JP7576389B2 - Flow organic synthesis method - Google Patents

Description

The present invention relates to a flow organic synthesis system and a flow organic synthesis method that perform a gas-liquid-solid three-phase reaction using a gas raw material, a liquid raw material, and a solid catalyst.

Traditionally, for example, in the production of organic compounds used in pharmaceuticals and agricultural chemicals, the batch method has been widely used, in which organic synthesis is carried out one reaction at a time using a batch reactor. This batch method is known to be able to relatively stably produce organic compounds, even those with complex structures, by repeatedly carrying out a specific reaction based on preset conditions.

On the other hand, in the batch process, due to its structure, it is not easy to improve the speed at which the raw materials move or the efficiency of contact with the catalyst, so it takes longer for the reaction to be completed than would be expected based on the actual reaction rate. In addition, when removing the reaction products after each reaction, problems such as exposure of the reaction products to the surroundings of the reactor and oxidation of the catalyst can occur.

In contrast, flow-type (continuous) synthesis reactions, in which raw materials are continuously fed into a reactor and reaction products are continuously removed, eliminate the problems associated with batch methods. In recent years, the advantages of flow-type organic synthesis reactions have been attracting attention, with the development of a flow method (see Non-Patent Document 1) that allows the synthesis of organic compounds with relatively complex structures while continuously progressing the synthesis reaction.

Flow "Fine" Synthesis: High Yielding and Selective Organic Synthesis by Flow Methods, S. Kobayashi, Chem. Asian J., Early View, (2015).

In the organic synthesis reaction described above, the operator can confirm whether the desired organic compound has been produced by analyzing the target substance (the main reaction product) obtained by the reaction (e.g., identification and quantification using liquid chromatography or gas chromatography).

Since such analysis of the target substance requires a certain amount of time (e.g., several minutes), the reaction continues even during the analysis of the target substance, particularly in a flow-type organic synthesis reaction. Therefore, even if the reaction becomes unstable (i.e., an inappropriate reaction occurs) in a flow-type organic synthesis reaction due to some factor, the unstable state will be left as it is until the analysis results of the target substance are obtained.

In addition, when analyzing the target substance using conventional liquid chromatography or gas chromatography, there is a relatively large time lag in detecting the reaction status (for example, changes in the amount of raw material input or conversion rate), making it difficult to monitor with a delay time small enough for practical use.

On the other hand, it is possible to monitor the status of an organic synthesis reaction based on temperature, but the temperature detected by a temperature sensor installed in a reactor or the like only provides localized information, and non-steady temperature distribution occurs due to the rate of heat transfer. Therefore, it is difficult to accurately monitor the status of an ongoing reaction based on temperature. Furthermore, in reactions that do not generate heat, temperature-based monitoring may not be appropriate.

The inventors of the present application conducted extensive research to solve such problems and discovered that, in a flow-type organic synthesis reaction, by measuring the flow rate of the gas raw materials at the outlet (downstream) side of the reactor, it is possible to monitor whether the organic synthesis reaction is proceeding stably while minimizing the lag time in the progress of the reaction, without waiting for the results of the analysis of the target product to be obtained.

The present invention was devised in consideration of the problems of the conventional technology, and has as its main object to provide a flow-type organic synthesis system and a flow-type organic synthesis method that make it possible to monitor the status of a flow-type organic synthesis reaction while suppressing the lag time for the progress of the reaction.

In a first aspect of the present invention, a flow-type organic synthesis system (1) for performing a gas-liquid-solid three-phase reaction using a gas raw material, a liquid raw material, and a solid catalyst is provided with a flow-type fixed bed reactor (2) for generating a reaction product by performing the gas-liquid-solid three-phase reaction, a first gas-liquid separator (25) connected downstream of the flow-type fixed bed reactor and for separating the reaction product supplied from the flow-type fixed bed reactor into a recovery liquid containing the target product of the gas-liquid-solid three-phase reaction and a residual gas containing the gas raw material, a residual gas transport line (L7, L8) connected to the first gas-liquid separator and through which the residual gas flows, and a measuring device connected to the residual gas transport line and used to measure the flow rate of a predetermined component in the residual gas.

This makes it possible to monitor the status of a flow-type organic synthesis reaction while minimizing the lag time in the progress of the reaction based on the flow rate of a specific component in the residual gas.

In a second aspect of the present invention, the measurement device includes a mass spectrometer (37) for indirectly determining the flow rate of the specified component, and further includes a standard gas transport line (L13) connected to the upstream side of the mass spectrometer in the residual gas transport line and supplying a standard gas to the residual gas transport line for relative quantification by the mass spectrometer.

This makes it possible to properly measure the flow rate of a specific component in residual gas using a simple configuration.

In a third aspect of the present invention, the measurement device includes a mass spectrometer (37) for indirectly determining the flow rate of the predetermined component, and further includes a flow meter (35) connected to the residual gas transport line for measuring the flow rate of the residual gas.

This makes it possible to properly measure the flow rate of a specific component in residual gas using a simple configuration.

In a fourth aspect of the present invention, the residual gas transport line further includes a second gas-liquid separator (31) disposed between the first gas-liquid separator and the measuring device, which separates the residual gas into gas and liquid, and the residual gas transport line includes a first line (L7) which transports the residual gas from the first gas-liquid separator to the second gas-liquid separator, and a second line (L8) which transports the gas phase component of the residual gas from the second gas-liquid separator to the measuring device.

As a result, even if the recovered liquid is not sufficiently condensed in the first gas-liquid separator (i.e., if the residual gas in the first line contains the target substance), it is possible to further separate the residual gas and the target substance in the second gas-liquid separator.

In a fifth aspect of the present invention, the configuration further includes a target recovery line (L9) connected to the first gas-liquid separator and through which the recovery liquid flows.

This makes it possible to easily recover the recovery liquid containing the target substance through the target substance recovery line.

In a sixth aspect of the present invention, the target recovery line is provided with a liquid level control valve (46) so that the liquid level (45) of the first gas-liquid separator is kept constant.

This makes it possible for the measuring device to stably measure the flow rate of a specific component in the residual gas.

In a seventh aspect of the present invention, the configuration further includes a target recovery drum (41) connected downstream of the target recovery line.

This makes it possible to easily recover the target substance from the target substance recovery drum without significantly affecting the liquid level in the first gas-liquid separator, and to use the target substance for identification or quantification using a liquid chromatograph or gas chromatograph.

In an eighth aspect of the present invention, the predetermined component is the gas raw material.

This makes it possible to easily monitor the status of a flow-type organic synthesis reaction while minimizing the lag time for the reaction's progress.

In a ninth aspect of the present invention, there is provided a flow-type organic synthesis method for carrying out a gas-liquid-solid three-phase reaction using a gas raw material, a liquid raw material, and a solid catalyst, the gas-liquid-solid three-phase reaction is carried out to generate a reaction product, the reaction product is separated into a recovered liquid containing a target product of the gas-liquid-solid three-phase reaction and a residual gas containing the gas raw material, and the flow rate of a predetermined component in the residual gas is measured.

This makes it possible to monitor the status of a flow-type organic synthesis reaction while minimizing the lag time in the progress of the reaction based on the flow rate of a specific component in the residual gas.

In a tenth aspect of the present invention, the gas-liquid-solid three-phase reaction is any one of a hydrogenation reaction of the liquid raw material using hydrogen as the gas raw material, a carbonylation reaction of the liquid raw material using carbon monoxide as the gas raw material, and an oxidation reaction of the liquid raw material using oxygen as the gas raw material.

This makes it possible to monitor the status of a hydrogenation reaction, carbonylation reaction, or oxidation reaction while suppressing the delay time in the progress of the reaction based on the flow rate of a specific component in the residual gas.

In an eleventh aspect of the present invention, the target substance contained in the recovery liquid is identified and quantified.

This makes it possible to retrospectively confirm the effectiveness of monitoring the reaction status based on the flow rate of a specific component in the residual gas.

In a twelfth aspect of the present invention, the flow rate of the specified component is measured before the start of the gas-liquid-solid three-phase reaction, and the measured value of the flow rate of the specified component before the start of the gas-liquid-solid three-phase reaction is compared with the measured value of the flow rate of the specified component in the residual gas after the start of the gas-liquid-solid three-phase reaction.

This makes it possible to quickly and easily determine whether an organic synthesis reaction has started normally.

In a thirteenth aspect of the present invention, the gas-liquid-solid three-phase reaction is carried out in a flow-type fixed bed reactor (2), and pressure fluctuations in the flow-type fixed bed reactor are detected based on the measured flow rate of the specified component in the residual gas.

This makes it possible to quickly and easily determine whether an organic synthesis reaction is proceeding normally.

In this way, the present invention makes it possible to monitor the status of a flow-type organic synthesis reaction while minimizing the lag time for the progress of the reaction.

Overall configuration diagram of a flow organic synthesis system according to an embodiment A model reaction diagram showing an example of an organic synthesis reaction according to an embodiment. FIG. 2 is a diagram showing a modified example of the flow organic synthesis system shown in FIG. FIG. 1 is an explanatory diagram showing the relationship between the reaction state and the amount of hydrogen consumed in the organic synthesis reaction in Example 1. An explanatory diagram showing a comparison between flow and batch reactions. FIG. 1 is a first explanatory diagram showing the relationship between the reaction status and the hydrogen flow rate in the organic synthesis reaction in Example 2. FIG. 2 is a second explanatory diagram showing the relationship between the reaction status and the hydrogen flow rate in the organic synthesis reaction in Example 2. FIG. 1 is a first explanatory diagram showing the relationship between the reaction status and the hydrogen flow rate in the organic synthesis reaction of Example 3. FIG. 2 is a second explanatory diagram showing the relationship between the reaction status and the hydrogen flow rate in the organic synthesis reaction in Example 3.

The following describes an embodiment of the present invention with reference to the drawings.

Figure 1 is an overall configuration diagram of a flow organic synthesis system 1 according to an embodiment.

The organic synthesis system 1 includes a flow-type fixed-bed reactor 2 that produces a desired reaction product by carrying out a gas-liquid-solid three-phase reaction using a gas feedstock, a liquid feedstock, and a solid catalyst.

The flow-type fixed-bed reactor 2 (hereinafter referred to as the reactor 2) is a known tubular reactor housing a catalyst layer 3 containing a solid catalyst. The reactor 2 reacts the gas and liquid raw materials continuously supplied from the inlet line L1 by flowing them through the catalyst layer 3. The reactor 2 is also provided with a temperature controller 4, which makes it possible to adjust the reaction temperature (here, the temperature of the catalyst layer 3) by supplying or removing heat as necessary. As the reactor 2, for example, not only a downflow reactor in which the raw materials flow in the same direction as gravity, but also an upflow reactor in which the raw materials flow in the opposite direction to gravity can be used.

As the solid catalyst, for example, a metal oxide carrier carrying a metal of Group 10 of the periodic table can be used. As the Group 10 metal, for example, palladium (Pd) and platinum (Pt) can be used, and as the metal oxide carrier, for example, alumina (pHS-Al ₂ O ₃ ), titania (pHS-TiO ₂ ), and hybrid titania (HBT) can be used. In addition, in the solid catalyst, a resin-based carrier or a carbon carrier may be used instead of the metal oxide carrier.

The solid catalyst using a hybrid titania carrier can have a configuration in which, for example, a Group 10 metal is supported on a composite carrier made of at least alumina and titania, and the composite carrier at least includes a substrate made of alumina coated with titania. For details of the solid catalyst using a hybrid titania carrier, please refer to, for example, the configurations of the hydrogenation catalysts disclosed in JP 2016-179440 A and JP 3781417 A.

The gas raw material is continuously supplied to the reactor 2 via a gas raw material supply line L2 connected to the inlet line L1. A flow rate control valve 6 is provided on the gas raw material supply line L2 to adjust the flow rate of the gas raw material. The gas raw material should be supplied in excess of the amount theoretically required for reaction with the liquid raw material so that it remains in the reaction product.

The inlet line L1 is connected to a purge gas supply line L3 through which a purge gas flows. In the organic synthesis system 1, by supplying a purge gas to the purge gas supply line L3 during maintenance or the like, it is possible to purge the equipment, piping, etc. within the system. The purge gas supply line L3 is provided with a flow rate adjustment valve 7 that adjusts the flow rate of the purge gas.

The liquid raw material is stored in the liquid raw material tank 11. The liquid raw material flows through the liquid raw material supply line L4 to the inlet line L1 and is continuously supplied to the reactor 2 together with the gas raw material. The liquid raw material supply line L4 is provided with a liquid raw material pump 12 for transporting the liquid raw material in the liquid raw material tank 11 toward the reactor 2. The liquid raw material supply line L4 is also provided with a preheater/precooler 13. The temperature of the liquid raw material supplied to the reactor 2 is adjusted to within a preset target range by heating or cooling with the preheater/precooler 13.

The liquid raw material supply line L4 is connected to a cleaning liquid supply line L5 through which a cleaning liquid flows. In the organic synthesis system 1, cleaning operations can be performed on the equipment and piping within the system by supplying a cleaning liquid to the cleaning liquid supply line L5 during maintenance or the like. The cleaning liquid is stored in a cleaning liquid tank 17. The liquid raw material supply line L4 is also provided with a cleaning liquid pump 18 for transporting the cleaning liquid in the cleaning liquid tank 17 to the reactor 2 or the like.

In addition, in the reactor 2, the reaction product is continuously discharged from the outlet line L6. The outlet line L6 is provided with a cooler 21. The temperature of the reaction product discharged from the reactor 2 is adjusted to within a preset target range by being cooled by the cooler 21.

The reaction product cooled by the cooler 21 is supplied to the main drum (first gas-liquid separator) 25 connected downstream of the outlet line L6. In the main drum 25, the reaction product is separated into an off-gas (residual gas) containing unreacted gas raw materials, etc., and a recovered liquid containing the target (product) of the reaction.

The off-gas (gas phase components) separated in the main drum 25 is supplied to the sub-drum (second gas-liquid separator) 31 via the off-gas transport line (first line of the residual gas transport line) L7. A pressure regulating valve 32 is provided in the first off-gas transport line L7.

In the sub-drum 31, the liquid containing the target substance remaining in the off-gas is separated into gas and liquid from the off-gas (gas). As a result, in the organic synthesis system 1, even if the recovered liquid is not sufficiently condensed in the main drum 25, it is possible to further separate the residual gas and the target substance in the sub-drum 31. Note that in the organic synthesis system 1, the sub-drum 31 can also be omitted.

The off-gas (gas) separated in the sub-drum 31 is discharged to the outside via the off-gas discharge line (the second line of the residual gas transport line) L8. The off-gas discharge line L8 is provided with a flowmeter 35 that measures the volumetric flow rate of the off-gas. The off-gas discharge line L8 is also provided with a branch line L8a that branches off from a branch section 36 located downstream of the flowmeter 35. The branch line L8a is provided with a mass spectrometer (measurement device) 37. The mass spectrometer 37 can measure the concentration of each component in the off-gas.

With this configuration, in the organic synthesis system 1, the flow rate of a specific component (e.g., the remaining gas raw material) can be continuously measured (indirectly determined) from the concentration of the specific component measured by the mass spectrometer 37 and the flow rate of the off-gas measured by the flow meter 35. At this time, the degree of progress of the reaction in the reactor 2 can be grasped based on the continuous measurements by the flow meter 35.

Such measurement of the flow rate of a specific component can be performed in a shorter time (with a practically small delay time relative to the progress of the reaction) than identification and quantification of the target substance using a liquid chromatograph or gas chromatograph. As a result, in the organic synthesis system 1, as described in detail below, it is possible to monitor the status of the reaction while suppressing the delay time relative to the progress of the reaction based on the flow rate of the specific component in the off-gas determined based on the measurement by the mass spectrometer 37. It should be noted that in the organic synthesis system 1, a mass flow meter can also be provided in the off-gas exhaust line L8.

Meanwhile, the recovered liquid from the main drum 25 is supplied to the product recovery drum 41 via the recovered liquid transport line (target recovery line) L9. In the product recovery drum 41, the gas remaining in the recovered liquid is separated from the recovered liquid. This separated gas is discharged to the outside via the separated gas discharge line L10. In addition, the recovered liquid (target) separated in the product recovery drum 41 is recovered via the product recovery line L11.

In the organic synthesis system 1, the operator can appropriately sample the recovered liquid from the product recovery line L11 at a predetermined timing and analyze it using a liquid chromatograph or gas chromatograph to identify and quantify the target substance (product). This allows the operator to retroactively confirm the effectiveness of monitoring the reaction status based on the measurement results (flow rate of the specified component) of the mass spectrometer 37 described above. Note that in the organic synthesis system 1, the product recovery drum 41 may be omitted and the recovered liquid may be appropriately sampled from the recovered liquid transport line L9 at a predetermined timing.

A liquid level control valve 46 is provided downstream of the recovered liquid transport line L9 so that the liquid level 45 in the main drum 25 measured by a level gauge (not shown) is constant. This liquid level control valve 46 makes it possible to stably maintain the liquid level in the main drum 25 at a desired height. As a result, fluctuations in the liquid level (and thus disturbances in the off-gas flow in the off-gas discharge line L8) during sampling of the recovered liquid, etc., are suppressed, and the flow rate of a specified component in the off-gas can be stably measured by the mass spectrometer 37.

The liquid separated in the sub-drum 31 is discharged into the liquid recovery line L12. The liquid discharged here can be recovered together with the recovery liquid separated in the product recovery drum 41 described above.

Although not shown, in the organic synthesis system 1, the line L6, main drum 25, sub drum 31, line L7, pressure control valve 32, line L9, liquid level control valve 46, and product recovery drum 41, which are located downstream of the cooler 21, may be cooled by an external cooling system. This makes it possible to suppress temperature rise due to heat input from the surroundings (external air, etc.) for the gas and liquid that constitute the reaction product cooled by the cooler 21.

An inert gas supply line L7a can be attached to the first off-gas transport line L7. This inert gas supply line L7a is connected to the upstream side of the pressure regulating valve 32 in the first off-gas transport line L7, and supplies inert gas to the off-gas flow in the first off-gas transport line L7. A flow rate regulating valve 56 that regulates the flow rate of the gas raw material is also provided in the inert gas supply line L7a.

For example, when the amount of gas raw material (here, hydrogen) supplied from the gas raw material supply line L2 is close to the reaction equivalent, the off-gas flow rate may be zero or very small, making it difficult to control the pressure or monitor the reaction status. Even in such a case, supplying a constant flow rate of inert gas from the inert gas supply line L7a has the advantage that the off-gas pressure can be controlled stably by the pressure adjustment valve 32 and the reaction status can be monitored stably by the flowmeter 35 and mass spectrometer 37.

Figure 2 is a model reaction diagram showing an example of an organic synthesis reaction according to an embodiment.

In the organic synthesis system 1, for example, a hydrogenation reaction of a liquid raw material can be carried out as a gas-liquid-solid three-phase reaction.

In one embodiment described later, a reaction is described in which a raw material solution in which the raw material 4-nitrostyrene (abbreviated as "NS") is dissolved in a solvent (methanol) is used as the liquid raw material, and hydrogen _H2 is used as the gas raw material. In this reaction, as shown in FIG. 2, 4-nitrostyrene is reduced with hydrogen to obtain 4-ethylaniline (abbreviated as "EA") as the final total reduced substance (target product). This reaction also passes through 4-aminostyrene (abbreviated as "AMS") or 4-ethylnitrobenzene (abbreviated as "ENB") as an intermediate.

In another example described later, a reaction is described in which 4-ethylaniline is obtained as the reduced substance (target product) by using a liquid raw material solution in which the raw material 4-ethylnitrobenzene is dissolved in a solvent (methanol) (see the area surrounded by the dashed line in Figure 2).

In addition, the organic synthesis system 1 is not limited to the above-mentioned hydrogenation reaction, and can also carry out other reactions, such as a carbonylation reaction of a liquid raw material using carbon monoxide as a gas raw material, or an oxidation reaction of a liquid raw material using oxygen as a gas raw material. As for the liquid raw material, the raw material can be diluted with a solvent at a desired ratio as described above, but the use of such a solvent is not essential.

Figure 3 is a diagram showing a modified example of the organic synthesis system 1 shown in Figure 1. In Figure 3, the same components as those in the organic synthesis system 1 shown in Figure 1 are given the same reference numerals. In addition, in the modified example shown in Figure 3, matters that are not specifically mentioned below are the same as those in the organic synthesis system 1 shown in Figure 1.

In the organic synthesis system 1 shown in FIG. 3, the flowmeter 35 shown in FIG. 1 is omitted. On the other hand, an inert gas supply line (standard gas transport line) L13 through which an inert gas (standard gas) flows is connected to the upstream side of the mass spectrometer 37 in the branch line L8a. A flow control valve 51 that adjusts the flow rate of the gas raw material is provided in the inert gas supply line L13.

With this configuration, in the organic synthesis system 1, an inert gas (e.g., Ar gas) can be entrained at a constant flow rate to the off-gas flowing through the off-gas exhaust line L8. As a result, by using the inert gas as an internal standard substance in the mass spectrometer 37 for relative quantification, it becomes possible to measure (indirectly determine) the flow rate of a specific component in the off-gas with a simple configuration.

Next, we will explain an example of an organic synthesis reaction using the organic synthesis system 1 (see Figure 1).

The raw material solution, in which the raw material 4-nitrostyrene was dissolved in a solvent (methanol), was used as the liquid raw material, and hydrogen was used as the gas raw material to carry out the hydrogenation reaction of the raw material (see Figure 2). The mass spectrometer 37 used was a D-35614 Asslar (Model: GSD 301 O2) manufactured by Pfeiffer Vacuum. The catalyst used was a palladium catalyst (5% Pd/C).

Table 1 shows the experimental conditions for Example 1. Table 1 shows the flow rate of the raw material solution supplied to the liquid raw material supply line L4, the flow rate of hydrogen supplied to the gas raw material supply line L2, the pressure of the reactor 2 (inlet section), and the temperature at the center of the catalyst layer 3 for Experiments 1 to 3 carried out in Example 1. A raw material solution of 4-nitrostyrene with a concentration of 2% and methanol as a solvent was used as the liquid raw material. Experiments 1 to 3 were carried out continuously by setting the flow rate (mL/min) of the raw material solution to 1.0, 0.5, and 0.1, respectively. The hydrogen flow rate and pressure were kept constant in Experiments 1 to 3.

FIG. 4 is an explanatory diagram showing the relationship between the reaction status and hydrogen consumption in the organic synthesis reaction of Example 1. In FIG. 4, the hydrogen (H ₂ ) consumption on the left vertical axis indicates the difference between the flow rate of hydrogen supplied to the gas raw material supply line L2 and the flow rate of hydrogen determined based on the online measurement at several second intervals by the mass spectrometer 37. In addition, the NS concentration (%), EA concentration (%), and ENB concentration (%) on the right vertical axis indicate the results (reaction status) of offline analysis by gas chromatograph (GC-FID) of each component of the recovered liquid obtained at several minute intervals from the product recovery line L11. In addition, FIG. 4 (upper part) also shows the transition of the catalyst temperature.

As shown in FIG. 4, the ENB concentration increases until about 10 minutes after the start of the introduction of the raw material solution (corresponding to 0 minutes). This indicates that a time lag occurs between when the product (recovered liquid) reaches the main drum 25 from the catalyst layer 3 filled in the reactor 2 and when the liquid in the main drum 25 is switched. In the experimental organic synthesis system used in Example 1, the inventory of the reactor 2 is relatively small, and the recovered liquid in the main drum 25 is fully recovered for each sampling, but despite this, such a time lag occurs. In a larger organic synthesis system used for commercial production, the inventory in the reactor 2 is larger, and a certain amount of liquid always remains in the main drum 25 where the liquid level is kept constant, so it is expected that a larger time lag will occur (it will take a longer time to replace the recovered liquid).

In addition, as the flow rate of the raw solution is sequentially decreased to 1.0, 0.5, and 0.1, the residence time of the raw solution in reactor 2 increases, and the concentration (yield) of EA, which is a completely reduced substance, increases.

On the other hand, the amount of hydrogen consumption rises quickly after the start of the introduction of the raw solution, which is thought to reflect the behavior of hydrogen consumption accompanying the progress of the reaction in the catalyst layer 3. In addition, when the flow rate of the raw solution is changed to 1.0, 0.5, and 0.1 in that order, the amount of hydrogen consumption changes quickly in response to the change, which is also thought to reflect the behavior of hydrogen consumption in the catalyst layer 3.

For example, after the start of Experiment 3 (approximately 50 minutes after the start of the experiment) when the flow rate of the raw material solution was relatively small, analysis of the recovered liquid by gas chromatography required more than 30 minutes for the behavior of hydrogen consumption to be reflected (approximately 80 minutes after the ENB concentration stabilized). In contrast, the amount of hydrogen consumption measured by mass spectrometer 37 indicated that the change in the amount of hydrogen reacted in reactor 2 was detected in about 1 minute.

For example, in experiment 1, after the start of the introduction of the raw material solution, the temperature of the catalyst layer 3 was not stable and gradually increased from 35°C to 40°C. At this time, analysis of the recovered liquid by gas chromatography showed that the ENB concentration in the recovered liquid increased and then gradually decreased, while the EA concentration increased. In contrast, the hydrogen consumption measured by the mass spectrometer 37 was not stable and gradually increased, which is thought to better reflect the behavior of hydrogen consumption within the catalyst layer 3.

Table 2 shows a comparison of the hydrogen consumption measured by mass spectrometer 37 in Experiments 1 to 3 (just before completion) and the hydrogen consumption based on the analysis results of the gas chromatograph (GC-FID). In Experiments 1 to 3, the hydrogen consumption measured by mass spectrometer 37 is in good agreement with the hydrogen consumption based on the analysis results of the gas chromatograph.

In this way, in organic synthesis system 1, it is possible to monitor the status of the reaction while minimizing the delay time for the progress of the reaction based on the flow rate of a specific component in the off-gas (here, hydrogen as a gas raw material).

Figure 5 is an explanatory diagram showing a comparison between a flow reaction (the organic synthesis reaction of Example 1) and the corresponding batch reaction. In Figure 5, the changes over time in NS conversion, ENB selectivity, and EA selectivity are shown, with (F) and (B) respectively used to distinguish the organic synthesis reaction of Example 1 from the batch reaction.

In a batch reaction, the N-S conversion rate reaches 100% about 20 minutes after the start of the reaction, whereas in a flow reaction, the N-S conversion rate reaches 100% in just a few tens of seconds. Similarly, in a flow reaction, the EA selectivity also reaches 100% in a shorter time than in a batch reaction.

A liquid raw material solution in which the raw material 4-ethylnitrobenzene was dissolved in a solvent (methanol) was used as the liquid raw material, and hydrogen was used as the gas raw material to carry out a hydrogenation reaction of the liquid raw material (see the one-step reduction reaction shown in the area surrounded by the dashed line in Figure 2). In addition, hybrid titania carrying palladium (0.2% Pd/HBT) was used as the catalyst. Note that matters not specifically mentioned below are the same as in Example 1.

Table 3 shows the experimental conditions for Example 2. Table 3 shows the flow rate of the raw material solution supplied to the liquid raw material supply line L4, the flow rate of hydrogen supplied to the gas raw material supply line L2, the pressure of the reactor 2, and the temperature at the center of the catalyst layer 3 for Experiments 1 to 4 performed in Example 2. Experiments 1 to 4 were performed continuously by setting the flow rate (mL/min) of the raw material solution to 1.0, 1.0, 1.2, and 0.8, respectively. The hydrogen flow rate and pressure were kept constant in Experiments 1 to 4.

6 and 7 are explanatory diagrams showing the relationship between the reaction status and the hydrogen flow rate in the organic synthesis reaction of Example 2. In FIG. 6, the hydrogen (H ₂ ) flow rate on the left vertical axis indicates the hydrogen flow rate determined based on the online measurement at intervals of several seconds by the mass spectrometer 37. The EA yield (%) on the right vertical axis indicates the result (reaction status) of offline analysis of each component of the recovered liquid obtained at intervals of several minutes from the product recovery line L11 by a gas chromatograph (GC-FID). The value in parentheses below the value indicating the EA yield (%) is the hydrogen flow rate estimated based on the EA yield (i.e., the amount of hydrogen consumed) by the analysis of the gas chromatograph. On the other hand, FIG. 7 is the same as FIG. 6, except that the hydrogen (H ₂ ) flow rate is measured using a mass flow meter.

In Example 2, we confirmed the behavior immediately after the start of the reaction, the slight disturbance of reaction factors (e.g., the temperature increase from Experiment 1 to Experiment 2), and the change in hydrogen consumption due to an increase or decrease in the flow rate of the raw solution (Experiment 2 → Experiment 3 → Experiment 4), as measured by a mass spectrometer and a mass flow meter.

[Process of Experiment 1 from before adding raw materials]
The supply of methanol (not including liquid raw material) at room temperature of 25° C. to the gas raw material supply line L2 was switched to the supply of liquid raw material (corresponding to 0 minutes), and immediately thereafter, the temperature rise in the catalyst layer 3 due to the exothermic reaction was detected by a thermocouple.

At this time, the hydrogen flow rate (see Figures 6 and 7) quickly drops from the level before the reaction started, which shows that the hydrogen consumption behavior in the reactor 2 immediately after the reaction started can be detected quickly. Meanwhile, the reaction temperature (here, the temperature of the catalyst layer 3) at this time rises slowly, and it takes a certain amount of time for the ongoing reaction status to be reflected (for the temperature to stabilize). Also, the temperature detected in the catalyst layer 3, etc. is merely local information.

Therefore, the hydrogen flow rate measured by a mass spectrometer and a mass flow meter makes it possible to monitor the overall (not local) state of the reaction while minimizing the delay time in the progress of the reaction. In particular, such a hydrogen flow rate has the advantage that the progress of the reaction immediately after the start of the reaction can be confirmed more quickly than in the case of temperature by comparing the measured hydrogen flow rate before the start of the reaction with the measured hydrogen flow rate after the start of the reaction (or by calculating the amount of change in the hydrogen flow rate over a specified time interval).

[Process from Experiment 1 to Experiment 2]
As shown in Table 3, in the temperature rise process moving from Experiment 1 to Experiment 2 (a test in which the reaction temperature was actively raised to simulate temperature disturbances in the catalyst layer 3), the EA yield also increases as the temperature of the catalyst layer 3 rises. At this time, the hydrogen flow rate (see Figures 6 and 7) decreases (has a slight downward slope), which shows that this reflects the hydrogen consumption behavior during the temperature rise in the reactor 2. For example, between 35 and 75 minutes, the hydrogen flow rates measured by the mass spectrometer and mass flow meter each decrease with a slope of 0.01 cm ³ /min.

[Process of Experiment 2, Experiment 3, and Experiment 4]
As shown in Table 3, in the process of changing the flow rate of the raw material solution from Experiment 2 to Experiment 3 to Experiment 4, the contact time of the raw material in catalyst layer 3 changes depending on the change in the flow rate of the raw material solution, and the EA yield reflected this change.

The behavior of the hydrogen flow rate (data value) at this time also reflects the behavior of hydrogen consumption within the catalyst layer 3 with a certain degree of accuracy.

Table 4 shows the results of measurements (estimates) of hydrogen flow rates using a mass flow meter (MFM), mass spectrometer (MS), and gas chromatograph (GC-FID) at the time of stabilization for each experiment.

As shown in Table 4, in Experiments 1 to 4, the hydrogen flow rate measured by the mass flow meter (MFM) agreed well with a certain degree of accuracy (error of 2% or less) with the relatively reliable hydrogen flow rate estimated based on the analysis results of the gas chromatograph (GC-FID). This confirms the effectiveness of monitoring based on the hydrogen flow rate measured by the mass flow meter.

In addition, although the hydrogen flow rate measured by a mass spectrometer (MS) is somewhat less accurate than that measured by a mass flowmeter, it matches well with the hydrogen consumption rate based on the analysis results of the gas chromatograph, with a certain degree of accuracy (error of 8% or less). This confirms the effectiveness of monitoring based on the hydrogen flow rate measured by a mass spectrometer.

The results of Experiments 1 to 4 show that by monitoring the hydrogen flow rate measured by a mass spectrometer or mass flow meter, it is possible to quickly confirm whether the desired reaction has started at the start of the reaction, compared to analysis by gas chromatography. In addition, although the hydrogen flow rate value measured by a mass spectrometer or mass flow meter does not allow for detailed understanding of the reaction in reactor 2, it is in good agreement with the relatively reliable hydrogen flow rate estimated based on the analysis results of the gas chromatography, and a practically sufficient accuracy can be ensured for the hydrogen flow rate value.

Furthermore, even after the reaction has started, it is possible to determine whether the reaction is stable over time by monitoring the hydrogen flow rate measured by a mass spectrometer or mass flow meter. If there is a change in the measured hydrogen flow rate, the cause can be identified by comparing it with fluctuations in process conditions such as temperature, flow rate, and pressure, and feedback control can be performed as necessary.

As in Example 2 above, a liquid raw material solution in which the raw material 4-ethylnitrobenzene was dissolved in a solvent (methanol) was used as the liquid raw material, and hydrogen was used as the gas raw material to carry out the hydrogenation reaction of the liquid raw material. Note that matters not specifically mentioned below are the same as in Examples 1 and 2.

Table 5 shows the experimental conditions for Example 3. Table 5 shows the flow rate of the raw material solution supplied to the liquid raw material supply line L4, the flow rate of hydrogen supplied to the gas raw material supply line L2, the pressure of the reactor 2, and the temperature at the center of the catalyst layer 3 for Experiments 1 and 2 carried out in Example 3. Experiments 1 and 2 were carried out continuously by setting the pressure (MPaG) to 0.008 and 0.016, respectively. Furthermore, the raw material solution flow rate, hydrogen flow rate, and temperature in Experiments 1 and 2 were kept constant.

8 and 9 are explanatory diagrams showing the relationship between the reaction status and the hydrogen flow rate in the organic synthesis reaction of Example 3. In FIG. 8, the hydrogen (H ₂ ) flow rate on the left vertical axis indicates the hydrogen flow rate determined based on the online measurement at intervals of several seconds by the mass spectrometer 37. The EA yield (%) indicates the result (reaction status) of offline analysis of each component of the recovered liquid obtained at intervals of several minutes from the product recovery line L11 by a gas chromatograph (GC-FID). The pressure on the right vertical axis is the pressure at the inlet of the reactor 2, and here, the pressure value is set assuming the occurrence of minute pressure fluctuations (e.g., blockages in the reactor, etc.) in the catalyst layer 3. FIG. 9 is similar to FIG. 8, except that the hydrogen (H ₂ ) flow rate is measured using a mass flow meter, as in the case of FIG. 7 described above.

As shown in Figures 8 and 9, in Experiments 1 and 2, even when the pressure (MPaG) was changed from 0.008 to 0.016, no effect was observed on the EA yield. On the other hand, the hydrogen flow rate measured by the mass spectrometer and mass flow meter fluctuated (decreased) significantly in response to the pressure fluctuation (increase) when moving from Experiment 1 to Experiment 2 (see the area surrounded by the dashed line in Figures 8 and 9). In this way, it was found that the hydrogen flow rate measured by the mass spectrometer and mass flow meter can be used to monitor the reaction status (here, pressure fluctuation in reactor 2) while suppressing delay time.

Although the present invention has been described above based on specific embodiments, these embodiments are merely illustrative and the present invention is not limited to these embodiments. For example, the measurement target (predetermined component in the off-gas) for monitoring the reaction status is not limited to the gas raw material, but may be a by-product (gas) in the reactor. Note that not all of the components of the flow organic synthesis system and flow organic synthesis method according to the present invention shown in the above-mentioned embodiments are necessarily essential, and they can be selected appropriately as long as they do not deviate from the scope of the present invention.

1: Flow-type organic synthesis system 2: Flow-type fixed-bed reactor 3: Catalyst layer 4: Temperature controller 6: Flow control valve 11: Liquid raw material tank 13: Preheater/precooler 21: Cooler 25: Main drum 31: Sub-drum 32: Pressure control valve 35: Flow meter 36: Branching section 37: Mass spectrometer (measuring device)
41: Product recovery drum 45: Liquid level 46: Liquid level adjustment valve 56: Flow rate adjustment valve

Claims (3)

A flow organic synthesis method for carrying out a gas-liquid-solid three-phase reaction using a gas raw material, a liquid raw material, and a solid catalyst, comprising:
carrying out the gas-liquid-solid three-phase reaction in a flow-type fixed bed reactor to produce a reaction product;
The reaction product is separated into a recovered liquid containing a target product of the gas-liquid-solid three-phase reaction and a residual gas containing the gas raw material by a first gas-liquid separator connected downstream of the flow-type fixed bed reactor;
A measuring device connected to the first gas-liquid separator continuously measures a flow rate of a predetermined component in the residual gas in the gas-liquid-solid three-phase reaction;
The measuring device is
a flowmeter for measuring a flow rate of the residual gas and a mass spectrometer for measuring a concentration of the predetermined component in the residual gas, the flowmeter and the mass spectrometer being connected to a residual gas transport line through which the residual gas flows;
the gas-liquid-solid three-phase reaction is a hydrogenation reaction of the liquid raw material using hydrogen as the gas raw material,
continuously measuring a flow rate of hydrogen as the predetermined component in the residual gas before the start of the gas-liquid-solid three-phase reaction, and comparing the measured value of the flow rate of hydrogen in the residual gas before the start of the gas-liquid-solid three-phase reaction with the measured value of the flow rate of hydrogen in the residual gas after the start of the gas-liquid-solid three-phase reaction to confirm whether the gas-liquid-solid three-phase reaction has started;
a flow type organic synthesis method , wherein after the gas-liquid-solid three-phase reaction is started, a state of the gas-liquid-solid three-phase reaction is monitored based on a flow rate of hydrogen measured by the measuring device. 2. The flow organic synthesis method according to claim 1 , wherein the target substance contained in the recovered solution is identified and quantified. 3. The flow organic synthesis process according to claim 1, wherein a pressure fluctuation in the flow fixed bed reactor is detected based on a measured value of a flow rate of the predetermined component in the residual gas.

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