Process for synthesizing isoflurane through micro-channel continuous flow
Through the microchannel continuous flow synthesis process, the problems of uneven reaction, inaccurate condition control and low separation efficiency in the traditional isoflurane synthesis method are solved, and the efficient, high-speed and safe production of isoflurane is achieved.
Patent Information
- Application Number
- CN202411671818.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-21
- Publication Date
- 2025-03-28
AI Technical Summary
In traditional isoflurane synthesis methods, batch reactions lead to uneven mixing of materials and inconsistent reaction rates, which affect the yield and quality of the product. At the same time, the reaction conditions are not controlled accurately, which easily triggers side reactions, and the separation and post-treatment efficiency are low.
The microchannel continuous flow synthesis process is adopted to achieve rapid mixing of reactants, precise temperature control, continuous fractionation and efficient washing and drying through etherification reactions, distillation separation, chlorination reaction and subsequent treatment steps.
It improves the yield and quality of isoflurane, ensures accurate control of reaction conditions, reduces the occurrence of side reactions, improves separation and post-treatment efficiency, and enhances the safety and production efficiency of the process.
Smart Images
Figure CN119707646A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of isoflurane preparation, in particular to a process for synthesizing isoflurane by microchannel continuous flow. Background Art
[0002] As an important inhalation anesthetic, isoflurane has a wide range of applications in the medical field. Traditional isoflurane synthesis methods often use intermittent reaction processes, which have many problems. For example, in intermittent reactions, the materials are not mixed evenly, resulting in inconsistent reaction rates, which affects the yield and quality of the product. Moreover, intermittent reactions do not accurately control the reaction conditions, especially key parameters such as temperature, pressure, and material ratios, which are prone to fluctuations due to different batches, thereby causing an increase in side reactions. In addition, traditional processes also have problems of low efficiency in product separation and post-processing stages, such as large material losses during the separation process, and cumbersome and time-consuming post-processing steps, which are not conducive to large-scale production and stable product quality. For this reason, we propose a microchannel continuous flow process for synthesizing isoflurane. Summary of the invention
[0003] The object of the present invention is to provide a process for synthesizing isoflurane in a microchannel continuous flow to solve the problems raised in the above background technology.
[0004] To achieve the above object, the present invention provides the following technical solution: a process for synthesizing isoflurane by microchannel continuous flow, the process for synthesizing isoflurane by microchannel continuous flow comprising: etherification reaction, distillation separation, chlorination reaction and subsequent treatment; In the etherification reaction stage, trifluoroethanol, N-methylpyrrolidone and Freon are pumped into the autoclave through the microchannel continuous flow design, and the autoclave is sealed and filled with nitrogen. After stirring, a 50% sodium hydroxide aqueous solution at 5-18°C is added, and the temperature in the autoclave is controlled between 35-40°C. After the sodium hydroxide aqueous solution is added, nitrogen is filled into the autoclave to 18-20kg / cm², and the reaction is stirred for 3 hours; In the distillation separation stage, a fractionation microchannel device is used, and the reaction liquid enters the fractionation microchannel from the autoclave after the etherification reaction. By controlling the temperature gradient and pressure gradient of the fractionation microchannel, a continuous fractionation process is performed to obtain and collect the fraction below 30°C, which is 2,2,2-trifluoroethyl difluoromethyl ether; In the chlorination reaction stage, the obtained 2,2,2-trifluoroethyl difluoromethyl ether is pressed into a microchannel chlorination reactor, and a high-precision mass flow controller is used to ensure that chlorine is continuously introduced into the microchannel chlorination reactor filled with 2,2,2-trifluoroethyl difluoromethyl ether at a precise flow rate, and a check valve and a leakage detection device are arranged on the chlorine feed pipeline to effectively prevent chlorine leakage and backflow; In the subsequent processing stage, a continuous washing and drying microchannel pipeline is constructed and connected to the microchannel chlorination reactor. In the washing stage, a 50% sodium hydroxide aqueous solution and cold water at 5°C are continuously pumped into the washing microchannel to allow them to fully contact and wash the reactants. The washed reactants flow to the drying microchannel, which is filled with a desiccant so that the reactants are dried when flowing through the desiccant. The crude isoflurane is obtained after drip filtration and then purified through continuous distillation to obtain the finished isoflurane.
[0005] Preferably, in the etherification reaction stage, a staggered baffle structure is provided in the etherification reaction microchannel. When the reactants flow through the baffles, violent vortex and flow separation are generated, which promotes rapid mixing between the reactants.
[0006] Preferably, the inner wall of the autoclave is provided with a temperature control unit, wherein the temperature control unit is a high-precision temperature sensor and a jacket of a fast-response heating and cooling system, which accurately controls the reaction temperature between 35-40°C and dynamically adjusts the heating or cooling power according to the thermal effect of the reaction to ensure temperature stability.
[0007] Preferably, in the distillation separation stage, a higher temperature and a lower pressure are set at one end of the distillation microchannel. As the reaction liquid flows in the distillation microchannel, the temperature gradually decreases and the pressure gradually increases, so that components with different boiling points can be separated at different positions. Under the premise of ensuring the separation effect, the length and flow rate of the distillation microchannel need to be optimized to reduce the loss of the reaction liquid during the separation process, so that the reaction liquid can be separated in the shortest time, while reducing the adsorption loss of the reaction liquid on the wall.
[0008] Preferably, the distillation separation stage controls the temperature and pressure gradients during the continuous distillation process of the fractionation microchannel so that 2,2,2-trifluoroethyl difluoromethyl ether can be separated more efficiently below 30° C., which is also beneficial to the recovery of TFE. Reasonable temperature and pressure gradients can effectively improve the separation efficiency.
[0009] Preferably, the chlorination reaction stage uses an ultraviolet lamp with a specific wavelength, which is installed on the outside of the microchannel chlorination reactor, and the reaction system is illuminated through the transparent outer wall of the microchannel chlorination reactor, so that the chlorine gas can effectively react with 2,2,2-trifluoroethyldifluoromethyl ether under illumination.
[0010] Preferably, a gas-liquid separation area is provided at the end of the microchannel chlorination reactor, so that unreacted chlorine can be separated out in time, reducing the accumulation of chlorine during the reaction process, improving the efficiency of the reaction, and also improving the overall safety.
[0011] Preferably, the desiccant used in the subsequent treatment stage is anhydrous calcium chloride.
[0012] Preferably, in the subsequent treatment stage, the reactant is washed once with a 50% sodium hydroxide aqueous solution at 5° C., and then washed with cold water until neutral.
[0013] Compared with the prior art, the present invention provides a process for synthesizing isoflurane in a microchannel continuous flow, which has the following beneficial effects: 1. In the process of synthesizing isoflurane by microchannel continuous flow, in the etherification reaction stage, the staggered baffle structure arranged in the microchannel causes the reactants to produce violent vortexes and diversions, promotes rapid mixing, and shortens the time for the reaction to reach equilibrium. At the same time, the temperature control unit on the inner wall of the autoclave can accurately control the reaction temperature at 35-40°C, dynamically adjust the heating or cooling power according to the thermal effect, ensure that the reaction is carried out under the optimal temperature conditions, and effectively improve the rate of the etherification reaction. In the chlorination reaction stage, a high-precision mass flow controller is used to control the chlorine flow rate to ensure the precise and continuous introduction of chlorine. In combination with the illumination system of a specific wavelength ultraviolet lamp and the gas-liquid separation area at the end of the microchannel chlorination reactor, not only can chlorine and 2,2,2-trifluoroethyl difluoromethyl ether react effectively, but also unreacted chlorine can be separated in time, reducing chlorine accumulation and further improving the efficiency of the chlorination reaction.
[0014] 2. The process of synthesizing isoflurane by microchannel continuous flow. The entire synthesis process realizes precise reaction control through microchannel continuous flow technology. In the distillation separation stage, by reasonably setting the temperature and pressure gradient of the fractionation microchannel, components with different boiling points can be effectively separated at different positions, which is beneficial to improve the separation purity of 2,2,2-trifluoroethyl difluoromethyl ether, and is also beneficial to the recovery and reuse of TFE, providing high-quality raw materials for subsequent reactions, thereby ensuring the quality of the final isoflurane product; in the subsequent treatment stage, the design of the continuous washing and drying microchannel pipeline can ensure that the reactant flow passes through 50% sodium hydroxide aqueous solution and cold water at 5°C to be fully washed to neutrality, and then effectively dried through the drying microchannel filled with anhydrous calcium chloride desiccant to obtain high-quality isoflurane crude product. After continuous distillation and purification, the quality of the isoflurane finished product is further improved.
[0015] 3. In the process of microchannel continuous flow synthesis of isoflurane, the check valve and leakage detection device installed on the chlorine feed pipeline in the chlorination reaction stage can effectively prevent chlorine leakage and backflow, reducing the safety risks caused by chlorine leakage; at the same time, the gas-liquid separation area at the end of the microchannel chlorination reactor reduces the accumulation of chlorine in the reaction system, avoids safety accidents that may be caused by excessive accumulation of chlorine, and improves the safety of the entire synthesis process. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 It is a schematic diagram of the process of the present invention; Figure 2It is a schematic diagram of the process steps of the present invention. DETAILED DESCRIPTION
[0017] like Figure 1-Figure 2 As shown, the present invention provides a technical solution: a process for synthesizing isoflurane by microchannel continuous flow, the process for synthesizing isoflurane by microchannel continuous flow comprising: etherification reaction, distillation separation, chlorination reaction and subsequent treatment; In the etherification reaction stage, trifluoroethanol, N-methylpyrrolidone and Freon are pumped into the autoclave through the microchannel continuous flow design, and the autoclave is sealed and filled with nitrogen. After stirring, a 50% sodium hydroxide aqueous solution at 5-18°C is added, and the temperature in the autoclave is controlled between 35-40°C. After the sodium hydroxide aqueous solution is added, nitrogen is filled into the autoclave to 18-20kg / cm², and the reaction is stirred for 3 hours; In the distillation separation stage, a fractionation microchannel device is used, and the reaction liquid enters the fractionation microchannel from the autoclave after the etherification reaction. By controlling the temperature gradient and pressure gradient of the fractionation microchannel, a continuous fractionation process is performed to obtain and collect the fraction below 30°C, which is 2,2,2-trifluoroethyl difluoromethyl ether; In the chlorination reaction stage, the obtained 2,2,2-trifluoroethyl difluoromethyl ether is pressed into a microchannel chlorination reactor, and a high-precision mass flow controller is used to ensure that chlorine is continuously introduced into the microchannel chlorination reactor filled with 2,2,2-trifluoroethyl difluoromethyl ether at a precise flow rate, and a check valve and a leakage detection device are arranged on the chlorine feed pipeline to effectively prevent chlorine leakage and backflow; In the subsequent treatment stage, a continuous washing and drying microchannel pipeline is constructed, and the washing and drying microchannel pipeline is connected to the microchannel chlorination reactor. In the washing stage, a 50% sodium hydroxide aqueous solution at 5°C and cold water are continuously pumped into the washing microchannel to make them fully contact and wash with the reactants. The reactants are first washed once with a 50% sodium hydroxide aqueous solution at 5°C, and then washed with cold water until neutral. The washed reactants flow to the drying microchannel, and the drying microchannel is filled with a desiccant so that the reactants are dried when flowing through the desiccant. The crude isoflurane is obtained after dripping filtration, and then the isoflurane product is obtained through continuous distillation and purification, wherein the desiccant is anhydrous calcium chloride.
[0018] During the etherification reaction stage, a staggered baffle structure is arranged in the etherification reaction microchannel. When the reactants flow through the baffles, violent vortices and split flows are generated, which promotes rapid mixing between the reactants.
[0019] The inner wall of the autoclave is provided with a temperature control unit, which is a high-precision temperature sensor and a jacket of a fast-response heating and cooling system. The reaction temperature is precisely controlled between 35-40°C, and the heating or cooling power is dynamically adjusted according to the thermal effect of the reaction to ensure temperature stability.
[0020] In the distillation separation stage, a higher temperature and a lower pressure are set at one end of the distillation microchannel. As the reaction liquid flows in the distillation microchannel, the temperature gradually decreases and the pressure gradually increases, so that components with different boiling points can be separated at different positions. Under the premise of ensuring the separation effect, the length and flow rate of the distillation microchannel need to be optimized to reduce the loss of the reaction liquid during the separation process, so that the reaction liquid can be separated in the shortest time, while reducing the adsorption loss of the reaction liquid on the wall.
[0021] In the distillation separation stage, by controlling the temperature and pressure gradients in the continuous distillation process of the fractionation microchannel, 2,2,2-trifluoroethyl difluoromethyl ether can be separated more efficiently below 30°C, which is also beneficial to the recovery of TFE. Reasonable temperature and pressure gradients can effectively improve the separation efficiency.
[0022] In the chlorination reaction stage, an ultraviolet lamp with a specific wavelength is used. The ultraviolet lamp is installed on the outside of the microchannel chlorination reactor. The reaction system is illuminated through the transparent outer wall of the microchannel chlorination reactor, so that the chlorine gas can effectively react with 2,2,2-trifluoroethyldifluoromethyl ether under the illumination.
[0023] A gas-liquid separation area is provided at the end of the microchannel chlorination reactor, so that the unreacted chlorine can be separated in time, reducing the accumulation of chlorine during the reaction process, improving the efficiency of the reaction, and also improving the overall safety.
[0024] The above generally describes the present invention in detail, but it is obvious to a person skilled in the art that some modifications or improvements can be made to the present invention. Therefore, modifications or improvements that do not depart from the spirit of the present invention are within the scope of protection of the present invention.
Claims
1. A process for synthesizing isoflurane in a microchannel continuous flow, characterized in that: The process for synthesizing isoflurane by microchannel continuous flow includes: etherification reaction, distillation separation, chlorination reaction and subsequent treatment; In the etherification reaction stage, trifluoroethanol, N-methylpyrrolidone and Freon are pumped into the autoclave through the microchannel continuous flow design, and the autoclave is sealed and filled with nitrogen. After stirring, a 50% sodium hydroxide aqueous solution at 5-18°C is added, and the temperature in the autoclave is controlled between 35-40°C. After the sodium hydroxide aqueous solution is added, nitrogen is filled into the autoclave to 18-20kg / cm², and the reaction is stirred for 3 hours; In the distillation separation stage, a fractionation microchannel device is used, and the reaction liquid enters the fractionation microchannel from the autoclave after the etherification reaction. By controlling the temperature gradient and pressure gradient of the fractionation microchannel, a continuous fractionation process is performed to obtain and collect the fraction below 30°C, which is 2,2,2-trifluoroethyl difluoromethyl ether; In the chlorination reaction stage, the obtained 2,2,2-trifluoroethyl difluoromethyl ether is pressed into a microchannel chlorination reactor, and a high-precision mass flow controller is used to ensure that chlorine gas is continuously passed into the microchannel chlorination reactor filled with 2,2,2-trifluoroethyl difluoromethyl ether at a precise flow rate, and a check valve and a leakage detection device are set on the chlorine gas feed pipeline; In the subsequent processing stage, a continuous washing and drying microchannel pipeline is constructed and connected to the microchannel chlorination reactor. In the washing stage, a 50% sodium hydroxide aqueous solution and cold water at 5°C are continuously pumped into the washing microchannel to allow them to fully contact and wash the reactants. The washed reactants flow to the drying microchannel, which is filled with a desiccant so that the reactants are dried when flowing through the desiccant. The crude isoflurane is obtained after drip filtration and then purified through continuous distillation to obtain the finished isoflurane.
2. A process for synthesizing isoflurane by microchannel continuous flow according to claim 1, characterized in that: In the etherification reaction stage, a staggered baffle structure is arranged in the etherification reaction microchannel, and when the reactants flow through the baffles, violent eddies and split flows are generated.
3. A process for synthesizing isoflurane by microchannel continuous flow according to claim 2, characterized in that: The inner wall of the autoclave is provided with a temperature control unit, wherein the temperature control unit is a high-precision temperature sensor and a jacket of a fast-response heating and cooling system, which can accurately control the reaction temperature between 35-40°C and dynamically adjust the heating or cooling power according to the thermal effect of the reaction.
4. The process for synthesizing isoflurane by microchannel continuous flow according to claim 1, characterized in that: In the distillation separation stage, a higher temperature and a lower pressure are set at one end of the distillation microchannel. As the reaction liquid flows in the distillation microchannel, the temperature gradually decreases and the pressure gradually increases, so that components with different boiling points can be separated at different positions. Under the premise of ensuring the separation effect, the length and flow rate of the distillation microchannel need to be optimized to reduce the loss of the reaction liquid during the separation process.
5. The process for synthesizing isoflurane by microchannel continuous flow according to claim 1, characterized in that: The distillation separation stage controls the temperature and pressure gradient in the fractionation microchannel continuous distillation process, so that 2,2,2-trifluoroethyl difluoromethyl ether can be separated more efficiently at below 30° C., and is also beneficial to the recovery of TFE.
6. The process for synthesizing isoflurane by microchannel continuous flow according to claim 1, characterized in that: The chlorination reaction stage uses an ultraviolet lamp with a specific wavelength, which is installed outside the microchannel chlorination reactor to illuminate the reaction system through the transparent outer wall of the microchannel chlorination reactor.
7. The process for synthesizing isoflurane by microchannel continuous flow according to claim 1, characterized in that: A gas-liquid separation area is provided at the end of the microchannel chlorination reactor so that unreacted chlorine can be separated out in time.
8. The process for synthesizing isoflurane by microchannel continuous flow according to claim 1, characterized in that: The desiccant used in the subsequent treatment stage is anhydrous calcium chloride.
9. The process for synthesizing isoflurane by microchannel continuous flow according to claim 1, characterized in that: In the subsequent treatment stage, the reactant is washed once with a 50% aqueous sodium hydroxide solution at 5° C., and then washed with cold water until neutral.