Iminodibenzyl cyclization continuous flow synthesis process

Abstract

The invention discloses a cyclization continuous flow synthesis process of iminodibenzyl. 2, 2 '-diamino bibenzyl is used as a raw material, polyphosphoric acid is used as a cyclization agent, toluene is used as a dispersion medium, the efficient heat and mass transfer characteristic of the microchannel reactor is utilized, the reaction temperature is controlled within 85 + / -2 DEG C, meanwhile, the material ratio and the retention time are optimized, generation of high-polymer impurities is inhibited from the source, no remarkable high-polymer impurities exist in reaction liquid, a rectification purification process is not needed, and the production cost is reduced. And washing the toluene layer with phosphoric acid, washing with clear water, and crystallizing to obtain a high-purity qualified product. In the product obtained by the process, the content of high polymer impurities is less than or equal to 0.003 wt%, the residue of 2, 2 '-diamino bibenzyl is less than or equal to 0.0002 wt%, the purity of the product is more than or equal to 99.8%, and the molar yield reaches 93.2%; the toluene solvent recycling rate is greater than or equal to 95%, the discharge amount of three wastes is reduced by more than 70% compared with that of a traditional intermittent process, and the method has the advantages of product quality improvement, production efficiency improvement and environmental protection, and can be directly applied to large-scale production of antiepileptic drug oxcarbazepine and carbamazepine intermediates.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a continuous flow synthesis process for iminodibenzyl cyclization, which is particularly suitable for the large-scale and efficient preparation of the antiepileptic drugs oxcarbazepine and carbamazepine, as well as the intermediate iminodibenzyl for antidepressants. Background Technology

[0002] Iminodibenzyl (10,11-dihydro-5H-dibenzo[b,f]azazepine) is a core intermediate in the synthesis of first-line antiepileptic drugs such as carbamazepine and oxcarbazepine. The efficiency of its synthesis process and the purity of the product directly determine the quality and production cost of the downstream drugs.

[0003] Currently, the core reaction for the industrial preparation of iminodibenzyl is the intramolecular cyclization reaction of 2,2'-diaminobibenzyl. Based on different reaction process modes and catalytic systems, four mainstream technical routes have been formed. The technical characteristics and existing problems of each route are as follows: 1. Cyclic acid phosphate batch process This route is the most widely used traditional process in industrial applications, using polyphosphoric acid as a cyclizing catalyst and carrying out a batch cyclization reaction at a high temperature of 275~285℃ (refer to patent CN116836117A). The core principle is that polyphosphoric acid has both strong acidity and dehydration properties, which can promote the formation of a six-membered nitrogen heterocycle within the 2,2'-diaminobibenzyl molecule. However, it has significant drawbacks: low mass and heat transfer efficiency in the batch reactor, temperature fluctuations of more than ±10℃ during polyphosphoric acid dropwise, and high polymeric impurity generation of 0.27~1.73wt%; uneven material mixing leads to local over-reaction, high residual 2,2'-diaminobibenzyl, and a product yield of only 88~90% (refer to patent CN117430553A). Although patent CN102391182A improves the purity to over 99.0% through nitrogen vacuum distillation, it requires an additional rectification step, making the process lengthy and energy-intensive, and it does not solve the problem of poor batch stability in batch operation.

[0004] 2. Phosphoric acid-catalyzed salt formation cyclization process This route, disclosed by a relevant company in patent CN102391182A, involves first forming a salt with 2,2'-diaminobibenzyl and phosphoric acid, then cyclizing it at a higher temperature, followed by washing and recrystallization for purification. Its advantages include increased reaction selectivity after salt formation, fewer side reactions, and a purity ≥99.0%. However, it requires additional salt formation and desalting steps, making the process cumbersome. Furthermore, the amount of phosphoric acid used is more than twice the molar amount of the raw materials, resulting in large amounts of waste acid emissions and high treatment costs, making it difficult to promote in small and medium-sized enterprises.

[0005] 3. Gas-phase catalytic cyclization process This route uses γ-alumina as a catalyst in a fixed-bed reactor at 300–500°C and 0.15–0.40 MPa, with steam as a diluent for gas-phase cyclization (refer to patent CN201110327979.8). Its advantages include a feed conversion rate of 90–99%, a selectivity of 95–98%, and the ability to recover waste heat to reduce energy consumption. However, the reaction temperature is too high, the reactor requires stringent high-temperature and corrosion resistance, the catalyst is prone to carbon buildup and deactivation requiring periodic regeneration, and the equipment investment and maintenance costs are high, making it only suitable for ultra-large-scale production.

[0006] 4. Liquid-phase cyclization process for supported catalysts Patent CN117430553A discloses a catalytic system in which boron trifluoride-ferric chloride composite catalyst is supported on diatomaceous earth. Cyclone is achieved under liquid phase conditions of 280-300℃ with a yield of 95.7-98.6% and no obvious high-polymer impurities. However, the catalyst preparation requires high precision, the loading of active components needs to be precisely controlled at around 8%, and the recovery and regeneration are difficult, resulting in high catalyst costs, which limits its industrial application.

[0007] In summary, existing iminodibenzyl cyclization processes suffer from drawbacks such as high reaction temperatures, numerous byproducts, lengthy processes (requiring distillation purification), high costs, and poor batch stability. Continuous flow synthesis technology, with its advantages of precise temperature control, uniform material mixing, and closed-loop operation, can achieve low-temperature and high-efficiency reactions, suppressing byproducts at the source and eliminating the need for distillation, thus becoming the key to solving the bottlenecks of traditional processes. Summary of the Invention

[0008] 1. Purpose of the invention The purpose of this invention is to provide a continuous flow synthesis process for iminodibenzyl cyclization. By utilizing the efficient heat and mass transfer characteristics of a microchannel reactor, precise low-temperature temperature control (83-87℃, temperature fluctuation ≤±2℃), and an integrated post-processing flow, this process solves the problems of large temperature fluctuations, numerous impurities, the need for high-temperature reactions, the need for distillation purification, and batch instability in traditional batch processes. At the same time, it improves product yield and purity, and reduces safety risks and environmental pressures in the production process.

[0009] 2. Technical Solution A continuous flow synthesis process for iminodibenzyl cyclization specifically includes four core steps: raw material pretreatment, continuous cyclization reaction, phosphoric acid washing and water washing, and crystallization drying. This process eliminates the traditional distillation purification step, high-temperature reaction conditions, and additional filtration for impurity removal. The core technology lies in the precise low-temperature temperature control and efficient material mixing of the microchannel reactor, suppressing the formation of high-polymer impurities at the source. (1) Raw material pretreatment: In storage tank A, a solution of toluene and 2,2'-diaminobibenzyl is prepared and preheated to 45-55°C to avoid material crystallization and blockage of pipelines at low temperature; in storage tank B, polyphosphoric acid is kept at a constant temperature of 40-50°C to maintain its good fluidity and ensure feed stability, laying the foundation for subsequent continuous reaction.

[0010] (2) Continuous cyclization reaction: Dual high-precision feed pumps (flow error ≤ ±1%) synchronously deliver materials to the microchannel reactor, precisely controlling the reaction temperature at 83-87℃, pressure at 0.1-0.3MPa, and residence time at 30-40min. The reaction temperature must be strictly controlled within the range of 83-87℃, with temperature fluctuations not exceeding ±2℃. This precise temperature control capability relies on the reactor's efficient heat transfer characteristics (heat transfer coefficient ≥6000W / (m²·K)), combined with ≥98% material mixing uniformity, to efficiently complete the cyclization reaction under low-temperature conditions, suppressing the generation of high-polymer impurities from the source, ensuring that the content of high-polymer impurities in the reaction liquid is ≤0.003wt%, eliminating the need for subsequent distillation purification and filtration, and greatly simplifying the process.

[0011] (3) Phosphoric acid washing and water washing: The cyclization reaction solution is directly fed into the washing vessel. At an optimized temperature of 50-60℃, 85% phosphoric acid is added dropwise according to the ratio. The mixture is thoroughly stirred (300-400 r / min, 40-50 min) to remove residual 2,2'-diaminobibenzyl by utilizing the specific salt formation reaction between amino groups and acids. After standing and separating the layers, the phosphoric acid solution containing impurities is discharged. The upper organic phase is directly washed with deionized water to remove residual phosphoric acid and further purify the organic phase. The purity of the organic phase can be increased to over 99.8%, replacing the traditional complex purification method. The phosphoric acid washing solution can be recycled 2-3 times, requiring only 30-40% of the initial amount to be replenished, reducing acid consumption.

[0012] (4) Crystallization and drying: The purified iminodibenzyltoluene solution is pumped into a crystallizer and crystallized using a segmented cooling mode (first cooling to 32℃ at a rate of 5℃ / h and holding for 10 min, then cooling to 5-10℃ at a rate of 10℃ / h and holding for 20-25 min) to facilitate subsequent solid-liquid separation; the separated solid product is sent to a vacuum dryer and dried for 2 h at 60-70℃ and -0.09~-0.1MPa to ensure a water content ≤0.1% and obtain a high-purity finished product. The filtered mother liquor is sent to a solvent recovery tower, and the toluene is dehydrated and recycled to reduce solvent consumption.

[0013] 3. Beneficial effects

[0014] (1) Extremely simplified process and significantly reduced energy consumption: The microchannel reactor achieves low-temperature reaction at 83-87℃, which reduces energy consumption by more than 70% compared with the traditional process (275-285℃); the reaction liquid does not need to be purified by distillation and filtered to remove impurities. It can obtain high-purity products by washing and crystallization, shortening the process by 40% and reducing equipment investment by 20%.

[0015] (2) Excellent product quality and yield: Continuous and precise control reduces material loss and side reactions, product purity ≥99.8%, molar yield reaches 93.2%, which is 3-5 percentage points higher than the traditional batch process; batch-to-batch product quality difference ≤0.05%, which completely solves the industry pain point of batch instability in the traditional process.

[0016] (3) Green environmental protection and cost advantages: Toluene solvent recycling rate ≥95%, solvent consumption per unit product reduced by 90%; phosphoric acid washing liquid recycling reduces acid consumption by 50%; waste emissions are reduced by more than 70% compared with traditional processes, and environmental treatment costs are reduced by 65%; unloaded catalyst cost, and the comprehensive cost per ton of product is reduced by 18%. Detailed Implementation

[0017] The present invention will be further described in detail below with reference to specific embodiments. The described embodiments are only used to explain the present invention and are not intended to limit the scope of protection of the present invention. Example 1

[0018] (1) Raw material pretreatment: Add 10 kg of toluene to storage tank A, then add 3 kg of 2,2'-diaminobibenzyl (purity 99.0%), turn on the stirrer and stir at a rate of 200 r / min for 30 min until completely dissolved, then send it to the preheater to heat to 45℃ and keep it at the temperature to obtain the material in storage tank A; add 2.85 kg of polyphosphoric acid to storage tank B, and control the temperature at 40℃ through a constant temperature jacket device to obtain the material in storage tank B.

[0019] (2) Continuous cyclization reaction: The first feed pump (flow error 0.8%) delivers the material from storage tank A at a flow rate of 180 ml / min, and the second feed pump (flow error 0.7%) delivers the material from storage tank B at a flow rate of 28 ml / min. The materials are simultaneously fed into the microchannel reactor (heat transfer coefficient 6200 W / (m²·K)). The reactor temperature is controlled at 83℃ (fluctuation ±1.2℃), the pressure is 0.1 MPa, and the material residence time is 40 min to obtain the cyclization reaction liquid. The content of high polymer impurities in the reaction liquid is 0.0028 wt%.

[0020] (3) Phosphoric acid washing and water washing: The cyclization reaction solution was transferred into a 50L washing vessel, and the temperature inside the vessel was controlled at 50℃. 0.4kg of 85% phosphoric acid (13.3% of the weight of 2,2'-diaminobibenzyl) was added dropwise. The stirrer was turned on and stirred at a rate of 300r / min for 40min. Then, the mixture was allowed to stand for 15min to separate into layers. The lower layer containing impurities of phosphoric acid solution was discharged. 24kg of deionized water was added to the upper organic phase. After stirring for 15min, the mixture was allowed to stand for 15min to separate into layers. The lower aqueous phase was removed to obtain the purified iminodibenzyl toluene solution.

[0021] (4) Crystallization and drying: The washed organic phase is pumped into the crystallizer, cooled to 32°C at a rate of 5°C / h and held for 10 min, then cooled to 8°C at a rate of 10°C / h and held for 25 min. The solid-liquid separation is then carried out by a plate and frame filter press. The solid product is sent to a vacuum dryer and dried at 60°C and -0.1 MPa for 2 h to obtain 2.56 kg of iminodibenzyl product.

[0022] Test results: Product purity 99.85%, molar yield 92.8%, high polymer impurity content 0.0028wt%, 2,2'-diaminobibenzyl residue 0.00015wt%, moisture content 0.08%. Example 2

[0023] (1) Raw material pretreatment: Add 12 kg of toluene to storage tank A, then add 3 kg of 2,2'-diaminobibenzyl (purity 99.2%), stir at 300 r / min for 30 min to dissolve, and preheat to 55℃ and keep warm; add 2.9 kg of polyphosphoric acid to storage tank B and control the temperature at 50℃.

[0024] (2) Continuous cyclization reaction: The first feed pump (flow error 0.9%) has a flow rate of 220 ml / min, and the second feed pump (flow error 0.8%) has a flow rate of 30 ml / min. They are simultaneously fed into the microchannel reactor (heat transfer coefficient 6500 W / (m²·K)). The reactor temperature is 87℃ (fluctuation ±1.5℃), the pressure is 0.3 MPa, the material residence time is 30 min, and the content of high polymer impurities in the reaction liquid is 0.0025 wt%.

[0025] (3) Phosphoric acid washing and water washing: The cyclization reaction solution was transferred into a 50L washing vessel, the temperature was controlled at 60℃, 0.45kg of 85% phosphoric acid (15% of the weight of 2,2'-diaminobibenzyl) was added dropwise, and the mixture was stirred at a rate of 400r / min for 50min. After standing and separating into layers, the phosphoric acid solution was discharged. The organic phase was washed with water in the same way as in Example 1.

[0026] (4) Crystallization and drying: Cool down to 5℃ and keep warm for 20 min. Vacuum drying conditions are 70℃ and -0.09MPa. Dry for 2 h to obtain 2.58 kg of iminodibenzyl product.

[0027] Test results: Product purity 99.88%, molar yield 93.2%, high polymer impurity content 0.0025wt%, 2,2'-diaminobibenzyl residue 0.00012wt%, moisture content 0.07%.

[0028] Example 3 (Phosphoric acid recycling) (1)-(2) are the same as in Example 1.

[0029] (3) Phosphoric acid washing and water washing: 0.4 kg of 85% phosphoric acid was used for the first washing. After stirring and washing, the lower layer of phosphoric acid solution was collected. The second time, the phosphoric acid solution was reused and 0.12 kg of fresh phosphoric acid (30% of the initial amount) was added. The other washing parameters were the same as in Example 1. When using it for the third time, 0.14 kg of fresh phosphoric acid (35% of the initial amount) was added. The washing effect was stable.

[0030] (4) The steps are the same as in Example 1, and finally 2.55 kg of iminodibenzyl product is obtained.

[0031] Test results: Product purity 99.84%, molar yield 92.5%, high polymer impurity content 0.0029wt%, 2,2'-diaminobibenzyl residue 0.00016wt%, and total phosphoric acid consumption reduced by 52% compared to Example 1.

[0032] Comparative Example 1 (Traditional batch polyphosphoric acid process) Add 3 kg of 2,2'-diaminobibenzyl to a 50 L batch reactor, heat to 230 °C, and then add 2.85 kg of polyphosphoric acid dropwise at a rate of 2.8 kg / min. After the addition is complete, raise the temperature to 275-285 °C and keep it at that temperature for 4 h. Let the reaction solution stand to separate into layers to remove waste acid, add 10 kg of toluene to dissolve it, add 0.4 kg of phosphoric acid dropwise at 83 °C to wash it, wash it with water, purify it by vacuum distillation, cool it down to crystallize it, filter and dry it to obtain 2.42 kg of iminobibenzyl product.

[0033] Test results: Product purity 98.62%, molar yield 88.5%, high polymer impurity content 0.135wt%, 2,2'-diaminobibenzyl residue 0.01095wt%, energy consumption 3.5 times that of Example 1, and waste emissions 3.8 times that of Example 1.

[0034] Effect Comparison and Analysis 1. Comparison with traditional batch polyphosphoric acid production process (Comparative Example 1) The process of this invention achieves low-temperature reaction (83-87℃ vs 275-285℃), reducing energy consumption by more than 70%; it eliminates distillation and filtration processes, shortening the process by 40%; it increases product yield by 4.3-4.7 percentage points, purity by 1.23-1.26 percentage points, reduces high-polymer impurity content by more than 98%, reduces 2,2'-diaminobibenzyl residue by more than 99%, reduces waste emissions by 70%, and lowers overall production costs by 18%.

[0035] 2. Impact Analysis of Key Process Parameters Reaction temperature is a key parameter affecting impurity formation. This invention strictly limits it to 83-87℃ with fluctuations ≤±2℃. This range ensures sufficient cyclization of 2,2'-diaminobibenzyl (conversion rate ≥99%) while avoiding high-polymerization reactions caused by excessively high temperatures. Comparative experiments show that when the temperature rises to 90℃, the content of high-polymer impurities increases sharply to 0.012wt%; when the temperature drops to 80℃, the reaction conversion rate is less than 90%, further confirming the scientific validity and necessity of this temperature range. The high-efficiency heat transfer capability of the microchannel reactor (heat transfer coefficient ≥6000W / (m²·K)) is the key guarantee for achieving this precise control.

[0036] Although specific embodiments have been used to describe the technical solutions of the present invention in detail in this specification, any modifications or improvements made by those skilled in the art based on the inventive concept in terms of specific implementation methods and application scope are all within the scope of protection claimed by the present invention. Therefore, the content described in this specification should not be construed as a limitation of the present invention.

Claims

1. A continuous flow synthesis process for iminodibenzyl cyclization, characterized in that, Includes the following steps: (1) Raw material pretreatment: Add 10-12 parts by weight of toluene to storage tank A, and then add 3 parts by weight of 2,2'-diaminobibenzyl (purity ≥99.0%). Turn on the stirrer and stir at a rate of 200-300 r / min for 30 min until completely dissolved. Then send the material to the preheater to heat to 45-55℃ and keep it at the temperature to avoid low-temperature crystallization, and obtain the material in storage tank A; add 2.85-2.9 parts by weight of polyphosphoric acid to storage tank B, and control the temperature in storage tank B at 40-50℃ through a constant temperature jacket device to maintain the fluidity of polyphosphoric acid, and obtain the material in storage tank B; (2) Continuous cyclization reaction: A high-precision plunger-type first feed pump is used to transport the material in storage tank A to the microchannel reactor at a flow rate of 180-220 ml / min. A second feed pump is used to simultaneously transport the material in storage tank B to the microchannel reactor at a flow rate of 28-30 ml / min. The reaction temperature of the microchannel reactor is controlled at 83-87℃ (temperature fluctuation ≤ ±2℃), the reaction pressure is 0.1-0.3 MPa, and the residence time of the material in the reactor is 30-40 min to complete the cyclization reaction and obtain the cyclization reaction liquid. The cyclization reaction solution contains ≤0.003wt% high polymer impurities, eliminating the need for distillation purification and filtration. (3) Phosphoric acid washing and water washing: The cyclization reaction solution is fed into the washing vessel and the temperature inside the washing vessel is controlled at 50-60℃. 85% phosphoric acid is added dropwise at a ratio of 13.3-15% of the weight of 2,2'-diaminobibenzyl. The stirrer is turned on and stirred at a rate of 300-400r / min for 40-50min. Then the material is allowed to stand for 15min to separate into layers. The lower layer containing impurities is discharged. 24 parts by weight of deionized water is added to the upper organic phase. After stirring for 15min, the material is allowed to stand for 15min to separate into layers. The lower aqueous phase is removed to obtain the purified iminodibenzyl toluene solution. (4) Crystallization and drying: The water-washed iminodibenzyl toluene solution is pumped into the crystallizer, first cooled to 32°C at a rate of 5°C / h and kept at that temperature for 10 min, then cooled to 5-10°C at a rate of 10°C / h and kept at that temperature for 20-25 min. Subsequently, the material is subjected to solid-liquid separation, and the solid product is sent to a vacuum dryer for drying to obtain the iminodibenzyl product. The filtered mother liquor is sent to a solvent recovery tower, and the recovered toluene is dehydrated and then recycled to storage tank A for reuse.

2. The continuous flow synthesis process for iminodibenzyl cyclization according to claim 1, characterized in that: In step (2), the flow rate error of the first feed pump and the second feed pump is ≤ ±1% to ensure that the mass ratio of 2,2'-diaminobibenzyl to polyphosphoric acid is stable at 1:0.95~0.

97.

3. The continuous flow synthesis process for iminodibenzyl cyclization according to claim 1, characterized in that: The heat transfer coefficient of the microchannel reactor described in step (2) is ≥6000W / (m²·K), and the mixing uniformity of the material in the reactor is ≥98%. The generation of high polymer impurities is suppressed from the source through efficient heat and mass transfer.

4. The continuous flow synthesis process for iminodibenzyl cyclization according to claim 1, characterized in that: The temperature of the continuous cyclization reaction in step (2) is strictly controlled within the range of 83-87℃, and the temperature fluctuation does not exceed ±2℃.

5. The continuous flow synthesis process for iminodibenzyl cyclization according to claim 1, characterized in that: The phosphoric acid washing unit described in step (3) can be circulated 2-3 times, with each phosphoric acid replenishment amount being 30-40% of the initial amount added, thereby reducing phosphoric acid consumption.

6. The continuous flow synthesis process for iminodibenzyl cyclization according to claim 1, characterized in that: The vacuum drying conditions described in step (4) are a drying temperature of 60-70℃, a system vacuum degree of -0.09~-0.1MPa, and a drying time of 2h, ensuring that the product moisture content is ≤0.1%.