Continuous synthesis method and system for 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride

Abstract

The present invention provides a continuous synthesis method and system of 3-bromo-1-(3-chloropyridine-2-yl)-1H-pyrazole-5-carbonyl chloride. Compared with the traditional intermittent preparation method, the continuous synthesis method provided by the present application can reduce the labor and time costs required for separate feeding, thereby improving production efficiency and shortening the synthesis cycle. At the same time, in the continuous synthesis method, only 2,3-dichloropyridine is fed in a solid state, and the remaining raw materials and reagents are fed in a liquid state, so that the utilization rate of each raw material can be improved, and then the yield of the target product 3-bromo-1-(3-chloropyridine-2-yl)-1H-pyrazole-5-carbonyl chloride can be improved. Moreover, compared with the feeding form of molten 2,3-dichloropyridine after the traditional high-temperature dissolution, the above-mentioned method of the present application can significantly improve the safety of raw material feeding. Recycling the first recovery solvent and the recovery acylating agent can reduce reagent waste and reduce production costs.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a continuous synthesis method and system for 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. Background Art

[0002] 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carbonyl chloride can be used as an intermediate of chlorantraniliprole. The Chinese trade name of chlorantraniliprole is Kangkuan. It is a new type of highly effective and low-toxic o-formylaminobenzamide insecticide developed by DuPont in the United States (chemical name is 3-bromo-N-{4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl}-1-(3-chloro-2-pyridinyl)-1H-pyridine-5-carboxamide). It has good insecticidal activity even at very low concentrations and is particularly effective against Lepidoptera insects.

[0003] At present, the main production process of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride includes the following steps: using 2,3-dichloropyridine as raw material, undergoing hydrazinolysis reaction, crystallization, cyclization reaction, crystallization, bromination reaction, crystallization, hydrolysis reaction, acylation reaction and simultaneous oxidation reaction to obtain a qualified product.

[0004] However, the existing production processes are all intermittent reactions, and multiple manual operations such as material transfer, material filtration, material extraction, material concentration, material drying and pulping are required, resulting in high labor costs and long production cycles; moreover, the raw materials required for the reactions in each step of the existing production process are all solid raw materials, which easily leads to low raw material utilization and low product yield; in addition, if the hydrazine hydrolysis reaction uses molten raw materials for feeding, there are safety hazards and other problems.

[0005] Therefore, it is of great significance to study and develop a continuous synthesis system and method for 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. Summary of the invention

[0006] The main purpose of the present invention is to provide a continuous synthesis method and system for 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, so as to solve the problems in the prior art of long production cycle, high labor cost, low product yield, low utilization rate of raw materials and reagents, and potential safety hazards in the feeding of molten 2,3-dichloropyridine of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride.

[0007] In order to achieve the above-mentioned object, the present invention provides a continuous synthesis method of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, which comprises: step S1, in a continuous hydrazinolysis reaction device, solid 2,3-dichloropyridine and hydrazine hydrate are subjected to continuous hydrazinolysis reaction in a first solvent to obtain a first product system containing a hydrazinolysis product; step S2, the hydrazinolysis product, diethyl maleate, a first alkali solution and a second solvent are introduced into a continuous cyclization reaction device for continuous cyclization reaction to obtain a second product system containing a cyclization product; step S3, the cyclization product, a brominating agent and a third solvent are introduced into a continuous bromination reaction device for continuous bromination reaction to obtain a third product system containing a brominated product; the third product system and the second alkali solution are introduced into a continuous neutralization reaction device for continuous neutralization reaction to obtain a mixture of a brominated product and a third solvent; step S4, the mixture of the brominated product and the third solvent, the third alkali solution and an optional fourth solvent are introduced into a continuous A continuous hydrolysis reaction is carried out in a hydrolysis reaction device to obtain a fourth product system containing a hydrolysis product; the fourth product system is subjected to a liquid separation treatment to obtain a first solvent phase and an aqueous phase containing a hydrolysis product; the first solvent phase is subjected to a first evaporation concentration treatment to obtain a first recovered solvent; at least part of the first recovered solvent is returned to the continuous bromination reaction device; the aqueous phase is subjected to a first acidification treatment and a first extraction treatment in sequence to obtain a first extraction system containing a hydrolysis product; step S5, the first extraction system, an acylating agent and an optional fifth solvent are introduced into a continuous acylation-oxidation reaction device to carry out a continuous acylation-oxidation reaction to obtain a fifth product system containing 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride; the fifth product system is subjected to a second evaporation concentration treatment to obtain 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride and recover the acylating agent; at least part of the recovered acylating agent is returned to the continuous acylation-oxidation reaction device.

[0008] In order to achieve the above-mentioned object, another aspect of the present invention further provides a continuous synthesis system of 3-bromo-1-3-chloropyridin-2-yl-1H-pyrazole-5-carbonyl chloride, the continuous synthesis system comprising: a continuous hydrazinolysis reaction unit, a continuous cyclization reaction unit, a continuous bromination reaction unit, a continuous hydrolysis reaction unit and a continuous acylation-oxidation reaction unit; the continuous hydrazinolysis reaction unit comprises a continuous hydrazinolysis reaction device, the continuous hydrazinolysis reaction device is provided with a solid 2,3-dichloropyridine inlet, a hydrazine hydrate inlet, a first solvent inlet and a first product system outlet, and the continuous hydrazinolysis reaction unit is provided with a first product outlet; the continuous cyclization reaction unit comprises a continuous cyclization reaction device, the continuous cyclization reaction device is provided with a first product system outlet The continuous cyclization reaction unit is provided with a second product outlet; the first product inlet is connected to the first product outlet through a first product delivery pipeline; the continuous bromination reaction unit comprises a continuous bromination reaction device and a continuous neutralization reaction device; the continuous bromination reaction device is provided with a second product inlet, a brominating agent inlet, a third solvent inlet and a third product outlet; the second product inlet is connected to the second product outlet; the continuous neutralization reaction device is provided with a third product inlet, a second alkali solution inlet and a mixture outlet; the third product inlet is connected to the third product outlet; the continuous hydrolysis reaction unit comprises a continuous hydrolysis reaction device connected in sequence The continuous hydrolysis reaction device is provided with a mixture inlet, a third alkali solution inlet and an optional fourth solvent inlet; the mixture inlet is connected to the mixture outlet; the liquid separation device is used to perform liquid separation treatment on the fourth product system to obtain a first solvent phase and an aqueous phase; the liquid separation device is provided with a first solvent phase outlet; the first acidification device is used to perform a first acidification treatment on the aqueous phase to obtain a first acidified product; the first acidification device is provided with a first acid solution inlet; the first extraction device is used to perform a first extraction treatment on the first acidified product; the first extraction device is provided with a first extractant inlet and a first extraction system outlet; the first evaporation concentration device is provided with a first solvent phase The continuous acylation-oxidation reaction unit comprises a continuous acylation-oxidation reaction device and a second evaporation and concentration device; the continuous acylation-oxidation reaction device is provided with a first extraction system inlet, an acylating agent inlet, an optional fifth solvent inlet and a fifth product system outlet; the second evaporation and concentration device is provided with a fifth product system inlet, a 3-bromo-1-3-chloropyridin-2-yl-1H-pyrazole-5-carbonyl chloride outlet and an acylating agent recovery outlet; the fifth product system inlet is connected to the fifth product system outlet; and the acylating agent recovery outlet is connected to the acylating agent inlet.

[0009] By applying the technical solution of the present invention, compared with the traditional intermittent preparation method, the continuous synthesis method provided by the present application can reduce the labor and time costs required for separate feeding, thereby improving production efficiency and shortening the synthesis cycle. At the same time, in the continuous synthesis method, only 2,3-dichloropyridine is fed in solid form, and the remaining raw materials and reagents are fed in liquid form, thereby improving the utilization rate of each raw material, thereby improving the yield of the target product 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. Moreover, the main raw material 2,3-dichloropyridine in the continuous hydrazinolysis reaction process of the present application is fed in solid form, which can significantly improve the safety of raw material feeding compared to the traditional high-temperature dissolution followed by molten feeding.

[0010] The present application sequentially performs liquid separation treatment, first acidification treatment and first extraction treatment on the fourth product system obtained after the continuous hydrolysis reaction to obtain a first recovered solvent, and returns at least part of the first recovered solvent to the first extraction treatment process for recycling, thereby improving the utilization rate of the third solvent, reducing reagent waste, and reducing production costs. Moreover, the present application returns at least part of the recovered acylating agent obtained by the fifth product system after the second evaporation and concentration treatment to the continuous acylation-oxidation reaction device for recycling, thereby improving the utilization rate of the acylating agent, reducing reagent waste, and reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The drawings constituting a part of the present application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0012] Figure 1 The schematic diagram of the structure of the continuous synthesis system of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carbonyl chloride in a preferred embodiment of the present application is shown.

[0013] The above drawings include the following reference numerals:

[0014] 100, continuous hydrazinolysis reaction unit; 110, continuous hydrazinolysis reaction device; 120, crystallization device; 130, drying device; 101, solid 2,3-dichloropyridine inlet; 102, hydrazine hydrate inlet; 103, first solvent inlet; 104, purification solvent inlet; 105, liquid product outlet;

[0015] 200, continuous ring-closure reaction unit; 210, continuous ring-closure reaction device; 220, second acidification device; 230, second extraction device; 240, fourth evaporation concentration device; 201, diethyl maleate inlet; 202, first alkali solution inlet; 203, second solvent inlet; 204, second acid solution inlet; 205, second extractant inlet; 206, second recovery extractant outlet;

[0016] 300, continuous bromination reaction unit; 310, continuous bromination reaction device; 320, continuous neutralization reaction device; 301, bromination agent inlet; 302, third solvent inlet; 303, second alkali solution inlet;

[0017] 400, continuous hydrolysis reaction unit; 410, continuous hydrolysis reaction device; 420, liquid separation device; 430, first acidification device; 440, first extraction device; 450, first evaporation concentration device; 460, third evaporation concentration device; 401, third alkali solution inlet; 402, fourth solvent inlet; 403, first solvent phase outlet; 404, first acid solution inlet; 405, first extractant inlet; 451, first solvent phase inlet; 452, first recovery solvent outlet; 461, second extraction system inlet; 462, first recovery extractant outlet;

[0018] 500, continuous acylation-oxidation reaction unit; 510, continuous acylation-oxidation reaction device; 520, second evaporation concentration device; 501, acylating agent inlet; 502, fifth solvent inlet; 503, 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride outlet; 504, acylating agent recovery outlet;

[0019] 600, brominating agent mixing device; 601, solid brominating agent inlet; 602, sixth solvent inlet; 603, brominating agent outlet. DETAILED DESCRIPTION

[0020] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0021] As described in the background technology, the existing synthesis system of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride has the problems of long production cycle, high labor cost, low product yield, low utilization rate of raw materials and reagents, and safety hazards of molten 2,3-dichloropyridine feed. In order to solve the above technical problems, the first aspect of the present application provides a continuous synthesis method of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, which comprises: step S1, in a continuous hydrazinolysis reaction device, solid 2,3-dichloropyridine and hydrazine hydrate are subjected to continuous hydrazinolysis reaction in a first solvent to obtain a first product system containing a hydrazinolysis product; step S2, the hydrazinolysis product, diethyl maleate, a first alkali solution and a second solvent are introduced into a continuous cyclization reaction device for continuous cyclization reaction to obtain a second product system containing a cyclization product; step S3, the cyclization product, a brominating agent and a third solvent are introduced into a continuous bromination reaction device for continuous bromination reaction to obtain a third product system containing a brominated product; the third product system and the second alkali solution are introduced into a continuous neutralization reaction device for continuous neutralization reaction to obtain a mixture of a brominated product and a third solvent; step S4, the mixture of the brominated product and the third solvent, the third alkali solution and an optional fourth solvent are introduced into a continuous bromination reaction device; The method comprises the following steps: performing a continuous hydrolysis reaction in a continuous hydrolysis reaction device to obtain a fourth product system containing a hydrolysis product; performing a liquid separation treatment on the fourth product system to obtain a first solvent phase and an aqueous phase containing a hydrolysis product; performing a first evaporation concentration treatment on the first solvent phase to obtain a first recovered solvent; returning at least a portion of the first recovered solvent to the continuous bromination reaction device; performing a first acidification treatment and a first extraction treatment on the aqueous phase in sequence to obtain a first extraction system containing a hydrolysis product; step S5, introducing the first extraction system, an acylating agent and an optional fifth solvent into a continuous acylation-oxidation reaction device to perform a continuous acylation-oxidation reaction to obtain a fifth product system containing 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride; performing a second evaporation concentration treatment on the fifth product system to obtain 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride and recovering the acylating agent; and returning at least a portion of the recovered acylating agent to the continuous acylation-oxidation reaction device.

[0022] Compared with the traditional intermittent preparation method, the continuous synthesis method provided by the present application can reduce the labor and time costs required for separate feeding, thereby improving production efficiency and shortening the synthesis cycle. At the same time, in the continuous synthesis method, only 2,3-dichloropyridine is fed in solid form, and the remaining raw materials and reagents are fed in liquid form, thereby improving the utilization rate of each raw material, thereby improving the yield of the target product 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. Moreover, the main raw material 2,3-dichloropyridine in the continuous hydrazine reaction process of the present application is fed in solid form, which can significantly improve the safety of raw material feeding compared to the traditional high-temperature dissolution followed by molten feeding.

[0023] The present application sequentially performs liquid separation treatment, first acidification treatment and first extraction treatment on the fourth product system obtained after the continuous hydrolysis reaction to obtain a first recovered solvent, and returns at least part of the first recovered solvent to the first extraction treatment process for recycling, thereby improving the utilization rate of the third solvent, reducing reagent waste, and reducing production costs. Moreover, the present application returns at least part of the recovered acylating agent obtained by the fifth product system after the second evaporation and concentration treatment to the continuous acylation-oxidation reaction device for recycling, thereby improving the utilization rate of the acylating agent, reducing reagent waste, and reducing production costs.

[0024] The synthetic route of the target product in this application is as follows:

[0025] .

[0026] In a preferred embodiment, in step S4, the temperature of the liquid separation treatment is 10-60°C, and the material residence time is 5-30 minutes. The temperature and time of the liquid separation treatment include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the separation efficiency of the first solvent phase and the water phase in the fourth product system, separating the hydrolyzate from the first solvent phase, thereby improving the yield of the subsequent hydrolyzate.

[0027] In a preferred embodiment, in step S4, a first acid solution is added during the first acidification treatment, the feed rate of the first acid solution is 5 to 15 g / min, the mass concentration of the acid in the first acid solution is 5 to 50%, and the pH of the reaction system after the first acidification treatment is 2 to 3. Compared with other ranges, limiting the above process parameters in the first acidification treatment to the above range is conducive to controlling the pH of the aqueous phase within the above range, thereby improving the extraction efficiency and yield of the subsequent hydrolysis product.

[0028] In a preferred embodiment, in step S4, the temperature of the first acidification treatment is 0-50°C, and the material residence time is 10-60 minutes. The temperature and material residence time of the first acidification treatment include but are not limited to the above ranges, and limiting them to the above ranges is conducive to improving the stability of the hydrolyzate in the aqueous phase, thereby improving the extraction efficiency and yield of the subsequent hydrolyzate.

[0029] In a preferred embodiment, in step S4, the temperature of the first extraction treatment is 0-50°C, and the material residence time is 10-60 minutes. The temperature and material residence time of the first extraction treatment include but are not limited to the above ranges, and limiting them to the above ranges is conducive to improving the extraction efficiency of the hydrolyzate, thereby improving the yield of the hydrolyzate.

[0030] In a preferred embodiment, in step S4, the first extraction treatment is performed using a first extractant, and the first extractant includes but is not limited to one or more of the group consisting of dichloromethane, 1,2-dichloroethane, ethyl acetate and toluene.

[0031] In a preferred embodiment, the temperature of the first evaporation concentration treatment is 40 to 80°C, the pressure is -0.09 to -0.04 MPa, and the material residence time is 30 to 180 min. The temperature, pressure and material residence time of the first evaporation concentration treatment include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the purity and recycling rate of the first recovery solvent.

[0032] In a preferred embodiment, the continuous synthesis method further comprises: performing a third evaporation concentration treatment on the first extraction system to obtain a hydrolyzate and a first recovered extractant; returning at least a portion of the first recovered extractant to the first extraction treatment process; and passing the hydrolyzate into a continuous acylation-oxidation reaction device. The third evaporation concentration treatment process is beneficial to improving the recovery rate of the first extractant and reducing the cost of the first extraction treatment.

[0033] In order to further improve the recovery rate of the first extractant, in a preferred embodiment, the temperature of the third evaporation concentration treatment is 30 to 60° C., the pressure is -0.09 to -0.06 MPa, and the material residence time is 10 to 30 min.

[0034] In a preferred embodiment, the continuous cyclization reaction and the continuous bromination reaction further include sequentially performing a second acidification treatment, at least one second extraction treatment and a fourth evaporation concentration treatment on the second product system to obtain a second recovery extractant; returning at least part of the second recovery extractant to the second extraction treatment process. Performing a second acidification treatment on the second product system can remove the alkaline substances remaining in the reaction system, and performing at least one second extraction treatment can separate the cyclization product from the second solvent, thereby improving the separation efficiency of the cyclization product. Performing a second evaporation concentration treatment on the obtained second solvent phase can remove the water therein, thereby improving its purity and facilitating recycling. Returning at least part of the second recovery solvent to the continuous bromination reaction device is conducive to improving its recycling rate, thereby reducing costs.

[0035] In a preferred embodiment, the acid solution added during the second acidification treatment includes, but is not limited to, one or more of the group consisting of hydrochloric acid, acetic acid and sulfuric acid. The above acid solution raw materials are easily available and have high treatment efficiency.

[0036] In a preferred embodiment, a second acid solution is added during the second acidification treatment, the feed rate of the second acid solution is 15 to 30 g / min, the mass concentration of the second acid solution is 20 to 40%, and the pH of the reaction system after the second acidification treatment is 7 to 8. The above-mentioned process parameters during the second acidification treatment include but are not limited to the above-mentioned ranges, and limiting them within the above-mentioned ranges is conducive to improving the removal rate of alkaline substances in the second product system, thereby facilitating improving the stability and yield of the cyclization product.

[0037] In a preferred embodiment, the temperature of the second acidification treatment is 20-40° C., and the material residence time is 10-30 min. The temperature and material residence time of the second acidification treatment include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the removal rate of alkaline substances in the second product system, thereby facilitating improving the stability and yield of the cyclization product.

[0038] In a preferred embodiment, the temperature of the second extraction treatment is 20-40°C, and the material residence time is 10-30 min. The temperature and material residence time of the second extraction treatment include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the extraction and separation efficiency of the cyclization product, thereby facilitating improving its yield and purity.

[0039] In a preferred embodiment, the second extraction treatment is carried out using a second extractant, which includes but is not limited to one or more of the group consisting of dichloromethane, dichloroethane and ethyl acetate. Compared with other types, the use of the above-mentioned second extractants is conducive to improving the extraction and separation efficiency of the cyclization product, thereby helping to improve its yield and purity.

[0040] In a preferred embodiment, the temperature of the fourth evaporation concentration treatment is 30 to 80°C, the pressure is -0.09 to -0.04 MPa, and the material residence time is 5 to 15 min. The temperature, pressure and material residence time of the fourth evaporation concentration treatment include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the recovery rate of the second extractant and reducing the cost of the second extraction treatment.

[0041] In a preferred embodiment, in step S4, the feed rate of the mixture of the brominated product and the third solvent is 15-25 g / min, the feed rate of the third alkali solution is 15-75 g / min, and the amount ratio of the mixture to the fourth solvent is 1 g: (1-5) mL. The above-mentioned process parameters in the continuous hydrolysis reaction process include but are not limited to the above-mentioned ranges, and limiting them within the above-mentioned ranges is conducive to improving the utilization rate of each raw material and reagent, thereby facilitating improving the yield of the hydrolyzate.

[0042] In a preferred embodiment, the temperature of the continuous hydrolysis reaction is 50-100°C, and the material residence time is 0.5-4h. The temperature and material residence time of the continuous hydrolysis reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the efficiency of the continuous hydrolysis reaction, inhibiting the occurrence of side reactions, and thus helping to improve the yield of the hydrolyzate.

[0043] In a preferred embodiment, the third alkali solution includes, but is not limited to, an aqueous solution formed by one or more of the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide. The third alkali solution raw materials of the above types are easily available and have low cost.

[0044] In a preferred embodiment, the fourth solvent includes, but is not limited to, one or more of the group consisting of dichloroethane, water, acetonitrile, DMF and 1,4-dioxane. Compared with other types, the use of the fourth solvent of the above type is conducive to improving the dispersibility of the bromination product, thereby improving the efficiency of the continuous hydrolysis reaction, and further improving the yield of the hydrolysis product.

[0045] In a preferred embodiment, in step S5, the feed rate of the hydrolyzate is 15 to 25 g / min, the feed rate of the acylating agent is 15 to 40 g / min, and the ratio of the hydrolyzate to the fifth solvent is 1 g: (1 to 5) mL. The process parameters in the continuous acylation-oxidation reaction process include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the utilization rate of the reaction raw materials, and is conducive to improving the efficiency of the acylation reaction and the oxidation reaction, thereby helping to improve the yield of the target product 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride.

[0046] In a preferred embodiment, the temperature of the continuous acylation-oxidation reaction is 60-100°C, and the material residence time is 0.5-3h. The temperature and material residence time of the continuous acylation-oxidation reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the reaction efficiency and inhibiting the occurrence of side reactions, thereby facilitating the improvement of the yield of the target product 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride.

[0047] In a preferred embodiment, the acylating agent includes, but is not limited to, one or more of the group consisting of oxalyl chloride, thionyl chloride, and phosphorus pentachloride. Compared with other types, the use of the above-mentioned types of acylating agents is conducive to the continuous reaction, reduces manual participation, and reduces the risk of material use.

[0048] In a preferred embodiment, the fifth solvent includes but is not limited to one or more of the group consisting of dichloroethane, acetonitrile, DMF and 1,4-dioxane. Compared with other types, the use of the fifth solvent of the above type is conducive to improving the dispersibility of the hydrolyzate, thereby improving the efficiency of the continuous acylation-oxidation reaction, and further helping to improve the yield of the target product.

[0049] In a preferred embodiment, the continuous hydrazinolysis reaction and the continuous cyclization reaction further include: sequentially crystallizing and drying the first product system to obtain a hydrazinolysis product; returning at least part of the liquid phase product obtained by crystallization to step S1 for reuse. The above crystallization process can cause the hydrazinolysis product in the first product system to crystallize to form a solid substance, and the drying process can remove the residual moisture therein, which is beneficial to improve the purity of the hydrazinolysis product, thereby facilitating subsequent reactions.

[0050] In a preferred embodiment, the crystallization temperature is 10-20°C, and the material residence time is 50-150 min. The crystallization temperature and material residence time include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the crystallization efficiency, thereby improving the yield and purity of the hydrazinolysis product.

[0051] In a preferred embodiment, the crystallization process is carried out in a purification solvent, and the weight ratio of the first product system to the volume of the purification solvent is 1g: (1-5)mL; the purification solvent includes but is not limited to one or more of the group consisting of hydrazine hydrate, water and pyridine. The amount and type of the purification solvent include but are not limited to the above range, and limiting it within the above range is conducive to improving the efficiency of crystallization, thereby improving the yield and purity of the hydrazine hydrolysis product.

[0052] In a preferred embodiment, the drying temperature is 40-100°C, and the material residence time is 10-60 minutes. The drying temperature and material residence time include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the drying treatment effect and reducing the moisture in the hydrazine hydrolysis product.

[0053] In a preferred embodiment, in step S1, the feeding rate of solid 2,3-dichloropyridine is 5 to 20 g / min, and the feeding rate of hydrazine hydrate is 10 to 35 g / min. The feeding rates of solid 2,3-dichloropyridine and hydrazine hydrate include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the efficiency of the continuous hydrazine hydrolysis reaction, thereby helping to improve the utilization rate of raw materials, and further helping to improve the yield of the hydrazine hydrolysis product.

[0054] In a preferred embodiment, the temperature of the continuous hydrazinolysis reaction is 60-100° C., and the material residence time is 4-7 hours. The temperature and material residence time of the continuous hydrazinolysis reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the efficiency of the continuous hydrazinolysis reaction, thereby helping to improve the utilization rate of raw materials, and further helping to improve the yield of the hydrazinolysis product.

[0055] In a preferred embodiment, the first solvent includes but is not limited to one or more of the group consisting of hydrazine hydrate, water and pyridine. Compared with other types, the use of the above-mentioned first solvents is conducive to improving the solubility of the raw materials, and is conducive to improving the reaction efficiency of the continuous hydrazinolysis reaction, thereby helping to improve the yield of the hydrazinolysis product.

[0056] In a preferred embodiment, the weight ratio of solid 2,3-dichloropyridine to the volume ratio of the first solvent is 1 g: (1 to 5) mL. The weight ratio of solid 2,3-dichloropyridine to the volume ratio of the first solvent includes but is not limited to the above range, and limiting it within the above range is conducive to improving the efficiency of the continuous hydrazinolysis reaction, thereby improving the utilization rate of raw materials, and further improving the yield of the hydrazinolysis product.

[0057] In a preferred embodiment, in step S2, the feed rate of the hydrazinolysis product is 6 to 9 g / min, the feed rate of diethyl maleate is 10 to 18 g / min, the feed rate of the first alkali solution is 20 to 25 g / min, the mass concentration of the alkali in the first alkali solution is 10 to 40%, and the feed rate of the second solvent is 1 to 30 g / min. In step S2, the feed rate of each material includes but is not limited to the above range, and limiting it within the above range is conducive to improving the utilization rate of raw materials, and is conducive to improving the efficiency of continuous cyclization reactions, thereby helping to improve the yield of cyclization products.

[0058] In a preferred embodiment, the temperature of the continuous cyclization reaction is 20 to 80° C., and the material residence time is 1 to 1.5 h. The temperature and time of the continuous cyclization reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the efficiency of the continuous cyclization reaction, inhibiting side reactions, and thus helping to improve the yield and purity of the cyclization product.

[0059] In a preferred embodiment, the first alkali solution includes, but is not limited to, an alcohol solution formed by one or more of the group consisting of sodium methoxide, sodium ethoxide, and sodium tert-butoxide. Compared with other types, the first alkali solution of the above type is convenient for continuous feeding.

[0060] In a preferred embodiment, the second solvent includes but is not limited to one or more of methanol, ethanol and tert-butyl alcohol. Compared with other types, the use of the second solvent of the above type is conducive to improving the solubility and dispersibility of the hydrazinolysis product and diethyl maleate, which is conducive to improving the utilization rate of raw materials, thereby helping to improve the yield of the cyclization product.

[0061] In a preferred embodiment, during the continuous bromination reaction, the feed rate of the cyclization product is 30-50 g / min, the feed rate of the brominating agent is 35-40 g / min, and the feed rate of the third solvent is 10-15 g / min. The feed rates of the cyclization product, the brominating agent, and the third solvent include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the raw material utilization rate of the cyclization product and the brominating agent, and is also conducive to improving the dispersibility of the cyclization product and the brominating agent in the third solvent, thereby helping to improve the reaction efficiency of the continuous bromination reaction, and further helping to improve the yield of the bromination product.

[0062] In a preferred embodiment, the temperature of the continuous bromination reaction is 30-80°C, and the material residence time is 0.5-1.5h. The temperature and material residence time of the continuous bromination reaction include but are not limited to the above ranges, and limiting them within the above ranges is beneficial to improving the reaction efficiency of the continuous bromination reaction, suppressing the occurrence of side reactions, and improving the yield and purity of the bromination product.

[0063] In a preferred embodiment, the brominating agent includes, but is not limited to, one or more of the group consisting of phosphorus tribromide, phosphorus pentabromide and phosphorus oxybromide. Compared with other types, the use of the above-mentioned types of brominating agents is conducive to improving the yield of the target product and reducing the by-products produced by the reaction.

[0064] In a preferred embodiment, the third solvent includes but is not limited to one or more of dichloromethane, dichloroethane, acetonitrile and 1,4-dioxane. Compared with other types, the use of the third solvent of the above type is conducive to improving the dispersibility of the cyclization product and the brominating agent in the third solvent, thereby facilitating the improvement of the reaction efficiency of the continuous bromination reaction and the improvement of the yield of the bromination product.

[0065] In a preferred embodiment, during the continuous neutralization reaction, the feed rate of the third product system is 60-80 g / min, the feed rate of the second alkali solution is 50-80 g / min, and the mass concentration of alkali in the second alkali solution is 5-25%. The feed rates of the third product system and the second alkali solution include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the utilization rate of raw materials and the efficiency of the continuous neutralization reaction.

[0066] In a preferred embodiment, the temperature of the continuous neutralization reaction is 0-40°C, and the material residence time is 5-40 minutes. The temperature and material residence time of the continuous neutralization reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the efficiency of the continuous neutralization reaction.

[0067] In a preferred embodiment, the second alkali solution includes, but is not limited to, an aqueous solution formed by one or more of the group consisting of sodium hydroxide, potassium hydroxide, and sodium bicarbonate. Compared with other types, the use of the above-mentioned second alkali solution is conducive to improving the efficiency of the continuous neutralization reaction.

[0068] The second aspect of the present application also provides a continuous synthesis system of 3-bromo-1-3-chloropyridin-2-yl-1H-pyrazole-5-carbonyl chloride, such as Figure 1As shown, the continuous synthesis system includes: a continuous hydrazinolysis reaction unit 100, a continuous cyclization reaction unit 200, a continuous bromination reaction unit 300, a continuous hydrolysis reaction unit 400 and a continuous acylation-oxidation reaction unit 500.The continuous hydrazinolysis reaction unit 100 includes a continuous hydrazinolysis reaction device 110, which is provided with a solid 2,3-dichloropyridine inlet 101, a hydrazine hydrate inlet 102, a first solvent inlet 103 and a first product system outlet, and the continuous hydrazinolysis reaction unit 100 is provided with a first product outlet; the continuous cyclization reaction unit 200 includes a continuous cyclization reaction device 210, which is provided with a first product inlet, a diethyl maleate inlet 201, a first alkali solution inlet 202, a second solvent inlet 203 and a second product system outlet, and the continuous cyclization reaction unit 200 is provided with a second product outlet; the first product inlet is connected to the first product outlet through a first product delivery pipeline; the continuous bromination reaction unit 30 0 includes a continuous bromination reaction device 310 and a continuous neutralization reaction device 320; the continuous bromination reaction device 310 is provided with a second product inlet, a brominating agent inlet 301, a third solvent inlet 302 and a third product outlet; the second product inlet is connected to the second product outlet; the continuous neutralization reaction device 320 is provided with a third product inlet, a second alkali solution inlet 303 and a mixture outlet; the third product inlet is connected to the third product outlet; the continuous hydrolysis reaction unit 400 includes a continuous hydrolysis reaction device 410, a liquid separation device 420, a first acidification device 430, a first extraction device 440 and a first evaporation concentration device 450 which are sequentially connected; the continuous hydrolysis reaction device 410 is provided with a mixture inlet, a third alkali solution inlet 401 and an optional The fourth solvent inlet 402; the mixture inlet is connected to the mixture outlet; the liquid separation device 420 is used to perform liquid separation treatment on the fourth product system to obtain a first solvent phase and an aqueous phase; the liquid separation device 420 is provided with a first solvent phase outlet 403; the first acidification device 430 is used to perform a first acidification treatment on the aqueous phase to obtain a first acidified product; the first acidification device 430 is provided with a first acid liquid inlet 404; the first extraction device 440 is used to perform a first extraction treatment on the first acidified product; the first extraction device 440 is provided with a first extractant inlet 405 and a first extraction system outlet; the first evaporation and concentration device 450 is provided with a first solvent phase inlet 451 and a first recovery solvent outlet 452; the first solvent phase inlet 451 and the first solvent phase outlet 403 The first recovery solvent outlet 452 is connected to the third solvent inlet 302; the continuous acylation-oxidation reaction unit 500 comprises: a continuous acylation-oxidation reaction device 510 and a second evaporation concentration device 520; the continuous acylation-oxidation reaction device 510 is provided with a first extraction system inlet, an acylating agent inlet 501, an optional fifth solvent inlet 502 and a fifth product system outlet; the second evaporation concentration device 520 is provided with a fifth product system inlet, a 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride outlet 503 and a recovery acylating agent outlet 504; the fifth product system inlet is connected to the fifth product system outlet; the recovery acylating agent outlet 504 is connected to the acylating agent inlet 501.

[0069] Compared with the traditional intermittent synthesis system, the above-mentioned continuous synthesis system of the present application can be used to continuously synthesize the target product 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride using solid 2,3-dichloropyridine as the starting material. The continuous synthesis system has a high degree of automation and can reduce the labor and time costs required for separate feeding, thereby improving production efficiency and shortening the synthesis cycle. At the same time, in the continuous synthesis system, only 2,3-dichloropyridine is the solid raw material feed port, and the remaining raw materials and reagent feed ports are all fed in liquid form, thereby improving the utilization rate of each raw material, and further improving the yield of the target product 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carbonyl chloride.

[0070] Moreover, the continuous hydrazine hydrolysis reaction device 110 of the present application is provided with a solid 2,3-dichloropyridine inlet 101, which can significantly improve the safety of raw material feeding compared to the traditional molten state feeding form.

[0071] In the above-mentioned continuous synthesis system of the present application, the continuous hydrolysis reaction device 410 is connected in sequence with the liquid separation device 420, the first acidification device 430, the first extraction device 440 and the first evaporation concentration device 450, and is provided with a first recovery solvent outlet 452; the first recovery solvent outlet 452 is connected to the third solvent inlet 302, and at least part of the first recovery solvent can be returned to the continuous bromination reaction device 310 for recycling, thereby improving the utilization rate of the third solvent, reducing reagent waste, and reducing production costs. Moreover, the above-mentioned continuous synthesis system in the present application includes a second evaporation concentration device 520, and the second evaporation concentration device 520 is provided with an acylating agent recovery outlet 504, and the acylating agent recovery outlet 504 is connected to the acylating agent inlet 501, and at least part of the recovered acylating agent obtained by the fifth product system after the second evaporation concentration treatment can be returned to the continuous acylation-oxidation reaction device 510 for recycling, thereby improving the utilization rate of the acylating agent, reducing reagent waste, and reducing production costs.

[0072] In a preferred embodiment, the continuous synthesis system further comprises a third evaporation and concentration device 460, which is provided with a second extraction system inlet 461, a first recovery extractant outlet 462 and a hydrolyzate outlet; the second extraction system inlet 461 is connected to the first extraction system outlet; the first recovery extractant outlet 462 is connected to the first extractant inlet 405; and the hydrolyzate outlet is connected to the first extraction system inlet. The provision of the third evaporation and concentration device 460 is conducive to improving the recovery rate of the first extractant and reducing the cost of the first extraction process.

[0073] In a preferred embodiment, the continuous cyclization reaction unit 200 further includes a second acidification device 220, at least one second extraction device 230 and a fourth evaporation concentration device 240, the second acidification device 220 is provided with a second product system inlet, a second acid solution inlet 204 and a second acidified product outlet; the second product system inlet is connected to the second product system outlet; the second extraction device 230 is provided with a second acidified product inlet, a second extractant inlet 205, a second solvent phase outlet and a second product outlet; the fourth evaporation concentration device 240 is provided with a second solvent phase inlet and a second recovered extractant outlet 206; the second solvent phase inlet is connected to the second solvent phase outlet; the second recovered extractant outlet 206 is connected to the second extractant inlet 205.

[0074] The configuration of the second acidification device 220, at least one second extraction device 230 and the fourth evaporation concentration device 240 of the present application can neutralize the alkaline substances remaining in the reaction system, separate the cyclization product from the second solvent through the second extraction, and the configuration of the fourth evaporation concentration device 240 can improve the recovery rate of the second extractant.

[0075] In a preferred embodiment, a crystallization device 120 and a drying device 130 are sequentially arranged on the first product delivery pipeline in the direction of conveying the first product; the crystallization device 120 is provided with a first product system inlet, a purification solvent inlet 104, a liquid product outlet 105 and a crystallized product outlet; the first product system inlet is connected to the first product system outlet; the liquid product outlet 105 is connected to the first solvent inlet 103; the drying device 130 is provided with a crystallized product inlet and a first product outlet; the crystallized product inlet is connected to the crystallized product outlet. The crystallization device 120 and the drying device 130 are sequentially arranged in the direction of conveying the first product so that the hydrazinolysis product in the first product system can be precipitated in the presence of the purification solvent, and then the moisture in the hydrazinolysis product is removed by the drying device 130, thereby obtaining a hydrazinolysis product with a higher yield and purity.

[0076] In a preferred embodiment, the crystallization device 120 includes but is not limited to a horizontal plug flow reactor or a horizontal stirred reactor. Compared with other types, the use of the above-mentioned type of crystallization device 120 is conducive to improving the crystallization efficiency, thereby improving the yield of the hydrazinolysis product.

[0077] In a preferred embodiment, the drying device 130 includes but is not limited to a fluidized bed dryer, preferably a countercurrent negative pressure fluidized bed dryer. Compared with other types, the use of the above type of drying device 130 is conducive to improving the treatment effect of the second drying and reducing the moisture in the hydrazine hydrolysis product.

[0078] In a preferred embodiment, the first evaporation and concentration device 450, the second evaporation and concentration device 520, the third evaporation and concentration device 460 and the fourth evaporation and concentration device 240 independently include but are not limited to thin film evaporators or falling film evaporators. The use of the first evaporation and concentration device 450, the second evaporation and concentration device 520, the third evaporation and concentration device 460 and the fourth evaporation and concentration device 240 of the above type is conducive to improving the purity and recycling rate of the solvent or extractant to be recovered, thereby helping to reduce the cost of the entire continuous synthesis system.

[0079] In a preferred embodiment, the first extraction device 440 and the second extraction device 230 include but are not limited to continuous extraction columns. Compared with other types, the first extraction device 440 and the second extraction device 230 of the above type are conducive to improving the extraction and separation efficiency, thereby helping to improve the yield of the target product.

[0080] In a preferred embodiment, the continuous hydrazinolysis reaction device 110 and the continuous bromination reaction device 310 independently include but are not limited to a continuous column reactor or a continuous tank reactor. Compared with other types, the continuous hydrazinolysis reaction device 110 and the continuous bromination reaction device 310 of the above types are conducive to continuous synthesis, and are also conducive to improving the reaction efficiency of the continuous hydrazinolysis reaction and the continuous bromination reaction, thereby helping to improve the yield of the target product.

[0081] In a preferred embodiment, the continuous cyclization reaction device 210, the continuous hydrolysis reaction device 410, and the continuous acylation-oxidation reaction device 510 independently include, but are not limited to, a continuous column reactor, a continuous tank reactor, or a continuous extraction column. Compared with other types, the use of the above-mentioned types of continuous cyclization reaction devices 210, continuous hydrolysis reaction devices 410, and continuous acylation-oxidation reaction devices 510 is conducive to continuous synthesis, and is also conducive to improving the reaction efficiency of continuous cyclization reaction, continuous hydrolysis reaction, and continuous acylation-oxidation reaction, thereby facilitating improving the yield of the target product.

[0082] In a preferred embodiment, the continuous synthesis system further comprises a brominating agent mixing device 600, which is provided with a solid brominating agent inlet 601, a sixth solvent inlet 602 and a brominating agent outlet 603, and the brominating agent outlet 603 is connected to the brominating agent inlet 301. The brominating agent mixing device 600 can disperse the solid brominating agent in the sixth solvent to form a liquid material, which is convenient for the continuous synthesis process.

[0083] The present application is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in the present application.

[0084] Example 1

[0085] Use Figure 1 The continuous synthesis system of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carbonyl chloride shown in the figure is used for continuous synthesis, and its synthesis route is as follows:

[0086] .

[0087] The continuous synthesis method comprises the following continuous process:

[0088] (1) 2,3-dichloropyridine solid was fed into a continuous columnar stirred reactor at a feeding rate of 8 g / min, 80% hydrazine hydrate was fed into a continuous hydrazine hydrolysis reactor at a feeding rate of 11.4 g / min, and after staying and reacting for 5 hours at 110°C, a first product system containing hydrazine hydrolysis product was obtained. The system was fed into a horizontal continuous stirred reactor at a feeding rate of 19.1 g / min, and after staying and crystallizing for 40 minutes at 10°C, the system overflowed into a fluidized bed dryer at a feeding rate of 8.5 g / min, and the temperature of the fluidized bed dryer was set to 80°C. After staying and drying for 10 minutes, 3-chloro-2-hydrazinepyridine was obtained. The yield of the 3-chloro-2-hydrazinepyridine was measured to be 96%;

[0089] (2) The 3-chloro-2-hydrazinopyridine prepared above was fed into a continuous reaction column at a feeding rate of 6 g / min, and diethyl maleate was fed at a feeding rate of 8.5 g / min and a sodium ethoxide ethanol solution with a mass concentration of 20% was fed at a feeding rate of 7.65 g / min. After staying at 70° C. and reacting for 1 hour, the obtained second product system containing the cyclization product was fed into a continuous reaction kettle at a feeding rate of 29.9 g / min. At the same time, acetic acid with a mass concentration of 20% was fed into the continuous reaction kettle at a feeding rate of 15.5 g / min. After staying at 20° C. and reacting for 1 hour, the obtained second product system containing the cyclization product was fed into a continuous reaction kettle at a feeding rate of 29.9 g / min. After 20 minutes of evaporation, the obtained system overflowed into the continuous extraction column at a feed rate of 45.4 g / min, and dichloroethane was introduced into the continuous extraction column at a feed rate of 31.8 g / min for a second extraction treatment. After staying at 40° C. for 30 minutes, the cyclization product and the second solvent phase were obtained respectively. The second solvent phase was introduced into a thin film evaporator at a feed rate of 54.6 g / min for a fourth evaporation concentration. After evaporation concentration at 70° C. and -0.07 MPa for 10 minutes, a second recovered extractant was obtained, and the second recovered extractant was returned to the continuous extraction column for a second extraction treatment.

[0090] (3) The cyclization product obtained above was fed into a continuous solid-liquid reactor at a feeding rate of 32.3 g / min, phosphorus oxybromide at a feeding rate of 11.5 g / min, and ethylene dichloride at a feeding rate of 11.5 g / min. After staying at 80° C. for 60 min, the third product system containing the brominated product was overflowed into a continuous extraction column at a feeding rate of 53.8 g / min. A 10% aqueous solution of sodium hydroxide was fed into the continuous extraction column at a feeding rate of 26 g / min. After staying at 40° C. for 20 min, an aqueous phase and an organic phase (a mixture of the brominated product and ethylene dichloride) were obtained.

[0091] (4) The organic phase (a mixture of bromination product and ethylene dichloride) prepared above was fed into a continuous reaction column at a feed rate of 47.7 g / min and the sodium hydroxide aqueous solution was fed at a feed rate of 36.9 g / min. After staying at 60° C. for 60 min, the fourth product system containing the hydrolyzed product was fed into a continuous extraction column at a feed rate of 84.6 g / min and stayed at 40° C. for 10 min to obtain a first solvent phase and an aqueous phase containing the hydrolyzed product. The first solvent phase was fed into a falling film evaporator at a feed rate of 46.2 g / min for a first evaporation concentration treatment, stayed at 60° C. and -0.07 MPa for 8 min, and the first recovered solvent was returned to the continuous reaction column for a continuous bromination reaction. The aqueous phase containing the hydrolyzed product was fed at a feed rate of 38.5 g / min. The first acidification product obtained is fed into a continuous extraction column at a feeding rate of 69.2 g / min and 1,2-dichloroethane is fed into a continuous extraction column at a feeding rate of 23.1 g / min for a first extraction treatment, and the reaction mixture is kept at 40°C for 20 min to obtain a first extraction system containing a hydrolyzate. The first extraction system is fed into a continuous falling film evaporator at a feeding rate of 40 g / min for a third evaporation concentration treatment, and the reaction mixture is kept at 50°C, -0.07 MPa, and 15 min to obtain a first recovery extractant (1,2-dichloroethane) and a hydrolyzate. The first recovery extractant is returned to the continuous extraction column for a first extraction treatment;

[0092] (5) The first extraction system containing the hydrolyzate obtained above and the hydrolyzate obtained by the third evaporation concentration were fed into a continuous reaction column at a feed rate of 20 g / min and a 1,2-dichloroethane solution of 31.25 g / min thionyl chloride at a feed rate of 35 g / min. After staying at 80°C for 60 min, the fifth product system containing 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride was fed into a continuous falling film evaporator at a feed rate of 55 g / min for second evaporation concentration. The system stayed at 50°C and -0.07 MPa for 10 min. The recovered acylating agent was returned to the continuous acylation-oxidation reaction process for recycling. The concentrated residue was the target product. The target product was 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, with a content of >98%, a maximum single impurity of <1%, and a yield of 57%; the continuous total yield was 55%.

[0093] Example 2

[0094] The continuous synthesis is carried out using the continuous synthesis system of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carbonyl chloride as shown in the figure. The continuous synthesis method includes the following continuous process:

[0095] (1) 2,3-dichloropyridine solid was fed into a continuous columnar stirred reactor at a feeding rate of 15 g / min, 80% hydrazine hydrate was fed into a continuous hydrazine hydrolysis reactor at a feeding rate of 20.5 g / min, and after staying and reacting for 8 hours at 90°C, a first product system containing a hydrazine hydrolysis product was obtained. The system was fed into a horizontal continuous stirred reactor at a feeding rate of 34.4 g / min, and after staying and crystallizing for 60 minutes at 20°C, the system overflowed into a fluidized bed dryer at a feeding rate of 15.3 g / min, and the temperature of the fluidized bed dryer was set to 60°C. After staying and drying for 30 minutes, 3-chloro-2-hydrazinepyridine was obtained. The yield of the 3-chloro-2-hydrazinepyridine was measured to be 94%;

[0096] (2) The 3-chloro-2-hydrazinopyridine prepared above was fed into a continuous reaction column at a feeding rate of 11 g / min, and diethyl maleate was fed at a feeding rate of 15.3 g / min and a sodium ethoxide isopropanol solution with a mass concentration of 20% was fed into the continuous reaction column at a feeding rate of 13.77 g / min. After staying and reacting for 3 hours at 40° C., the obtained second product system containing the cyclization product was fed into a continuous reaction kettle at a feeding rate of 53.8 g / min. At the same time, acetic acid with a mass concentration of 10% was fed into the continuous reaction kettle at a feeding rate of 55.8 g / min. After staying and reacting at 20° C., the reaction mixture was stirred for 3 hours. After 60 minutes of evaporation, the obtained system overflowed into the continuous extraction column at a feed rate of 109.6 g / min, and dichloroethane was introduced into the continuous extraction column at a feed rate of 57.3 g / min for a second extraction treatment. After staying at 30° C. for 30 minutes, the cyclization product and the second solvent phase were obtained respectively. The second solvent phase was introduced into a thin film evaporator at a feed rate of 54.6 g / min for a fourth evaporation concentration treatment. After evaporation and concentration at 60° C. and -0.07 MPa for 10 minutes, a second recovered extractant was obtained, and all the second recovered extractant was returned to the continuous extraction column for a second extraction treatment;

[0097] (3) The cyclization product obtained above was fed into a continuous solid-liquid reactor at a feeding rate of 58.2 g / min, phosphorus oxybromide at a feeding rate of 20.7 g / min, and ethylene dichloride at a feeding rate of 20.7 g / min. After staying at 70° C. for 90 min, the third product system containing the brominated product was overflowed into a continuous extraction column at a feeding rate of 99.6 g / min. A 20% aqueous sodium hydroxide solution was fed into the continuous extraction column at a feeding rate of 23.4 g / min. After staying at 40° C. for 30 min, an aqueous phase and an organic phase (a mixture of the brominated product and ethylene dichloride) were obtained.

[0098] (4) The organic phase prepared above was fed into a continuous reaction column at a feed rate of 85.9 g / min and the potassium hydroxide aqueous solution was fed at a feed rate of 66.4 g / min. After staying at 80° C. for 60 min, the fourth product system containing the hydrolyzate was fed into a continuous extraction column at a feed rate of 152.3 g / min and stayed at 40° C. for 10 min to obtain a first solvent phase and an aqueous phase containing the hydrolyzate. The first solvent phase was fed into a falling film evaporator at a feed rate of 83.2 / min for a first evaporation concentration treatment, stayed at 60° C. and -0.07 MPa for 8 min, and the first recovered solvent was returned to the continuous solid-liquid reactor for a continuous bromination reaction. The aqueous phase containing the hydrolyzate was fed at a feed rate of 69.3 g / min and 30% The hydrochloric acid is fed into the continuous reactor at a feed rate of 37 g / min for the first acidification treatment, and stays at 40°C for 30 min. The first acidification product obtained is fed into the continuous extraction column at a feed rate of 106.3 g / min, and 1,2-dichloroethane is fed into the continuous extraction column at a feed rate of 106.3 g / min for the first extraction treatment, and stays at 40°C for 30 min to obtain the first extraction system containing the hydrolyzate and waste water. The first extraction system is fed into the continuous falling film evaporator at a feed rate of 40 g / min for the third evaporation concentration treatment, at 50°C, -0.07 MPa, and stays for 15 min to obtain the hydrolyzate and dichloroethane (the first recovered extractant), and the concentrated dichloroethane is returned to the continuous extraction column for the first extraction treatment;

[0099] (5) The hydrolyzate obtained above was fed into a continuous reaction column at a feed rate of 30 g / min and a 1,2-dichloroethane solution of 46.9 g / min thionyl chloride at a feed rate of 63 g / min. After staying at 80°C for 60 min, the fifth product system containing 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride was fed into a continuous falling film evaporator at a feed rate of 139.9 g / min for second evaporation concentration. The system stayed at 50°C and -0.07 MPa for 10 min. The recovered acylating agent was returned to the continuous acylation-oxidation reaction process for recycling. The concentrated residue was the target product. The target product was 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, with a content of >98%, a maximum single impurity of <1%, and a yield of 56%; the continuous total yield was 54%.

[0100] Example 3

[0101] The difference from Example 1 is that in step (4), the temperature for liquid separation treatment of the fourth product system is 10° C., and the material residence time is 30 min; the temperature for the first evaporation concentration treatment of the first solvent phase is 40° C., the pressure is -0.09 MPa, and the residence time is 180 min; the temperature for the first acidification treatment of the aqueous phase is 0° C., and the residence time is 60 min.

[0102] Example 4

[0103] The difference from Example 1 is that in step (4), the temperature for liquid separation treatment of the fourth product system is 60° C., and the material residence time is 5 min; the temperature for the first evaporation concentration treatment of the first solvent phase is 80° C., the pressure is -0.04 MPa, and the residence time is 30 min; the temperature for the first acidification treatment of the aqueous phase is 50° C., and the residence time is 10 min.

[0104] Example 5

[0105] The difference from Example 1 is that in step (4), the temperature for liquid separation treatment of the fourth product system is 5° C., and the material residence time is 3 min; the temperature for the first evaporation concentration treatment of the first solvent phase is 90° C.; and the residence time for the first acidification treatment of the aqueous phase is 5 min.

[0106] Example 6

[0107] The difference from Example 1 is that the temperature of the third evaporation concentration treatment is 30° C., the pressure is −0.09 MPa, and the material residence time is 30 min.

[0108] Example 7

[0109] The difference from Example 1 is that the temperature of the third evaporation concentration treatment is 60° C., the pressure is −0.06 MPa, and the material residence time is 10 min.

[0110] Example 8

[0111] The difference from Example 1 is that the temperature of the third evaporation concentration treatment is 25°C.

[0112] Comparative Example 1

[0113] The difference from Example 1 is that 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride is prepared by a batch process.

[0114] Comparative Example 2

[0115] The difference from Example 1 is that the solvent is not recovered, that is, the first recovered solvent obtained in step (4) is discharged as waste.

[0116] Comparative Example 3

[0117] The difference from Example 1 is that the acylating agent is not recovered, that is, the recovered acylating agent obtained in step (5) is discharged as waste.

[0118] The product yields and continuous total yields obtained in the above examples and comparative examples of the present application are summarized in Table 1.

[0119] Table 1

[0120]

[0121] From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects: compared with the traditional intermittent preparation method, the continuous synthesis method provided by the present application can reduce the labor and time costs required for separate feeding, thereby improving production efficiency and shortening the synthesis cycle. At the same time, in the continuous synthesis method, only 2,3-dichloropyridine is fed in solid form, and the remaining raw materials and reagents are fed in liquid form, thereby improving the utilization rate of each raw material, thereby improving the yield of the target product 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. Moreover, the main raw material 2,3-dichloropyridine in the continuous hydrazine reaction process of the present application is fed in the form of solid feeding, which can significantly improve the safety of raw material feeding compared to the traditional high-temperature dissolution followed by molten feeding.

[0122] The present application sequentially performs liquid separation treatment, first acidification treatment and first extraction treatment on the fourth product system obtained after the continuous hydrolysis reaction to obtain a first recovered solvent, and returns at least part of the first recovered solvent to the first extraction treatment process for recycling, thereby improving the utilization rate of the third solvent, reducing reagent waste, and reducing production costs. Moreover, the present application returns at least part of the recovered acylating agent obtained by the fifth product system after the second evaporation and concentration treatment to the continuous acylation-oxidation reaction device for recycling, thereby improving the utilization rate of the acylating agent, reducing reagent waste, and reducing production costs.

[0123] It should be noted that the terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not necessarily used to describe a specific order or sequence. It should be understood that the terms used in this way can be interchangeable where appropriate, so that the embodiments of the present application described herein can be implemented in an order other than those described herein, for example.

[0124] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A continuous synthesis method of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride, characterized in that: The continuous synthesis method comprises: Step S1, in a continuous hydrazinolysis reaction device, solid 2,3-dichloropyridine and hydrazine hydrate are subjected to continuous hydrazinolysis reaction in a first solvent to obtain a first product system containing a hydrazinolysis product; the feed rate of the solid 2,3-dichloropyridine is 5 to 20 g / min, and the feed rate of the hydrazine hydrate is 10 to 35 g / min; Step S2, introducing the hydrazinolysis product, diethyl maleate, a first alkali solution and a second solvent into a continuous cyclization reaction device for continuous cyclization reaction to obtain a second product system containing a cyclization product; in the step S2, the feed rate of the hydrazinolysis product is 6 to 9 g / min, the feed rate of the diethyl maleate is 10 to 18 g / min, the feed rate of the first alkali solution is 20 to 25 g / min, the mass concentration of the alkali in the first alkali solution is 10 to 40%, and the feed rate of the second solvent is 1 to 30 g / min; Step S3, passing the cyclization product, the brominating agent and the third solvent into a continuous bromination reaction device for continuous bromination reaction to obtain a third product system containing the brominated product; passing the third product system and the second alkali solution into a continuous neutralization reaction device for continuous neutralization reaction to obtain a mixture of the brominated product and the third solvent; during the continuous bromination reaction, the feed rate of the cyclization product is 30-50 g / min, the feed rate of the brominating agent is 35-40 g / min, and the feed rate of the third solvent is 10-15 g / min; during the continuous neutralization reaction, the feed rate of the third product system is 60-80 g / min, the feed rate of the second alkali solution is 50-80 g / min, and the mass concentration of alkali in the second alkali solution is 5-25%; Step S4, introducing the mixture of the brominated product and the third solvent, the third alkali solution and an optional fourth solvent into a continuous hydrolysis reaction device for continuous hydrolysis reaction to obtain a fourth product system containing a hydrolyzed product; performing liquid separation treatment on the fourth product system to obtain a first solvent phase and an aqueous phase containing the hydrolyzed product; in the step S4, the feed rate of the mixture of the brominated product and the third solvent is 15 to 25 g / min, and the feed rate of the third alkali solution is 15 to 75 g / min; Performing a first evaporation concentration treatment on the first solvent phase to obtain a first recovered solvent; returning at least a portion of the first recovered solvent to the continuous bromination reaction device; wherein the temperature of the first evaporation concentration treatment is 40 to 80° C., the pressure is -0.09 to -0.04 MPa, and the material residence time is 30 to 180 min; sequentially performing a first acidification treatment and a first extraction treatment on the aqueous phase to obtain a first extraction system containing the hydrolyzate; Step S5, introducing the hydrolyzate, the acylating agent and the optional fifth solvent into a continuous acylation-oxidation reaction device for continuous acylation-oxidation reaction to obtain a fifth product system containing the 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride; subjecting the fifth product system to a second evaporation concentration treatment to obtain the 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride and recovering the acylating agent; returning at least a portion of the recovered acylating agent to the continuous acylation-oxidation reaction device; in the step S5, the feed rate of the hydrolyzate is 15 to 25 g / min, and the feed rate of the acylating agent is 15 to 40 g / min; The continuous synthesis method further comprises: performing a third evaporation concentration treatment on the first extraction system to obtain the hydrolyzate and a first recovered extractant; returning at least a portion of the first recovered extractant to the first extraction treatment process; and passing the hydrolyzate into the continuous acylation-oxidation reaction device; wherein the temperature of the third evaporation concentration treatment is 30 to 60° C., the pressure is -0.09 to -0.06 MPa, and the material residence time is 10 to 30 min; The continuous cyclization reaction and the continuous bromination reaction also include sequentially performing a second acidification treatment, at least one second extraction treatment and a fourth evaporation concentration treatment on the second product system to obtain a second recovered extractant; returning at least part of the second recovered extractant to the second extraction treatment process; the temperature of the fourth evaporation concentration treatment is 30 to 80° C., the pressure is -0.09 to -0.06 MPa, and the material residence time is 5 to 15 minutes.

2. The continuous synthesis method according to claim 1, characterized in that The temperature of the liquid separation treatment is 10-60°C, and the material residence time is 5-30 min; and / or, a first acid solution is added during the first acidification treatment, the feed rate of the first acid solution is 5-15 g / min, the mass concentration of acid in the first acid solution is 5-50%, and the pH of the reaction system after the first acidification treatment is 2-3; and / or, the temperature of the first acidification treatment is 0-50°C, and the material residence time is 10-60 min; and / or, the temperature of the first extraction treatment is 0-50°C, and the material residence time is 10-60 min; and / or, the first extraction treatment is carried out using a first extractant, and the first extractant is selected from one or more of the group consisting of dichloromethane, 1,2-dichloroethane, ethyl acetate and toluene.

3. The continuous synthesis method according to claim 1, characterized in that During the second acidification treatment, a second acid solution is added, the feed rate of the second acid solution is 10 to 30 g / min, the mass concentration of the second acid solution is 20 to 40%, and the pH of the reaction system after the second acidification treatment is 7 to 8; and / or, the temperature of the second acidification treatment is 20 to 40° C., and the material residence time is 15 to 30 min; and / or, the second extraction treatment is carried out using a second extractant, the temperature of the second extraction treatment is 20 to 40° C., and the material residence time is 10 to 30 min; and / or, the second extractant is selected from one or more of the group consisting of dichloromethane, dichloroethane and ethyl acetate.

4. The continuous synthesis method according to claim 1, characterized in that In the step S4, the dosage ratio of the mixture to the fourth solvent is 1 g: (1-5) mL; and / or, the temperature of the continuous hydrolysis reaction is 50-100° C., and the material residence time is 0.5-4 h; and / or, the third alkali solution is an aqueous solution formed by one or more selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide; and / or, the fourth solvent is selected from one or more selected from the group consisting of dichloroethane, water, acetonitrile, DMF and 1,4-dioxane.

5. The continuous synthesis method according to any one of claims 1 to 4, characterized in that In the step S5, the dosage ratio of the hydrolyzate to the fifth solvent is 1 g: (1 to 5) mL; and / or, the temperature of the continuous acylation-oxidation reaction is 60 to 100° C., and the material residence time is 0.5 to 3 h; and / or, the acylating agent is selected from one or more of the group consisting of oxalyl chloride, thionyl chloride and phosphorus pentachloride; and / or, the fifth solvent is selected from one or more of the group consisting of dichloroethane, acetonitrile, DMF and 1,4-dioxane.

6. The continuous synthesis method according to claim 1, characterized in that The method between the continuous hydrazinolysis reaction and the continuous cyclization reaction also includes: sequentially crystallizing and drying the first product system to obtain the hydrazinolysis product; and returning at least part of the liquid phase product obtained by the crystallization to the step S1 for reuse.

7. The continuous synthesis method according to claim 6, characterized in that The crystallization temperature is -10 to 20°C, and the material residence time is 50 to 150 min; and / or, the crystallization process is carried out in a purification solvent, the weight ratio of the first product system to the volume of the purification solvent is 1 g: (1 to 5) mL, and the purification solvent is selected from one or more of the group consisting of hydrazine hydrate, water and tetrahydrofuran; and / or, the drying temperature is 40 to 100°C, and the material residence time is 10 to 60 min.

8. The continuous synthesis method according to claim 1, characterized in that In the step S1, the temperature of the continuous hydrazine hydrolysis reaction is 60-100° C., and the material residence time is 4-7 hours; and / or, the first solvent is selected from one or more of the group consisting of hydrazine hydrate, water and tetrahydrofuran; and / or, the weight ratio of the solid 2,3-dichloropyridine to the volume ratio of the first solvent is 1 g: (1-5) mL.

9. The continuous synthesis method according to claim 1, characterized in that: In the step S2, the temperature of the continuous cyclization reaction is 20-80° C., and the material residence time is 1-1.5 h; and / or, the first alkali solution is selected from an alcohol solution formed by one or more of the group consisting of sodium methoxide, sodium ethoxide and sodium tert-butoxide; and / or, the second solvent is selected from one or more of methanol, ethanol and tert-butanol.

10. The continuous synthesis method according to claim 1, characterized in that: During the continuous bromination reaction, the temperature of the continuous bromination reaction is 30-80° C., and the material residence time is 0.5-1.5 h; and / or, the brominating agent is selected from one or more of the group consisting of phosphorus tribromide, phosphorus pentabromide and phosphorus oxybromide; and / or, the third solvent is selected from one or more of dichloromethane, dichloroethane, acetonitrile and 1,4-dioxane.

11. The continuous synthesis method according to claim 10, characterized in that: During the continuous neutralization reaction, the temperature of the continuous neutralization reaction is 0-40° C., and the material residence time is 5-40 min; and / or, the second alkali solution is selected from an aqueous solution formed by one or more of the group consisting of sodium hydroxide, potassium hydroxide, and sodium bicarbonate.

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