supported composite metal fluoride intermediate.

[0039] A3. 250g of the supported composite metal fluoride intermediate was dispersed in 3750g of anhydrous toluene and ultrasonically dispersed at 40kHz for 30min using an ultrasonic cleaner with an ultrasonic power of 200W. 62.5g of 3-aminopropyltrimethoxysilane and 1.25g of glacial acetic acid were added to the dispersion system. Under nitrogen protection (nitrogen flow rate of 50mL / min), the reaction system was heated to 110℃ and refluxed for 27h. Cooling water was circulated in the reflux condenser to control the temperature at 12℃. After the reaction was completed, the mixture was naturally cooled to room temperature, and the solid was collected by vacuum filtration. The solid was washed three times each with 400g of toluene, 400g of anhydrous ethanol, and 400g of deionized water. During each wash, the solid was stirred and contacted with the washing liquid for 10min before vacuum filtration. The washed solid was placed in a vacuum drying oven and dried at 80℃ and a vacuum of 0.09MPa for 12h to obtain the amino-modified supported catalyst.

[0040] A4. 250g of amino-modified supported catalyst was dispersed in 3000g of N,N-dimethylformamide. The dispersion was ultrasonically dispersed at 40kHz for 30min using an ultrasonic cleaner with an ultrasonic power of 200W to obtain a dispersion. The dispersion was transferred to a three-necked flask equipped with a mechanical stirrer, reflux condenser, and thermometer. Under a continuous nitrogen atmosphere (nitrogen flow rate of 50mL / min), 75g of trimethyl phosphate was added dropwise to the dispersion at a rate of 0.5mL / min. This utilized the metal sites on the catalyst surface for endogenous catalysis. The temperature was raised to 130℃, and the reaction was stirred for 16h at a stirring speed of 300rpm. 50g of dehydrated 2-phosphonobutane-1,2,4-tricarboxylic acid (prepared by pre-removing water from a 50% aqueous solution of 2-phosphonobutane-1,2,4-tricarboxylic acid under reduced pressure at 60℃ and a vacuum of 0.09MPa by rotary evaporation until no liquid distilled off) was added to the mixture. After maintaining the temperature for another 30 minutes, a viscous anhydrous pure product was obtained, along with 1250 g of N,N-dimethylformamide. The mixture was then stirred at 130 °C for 12 hours at a stirring speed of 300 rpm. After the reaction was completed, the temperature was lowered to 80 °C, and 20 g of ammonia water (25% by mass) was slowly added dropwise at a rate of 0.5 mL / min to adjust the pH of the system to 6.8. The mixture was stirred continuously during the addition process. The mixture was then aged at 80 °C with constant temperature stirring for 9 hours at a stirring speed of 200 rpm. After aging, the solid was collected by vacuum filtration. The solid was then washed five times each with 650 g of N,N-dimethylformamide, 650 g of anhydrous ethanol, and 650 g of deionized water. Each time, the solid was stirred and contacted with the washing liquid for 10 minutes before vacuum filtration. The washed solid was transferred to a vacuum drying oven and dried and activated at 110 °C and a vacuum of 0.09 MPa for 5 hours to obtain a lanthanum-doped composite metal fluoride-diatomite supported catalyst.

[0041] Example 2

[0042] The difference between this embodiment and Embodiment 1 is that this embodiment provides a highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates, including the following steps:

[0043] S1. Under nitrogen protection, add 100g of 2-chloronicotinic acid, 500g of toluene, 2.5g of lanthanum-doped composite metal fluoride-diatomite supported catalyst and 20g of encapsulated 4A molecular sieve to the pressure reactor.

[0044] S2. Purge with nitrogen three times, heat to 80°C, and stir at a constant temperature for 30 minutes.

[0045] S3. Control the pressure of the reactor to 0.2 MPa, and introduce 50 g of anhydrous dimethylamine gas into the reactor. After the gas is introduced, continue stirring the reaction at 80°C for 4 hours.

[0046] S4. After the reaction is complete, the mixture is allowed to cool naturally to room temperature. The encapsulated 4A molecular sieve is removed and filtered to obtain the catalyst and filtrate. The filtrate is transferred to a separatory funnel and washed once with 300g of 5% sodium bicarbonate aqueous solution, followed by two washes with 500g of deionized water to separate the organic phase. The organic phase is dried with 10g of anhydrous sodium sulfate and concentrated under reduced pressure (0.08MPa, temperature not exceeding 60℃) to obtain the crude product. The crude product is recrystallized with a mixed solvent of 300g of ethyl acetate and n-hexane (volume ratio 1:3), filtered, and dried to obtain 2-chloro-N,N-dimethylnicotinamide.

[0047] Preparation of lanthanum-doped composite metal fluoride-diatomite supported catalysts:

[0048] A1. 100g sodium hexafluoroaluminate, 30g potassium hexafluorozirconate, 20g potassium hexafluorotitanate and 10g anhydrous lanthanum fluoride were put into a planetary ball mill, and 1280g zirconium oxide grinding balls were added. The mixture was ball-milled at 400 rpm for 4 hours at room temperature, and then passed through a 200-mesh sieve to collect the mixed powder. The mixed powder was transferred to a tube furnace and calcined at 445℃ for 6 hours under nitrogen protection at a temperature of 5℃ / min. The mixture was then allowed to cool naturally to room temperature to obtain the precursor powder.

[0049] A2. Mix 160g of precursor powder with 40g of diatomaceous earth, add 600g of anhydrous ethanol, and disperse using a high-speed shear disperser at 10000rpm for 30min to obtain a mixed slurry; place the mixed slurry in a rotary evaporator and evaporate the anhydrous ethanol under a 48℃ water bath and a vacuum of 0.09MPa to obtain a dry supported composite powder; transfer the powder to a muffle furnace and calcine at 348℃ for 4h at a rate of 2℃ / min to obtain a supported composite metal fluoride intermediate.

[0050] A3. 200g of the supported composite metal fluoride intermediate was dispersed in 3000g of anhydrous toluene and ultrasonically dispersed for 30min. 50g of 3-aminopropyltrimethoxysilane and 1.0g of glacial acetic acid were added. The mixture was heated to 108℃ and refluxed for 24h under nitrogen protection. After the reaction was completed, the solid was collected by filtration and washed three times each with 300g of toluene, 300g of anhydrous ethanol and 300g of deionized water. The solid was then dried in a vacuum drying oven at 78℃ for 12h to obtain the amino-modified supported catalyst.

[0051] A4. 200g of amino-modified supported catalyst was dispersed in 2400g of N,N-dimethylformamide and ultrasonically dispersed for 30min to obtain a dispersion. Under continuous nitrogen atmosphere protection, 60g of trimethyl phosphate was added dropwise to the dispersion to utilize the metal sites on the catalyst surface for endogenous catalysis. The reaction was stirred at 128℃ for 16h. 40g of dehydrated 2-phosphonobutane-1,2,4-tricarboxylic acid (prepared from a commercially available 50% aqueous solution by pre-removing water by rotary evaporation under reduced pressure) and 1000g of N,N-dimethylformamide were added to the mixture. The reaction mixture was stirred at 128°C for 12 hours with N,N-dimethylformamide. The temperature was then lowered to 78°C, and 10 g of ammonia (26% by mass) was added dropwise to adjust the pH of the system to 6.5. The mixture was then stirred and aged at 78°C for 8 hours. The mixture was filtered and the solid was collected. The solid was washed sequentially with 500 g of N,N-dimethylformamide, 500 g of anhydrous ethanol, and 500 g of deionized water. The solid was then transferred to a vacuum drying oven and dried and activated at 100°C and a vacuum of 0.09 MPa for 4 hours to obtain a lanthanum-doped composite metal fluoride-diatomite supported catalyst.

[0052] Example 3

[0053] The difference between this embodiment and Embodiment 1 is that this embodiment provides a highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates, including the following steps:

[0054] S1. Under nitrogen protection, add 200g of 2-chloronicotinic acid, 2000g of xylene, 10g of lanthanum-doped composite metal fluoride-diatomite supported catalyst and 50g of encapsulated 4A molecular sieve to the pressure reactor.

[0055] S2. Purge with nitrogen three times, heat to 110℃, and stir at a constant temperature for 60 minutes.

[0056] S3. Control the pressure of the reactor to 0.5 MPa, and introduce 120 g of anhydrous dimethylamine gas into the reactor. After the gas is introduced, continue stirring the reaction at 110°C for 8 hours.

[0057] S4. After the reaction is complete, the mixture is allowed to cool naturally to room temperature. The encapsulated 4A molecular sieve is removed and filtered to obtain the catalyst and filtrate. The filtrate is transferred to a separatory funnel and washed once with 500g of 5% sodium bicarbonate aqueous solution, followed by two washes with 1000g of deionized water to separate the organic phase. The organic phase is dried with 30g of anhydrous sodium sulfate and concentrated under reduced pressure (0.1MPa, temperature not exceeding 60℃) to obtain the crude product. The crude product is recrystallized with a mixed solvent of 600g of ethyl acetate and n-hexane (volume ratio 1:3), filtered, and dried to obtain 2-chloro-N,N-dimethylnicotinamide.

[0058] Preparation of lanthanum-doped composite metal fluoride-diatomite supported catalysts:

[0059] A1. 150g sodium hexafluoroaluminate, 45g potassium hexafluorozirconate, 30g potassium hexafluorotitanate and 15g anhydrous lanthanum fluoride were put into a planetary ball mill, and 1920g zirconium oxide grinding balls were added. The mixture was ball-milled at 400 rpm for 4 hours at room temperature, and then passed through a 200-mesh sieve to collect the mixed powder. The mixed powder was transferred to a tube furnace and calcined at 455℃ for 8 hours under nitrogen protection at a temperature of 5℃ / min. The mixture was then allowed to cool naturally to room temperature to obtain the precursor powder.

[0060] A2. Mix 240g of precursor powder with 60g of diatomaceous earth, add 900g of anhydrous ethanol, and disperse using a high-speed shear disperser at 10000rpm for 30min to obtain a mixed slurry; place the mixed slurry in a rotary evaporator and evaporate the anhydrous ethanol under a 52℃ water bath and a vacuum of 0.09MPa to obtain a dry supported composite powder; transfer the powder to a muffle furnace and calcine at 352℃ for 6h at a rate of 2℃ / min to obtain a supported composite metal fluoride intermediate.

[0061] A3. 300g of the supported composite metal fluoride intermediate was dispersed in 4500g of anhydrous toluene and ultrasonically dispersed for 30min. 75g of 3-aminopropyltrimethoxysilane and 1.5g of glacial acetic acid were added. The mixture was heated to 112℃ and refluxed for 30h under nitrogen protection. After the reaction was completed, the solid was collected by filtration and washed three times each with 500g of toluene, 500g of anhydrous ethanol and 500g of deionized water. The solid was then dried in a vacuum drying oven at 82℃ for 12h to obtain the amino-modified supported catalyst.

[0062] A4. 300g of amino-modified supported catalyst was dispersed in 3600g of N,N-dimethylformamide and ultrasonically dispersed for 30min to obtain a dispersion. Under continuous nitrogen atmosphere protection, 90g of trimethyl phosphate was added dropwise to the dispersion to utilize the metal sites on the catalyst surface for endogenous catalysis. The reaction was stirred at 132℃ for 16h. 60g of dehydrated 2-phosphonobutane-1,2,4-tricarboxylic acid (prepared from a commercially available 50% aqueous solution by pre-removing water by rotary evaporation under reduced pressure) and 1500g of N,N-dimethylformamide were added to the mixture. Methylformamide was stirred at 132℃ for 12 h; the temperature was lowered to 82℃, and 30 g of ammonia (mass fraction 25-28%) was added dropwise to adjust the pH of the system to 7.0; the mixture was stirred and aged at 82℃ for 10 h; the mixture was filtered and the solid was collected; the solid was washed sequentially with 800 g of N,N-dimethylformamide, 800 g of anhydrous ethanol and 800 g of deionized water, and then transferred to a vacuum drying oven and dried and activated at 120℃ and a vacuum degree of 0.09 MPa for 6 h to obtain a lanthanum-doped composite metal fluoride-diatomite supported catalyst.

[0063] Comparative Example 1

[0064] The difference between this comparative example and Example 1 is that this comparative example omits the 3-aminopropyltrimethoxysilane modification in step A3 of the preparation of the lanthanum-doped composite metal fluoride-diatomite supported catalyst, that is, it does not perform aminosilane grafting. The other steps are the same as in Example 1.

[0065] Comparative Example 2

[0066] The difference between this comparative example and Example 1 is that the trimethyl phosphate modification in step A4 of the preparation of the lanthanum-doped composite metal fluoride-diatomite supported catalyst is omitted in this comparative example, that is, the methylation-phosphorylation dual modification is not performed. The other steps are the same as in Example 1.

[0067] Comparative Example 3

[0068] The difference between this comparative example and Example 1 is that this comparative example omits the 2-phosphonobutane-1,2,4-tricarboxylic acid modification in step A4 of the preparation of the lanthanum-doped composite metal fluoride-diatomite supported catalyst, that is, it does not carry out the introduction of carboxylic acid groups and the construction of three-dimensional cross-linked networks. The other steps are the same as in Example 1.

[0069] In accordance with national and industry standard testing specifications, a series of standardized tests were conducted on the high-efficiency catalytic synthesis process of nicosulfuron-methyl nicotinamide intermediates described in Examples 1-3 and Comparative Examples 1-3.

[0070] Product purity was determined by high-performance liquid chromatography (HPLC). The chromatographic conditions were as follows: a C18 reversed-phase column, 250 mm in length and 4.6 mm in inner diameter, with a packing particle size of 5 μm; a mobile phase of acetonitrile and water (60:40 v / v), filtered through a 0.45 μm filter and degassed by sonication for 15 min before use; a flow rate of 1.0 mL / min; a column temperature of 30 °C; a detection wavelength of 254 nm; and an injection volume of 10 μL. Sample preparation was as follows: accurately weigh 10 mg of the sample, place it in a 10 mL volumetric flask, dissolve and dilute to the mark with the mobile phase, mix well, filter through a 0.45 μm organic filter, and then inject for analysis. Sample purity was calculated using the area normalization method, and the ratio of the main peak area to the total peak area was recorded as the product purity.

[0071] The product yield is calculated as follows: the ratio of the actual product mass to the theoretical product mass multiplied by 100%. The molecular weight of 2-chloronicotinic acid is 157.55, and the molecular weight of the target product, 2-chloro-N,N-dimethylnicotinamide, is 184.62. The theoretical product mass is calculated using the following formula: 2-chloronicotinic acid feed mass / (157.55 × 184.62). The actual product mass is the mass of the pure product obtained after recrystallization and drying following the reaction. Yield = Actual product mass / Theoretical product mass × 100%.

[0072] The test method for catalyst recycling performance is as follows: The catalyst recovered by filtration after the first reaction in Examples 1-3 and Comparative Examples 1-3 was washed three times with toluene, using 50 mL of toluene each time, with stirring for 10 min before filtration. The washed catalyst was placed in a vacuum drying oven and dried for 4 h at 80 °C and a vacuum of 0.09 MPa. The amidation reaction was repeated under the same reaction conditions (including reactant ratio, solvent, temperature, pressure, reaction time, etc.) as in each example or comparative example. After each reaction, the catalyst was recovered and dried using the same method, and this process was repeated for 5 cycles. The product yields for the first reaction and each cycle were calculated and recorded as the first yield, the first cycle yield, the second cycle yield, the third cycle yield, the fourth cycle yield, and the fifth cycle yield.

[0073] The performance test data above are shown in Table 1.

[0074] Table 1 Performance Test Results

[0075] Test Project Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Product purity (%) 98.9 98.5 99.1 87.3 89.6 86.9 First-time yield (%) 93.5 92.1 94.2 76.8 81.3 74.5 Yield (%) of the first cycle 93.5 92.1 94.2 76.8 81.3 74.5 Second cycle yield (%) 92.8 91.4 93.6 74.2 78.6 71.8 Third cycle yield (%) 91.9 90.3 92.8 70.5 75.2 68.2 Yield (%) of the 4th cycle 90.7 89.1 91.5 65.8 71.4 64.0 Yield (%) of the 5th cycle 89.2 87.6 90.1 60.1 66.8 59.3

[0076] As can be seen from the above, the purity of the products in Examples 1-3 all reached above 98.5%, the initial yield was above 92.1%, and the yield remained between 87.6% and 90.1% after 5 cycles, demonstrating excellent and stable catalytic performance.

[0077] In contrast, Comparative Example 1, due to the omission of 3-aminopropyltrimethoxysilane modification, lacked amino grafting sites on the catalyst surface, making subsequent methylation-phosphorylation modification and carboxylic acid crosslinking network construction impossible. Its product purity was only 87.3%, the first yield was only 76.8%, and the yield dropped sharply to 60.1% in the fifth cycle. This indicates that aminosilane grafting is the basis for constructing active sites, and its absence significantly reduces catalyst activity and makes it extremely prone to deactivation.

[0078] Comparative Example 2, lacking the dual modification of methylation and phosphorylation due to the omission of trimethyl phosphate modification, failed to form effective phosphorylation active centers on the catalyst surface. Its product purity was 89.6%, the initial yield was 81.3%, and the yield dropped to 66.8% in the fifth cycle. This indicates that trimethyl phosphate modification plays an indispensable role in improving the initial activity of the catalyst and maintaining cycle stability.

[0079] Comparative Example 3, due to the omission of 2-phosphonobutane-1,2,4-tricarboxylic acid modification, could not form a three-dimensional phosphoric acid-carboxylic acid crosslinking network. The catalyst surface lacked a multidentate coordination anchoring structure, and its product purity was only 86.9%, the first yield was only 74.5%, and the yield in the fifth cycle was as low as 59.3%. This proves that phosphonobutane-tricarboxylic acid crosslinking modification is crucial for constructing a stable three-dimensional network and preventing the loss of active components.

[0080] In summary, Examples 1 to 3 successfully solved the technical problems of low catalyst activity, poor selectivity, and poor recycling stability in the prior art by performing triple synergistic modification on the catalyst through aminosilane grafting, trimethyl phosphate methylation-phosphorylation modification, and phosphonobutane tricarboxylic acid crosslinking network construction. This achieved the technical effects of high purity, high yield, and multiple recycling.

Claims

1. A highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates, characterized in that, Includes the following steps: S1. By weight, under nitrogen protection, add 100-200 parts of 2-chloronicotinic acid, 500-2000 parts of organic solvent, 2.5-10 parts of lanthanum-doped composite metal fluoride-diatomite supported catalyst and 20-50 parts of encapsulated 4A molecular sieve to the reactor. S2. Purge with nitrogen gas, heat to 80-110℃, and stir. S3. Then introduce 50-120 parts of anhydrous dimethylamine gas and stir. After the anhydrous dimethylamine gas has been introduced, continue stirring the reaction at 80-110℃. S4. After the reaction is complete, the mixture is allowed to cool naturally to room temperature. The encapsulated 4A molecular sieve is removed and filtered to obtain a lanthanum-doped composite metal fluoride-diatomaceous earth supported catalyst and filtrate. The filtrate is transferred to a separatory funnel, washed with sodium bicarbonate aqueous solution and then with deionized water to separate the organic phase. The organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product is recrystallized with a mixed solvent of ethyl acetate and n-hexane, filtered, and dried.

2. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 1, characterized in that, In step S1, the organic solvent is toluene or xylene.

3. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 1, characterized in that, In step S2, the stirring time is 30-60 minutes.

4. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 1, characterized in that, In step S3, the reaction is continued to be stirred at 80-110℃ for 4-8 hours.

5. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 1, characterized in that, In step S4, the vacuum degree under reduced pressure conditions is 0.08-0.1 MPa.

6. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to any one of claims 1-5, characterized in that, The preparation steps of the lanthanum-doped composite metal fluoride-diatomite supported catalyst include: A1. By weight, 100-150 parts of sodium hexafluoroaluminate, 30-45 parts of potassium hexafluorozirconate, 20-30 parts of potassium hexafluorotitanate and 10-15 parts of anhydrous lanthanum fluoride are added to a ball mill, zirconium oxide grinding balls are added, the mixture is ball-milled at room temperature, sieved, and the mixed powder is collected. The mixed powder is transferred to a tube furnace and calcined at 445-455℃ under nitrogen protection, and then cooled naturally to room temperature to obtain the precursor powder. A2. Mix 160-240 parts of precursor powder with 40-60 parts of diatomaceous earth, add 600-900 parts of anhydrous ethanol, and shear and disperse to obtain a mixed slurry; place the mixed slurry in a rotary evaporator and evaporate it in a water bath at 48-52℃ to obtain a dry supported composite powder; transfer the dry supported composite powder to a muffle furnace and calcine it at 348-352℃ to obtain a supported composite metal fluoride intermediate; A3. Disperse 200-300 parts of the supported composite metal fluoride intermediate in 3000-4500 parts of anhydrous toluene and sonicate; add 50-75 parts of 3-aminopropyltrimethoxysilane and 1-1.5 parts of glacial acetic acid; under nitrogen protection, heat to 108-112℃ and reflux; after the reaction is complete, filter and collect the solid; wash the solid with toluene, anhydrous ethanol and deionized water respectively, and dry in a vacuum drying oven at 78-82℃ to obtain the amino-modified supported catalyst; A4. Disperse 200-300 parts of amino-modified supported catalyst in 2400-3600 parts of N,N-dimethylformamide and sonicate to obtain a dispersion. Under nitrogen protection, add 60-90 parts of trimethyl phosphate dropwise to the dispersion, heat to 128-132℃ and stir to obtain a mixture. Add 40-60 parts of dehydrated 2-phosphonobutane-1,2,4-tricarboxylic acid and 1000-1500 parts of N,N-dimethylformamide to the mixture and continue stirring at 128-132℃. Cool to 78-82℃ and add ammonia to adjust the pH to 6.5-7.

0. Aged at 78-82℃ with stirring. Filter and collect the solid. Wash the solid sequentially with N,N-dimethylformamide, anhydrous ethanol and deionized water, transfer to a vacuum drying oven and dry and activate at 100-120℃.

7. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 6, characterized in that, In step A1, the calcination time at 445-455℃ is 6-8 hours.

8. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 6, characterized in that, In step A2, the calcination time at 348-352℃ is 4-6 hours.

9. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 6, characterized in that, In step A3, the reflux reaction at 108-112℃ takes 24-30 hours.

10. The highly efficient catalytic synthesis process for nicosulfuron-methyl nicotinamide intermediates according to claim 6, characterized in that, In step A4, the stirring and aging time at 78-82℃ is 8-10 hours.