Triazole microjet continuous synthesis process

Abstract

The invention discloses a microjet continuous synthesis process of triazole. The method comprises the following steps: preheating formamide, keeping hydrazine hydrate at normal temperature, continuously conveying hydrazine hydrate to a microjet mixing reactor through independent feeding channels according to a molar ratio of 4: 1 to 6: 1, and carrying out high-speed jet mixing and reaction in a mixing cavity; continuously conveying a reaction product to a buffer heat preservation tank for heat preservation reaction; and rectifying to recover formamide for recycling, and crystallizing a tower bottom material to obtain a triazole product. According to the invention, the whole-process continuous production of triazole synthesis is realized, so that the product quality is stable, the batch-to-batch fluctuation is small, the occupied area of equipment is reduced by about 80%, and the automation degree is high. By implementing the method disclosed by the invention, a high-quality triazole product with the yield of more than or equal to 95%, the purity of more than or equal to 99% and the content of 4-aminotriazole by-products of less than or equal to 1% can be produced, the pharmaceutical-grade standard requirements are completely met, and a new process route which is advanced in technology, economical, reasonable and environment-friendly is provided for industrial production of triazole.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a triazole microfluidic continuous synthesis process. Background Technology

[0002] 1,2,4-Triazole is an important nitrogen-containing heterocyclic compound widely used in the pharmaceutical, pesticide, and fine chemical industries. In particular, it serves as a key intermediate for various triazole fungicides (such as tebuconazole and hexaconazole), and its purity is extremely important in the pharmaceutical industry. Currently, the industrial method commonly uses the condensation of formamide and hydrazine hydrate at high temperatures to prepare triazole. This process is typically carried out in a batch reactor, where hydrazine hydrate is slowly added dropwise to formamide preheated to 175-185°C, and the reaction takes 2-4 hours. Although the raw materials are readily available and the operation is relatively simple, this method has several technical drawbacks: First, the materials in the reactor are not mixed evenly, resulting in a significant concentration gradient, which leads to a local decrease in formamide concentration and easily generates byproducts such as 4-aminotriazole. The content of byproducts usually reaches 5-8%, which seriously affects the quality requirements of pharmaceutical-grade products. Second, the intermittent operation leads to large quality fluctuations between batches of products, with a yield of generally around 91% and poor stability. Third, the reaction time is long and the energy consumption is high, and high-vacuum distillation or high-temperature decomposition is required to recover formamide, resulting in large equipment investment and complex operation. Fourth, the level of automation is low, material transfer is difficult, and there are certain safety hazards.

[0003] Therefore, developing an efficient, continuous, and low-byproduct triazole synthesis process, especially a technical solution suitable for the production of pharmaceutical-grade products, has significant industrial application value. Summary of the Invention

[0004] Based on the problems existing in the background technology, the present invention provides a method for synthesizing triazole using microfluidic continuous technology, which realizes efficient, continuous and clean industrial production, with a product yield ≥95%, 4-aminotriazole by-product content ≤1%, and formamide recovery rate ≥98%.

[0005] This invention is implemented through the following technical solutions: A microfluidic continuous synthesis process for triazole includes the following steps: (1) Preheat the formamide, and keep the hydrazine hydrate at room temperature; (2) The formamide and the hydrazine hydrate are continuously fed into the microjet mixing reactor through independent feed channels, and mixed and reacted in the microjet mixing reactor; (3) The reaction product obtained in step (2) is continuously transported to a buffer tank for heat preservation reaction; (4) The reaction product obtained in step (3) is continuously fed to a distillation column for distillation to recover formamide; (5) The bottom material of the distillation in step (4) is transported to the crystallizer, cooled and precipitated as triazole crystals, and the triazole product is obtained by solid-liquid separation; (6) Return the formamide recovered in step (4) to step (1) for recycling.

[0006] Preferably, in step (1), the formamide is preheated to 150-160°C, and the temperature of the hydrazine hydrate is 20-30°C. By utilizing the temperature difference between the preheated formamide and the room-temperature hydrazine hydrate, rapid heat transfer and reaction are achieved during microjet mixing, effectively suppressing the occurrence of side reactions.

[0007] Preferably, in step (2), the microjet mixing reactor includes a first feed channel, a second feed channel, and a mixing chamber. The first feed channel is used to transport preheated formamide, and the second feed channel is used to transport hydrazine hydrate. The first and second feed channels converge into the mixing chamber at an angle of 60-90°. This design allows the two materials to collide and mix at high speed, achieving rapid nanoscale dispersion.

[0008] Preferably, in step (2), the molar ratio of formamide to hydrazine hydrate is 4:1 to 6:1, ensuring that hydrazine hydrate is always surrounded by an excess of high concentration of formamide, thereby maximally suppressing the formation of the byproduct 4-aminotriazole.

[0009] Preferably, in step (2), the jet velocity of formamide and hydrazine hydrate when entering the microjet mixing reactor is 10-50 m / s. At such a high jet velocity, the two materials collide and shear violently in the mixing chamber, achieving microsecond-level rapid mixing.

[0010] Preferably, in step (2), the reaction temperature is 160-175℃, the reaction pressure is 0.8-2.0MPa, and the residence time is 4-6 minutes. The rapid condensation reaction of formamide and hydrazine hydrate is completed in a microfluidic mixing reactor to generate an intermediate.

[0011] Preferably, in step (3), the temperature of the buffer insulation tank is 150-170℃, and the residence time of the material in the buffer insulation tank is 30-60 minutes.

[0012] Preferably, in step (4), the top temperature of the distillation column is 140-160℃ and the operating pressure is 0.01-0.08MPa.

[0013] Preferably, in step (5), the crystallization temperature is 60-80℃ and the cooling rate is 0.5-2℃ / min.

[0014] The present invention also provides a triazole product prepared according to the above method, wherein the purity of the triazole product is ≥99% and the content of 4-aminotriazole byproduct is ≤1%.

[0015] The beneficial effects of this invention are: 1. This invention employs a microjet mixing reactor to replace the traditional batch reactor, achieving rapid mixing and continuous reaction of materials. Preheated formamide and room-temperature hydrazine hydrate are fed into the mixing chamber through their respective independent feed channels in the form of high-speed jets at 10-50 m / s, completing mixing within microseconds and instantly dispersing the hydrazine hydrate into nano-sized droplets. Due to the use of a large excess of formamide, each hydrazine hydrate droplet is always surrounded by a high concentration of formamide, fundamentally avoiding the opportunity for hydrazine hydrate to come into contact with low-concentration formamide and generate byproducts, reducing the content of 4-aminotriazole byproducts from 5-8% in traditional processes to below 1%.

[0016] 2. The buffer tank designed in this invention has the dual functions of stabilizing material flow and maintaining reaction temperature. It provides a residence time of 30-60 minutes at 150-170℃, ensuring the complete cyclization reaction of triazole and increasing the yield from 85-91% in traditional processes to over 95%. After the reaction products enter the buffer tank, the water and ammonia become gases and directly enter the distillation column through the connection between the buffer tank and the distillation column. A vacuum distillation system is used to recover formamide, achieving a high-purity recovery rate of over 98% at a safe temperature of 140-160℃ under a pressure of 0.01-0.08 MPa. This solves the resource waste and environmental pollution problems caused by the inability to recover formamide in traditional processes.

[0017] 3. This invention enables continuous production of triazole throughout the entire process, resulting in stable product quality, minimal batch-to-batch fluctuations, and a reduction of equipment footprint by approximately 80%, along with a high degree of automation. By implementing this invention, high-quality triazole products with a yield ≥95%, purity ≥99%, and 4-aminotriazole byproduct content ≤1% can be produced, fully meeting pharmaceutical-grade standards. This provides a technologically advanced, economically sound, and environmentally friendly new process route for the industrial production of triazole. Detailed Implementation

[0018] The technical solution of the present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited to the following embodiments.

[0019] Example 1: Triazole microfluidic continuous synthesis process.

[0020] Raw material ratio: formamide (purity 99.5%) and 64% hydrazine hydrate aqueous solution, fed at a molar ratio of 5:1, corresponding to a volume ratio of approximately 2.63:1.

[0021] Step (1) Raw material pretreatment: Formamide was preheated to 155°C using a plate heat exchanger and then stored in an insulated tank at a temperature maintained at 150-160°C. A 64% hydrazine hydrate aqueous solution was stored in an ambient temperature tank at 25°C. Both raw materials were separately delivered to a microjet mixing reactor using high-precision metering pumps (flow rate accuracy ±0.5%). The formamide flow rate was set at 26.3 L / h, and the 64% hydrazine hydrate flow rate was set at 10 L / h, with a molar ratio of 5:1.

[0022] Step (2) Microjets mixing reaction: The microjet mixing reactor employs a Y-shaped mixing chamber structure, with the mixing chamber constructed from titanium alloy (TA2). The first feed channel delivers preheated formamide, while the second feed channel delivers a 64% hydrazine hydrate aqueous solution at room temperature. The two feed channels converge into the mixing chamber at a 65° angle. The equivalent diameter of the mixing chamber is 2 mm. The two materials enter the mixing chamber as high-speed jets (formamide jet velocity approximately 25 m / s, hydrazine hydrate jet velocity approximately 26 m / s), where they undergo intense collisions and shear mixing.

[0023] The mixing chamber temperature is controlled at 165℃ by a heat transfer oil circulating heating jacket, and the reaction pressure is controlled at 1.2MPa by a back pressure valve. The mixed material enters the reaction pipeline, which is a spiral coil structure with an inner diameter of 8mm and a total length of 60m. A heat transfer oil heating jacket is installed outside the pipeline to maintain the temperature at 165℃. The material stays in the reaction pipeline for approximately 5 minutes.

[0024] Step (3) Buffering and heat preservation reaction: The material from the reaction pipeline outlet continuously flows into a buffer tank. The buffer tank is made of stainless steel (316L), has a volume of 50L, and is equipped with an external electric heating jacket, maintaining the temperature at 160℃. After the reaction products enter the buffer tank, the water and ammonia products are converted into gases and directly enter the distillation column through the connection between the buffer tank and the distillation column. The buffer tank is equipped with a level sensor, with a setpoint of 60% (effective volume 30L). The material is kept at this temperature in the buffer tank for 40-50 minutes. When the level reaches the set value, the automatic control valve opens, and the material continuously flows to the distillation system.

[0025] Step (4) Fractional distillation separation: The gases (water vapor and ammonia) in the buffer tank and the feed material enter a distillation column separately. The distillation column operates under reduced pressure, with an operating pressure of approximately 20 kPa and a top temperature controlled at 150°C. Water vapor and ammonia are first condensed at the top of the column, separated by a gas-liquid separator; the aqueous phase is discharged, and the ammonia is absorbed. Further distillation recovers high-purity formamide (purity ≥99%), which is then returned to the feed storage tank for recycling. Crude triazole is obtained.

[0026] Step (5) Crystallization: The crude triazole product (approximately 155°C) from the bottom of the second-stage distillation column is cooled to 90°C via a heat exchanger. High-pressure air (0.3 MPa) is then continuously forced into the crystallizer. The crystallizer is equipped with a jacketed cooling system that gradually reduces the material temperature from 90°C to 70°C at a cooling rate of 1°C / min. During this process, triazole gradually crystallizes out. The crystallized slurry undergoes solid-liquid separation using a continuous centrifuge. The separated solid is then dried in a vacuum drying oven at 80°C for 4 hours to obtain white to slightly yellow triazole crystals.

[0027] Results analysis: In this embodiment, the process was carried out continuously for 24 hours. 240L of a 64% hydrazine hydrate aqueous solution (158.2kg of pure hydrazine hydrate, 3164 mol) and 630L of formamide (711.9kg, 15821 mol, of which approximately 20% was fresh formamide and the remaining 80% was recovered formamide) were added, with an actual molar ratio of 5.00:1. 210.2kg of triazole product was produced, with a purity of 99.2% (HPLC analysis), equivalent to 208.5kg of pure triazole (approximately 3022 mol). Based on the hydrazine hydrate conversion rate, the yield was 3022 ÷ 3164 × 100% = 95.5%.

[0028] The content of the byproduct 4-aminotriazole was 0.3% (HPLC analysis), and the content of other impurities was 0.5%.

[0029] The formamide consumption was 272.0 kg (calculated at a stoichiometric ratio of 2:1), and the unconsumed formamide was 440.0 kg. 434.3 kg (384.3 L, purity ≥99%) of formamide was recovered through a vacuum distillation system, with a recovery rate of 434.3 ÷ 440.0 × 100% = 98.7%. The recovered formamide was returned to the raw material storage tank for recycling. Due to the use of a 5:1 excess ratio, most of the formamide did not participate in the reaction and was efficiently recovered and recycled. The cumulative formamide consumption of the system conforms to the stoichiometric ratio (approximately 2:1).

[0030] Example 2: The difference between this example and Example 1 is that a higher formamide molar ratio and a higher jet velocity are used.

[0031] Raw material ratio: formamide (99.5% purity) and 64% hydrazine hydrate aqueous solution, molar ratio 6:1, corresponding to a volume ratio of approximately 3.15:1. Formamide flow rate 31.5 L / h, 64% hydrazine hydrate flow rate 10 L / h.

[0032] (1) The preheating temperature of formamide is 158℃ and the temperature of hydrazine hydrate is 25℃.

[0033] (2) The microjet mixing reactor adopts a Y-shaped mixing chamber structure with a jet angle of 65° and an equivalent diameter of 2 mm. The jet velocity is approximately 28 m / s. The mixing chamber temperature is 165℃, and the reaction pressure is 1.5 MPa. The reaction pipeline is a spiral coil structure with an inner diameter of 8 mm, a length of 60 m, and a residence time of approximately 4.4 minutes. The pipeline temperature is 165℃.

[0034] (3) The temperature of the buffer insulation tank is 165℃, the volume is 50L, the liquid level is 60% (effective volume is 30L), and the material insulation time is 35-45 minutes.

[0035] (4) Distillation system: vacuum distillation, operating pressure 15 kPa, top temperature 145 °C.

[0036] (5) Crystallization system: After cooling to 88℃, it is pressed into the crystallizer. The crystallization temperature drops from 88℃ to 68℃, and the cooling rate is 0.8℃ / min.

[0037] Results analysis: After 24 hours of continuous operation, 240 L of 64% hydrazine hydrate aqueous solution (158.2 kg of pure hydrazine hydrate, 3164 mol) and 756 L of formamide (molar ratio 6:1) were added, producing 215.5 kg of triazole with a purity of 99.5%, equivalent to 214.4 kg of pure triazole (3104 mol). Yield: 3104 ÷ 3164 × 100% = 98.1% (based on hydrazine hydrate conversion rate).

[0038] 4-Aminotriazole content: 0.15% (HPLC analysis), meeting pharmaceutical grade standards.

[0039] The amount of formamide consumed was 279.4 kg, 577.9 kg was not consumed, and 567.5 kg was recovered. The recovery rate was 567.5 ÷ 577.9 × 100% = 98.2%.

[0040] Example 3: This example is used to produce pharmaceutical-grade triazole products that meet USP / EP standards, with the addition of a recrystallization step based on the present invention.

[0041] Raw materials: Premium formamide (99.8% purity) and 64% hydrazine hydrate aqueous solution. Molar ratio 5.5:1, corresponding to a volume ratio of approximately 2.89:1.

[0042] (1) The preheating temperature of formamide is 152℃ and the flow rate is 28.9L / h; the temperature of hydrazine hydrate is 25℃ and the flow rate is 10L / h.

[0043] (2) Microjet mixing reactor: Y-shaped mixing chamber, injection angle 65°, equivalent diameter of mixing chamber 2mm, jet velocity 22m / s, mixing chamber temperature 158℃, reaction pressure 1.0MPa. Reaction pipe: inner diameter 8mm, length 60m, residence time 4.7 minutes, pipe temperature 158℃.

[0044] (3) Buffer and heat preservation tank: temperature 158℃, volume 60L, liquid level 60% (effective volume 36L), material feed flow rate 38.9L / h, residence time 45-55 minutes.

[0045] (4) Distillation system: vacuum distillation, operating pressure 25 kPa, top temperature 155 °C.

[0046] (5) Crystallization system: Crystallize after cooling to 92℃. The crystallization temperature drops from 92℃ to 75℃, and the cooling rate is 1.2℃ / min.

[0047] (6) Recrystallization step: The crude triazole obtained from the initial crystallization was dissolved in a water-ethanol mixed solvent (volume ratio 7:3) at 80°C, cooled to 20°C for recrystallization, centrifuged and then vacuum dried at 80°C for 6 hours.

[0048] Results analysis: After 24 hours of continuous operation, 240 L of 64% hydrazine hydrate aqueous solution (158.2 kg of pure hydrazine hydrate, 3164 mol) and 693.6 L of formamide (molar ratio 5.5:1) were added, producing 210.2 kg of triazole (after recrystallization) with a purity of 99.8%. Yield: 96.0% (including recrystallization loss, based on hydrazine hydrate conversion rate).

[0049] 4-Aminotriazole content: <0.05% (below the limit of detection, HPLC detection limit 0.05%), meeting USP / EP pharmaceutical grade standards. Other single impurities: all <0.1%. Total impurities: <0.2%.

[0050] The amount of formamide consumed was 273.3 kg, 513.2 kg was not consumed, and 505.5 kg was recovered. The recovery rate was 505.5 ÷ 513.2 × 100% = 98.5%.

[0051] Comparative Example 1: Triazole was synthesized using a traditional batch reactor process.

[0052] Raw materials (single batch): 1500L (1695kg, approximately 37667mol) of formamide (99.0% purity), 1200L (791kg, approximately 15821mol) of 64% hydrazine hydrate aqueous solution, with a molar ratio of approximately 2.38:1, slightly higher than the theoretical stoichiometric ratio of 2:1.

[0053] Operating steps: (1) Add formamide to the reaction vessel and heat to 180°C.

[0054] (2) Under stirring conditions, a 64% hydrazine hydrate aqueous solution was slowly added dropwise at a rate of approximately 360 L / h for approximately 3 hours and 20 minutes. The reaction temperature was maintained at 180°C during the addition process, and the distilled water and ammonia were recovered using a reflux condenser. Due to the intermittent addition, the formamide concentration in the reaction system gradually decreased during the addition process. When hydrazine hydrate came into contact with low-concentration formamide, 4-aminotriazole byproducts were easily generated.

[0055] (3) After the addition is complete, continue to keep the reaction at 180℃ for 1.5 hours.

[0056] (4) After the reaction is complete, cool the mixture to below 130°C and transfer the reaction mixture to the post-processing step. The reaction mixture contains triazole, unreacted formamide, water, byproducts, etc., and the system is complex.

[0057] (5) Triazole is separated by vacuum distillation or cooling crystallization. Due to the complex composition of the material system, unreacted formamide is mixed with triazole, water and by-products, resulting in high separation costs. Formamide is usually not recovered, or only simple distillation is performed, which results in low recovery efficiency.

[0058] (6) Clean the reactor and prepare for the next batch. The total time for a single batch is about 10 hours, and about 2 batches can be completed within 24 hours.

[0059] Results analysis: Two batches were run over 24 hours, with a total input of 2400L of 64% hydrazine hydrate aqueous solution (1582kg of pure hydrazine hydrate, 31642 mol), and a total output of 2045.4kg of triazole (1943.2kg of pure triazole). Overall yield: 89.0%.

[0060] 4-Aminotriazole content: 4.1% (HPLC analysis), exceeding the pharmaceutical grade standard requirement (<0.1%), suitable only for industrial grade products. Other impurities: 0.9%, including unreacted intermediates and by-products. Total impurities: 5.0%, product purity 95.0%.

[0061] Formamide recovery: Approximately 1267 kg of formamide is consumed per batch, with about 428 kg of unreacted formamide. Due to the complexity of the post-reaction material system, formamide is mixed with triazole, water, and byproducts, making separation and purification difficult and costly. Traditional processes typically do not perform formamide recovery, or only perform simple recovery (with a recovery rate of about 10-20%), with most of the formamide being treated as a loss or mixed into the waste liquid system.

[0062] Inter-batch quality fluctuations: Three batches were tested, with yields ranging from 86.5% to 91.2% and 4-aminotriazole content ranging from 3.8% to 4.8%. Inter-batch fluctuations were ±2-3 percentage points, indicating that the product quality stability was generally good.

[0063] As can be seen from the above examples and comparative examples, the continuous microfluidic synthesis method of the present invention is significantly superior to the traditional batch process in terms of yield, purity, by-product control, and formamide recovery. The microfluidic rapid mixing technology combined with an excess formamide ratio (molar ratio 4:1 to 6:1) effectively suppresses the formation of by-products. The buffer tank provides a residence time of 30-60 minutes to ensure the complete cyclization reaction of triazole, guaranteeing high yield and high purity. The vacuum distillation system efficiently recovers formamide at temperatures below its decomposition temperature, achieving a recovery rate of over 98%, thus realizing resource recycling and clean production.

[0064] Finally, it should be noted that the above embodiments are merely illustrative of several implementations of the present invention and are not intended to limit the scope of the invention. For those skilled in the art, any modifications, equivalent substitutions, or improvements made without departing from the concept of the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A microfluidic continuous synthesis process for triazole, characterized in that, Includes the following steps: (1) Preheat the formamide, and keep the hydrazine hydrate at room temperature; (2) The formamide and the hydrazine hydrate are continuously fed into the microjet mixing reactor through independent feed channels, and mixed and reacted in the microjet mixing reactor; (3) The reaction product obtained in step (2) is continuously transported to a buffer tank for heat preservation reaction; (4) The reaction product obtained in step (3) is continuously fed to a distillation column for distillation to recover formamide; (5) The bottom material of the distillation in step (4) is transported to the crystallizer, cooled and precipitated as triazole crystals, and the triazole product is obtained by solid-liquid separation; (6) Return the formamide recovered in step (4) to step (1) for recycling.

2. The synthesis process according to claim 1, characterized in that, In step (1), the formamide is preheated to 150-160°C, and the temperature of the hydrazine hydrate is 20-30°C.

3. The synthesis process according to claim 1, characterized in that, In step (2), the microjet mixing reactor includes a first feed channel, a second feed channel, and a mixing chamber. The first feed channel is used to transport preheated formamide, and the second feed channel is used to transport hydrazine hydrate. The first feed channel and the second feed channel converge into the mixing chamber at an angle of 60-90°.

4. The synthesis process according to claim 1, characterized in that, In step (2), the molar ratio of formamide to hydrazine hydrate is 4:1 to 6:

1.

5. The synthesis process according to claim 1, characterized in that, In step (2), the jet velocity of the formamide and hydrazine hydrate when entering the microjet mixing reactor is 10-50 m / s.

6. The synthesis process according to claim 1, characterized in that, In step (2), the reaction temperature is 160-175℃, the reaction pressure is 0.8-2.0MPa, and the residence time is 4-6 minutes.

7. The synthesis process according to claim 1, characterized in that, In step (3), the temperature of the buffer insulation tank is 150-170℃, and the residence time of the material in the buffer insulation tank is 30-60 minutes.

8. The synthesis process according to claim 1, characterized in that, In step (4), the top temperature of the distillation column is 140-160℃ and the operating pressure is 0.01-0.08MPa.

9. The synthesis process according to claim 1, characterized in that, In step (5), the crystallization temperature is 60-80℃ and the cooling rate is 0.5-2℃ / min.

10. A triazole product prepared by the synthesis process according to any one of claims 1-9, characterized in that, The purity of the triazole product is ≥99%, and the content of 4-aminotriazole byproduct is ≤1%.