A new process for solvent-free low-temperature micro-negative pressure segmented preparation of benzimidazolone

Abstract

The application relates to the technical field of organic synthesis, and discloses a new process for preparing benzimidazolone by means of solvent-free low-temperature micro-negative pressure and sectioning, which comprises the following five steps: 1. low-temperature solid-phase premixing: putting in o-phenylenediamine, the first batch of urea and color inhibitor additives compounded from ascorbic acid and anhydrous citric acid; 2. sectional temperature-rising micro-negative pressure melt cyclization: putting in the second batch of urea, sectional gradient negative pressure and intermittent spraying; 3. gradient temperature control deep deamination; 4. sectional temperature reduction water supplementing and beating; and 5. low-temperature centrifugal filtration and mother liquor circulation. The application adopts an integrated coupling process mainly characterized by batch feeding of urea, addition of organic additives and sectional control of low temperature and negative pressure, does not add organic solvents in the whole process, does not cause high-temperature coking and blocking, does not cause oxidation and yellowing, has low impurity content, has zero urea sublimation pipe blocking, has extremely low ammonia escape, does not need in-kettle crushing, is suitable for downstream hydrogenation, has strong equipment versatility, does not discharge waste, greatly improves yield, purity and whiteness, and has remarkable economic and environmental protection benefits.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a novel solvent-free, low-temperature, micro-negative-pressure segmented preparation process for benzimidazole ions. Background Technology

[0002] Benzimidazolone is a key precursor intermediate in the synthesis of 5-aminobenzimidazolone, high-grade organic pigments, and pharmaceuticals. Traditional industrial preparation methods employ a xylene / high-boiling-point aromatic solvent reflux process: o-phenylenediamine and urea undergo condensation with water under reflux at 140–150°C, and the ammonia and water generated in the reaction are removed by azeotropic extraction with an organic solvent. Existing solvent-based processes have significant drawbacks: ① High consumption of aromatic solvents, high energy consumption in distillation recovery, large VOC emissions, and difficult treatment of solvent waste; ② High-temperature, long-term reflux easily leads to carbonization and discoloration, resulting in fluctuating product purity and poor whiteness.

[0003] Existing solvent-free synthesis patents generally rely on boric acid, boron salts, inorganic salts, and sulfur-based additives for color suppression, which easily introduces boron and sulfur heteroatom impurities. Subsequent purification processes are necessary, and boron impurities can easily poison downstream palladium-on-carbon hydrogenation catalysts, limiting product applications. Furthermore, existing solvent-free processes have several shortcomings: First, single-stage urea feeding easily leads to low-temperature accumulation and decomposition, generating biuret organic impurities and reducing product purity; second, the entire process relies on a fixed negative pressure. Excessive negative pressure in the early stages easily causes excessive urea sublimation, crystallization blockage of vacuum pipelines, and severe raw material loss, while insufficient negative pressure in the later stages results in incomplete ammonia removal and low raw material conversion rates; third, relying solely on displacement deoxygenation within the reactor results in continuous trace oxygen infiltration during the reaction process, still causing material oxidation and yellowing; fourth, the absorption of dry ammonia extracted under negative pressure is difficult, leading to excessive ammonia escape and significant environmental pressure; fifth, the product easily forms hard lumps, requiring in-reactor crushing equipment, which involves high equipment investment and cumbersome operation.

[0004] The latest publicly disclosed solvent-free melting process can be found in patent CN117447405A. This patent uses o-phenylenediamine and urea to melt and feed in one go, and then reacts at high temperature for a long time under normal pressure. Although it achieves solvent-free production, the process is relatively simple and has limited room for optimization. It also has problems such as long high-temperature reaction time, high energy consumption, easy oxidation and discoloration of the product, large loss of raw material sublimation, and general batch stability. Summary of the Invention

[0005] To address the technical problems of existing solvent-based methods and conventional solvent-free high-temperature processes, boron / sulfur additive systems, urea sublimation clogging, ammonia escape, material oxidation, excessive impurities, and high equipment investment, this invention provides a novel solvent-free, low-temperature, micro-negative-pressure segmented process for the preparation of benzimidazolone. The technical solution is as follows: A novel solvent-free, low-temperature, micro-negative-pressure segmented preparation process for benzimidazolone includes the following steps: (1) Low-temperature solid-phase premixing: o-phenylenediamine, the first batch of urea, and a color-inhibiting agent composed of ascorbic acid and anhydrous citric acid are added to a closed reactor. The molar ratio of o-phenylenediamine to the first batch of urea is 1:(0.99~1.02). The total amount of additives added is 0.32wt%~0.55wt% of the mass of o-phenylenediamine. The mass ratio of ascorbic acid to anhydrous citric acid is 1:2.5. The organic compound additive has the functions of anti-oxidation, color inhibition and dispersion. It can be completely decomposed without residue at a high temperature of 140℃ or above. The color inhibition and anti-oxidation effect is better than boric acid and it is suitable for downstream palladium carbon hydrogenation process. No boric acid, boron salt, sulfide, sulfite and inorganic salt additives are added throughout the process. Nitrogen replaces the air in the reactor and continuously purges with a small flow of nitrogen to prevent oxygen from penetrating and to slowly remove trace amounts of free ammonia. The temperature is raised to 90~95℃ by low-speed stirring and solid-phase heat preservation. The material remains solid and does not melt throughout the process. This low-temperature solid-phase insulation process has significant technical advantages: the raw materials slowly penetrate and fully wet and pre-complex under low-temperature solid conditions, completely solving the problems of local overheating, local overheating and coking, and oxidation and blackening caused by direct heating and melting, and greatly improving the whiteness of the product; at the same time, it can release the free ammonia and trace moisture from the trace decomposition of urea in advance, breaking the agglomeration of raw materials, making the subsequent melting and condensation reaction more uniform and stable, fundamentally avoiding the formation of hard lumps of materials, and allowing them to disperse naturally without in-vessel crushing; at the same time, pre-complexation reduces the activation energy of cyclization reaction, achieving true low-temperature condensation, effectively reducing side reactions and improving product yield and purity. This invention combines organic acids to synergistically capture oxidative free radicals, and the dual combination with nitrogen deoxygenation achieves strong anti-oxidation and color inhibition, with a color inhibition effect far exceeding that of boric acid alone; moreover, the additives can be completely decomposed into CO2 and H2O at high temperatures, with no solid salt, boron, sulfur heteroatoms remaining, eliminating the need for additional impurity removal processes, and avoiding poisoning of downstream palladium on carbon hydrogenation catalysts, thus broadening the product's application scenarios.

[0006] (2) Segmented heating and micro-negative pressure melting and cyclization: When the system is precisely heated to 118±2℃, the second batch of urea is added to avoid urea accumulation and premature hydrolysis and decomposition to generate biuret impurities under low temperature conditions; the molar ratio of o-phenylenediamine to the second batch of urea is 1:(0.11~0.13), and feeding is strictly prohibited if the temperature does not meet the standard; continue to slowly heat to 122~125℃, and the material gradually melts; start segmented gradient negative pressure: the negative pressure is controlled at -0.01~-0.02MPa in the early stage of melting and heating, and the low negative pressure inhibits the extraction of urea vapor and minimizes sublimation loss; the negative pressure is adjusted to -0.03~-0.04MPa in the stable stage of melting and cyclization, and the by-product ammonia gas is steadily extracted to promote the forward reaction; (3) Gradient temperature control for deep ammonia removal: After the melting cyclization is completed, the temperature is kept at 128-130℃ for deep closed-loop reaction, while maintaining a negative pressure of -0.03--0.04MPa. Then the temperature is raised to 133-135℃ and kept at that temperature to completely remove residual ammonia. During this stage, the negative pressure is increased to -0.04--0.05MPa to enhance deep ammonia removal and ensure complete conversion of raw materials. (4) Segmented cooling, water replenishment, and pulping: After the reaction reaches the standard, cool down to 80-85℃, add 85℃ hot water in stages for pulping, with a material-to-water ratio of 1:(2.5-2.8); after water replenishment, cool down to 40-45℃, and the material will naturally disperse and suspend. No in-vessel crushing is performed throughout the process. After condensation, the temperature must be lowered before water replenishment to avoid splashing of materials at high temperatures, localized sudden cooling and clumping, and product yellowing.

[0007] (5) Low-temperature centrifugal filtration and mother liquor circulation: the material and liquid are separated by centrifugation, and the filter cake is washed with hot water to obtain the finished product; the centrifugal mother liquor is concentrated to recover unreacted urea and trace products, and all of them are recycled to the next batch of pulping process, and the wastewater is not discharged.

[0008] Furthermore, in step (1), nitrogen is used to replace the air in the reactor three times; the flow rate of the micro-flow nitrogen gas phase purge is 0.05 times the gas phase volume in the reactor / min, and only the gas phase is purged without stirring the bottom solid phase material to prevent raw material dust loss; the stirring rate is 40 rpm.

[0009] Furthermore, in steps (1) and (2), the total molar ratio of o-phenylenediamine to urea is 1:(1.10~1.15). When the molar ratio of urea is higher than 1.15, biuret impurities are easily generated, and the negative pressure instantaneous surge of the reactor is likely to occur.

[0010] Furthermore, in step (2), during the entire melting and cyclization process, low-pressure atomized water vapor of 0.1–0.2 MPa is intermittently injected into the upper gas phase space inside the reactor. The water mist only contacts the gas phase and does not enter the liquid phase; it floats in the gas phase space and does not drip into the bottom reaction liquid phase. The water mist cools the urea vapor in the gas phase, causing it to condense into droplets, which fall back into the reactor by gravity, preventing dry urea crystals from clogging the vacuum pipeline. At the same time, the water mist increases the humidity of the gas phase, significantly improving the water solubility of ammonia and reducing the escape of ammonia from the tail gas. The water mist vaporizes instantly at a reactor temperature above 118°C, without changing the ratio of reactants, without causing hydrolysis of raw materials, and without interfering with the cyclization reaction.

[0011] Furthermore, in step (2), each spray lasts 4-5 seconds, and sprays are repeated every 15 minutes.

[0012] Furthermore, in step (2), the water mist particle size is 80 μm.

[0013] Furthermore, in step (3), the temperature is kept at 128-130℃ for 2 hours.

[0014] Furthermore, in step (3), the temperature is maintained at 133-135℃ for 1.5 hours.

[0015] Furthermore, in step (3), the condensation endpoint is determined by using high performance liquid chromatography (HPLC) to detect the residual o-phenylenediamine raw material in the reactor to be ≤0.3%; the maximum reaction temperature in the reactor is strictly controlled not to exceed 135℃.

[0016] Compared with the prior art, the present invention has the following main advantages: 1. This invention employs a low-temperature solid-phase premixing process, organic acid compounding for oxidation and color inhibition, micro-flow nitrogen for full-process gas-phase deoxygenation, temperature-triggered batch urea feeding, segmented gradient negative pressure control, gas-phase micro-water mist condensation to prevent sublimation, pre-cooling followed by hot water pulping, and direct centrifugation without pulverization—an integrated coupled process that solves all industry pain points at once, achieving unexpected synergistic technological effects. The entire process is solvent-free, involves low-temperature reactions (maximum reaction temperature ≤135℃), eliminates high-temperature coking and agglomeration, removes boron, sulfur, and heteroatom residues, prevents urea sublimation and pipe blockage, minimizes ammonia escape, minimizes impurity content, eliminates the need for in-vessel pulverization, is compatible with downstream hydrogenation, and requires no modification to existing equipment (using existing conventional closed intermittent vessel operation). The product can be directly adapted to downstream hydrogenation processes, ensuring high yield and purity. The product yield is consistently maintained at 99.6%, with a purity of 99.8%–99.9%.

[0017] 2. This invention adopts a three-stage segmented temperature control and gradient negative pressure deammoniation process, which is different from solvent azeotropic deammoniation and solvent-free patent CN117447405A, which discloses a one-step melting and feeding process and a single high-temperature heat preservation synthesis process under normal pressure. The entire process is carried out at low temperature to avoid carbonization and discoloration of materials, and the raw material conversion rate is higher.

[0018] 3. This invention employs a low-temperature solid-phase premixing and heat preservation technology at 85–95℃, ensuring uniform pre-complexation of raw materials, eliminating localized hot spots, preventing charring and discoloration, and resulting in a stable blue light whiteness of the product ≥90. Blue light whiteness is an index representing the whiteness of the sample using the blue light diffuse reflectance factor (R457).

[0019] 4. This invention employs a three-stage low-temperature segmented condensation + a three-stage gradient negative pressure differential control, which protects raw materials in the early stage and ensures conversion in the later stage, resulting in very few side reactions and extremely high raw material conversion rate.

[0020] 5. This invention uses micro-flow nitrogen gas for full-process gas-phase deoxygenation, combined with organic compound additives, to form a dual anti-oxidation system, completely solving the problem of material oxidation and yellowing.

[0021] 6. This invention uses temperature-triggered precision batch feeding of urea to eliminate the generation of biuret impurities, thus significantly improving product purity.

[0022] 7. This invention uses gas-phase micro-volume intermittent atomization of water mist, which does not require equipment modification and simultaneously achieves the triple effects of preventing urea sublimation, preventing pipeline blockage, and reducing ammonia escape, without any risk of pipe blockage.

[0023] 8. This invention employs a method of cooling down after condensation and then adding water, resulting in stable crystallization and dispersion of the material, eliminating the need for expensive in-vessel crushing equipment, and allowing direct filtration via centrifuge.

[0024] 9. This invention involves no organic solvents, no solvent VOCs, no waste liquid discharge, and full recycling of the mother liquor, making it green and environmentally friendly.

[0025] 10. This invention uses boron- and sulfur-free inorganic salt additives, leaving no impurity atoms, eliminating the need for subsequent impurity removal processes, and allowing the product to be directly adapted to downstream palladium-carbon hydrogenation deep processing. Detailed Implementation

[0026] The technical solution of the present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0027] Example 1 A novel solvent-free, low-temperature, micro-negative-pressure segmented preparation process for benzimidazolone: (1) Low-temperature solid-phase premixing: 1000 kg o-phenylenediamine (9.25 kmol) was added to a closed reactor, followed by the first batch of 550 kg urea (9.16 kmol), and 0.9 kg ascorbic acid + 2.25 kg anhydrous citric acid were added as a compound color-inhibiting agent (the total amount added accounted for 0.32 wt% of the mass of o-phenylenediamine); nitrogen was purged 3 times, stirred at 40 rpm, and micro-flow nitrogen was turned on for gas phase purging. The temperature was raised to 90℃ and the solid phase was kept warm for 1 hour. The material remained solid throughout the process.

[0028] (2) Medium-temperature melting and cyclization: wait for the temperature inside the reactor to reach 118°C precisely, and add the second batch of 60kg of urea (the total molar ratio of urea is o-phenylenediamine: urea = 1:1.10); heat up to 122°C to melt the material, initially turn on the low negative pressure of -0.015MPa, and adjust it to -0.03MPa after the cyclization is stable; spray low-pressure atomized water vapor into the gas phase for 4s every 15 minutes, and the water mist does not contact the liquid phase throughout the process.

[0029] (3) Gradient deep deammoniation: Heat to 128℃ and hold for 2 hours for deep cyclization, and maintain negative pressure at -0.03MPa; continue to heat to 133℃ and hold for 1.5 hours for complete deammoniation, and adjust negative pressure to -0.045MPa; control the residual o-phenylenediamine to 0.27%, and reach the reaction endpoint.

[0030] (4) Segmented cooling and water replenishment: After the condensation is completed, the temperature is first reduced to 80℃, and 2500kg of 85℃ hot water (material-to-water ratio 1:2.5) is slowly added in 3 batches to make a pulp; after the water replenishment is completed, the temperature is further reduced to 40℃, and the material is naturally dispersed and suspended without in-vessel crushing.

[0031] (5) Centrifugal filtration: The liquid in the vessel is discharged to a centrifuge, centrifuged and separated, and rinsed with a small amount of hot water to obtain benzimidazole wet product; the centrifugal mother liquor is collected, concentrated and recycled to the next batch of water replenishment process.

[0032] Test results: The products in this embodiment are all high-whiteness white crystalline particles, with a product yield of 99.6% and a purity of 99.9%. This invention is free of organic solvents, boron and sulfur impurities, and pipeline blockages throughout the entire process. Ammonia escape is reduced by 42%. It does not require in-reactor crushing, has low equipment investment, and can be directly matched with downstream hydrogenation production lines, effectively reducing overall production costs.

[0033] Example 2 A novel solvent-free, low-temperature, micro-negative-pressure segmented preparation process for benzimidazolone: (1) Low-temperature solid-phase premixing: 1000 kg o-phenylenediamine (9.25 kmol) was put into a closed reactor, the first batch of urea was 570 kg (9.49 kmol), and 1.50 kg ascorbic acid + 3.75 kg anhydrous citric acid were added as compound additives (the total amount added accounted for 0.55 wt% of the mass of o-phenylenediamine); nitrogen was replaced 3 times, stirred at 40 rpm, purged with micro-flow nitrogen, and heated to 95℃ and kept in solid phase for 1 hour. The material was solid throughout the process.

[0034] (2) Melting and cyclization: The temperature of the kettle is precisely set to 118℃ and 75kg of the second batch of urea is added (the total molar ratio of urea is o-phenylenediamine: urea = 1:1.15); the temperature is raised to 125℃ for melting, the negative pressure is -0.02MPa in the early stage, and then switched to -0.04MPa after stabilization; spray gas phase water mist for 5s every 15min, the water mist particle size is 80μm, the pressure is 0.2MPa, and it only contacts the gas phase.

[0035] (3) Deep deammoniation: keep warm at 130℃ for 2 hours, negative pressure -0.04MPa; raise the temperature to 135℃ and keep warm for 1.5 hours, negative pressure increased to -0.05MPa; the residual o-phenylenediamine is controlled at 0.24%, reaching the endpoint.

[0036] (4) Cooling and pulping: First cool down to 85℃, then add 2580kg of 85℃ hot water in batches, with a material-to-water ratio of 1:2.8; after adding water, cool down to 45℃, and the material will naturally loosen and suspend without being crushed in the kettle.

[0037] (5) Centrifugal filtration: Wash the filter cake with hot water and concentrate the mother liquor for recycling.

[0038] Test results: Product purity 99.8%, yield 99.6%, pure white crystal appearance, no oxidation or yellowing, and no urea crystal blockage in the vacuum pipeline.

Claims

1. A novel solvent-free, low-temperature, micro-negative-pressure segmented preparation process for benzimidazolone, characterized in that, Includes the following steps: (1) Low-temperature solid-phase premixing: o-phenylenediamine, the first batch of urea, and a color-inhibiting agent composed of ascorbic acid and anhydrous citric acid are added to a closed reactor. The molar ratio of o-phenylenediamine to the first batch of urea is 1: (0.99~1.02). The total amount of additives added is 0.32wt%~0.55wt% of the mass of o-phenylenediamine. The mass ratio of ascorbic acid to anhydrous citric acid is 1:2.

5. Nitrogen replaces the air in the reactor. Nitrogen is continuously purged at a low flow rate to isolate oxygen. The mixture is stirred at low speed and heated to 90~95℃ for solid-phase heat preservation. The material remains solid and does not melt throughout the process. (2) Segmented heating and micro-negative pressure melting and cyclization: When the system is precisely heated to 118±2℃, the second batch of urea is added. The molar ratio of o-phenylenediamine to the second batch of urea is 1:(0.11~0.13). If the temperature does not meet the standard, the material is strictly prohibited from being added. Continue to slowly heat up to 122~125℃, and the material gradually melts. Turn on segmented gradient negative pressure: In the early stage of melting and heating, the negative pressure is controlled at -0.01~-0.02MPa. In the stable stage of melting and cyclization, the negative pressure is adjusted to -0.03~-0.04MPa. (3) Gradient temperature control for deep ammonia removal: After the melting cyclization is completed, the temperature is kept at 128-130℃ for deep closed-loop reaction, while maintaining a negative pressure of -0.03--0.04MPa. Then the temperature is raised to 133-135℃ and kept at that temperature to completely remove residual ammonia. During this stage, the negative pressure is increased to -0.04--0.05MPa to enhance deep ammonia removal. (4) Segmented cooling and water replenishment for pulping: After the reaction reaches the standard, cool down to 80-85℃, add 85℃ hot water in stages for pulping, with a material-to-water ratio of 1:(2.5-2.8); after replenishing water, cool down to 40-45℃; (5) Low-temperature centrifugal filtration and mother liquor circulation: the material and liquid are separated by centrifugation, and the filter cake is washed with hot water to obtain the finished product; the centrifugal mother liquor is concentrated to recover unreacted urea and trace products, and all of them are recycled to the next batch of pulping process, and the wastewater is not discharged.

2. The novel process for solvent-free, low-temperature, micro-negative pressure segmented preparation of benzimidazolone according to claim 1, characterized in that, In step (1), the air inside the reactor is replaced with nitrogen three times; the flow rate of the micro-flow nitrogen gas phase purging is 0.05 times the gas phase volume inside the reactor / min, only the gas phase is purged without stirring the bottom solid phase material to prevent raw material dust loss; the stirring speed is 40 rpm.

3. The novel process for solvent-free, low-temperature, micro-negative pressure segmented preparation of benzimidazolone according to claim 1, characterized in that, In steps (1) and (2), the total molar ratio of o-phenylenediamine to urea is 1:(1.10 to 1.15).

4. The novel process for solvent-free, low-temperature, micro-negative pressure segmented preparation of benzimidazolone according to claim 1, characterized in that, In step (2), during the entire melting and cyclization process, low-pressure atomized water vapor of 0.1 to 0.2 MPa is intermittently injected into the upper gas phase space inside the reactor.

5. A novel solvent-free, low-temperature, micro-negative pressure segmented preparation process for benzimidazolone according to claim 4, characterized in that, In step (2), each spray lasts 4-5 seconds, and sprays are repeated every 15 minutes.

6. The novel process for solvent-free, low-temperature, micro-negative pressure segmented preparation of benzimidazolone according to claim 4, characterized in that, The water mist particle size in step (2) is 80 μm.

7. The novel process for solvent-free, low-temperature, micro-negative pressure segmented preparation of benzimidazolone according to claim 1, characterized in that, In step (3), keep warm at 128-130℃ for 2 hours.

8. The novel process for solvent-free, low-temperature, micro-negative pressure segmented preparation of benzimidazolone according to claim 1, characterized in that, In step (3), keep warm at 133-135℃ for 1.5 hours.

9. A novel solvent-free, low-temperature, micro-negative pressure segmented preparation process for benzimidazolone according to claim 1, characterized in that, In step (3), the condensation endpoint is determined by detecting the residual o-phenylenediamine raw material in the reactor at ≤0.3% using high performance liquid chromatography; the maximum reaction temperature in the reactor is strictly controlled not to exceed 135℃.

10. A novel solvent-free, low-temperature, micro-negative pressure segmented preparation process for benzimidazolone according to claim 1, characterized in that, The finished product in step (5) has a stable blue light whiteness of ≥90.