Continuous preparation method and system of diazomethane derivative

Abstract

The invention belongs to the technical field of diazomethane derivative synthesis, and relates to a diazomethane derivative continuous preparation method and system.The preparation method comprises the steps that a strong alkali solution in an alkali liquor container and a benzenesulfonyl hydrazone suspension liquid in a suspension liquid container are preheated respectively; conveying the preheated strong alkali solution and benzenesulfonyl hydrazone suspension into a reaction device according to a certain proportion, mixing, and heating for reaction; respectively conveying an extracting agent and a diazomethane derivative crude product mixed solution obtained by the reaction to an online extraction device for mixing, extraction and online separation, and conveying a diazomethane derivative solution obtained by separation to a solid-liquid separation device for solid-liquid separation. By separately preheating reactants, optimizing parameters such as reaction temperature and the like, and communicating a reactant container, a preheating device, a reaction device and the like, the reaction can be continuously carried out, and accumulation of a large number of reactants, intermediate products and final products is reduced, so that side reactions are reduced, the reaction scale is expanded, and the yield and the yield of the products are improved.

Description

Technical Field

[0001] This application relates to the technical field of diazomethane derivative synthesis, and particularly to a continuous preparation method and system for diazomethane derivatives. Background Art

[0002] Diazo compounds and their derivatives are very important starting reactants or organic synthesis intermediates and are of great significance in the development of organic synthesis methods. For example, diazo compounds are used as 1,3-dipoles in the synthesis of nitrogen-containing heterocyclic compounds, and diazo compounds are also common carbene donors. As can be seen from the following resonance formula: 1) When the central carbon atom and the nitrogen atom at the end of the diazo group carry partial negative charges, the diazo compound exhibits nucleophilic characteristics; 2) When the middle nitrogen atom carries partial positive charges, the diazo compound exhibits electrophilic characteristics. Diazo compounds have multiple resonance structures, and the mutual transformation of these resonance structures makes such compounds have rich and diverse reaction activities.

[0003]

[0004] Regarding the preparation methods of diazomethane derivatives, there have been many related reports. For example, Chinese Patent with publication number CN106608788A discloses a mild synthesis method of diazomethane derivatives. An electron-withdrawing group (EWG)-substituted benzenesulfonyl chloride is reacted with hydrazine hydrate to obtain EWG-substituted benzenesulfonyl hydrazide; then EWG-substituted benzenesulfonyl hydrazide is reacted with an aldehyde or a ketone to obtain EWG-substituted benzenesulfonyl hydrazone; then EWG-substituted benzenesulfonyl hydrazone is mixed with a base and an organic solvent and decomposed to obtain a diazomethane derivative.

[0005] However, since benzenesulfonyl hydrazide is an explosive compound, with the expansion of the reaction scale, the usage amount of benzenesulfonyl hydrazide will also increase, which will undoubtedly greatly increase the safety risk, management difficulty and cost, making large-scale production difficult to achieve. At the same time, as an intermediate, benzenesulfonyl hydrazone has unstable properties and large accumulation, which also poses a threat to the safety and stability of the entire production process. In addition, diazo compounds also have high reaction activity and instability, and the accumulation and improper treatment of diazo compounds may trigger serious safety accidents such as explosions. Therefore, this method uses a reaction flask to prepare diazomethane derivatives, which is suitable for the preparation of small-scale diazo compounds. However, restricted by the process safety requirements of explosive compounds such as benzenesulfonyl hydrazide, benzenesulfonyl hydrazone, and diazo compounds, it is not conducive to scale-up, and the yield and productivity are low. Summary of the Invention

[0006] Based on this, the present application provides a continuous preparation method and system for diazomethane derivatives. In the present application, after separately preheating the reactant strong base solution and the benzenesulfonyl hydrazone suspension, they are mixed and heated for reaction. At the same time, parameters such as the reaction temperature and the volume ratio of material mixing are optimized, and by connecting the containers of the reactants, the preheating device, the reaction device, the on-line extraction device, and the solid-liquid separation device, the reaction can proceed continuously. The reactants are consumed while being added, the intermediate products and the final products are continuously synthesized, and are immediately transferred or separated from the reaction system, reducing the accumulation of a large amount of reactants, intermediate products and final products, thereby reducing the generation of side reactions, expanding the scale of the reaction, increasing the yield and productivity of the product, and the reaction process is simple and easy to operate.

[0007] According to the first aspect of the present application, there is provided a continuous preparation method for diazomethane derivatives, comprising the following steps:

[0008] Step 1, synthesizing the crude product of diazomethane derivatives: respectively transporting the strong base solution in the alkali solution container and the benzenesulfonyl hydrazone suspension in the suspension container to the preheating device through pipelines for preheating to 50°C - 80°C, and then transporting the preheated strong base solution and benzenesulfonyl hydrazone suspension to the reaction device through pipelines according to a volume flow ratio of 1 - 3:1 for mixing, and heating to 60°C - 80°C for reaction to obtain a mixed solution of the crude product of diazomethane derivatives;

[0009] Step 2, separation and purification: transporting the extractant and the mixed solution of the crude product of diazomethane derivatives in the reaction device to the on-line extraction device through pipelines for mixing, performing extraction and on-line separation to obtain a diazomethane derivative solution, and transporting the diazomethane derivative solution to the solid-liquid separation device through pipelines for solid-liquid separation to obtain diazomethane derivatives.

[0010] After separately preheating the reactant strong base solution and the benzenesulfonyl hydrazone suspension, they are mixed and heated for reaction. At the same time, parameters such as the reaction temperature and the volume of material mixing are optimized, and by connecting the containers of the reactants, the preheating device, the reaction device, the on-line extraction device, and the solid-liquid separation device, the reaction can proceed continuously to form a continuous flow reaction. The reactants are consumed while being added, the intermediate products and the final products are continuously synthesized, and are immediately transferred or separated from the reaction system, reducing the accumulation of a large amount of reactants, intermediate products and final products, reducing the generation of side reactions, increasing the yield and productivity of the product, which is equivalent to expanding the scale of the reaction, and the entire reaction process is simple and easy to operate.

[0011] In some embodiments, the temperature of the preheating is 65°C - 75°C, and the temperature of the reaction is 65°C - 75°C.

[0012] For example, the preheating temperatures are 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, etc., and the reaction temperatures are 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, etc.

[0013] In some embodiments, the preheating temperature is the same as the reaction temperature.

[0014] In some embodiments, the solid-liquid separation method is: placing the diazomethane derivative solution in a liquid nitrogen-ethanol bath at -110°C to -130°C for freezing, and separating the solvent after solid substances precipitate.

[0015] For example, the temperatures of the liquid nitrogen-ethanol bath are -110°C, -115°C, -120°C, -123°C, -125°C, -130°C, etc.

[0016] In some embodiments, the preheated strong base solution and the benzenesulfonyl hydrazone suspension are mixed at a volume flow rate ratio of 1.5 - 2.5:1.

[0017] For example, the volume flow rate ratios of the preheated strong base solution and the benzenesulfonyl hydrazone suspension are 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 1.5:1, 2.5:1, etc.

[0018] In some embodiments, the diazomethane derivative crude product mixture and the extractant are mixed at a volume flow rate ratio of 0.5 - 1.5:1.

[0019] For example, the ratios of the diazomethane derivative crude product mixture and the extractant are 0.5:1, 0.6:1, 0.8:1, 1.0:1, 1.3:1, 1.5:1, etc.

[0020] In some embodiments, the reaction time is 800 - 1000 s and the pressure is 0 - 0.1 MPa.

[0021] For example, the reaction times are 800 s, 830 s, 850 s, 880 s, 900 s, 920 s, 950 s, 980 s, 1000 s, etc., and the pressures are 0 MPa, 0.03 MPa, 0.05 MPa, 0.08 MPa, 0.1 MPa, etc.

[0022] In some embodiments, the reaction time is 850 - 950 s and the pressure is 0.03 - 0.08 MPa.

[0023] In some embodiments, the strong base solution is at least one of a sodium hydroxide solution, a potassium tert-butoxide solution, a n-butyllithium solution, or a sodium methoxide solution.

[0024] In some embodiments, the concentration of the strong base solution is 3.0 - 3.5 mol / L.

[0025] For example, the concentration of the strong base solution is 3.0 mol / L, 3.1 mol / L, 3.2 mol / L, 3.3 mol / L, 3.4 mol / L, 3.5 mol / L, etc.

[0026] In some embodiments, the benzenesulfonyl hydrazone suspension is obtained by mixing benzenesulfonyl hydrazone into a dispersant, and the mass-volume ratio of the benzenesulfonyl hydrazone to the dispersant is 130 - 135 g : 600 ml.

[0027] For example, the mass-volume ratio of the benzenesulfonyl hydrazone to the dispersant is 130 g : 600 ml, 131 g : 600 ml, 132 g : 600 ml, 133 g : 600 ml, 135 g : 600 ml, etc.

[0028] In some embodiments, the dispersant is at least one of 1,2-dichloroethane, ethylene glycol, or ethylene glycol monomethyl ether.

[0029] In some embodiments, the extractant is at least one of ethyl acetate, dichloromethane, n-hexane, toluene, or n-pentane.

[0030] On the other hand, the present application provides a continuous preparation system for diazomethane derivatives, which is applied to the continuous preparation method described in any one of the above, and includes:

[0031] A sample injection device, which includes an alkali solution container storing a strong base solution and a suspension container storing a benzenesulfonyl hydrazone suspension;

[0032] A preheating device, which includes two preheaters. The two preheaters are respectively connected to the alkali solution container and the suspension container, and preheat the flowing strong base solution and the benzenesulfonyl hydrazone suspension respectively;

[0033] A reaction device, which is connected to the preheater. The strong base solution and the benzenesulfonyl hydrazone suspension are mixed in the reaction device to carry out a reaction;

[0034] A cooling device, which is connected to the reaction device and cools the product output from the reaction device;

[0035] An on-line extraction device, which is connected to the cooling device and performs on-line separation on the product output from the cooling device;

[0036] A solid-liquid separation device, connected to the on-line extraction device, separates the solid and liquid of the product output by the on-line extraction device.

[0037] In one embodiment, the solid-liquid separation device includes a dryer, a product container, a freezer and a double-headed needle. The inlet of the dryer is connected to the on-line extraction device, the outlet of the dryer is connected to the product container, the product container is arranged in the freezer, and the double-headed needle is used to separate the solid substance precipitated after freezing in the product container from the solvent.

[0038] In one embodiment, the preheater and the temperature reduction device are heat exchangers; the reaction device is a static mixer, a two-stage series Y-type micro-reaction device or a micro-reaction device, and the heat exchanger, the static mixer and the micro-reaction device are micro-reaction chips, pipe reactors or T-type mixers; the on-line extraction device is a polymer membrane separator, a centrifugal separator or a gravity separator.

[0039] This application has at least one of the following beneficial effects:

[0040] After separately preheating the reactant strong alkali solution and the benzenesulfonylhydrazone suspension, they are mixed and heated for reaction. At the same time, parameters such as the reaction temperature and the volume ratio of material mixing are optimized. By connecting the containers of the reactants, the preheating device, the reaction device, the on-line extraction device and the solid-liquid separation device, the reaction can proceed continuously. The reactants are consumed while being added, the intermediate products and the final products are continuously synthesized, and are immediately transferred or separated from the reaction system, reducing the accumulation of a large amount of reactants, intermediate products and final products, thereby reducing the generation of side reactions, expanding the scale of the reaction, increasing the yield and productivity of the product, and the reaction process is simple and easy to operate. Detailed implementation manners

[0041] In order to make the purpose, technical solutions and advantages of this application clearer, the following further describes this application in detail with reference to embodiments. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit this application.

[0042] As used herein, the terms "about", "substantially" or "generally" are used to describe and explain small changes. When used in combination with an event or situation, the terms can refer to examples in which the event or situation occurs precisely and examples in which the event or situation occurs very approximately. For example, when used in combination with a numerical value, the terms can refer to a range of changes of ±10% less than or equal to the numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%.

[0043] In addition, quantities, ratios, and other numerical values are sometimes presented in a range format in this document. It should be understood that such range formats are for convenience and brevity and should be interpreted flexibly to include not only the explicitly specified numerical values as range limits but also all individual numerical values or sub-ranges subsumed within the stated range as if each numerical value and sub-range were explicitly specified.

[0044] In the detailed description and claims, a list of items joined by the terms "at least one of", "at least a", "at least a kind of", or other similar terms may mean any combination of the listed items. For example, if items A and B are listed, then the phrase "at least one of A, B" means only A; only B; or A and B. In another example, if items A, B, and C are listed, then the phrase "at least one of A, B, C" means only A; or only B; only C; A and B (excluding C); A and C (excluding B); B and C (excluding A); or all of A, B, and C.

[0045] Currently, the existing preparation of diazomethane derivatives is mainly carried out by reacting a strong alkali solution and a benzenesulfonylhydrazone suspension in a reaction flask. During the preparation, pure water, sodium hydroxide, and ethylene glycol are added to the reaction flask and stirred at room temperature until a clear and transparent state is achieved. Then, the benzenesulfonylhydrazone suspension is added to the reaction flask and reacted at 70 °C. However, due to the safety risk limitations on the amounts of reactants participating in the reaction in the reaction flask, the yields and production rates of the obtained products are relatively low. To expand production, the applicant has attempted to optimize the preparation process to increase the yields and production rates of the products.

[0046] To increase the production of the product, one improved direction is to improve the reaction efficiency and reduce side reactions. However, it has been difficult to significantly increase the yields and production rates of the products by optimizing reaction parameters such as reaction temperature and material ratio in the above reaction flask reaction mode. Another direction is to attempt to increase the amounts of reactants while ensuring production safety. However, in the above reaction flask system, the current amounts of reactants are already close to the limit, and it is difficult to significantly increase the yields and production rates of the products by increasing the amounts of reactants.

[0047] Based on this, we attempted to make the reaction proceed continuously by adding new reactants while consuming the reactants, so as to significantly increase the amount of reactants actually participating in the reaction, thereby increasing the yield and productivity. First, condition screening was carried out through small-scale experiments. A strong base solution was prepared in a 1L beaker. Another 1L beaker was taken to add benzenesulfonyl hydrazone and a dispersant, and they were sheared at high speed to form a benzenesulfonyl hydrazone suspension. Then, the two solutions were respectively transported to the same static mixer through a plunger pump and a pipeline for reaction. After the reaction, the product was directly transported to a heat exchanger through a connected pipeline for cooling. After cooling, it was continuously transported through the pipeline to an on-line separation device for on-line separation to obtain the crude product. Throughout the process, the final product was immediately separated from the reaction system after synthesis, and there was no need to take out the intermediate product for treatment. During the reaction process, according to the reaction time, the strong base solution and the benzenesulfonyl hydrazone suspension could be continuously transported through the plunger pump and the pipeline to achieve continuous flow reaction. When it was necessary to expand the production scale to increase the yield, only by adding new reactants in the reactant container at the reaction consumption rate could the raw materials be continuously supplied to the reaction system, which not only ensured the continuous progress of the reaction, the expansion of the production scale, and the increase in the yield, but also reduced the safety risks brought by the accumulation of a large amount of reactants.

[0048] During this process, it was also found that when the reaction materials entered the static mixer, the residence time was different, and there were also significant differences in the product yield. The reason for the analysis might be that due to the large flow rate of the reactants, the residence time of the materials in the pipeline or the static mixer was relatively short. When the materials entered the static mixer, it was difficult to uniformly heat a large amount of materials to the reaction temperature in a short time. Based on this, while regulating the residence time of the materials in the static mixer, in order to save time, we also tried to improve the reaction efficiency by other means. Finally, it was found that preheating the materials during the transportation process before they reached the static mixer had a significant effect on improving the reaction efficiency. Compared with preheating during the transportation process, preheating the strong base solution and the benzenesulfonyl hydrazone suspension to a certain temperature before transportation respectively, and then transporting them to the static mixer for mixing and reaction had a better effect on increasing the yield. In addition, by exploring the preheating temperature of the two materials, it was found that the product yield showed a trend of first increasing and then decreasing after mixing after being preheated from 50°C to 80°C respectively. The reason for the analysis might be that when the preheating temperature was too low, there might still be a problem that when the materials entered the static mixer, it was difficult to uniformly heat a large amount of materials to the reaction temperature in a short time. When the preheating temperature was too high, it would cause the temperature of the materials to be higher than the reaction temperature after entering the static mixer, and side reactions would occur during the high-temperature mixing of the two materials, thus affecting the product yield. Finally, it was found that when the strong base solution and the benzenesulfonyl hydrazone suspension were preheated to 50°C - 80°C before transportation respectively, transported to the static mixer for mixing according to the volume flow ratio of 1:1 to 3:1, and stayed for 800 - 1000s and other experimental conditions, the yield and productivity could be further improved.

[0049] Hereinafter, the embodiments of the present application will be described in more detail through specific examples and comparative examples.

[0050] Example 1

[0051] A continuous preparation method of a diazomethane derivative, comprising the following steps:

[0052] Step 1: Synthesize the crude diazomethane derivative

[0053] 1.1 Prepare a strong base solution: Add an appropriate amount of pure water to a 1 L beaker (alkali solution container), then add 40 g of sodium hydroxide and stir to dissolve. After cooling to room temperature, make up the volume to 300 ml with pure water for standby to obtain a strong base solution;

[0054] 1.2 Prepare a benzenesulfonylhydrazone suspension: Take another 1 L beaker (suspension container), add 132 g (0.5 mol) of p-toluenesulfonylhydrazone, add 0.2 - 0.3 g / ml of ethylene glycol as a dispersant, form a homogeneous suspension through a high-speed shear emulsifier, and make up the volume to 600 ml with ethylene glycol for standby to obtain a benzenesulfonylhydrazone suspension;

[0055] 1.3 Synthesize the crude diazomethane derivative: The alkali solution container and the suspension container are connected with a preheating device, and the preheating device includes two preheaters. In this embodiment, the preheater is specifically a heat exchanger, and the two preheaters are heat exchanger 1 and heat exchanger 2 respectively.

[0056] Connect the alkali solution container storing the strong alkali solution to the inlet of heat exchanger 1 (preheater) through a pipeline, connect the suspension container storing the benzenesulfonyl hydrazone suspension to the inlet of another heat exchanger 2 (preheater) through a pipeline, and connect the outlets of heat exchanger 1 and heat exchanger 2 to a static mixer (reaction device) through a pipeline. Plunger pumps 1 and 2 are respectively installed on the pipelines between heat exchanger 1 and heat exchanger 2 and the static mixer. After the strong alkali solution and the benzenesulfonyl hydrazone suspension are respectively preheated to 70 °C by flowing through heat exchanger 1 and heat exchanger 2, the preheated strong alkali solution and benzenesulfonyl hydrazone suspension are respectively transported to the static mixer (model: SK-316, packing specification: 4 mm × 6 mm, liquid holdup: 10 L, reaction stream flow path length: 40 m) for mixing according to a volume flow ratio of 1:1 by plunger pumps 1 and 2. Place the static mixer in a 70 °C water bath, heat it to 70 °C and keep it for reaction. The residence time of the strong alkali solution and the benzenesulfonyl hydrazone suspension in the static mixer is 900 s, and the reaction pressure is 0.05 MPa. The outlet of the static mixer is connected to a heat exchanger 3 (cooling device) through a pipeline. After the reaction, the product stream in the static mixer flows through heat exchanger 3 and is cooled to 0 °C to obtain a crude product mixture solution of diazomethane derivatives; in this embodiment, heat exchanger 1, heat exchanger 2, and heat exchanger 3 are specifically tubular reactors. In other embodiments, heat exchanger 1, heat exchanger 2, and heat exchanger 3 can also be other heat exchange devices such as microreaction chips or T-shaped mixers.

[0057] Step 2, separation and purification: The outlet of heat exchanger 3 is connected to an online extraction device through a pipeline. The inlet of the online extraction device is also connected to an extractant container and a saturated brine container through pipelines. The crude product mixture solution of diazomethane derivatives, the extractant n-pentane, and the saturated brine are transported to the online extraction device according to a volume flow ratio of 1:1:1 for online separation. The outlet of the online extraction device is connected to a solid-liquid separation device through a pipeline. The solid-liquid separation device includes a dryer, a product container, a freezer, and a double-headed needle. The inlet of the dryer is connected to the outlet of the online extraction device. The crude product obtained from the online separation flows through the dryer for drying to obtain a diazomethane derivative solution. The outlet of the dryer is connected to the product container, and the diazomethane derivative solution is transported to the product container. After placing the product container in a liquid nitrogen-ethanol bath (freezer) and freezing it at -120 °C for 4 hours, a large amount of red solid substances precipitate. The liquid solvent is separated using a double-headed needle to obtain phenyl diazomethane solid in an enriched state, which is the diazomethane derivative. In this embodiment, the online extraction device is specifically a high-efficiency liquid-liquid separator (model: SEP-10). The dryer used in this embodiment is specifically a glass tube with an inner diameter of 10 mm, a length of 20 cm, and filled with 4A molecular sieve inside.

[0058] Example 2

[0059] A continuous preparation method of a diazomethane derivative, based on Example 1, explores the effect of the volume flow ratio of the two materials on the yield and yield during the continuous flow reaction in step 1, and the other conditions are consistent with Example 1, as follows:

[0060] In step 1.3, the strong base solution and the benzenesulfonylhydrazone suspension are preheated to 70°C, and then the preheated strong base solution and the benzenesulfonylhydrazone suspension are respectively transported to a static mixer at a volume flow ratio of 2:1 by a plunger pump, heated to 70°C and maintained for reaction. The residence time of the strong base solution and the benzenesulfonylhydrazone suspension in the static mixer is 900s. After the reaction is completed, the mixture is cooled to 0°C through a heat exchanger to obtain a crude diazomethane derivative product mixture.

[0061] Comparative Example 1

[0062] A method for preparing a diazomethane derivative, wherein the entire reaction is carried out in a reaction flask, specifically:

[0063] Add 300 ml of pure water, 40 g of sodium hydroxide, and 600 ml of ethylene glycol to the reaction flask, and stir at room temperature for 15 min. At this time, the reaction flask is clear and transparent. Heat to 70 ° C, add 132 g of p-toluenesulfonylhydrazone to the reaction flask, keep stirring at 70 ° C for 900 s, and obtain a dark red liquid diazomethane derivative crude product. The reaction is complete.

[0064] After the reaction solution is cooled to room temperature, 200 mL of ice water and 200 mL of n-pentane are added for extraction. After sufficient shaking and standing for stratification, the upper oil phase is retained, and 50 mL of saturated brine is added to the upper oil phase for washing to remove any water-soluble impurities that may remain therein, followed by the addition of anhydrous magnesium sulfate for drying. The ratio of the mass of anhydrous magnesium sulfate to the volume of the liquid is 20-30 g / 100 ml. After drying, the anhydrous magnesium sulfate solid is removed by filtration. The filtrate is added to a dry ice and ethanol mixed system and frozen at -80 ° C for 4 hours to precipitate a red solid and adsorb on the bottle wall. Next, the liquid solvent is separated by a double-ended needle, and after the separation is complete, an enriched phenyldiazomethane solid is obtained.

[0065] Comparative Example 2

[0066] A continuous preparation method of a diazomethane derivative, based on Example 1, explores the effect of the separation and purification method of the diazomethane derivative solution prepared in step 2 on the yield and yield, and the other conditions are consistent with Example 1, specifically as follows:

[0067] The diazomethane derivative solution is placed in a constant temperature water bath at 25°C for vacuum extraction and concentration until all volatile solvents are completely extracted to obtain an enriched phenyldiazomethane solid.

[0068] Comparative Example 3

[0069] A continuous preparation method of a diazomethane derivative. Based on Example 1, mainly exploring the influence of the reaction after preheating the strong base solution and the benzenesulfonylhydrazone suspension in Step 1 on the results. Other conditions are the same as those in Example 1, and are specifically as follows:

[0070] In Step 1.3, without preheating the strong base solution and the benzenesulfonylhydrazone suspension prepared in Steps 1.1 and 1.2, directly feed the two streams of the strong base solution and the benzenesulfonylhydrazone suspension into the static mixer according to a volume flow ratio of 1:1, heat to 70 °C and hold for reaction. The residence time of the strong base solution and the benzenesulfonylhydrazone suspension in the static mixer is 900 s. After the reaction, it flows through the heat exchanger to cool down to 0 °C to obtain a crude diazomethane derivative mixture.

[0071] Comparative Example 4

[0072] A continuous preparation method of a diazomethane derivative. Based on Example 1, mainly exploring the influence of the reaction time in Step 1 on the results. Other conditions are the same as those in Example 1, and are specifically as follows:

[0073] In Step 1.3, after preheating the strong base solution and the benzenesulfonylhydrazone suspension to 70 °C respectively, feed the two streams of the preheated strong base solution and the benzenesulfonylhydrazone suspension into the static mixer according to a volume flow ratio of 1:1, heat to 70 °C and hold for reaction. The residence time of the strong base solution and the benzenesulfonylhydrazone suspension in the static mixer is 1200 s. After the reaction, it flows through the heat exchanger to cool down to 0 °C to obtain a crude diazomethane derivative mixture.

[0074] Comparative Example 5

[0075] A continuous preparation method of a diazomethane derivative. Based on Example 1, mainly exploring the influence of the solvent type for preparing the benzenesulfonylhydrazone suspension in Step 1 on the results. Other conditions are the same as those in Example 1, and are specifically as follows:

[0076] When preparing the benzenesulfonylhydrazone suspension in Step 1.2, take another 1 L beaker, add 132 g of p-toluenesulfonylhydrazone, add an appropriate amount of ethanol with a volume concentration of 95%, form a homogeneous suspension through a high-speed shear emulsifier, and make up the volume to 600 ml with ethanol with a volume concentration of 95% for standby to obtain the benzenesulfonylhydrazone suspension.

[0077] Comparative Example 6

[0078] A continuous preparation method of a diazomethane derivative. Based on Example 1, mainly exploring the influence of the solvent type for preparing the benzenesulfonylhydrazone suspension in Step 1 on the results. Other conditions are the same as those in Example 1, and are specifically as follows:

[0079] When preparing the benzenesulfonylhydrazone suspension in Step 1.2, take another 1 L beaker, add 132 g of p-toluenesulfonylhydrazone, add ethylene glycol dimethyl ether at 0.2 - 0.3 g / ml, form a homogeneous suspension through a high-speed shear emulsifier, make up the volume to 600 ml with ethylene glycol dimethyl ether for standby, and obtain the benzenesulfonylhydrazone suspension.

[0080] Comparative Example 7

[0081] A continuous preparation method of a diazomethane derivative, based on Example 1, mainly explores the influence of the type of strong base solution in Step 1 on the result. Other conditions are the same as those in Example 1, specifically as follows:

[0082] When preparing the strong base solution in Step 1.1, add an appropriate amount of pure water to a 1 L beaker, then add 40 g of sodium ethoxide and stir to dissolve. After cooling to room temperature, make up the volume to 300 ml with pure water for standby, and obtain the strong base solution.

[0083] Comparative Example 8

[0084] A continuous preparation method of a diazomethane derivative, based on Example 1, mainly explores the influence of the reaction temperature in Step 1 on the result. Other conditions are the same as those in Example 1, specifically as follows:

[0085] In Step 1.3, after preheating the strong base solution and the benzenesulfonylhydrazone suspension to 70 °C respectively, the two streams of the preheated strong base solution and the benzenesulfonylhydrazone suspension are fed into a static mixer according to a volume flow ratio of 1:1, heated to 60 °C and maintained for reaction. The residence time of the strong base solution and the benzenesulfonylhydrazone suspension in the static mixer is 900 s. After the reaction, it flows through a heat exchanger and cools down to 0 °C to obtain a crude diazomethane derivative mixture.

[0086] Comparative Example 9

[0087] A continuous preparation method of a diazomethane derivative, based on Example 1, mainly explores the influence of the preheating temperature of the two materials in Step 1 on the result. Other conditions are the same as those in Example 1, specifically as follows:

[0088] In Step 1.3, after preheating the strong base solution and the benzenesulfonylhydrazone suspension to 40 °C respectively, the two streams of the preheated strong base solution and the benzenesulfonylhydrazone suspension are fed into a static mixer according to a volume flow ratio of 1:1, heated to 70 °C and maintained for reaction. The residence time of the strong base solution and the benzenesulfonylhydrazone suspension in the static mixer is 900 s. After the reaction, it flows through a heat exchanger and cools down to 0 °C to obtain a crude diazomethane derivative mixture.

[0089] Comparative Example 10

[0090] A continuous preparation method of a diazomethane derivative. Based on Example 1, mainly explore the influence of different reaction raw materials in Step 1 on the results. Other conditions are the same as those in Example 1, specifically as follows:

[0091] In Step 1.2, take another 1 L beaker, add 155 g (0.5 mol) of o-nitrobenzenesulfonylhydrazone, add an appropriate amount of ethylene glycol, form a homogeneous suspension through a high-speed shear emulsifier, and make up the volume to 600 ml with ethylene glycol for standby to obtain an o-nitrobenzenesulfonylhydrazone suspension.

[0092] Comparative Example 11

[0093] A continuous preparation method of a diazomethane derivative. Based on Example 1, mainly explore the influence of different reaction raw materials in Step 1 on the results. Other conditions are the same as those in Example 1, specifically as follows:

[0094] Prepare a strong base solution in Step 1.1: Add an appropriate amount of pure water to a 1 L beaker, then add 40 g of potassium hydroxide and stir to dissolve. After cooling to room temperature, make up the volume to 300 ml with pure water for standby to obtain a strong base solution.

[0095] Weigh the products obtained in the examples and comparative examples respectively and calculate the yield. The calculation method of the yield is as follows:

[0096]

[0097] Among them, m x is the total mass of the sample bottle and phenyl diazomethane; m0 is the mass of the sample bottle; V 正 is the total volume of n-pentane added during the collection of the sample; m 理 is the theoretical yield of phenyl diazomethane obtained by consuming the reaction raw materials during the collection of the sample.

[0098] The results are shown in the following table:

[0099] Yield and productivity of the product

[0100]

[0101]

[0102] In Example 1 of the present application, the two reactants are separately preheated to the reaction temperature, then mixed and heated for continuous flow reaction, enabling the product to be immediately separated from the reaction system after continuous synthesis, reducing the generation of side reactions. The reaction process is simple, easy to operate, and has a relatively high production efficiency, which is conducive to large-scale production. By using a static mixer with a smaller size, the materials are mixed more quickly and evenly in the microchannels of the static mixer, which can effectively improve the reaction efficiency and selectivity. Due to the small reaction space and large specific surface area, heat transfer is faster and more uniform, and the heat generated by the reaction can be taken away in time, avoiding thermal runaway caused by local overheating, effectively controlling the reaction heat, reducing the occurrence of side reactions, and increasing the product yield and productivity.

[0103] In large-scale continuous flow reactions, the flow rate of the reactants is large, and the residence time of the materials in the pipeline or reactor is relatively short. Without preheating, when the materials enter the reaction zone, it is difficult for the heating source to uniformly heat a large amount of materials to the reaction temperature in a short time. This may lead to non-uniform material temperatures at the beginning of the reaction, affecting the reaction rate and product quality, and may even trigger side reactions. Preheating can bring the materials to a state close to the reaction temperature before entering the reaction zone, reducing temperature fluctuations during the reaction, thereby increasing the yield. By separately preheating the reactants and optimizing the reaction temperature and the mixing volume of the materials, etc., it is possible to achieve the same yield and productivity as in small-scale production in a reaction flask. When it is necessary to further increase the reaction scale and improve the yield, simply continuously input the reactants into the reactant container.

[0104] In Example 2, the two materials are fed into the static mixer at a volume flow rate ratio of 2:1 for reaction, and the product yield and productivity increase. It can be seen that both the strong base solution and the benzenesulfonylhydrazone suspension can obtain better yields and productivities at a volume flow rate ratio of 2:1.

[0105] In Comparative Example 1, the reactants are subjected to small-scale reaction in a reaction flask, and good yields and productivities can be obtained without separately preheating the reactants. In a small-scale reaction flask, the total amount of reactants is small and the reaction system is relatively small. The contact area between the heating source and the reactants is relatively large, and heat transfer is relatively rapid and uniform, making it easy for the entire reaction system to quickly reach the required reaction temperature. Moreover, the reactant concentration is high, the intermolecular collision frequency is high, and the reaction rate is relatively fast. Even without preheating, the reaction can start and proceed completely relatively quickly. Therefore, special preheating is not required. Also, in small-scale reactions, the temperature gradient in the reaction flask is small, and there will be no local overheating or overcooling, which is conducive to the reaction.

[0106] In Comparative Example 2, through the enrichment method of vacuum extraction and concentration in a 25°C constant temperature water bath, the product yield and productivity decrease, indicating that the enrichment method of freezing in a -120°C liquid nitrogen-ethanol bath for 4 hours in Example 1 is more conducive to increasing the product yield and productivity.

[0107] In Comparative Example 3, the two materials were directly reacted without preheating, and the yield and productivity of the product were much lower than those in Example 1 where the two materials were preheated to the reaction temperature separately and then mixed and heated for reaction. This shows that preheating the two materials to the reaction temperature separately and then mixing and heating for reaction is beneficial to improving the yield and productivity of the product. At the same time, when the two materials are mixed together and preheated simultaneously, side reactions may occur when the preheating temperature has not reached the reaction temperature, thus affecting the yield of the product. Separated preheating is beneficial to avoiding this situation. Therefore, the final preheating method of the present invention is to preheat the two materials separately to the reaction temperature and then mix and heat for reaction.

[0108] In Comparative Example 4, when the reaction time was further extended, the yield and productivity of the product decreased instead, probably due to the fact that too long reaction time produced more by-products. It can be seen that about 900 s is the optimal reaction duration in this application.

[0109] In Comparative Example 5, ethanol with a volume concentration of 95% was used as a solvent to replace ethylene glycol in Example 1, and in Comparative Example 6, ethylene glycol dimethyl ether was used as a solvent to replace ethylene glycol in Example 1. The yield and productivity of the product both decreased, indicating that using ethylene glycol as the solvent for preparing the benzenesulfonylhydrazone suspension in this application is beneficial to the formation of the product.

[0110] In Comparative Example 7, sodium ethoxide was used to replace sodium hydroxide to prepare the strong base solution, and the yield and productivity of the product decreased, indicating that using sodium hydroxide to prepare the strong base solution in this application is beneficial to the formation of the product.

[0111] In Comparative Example 8, when the reaction temperature was set at 60 °C, the yield and productivity of the product decreased, indicating that the reaction temperature of 70 °C in this application is beneficial to the formation of the product.

[0112] In Comparative Example 9, the two materials were preheated to 40 °C separately and then mixed and heated for reaction, and the yield and productivity of the product decreased, indicating that preheating the two materials to the reaction temperature of 70 °C in this application and then reacting is more beneficial to the formation of the product.

[0113] In Comparative Example 10, p-toluenesulfonylhydrazone was replaced with o-nitrobenzenesulfonylhydrazone to prepare the suspension, and the yield and productivity of the product decreased, indicating that using toluenesulfonylhydrazone as the reaction raw material for continuous flow reaction in this application is more beneficial to the formation of the product.

[0114] In Comparative Example 11, sodium hydroxide was replaced with potassium hydroxide to prepare the strong base solution, and the yield and productivity of the product decreased, indicating that using sodium hydroxide as the reaction raw material for continuous flow reaction in this application is more beneficial to the formation of the product.

[0115] The technical features of the above embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0116] The above-described embodiments merely represent several implementation manners of the present application. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A continuous preparation method of a diazomethane derivative, characterized in that, It includes the following steps: Step 1, synthesize the crude product of diazomethane derivative: Respectively transport the strong base solution in the alkali solution container and the benzenesulfonylhydrazone suspension in the suspension container to the preheating device to be preheated to 50°C - 80°C, and then transport the preheated strong base solution and benzenesulfonylhydrazone suspension to the reaction device for mixing according to the volume flow ratio of 1 - 3:1, and heat to 60°C - 80°C for reaction to obtain a mixed solution of the crude product of diazomethane derivative; Step 2, separation and purification: Respectively transport the extractant and the mixed solution of the crude product of diazomethane derivative in the reaction device to the online extraction device for mixing, carry out extraction and online separation to obtain a diazomethane derivative solution, and transport the diazomethane derivative solution to the solid-liquid separation device for solid-liquid separation to obtain diazomethane derivative.

2. The continuous preparation method according to claim 1, characterized in that, The temperature of the preheating is 65°C - 75°C, and the temperature of the reaction is 65°C - 75°C; Preferably, the temperature of the preheating is the same as the temperature of the reaction.

3. The continuous preparation method according to claim 1, characterized in that, The method of solid-liquid separation is: Place the diazomethane derivative solution in a liquid nitrogen ethanol bath at -110°C to -130°C for freezing, and separate the solvent after solid substances precipitate.

4. The continuous preparation method according to claim 1, characterized in that, The preheated strong base solution and benzenesulfonylhydrazone suspension are mixed according to the volume flow ratio of 1.5 - 2.5:1; Preferably, the mixed solution of the crude product of diazomethane derivative and the extractant are mixed according to the volume flow ratio of 0.5 - 1.5:

1.

5. The continuous preparation method according to claim 1, characterized in that, The time of the reaction is 800 - 1000 s, and the pressure is 0 - 0.1 MPa; Preferably, the time of the reaction is 850 - 950 s, and the pressure is 0.03 - 0.08 MPa.

6. The continuous preparation method according to claim 1, characterized in that, The strong base solution is at least one of sodium hydroxide solution, potassium tert-butoxide solution, n-butyllithium solution or sodium methoxide solution; Preferably, the concentration of the strong base solution is 3 - 3.5 mol / L.

7. The continuous preparation method according to claim 1, characterized in that, The benzenesulfonylhydrazone suspension is obtained by mixing benzenesulfonylhydrazone into a dispersant, and the mass-volume ratio of benzenesulfonylhydrazone to the dispersant is 130 - 135 g:600 ml; Preferably, the dispersant is at least one of 1,2-dichloroethane, ethylene glycol, ethylene glycol monomethyl ether.

8. The continuous preparation method according to claim 1, characterized in that, The extractant is at least one of ethyl acetate, dichloromethane, n-hexane, toluene, n-pentane.

9. A continuous preparation system for diazomethane derivatives, which is applied to the continuous preparation method described in any one of claims 1-8, and is characterized in that, It includes: A sample injection device, which includes an alkali solution container storing a strong base solution and a suspension container storing a benzenesulfonylhydrazone suspension; A preheating device, which includes two preheaters. The two preheaters are respectively connected to the alkali solution container and the suspension container, and preheat the flowing strong base solution and benzenesulfonylhydrazone suspension respectively; A reaction device, which is connected to the preheater. The strong base solution and benzenesulfonylhydrazone suspension are mixed in the reaction device for reaction; A cooling device, which is connected to the reaction device and cools the product output from the reaction device; An online extraction device, which is connected to the cooling device and performs online separation on the product output from the cooling device; A solid-liquid separation device, which is connected to the online extraction device and performs solid-liquid separation on the product output from the online extraction device.

10. The continuous preparation system according to claim 9, characterized in that, The solid-liquid separation device includes a dryer, a product container, a freezer and a double-headed needle. The inlet of the dryer is connected to the on-line extraction device, the outlet of the dryer is connected to the product container, the product container is arranged in the freezer, and the double-headed needle is used to separate the solid substances precipitated after freezing in the product container from the solvent.

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