KR102244893B1 - Modular numbering-up microreactor for increasing the production of pharmaceuticals - Google Patents

Abstract

The present invention relates to a modular numbering-up metal microreactor for increasing pharmaceutical production. Specifically, it relates to a numbering-up microreactor constructed by assembling a raw material injection and mixing module, a flow distribution module, a catalytic reaction module, and an integrated discharge module, and a method of producing pharmaceuticals or pharmaceutical raw material compounds using the same. The present invention relates to a multi-purpose microreactor capable of exchanging catalyst modules and a scale-up production method of various pharmaceuticals or pharmaceutical raw material compounds using the same.

Description

MODULAR NUMBERING-UP MICROREACTOR FOR INCREASING THE PRODUCTION OF PHARMACEUTICALS}

The present invention relates to a modular numbering-up metal microreactor for increasing pharmaceutical production. Specifically, it relates to a numbering-up microreactor constructed by assembling a raw material injection and mixing module, a flow distribution module, a catalytic reaction module, and an integrated discharge module, and a method of producing pharmaceuticals or pharmaceutical raw material compounds using the same. The present invention relates to a multi-purpose microreactor capable of exchanging catalyst modules and a scale-up production method of various pharmaceuticals or pharmaceutical raw material compounds using the same.

Microfluidic systems have a high surface area-to-volume ratio that promotes mass transfer and heat transfer over a narrow surface area, providing higher reaction yields and selectivity in less time than conventional batch processes. In addition, the microreactor ensures high stability by preventing external exposure of toxic or explosive chemical reactants. In addition, by changing the flow rate, the reaction intermediate can be controlled over a wide range of reaction times. Several steps for synthesizing complex organic molecules can be simplified to one-flow through a series of reactions, which enables rapid and efficient development of new pharmaceutical ingredients. However, the throughput of a single microreactor is not sufficient to meet the industrial requirements due to its low productivity. To solve this problem, paralleling or stacking multiple microreactors is the most effective way to increase the overall throughput of a microreactor system. This numbering-up approach maintains the advantages of intrinsic transport phenomena and adopts the optimized conditions previously derived through a single microreactor, while the batch process requires redesign and verification based on the reaction kinetics model.

Uniform production of chemicals with minimal by-products requires an efficient flow divider that evenly supplies reagents through a series of microchannels. In addition, the use of a single pumping system is desirable to reduce the total inventory of equipment and reduce the footprint of scale-up setups. However, the commonly adopted two-dimensional bifurcation type distributor is not suitable for use at high flow rates. In addition, branched distributors can often cause problems due to clogging by solid products or salts produced in chemical reactions, and approaches have been attempted to solve this problem at reasonable cost.

Packing or fixing of the heterogeneous catalyst in the microreactor facilitates the chemical process by eliminating an additional catalyst separation step. This can increase energy efficiency and reduce production costs because it is easy to configure a multi-step process and a high catalyst recovery rate. The most common method is to pack the powder catalyst into the reactor column space, but this can cause a significant pressure drop. Alternatively, fixing the catalyst to the wall of the reactor can avoid severe pressure drops while maintaining the catalyst efficiency due to good mixing in the microchannels. However, even in this case, leaching of the catalyst may occur due to insufficient fixation of the catalyst particles on the surface. On the other hand, if the microreactor itself functions as a heterogeneous catalyst, all of these problems can be prevented.

In the present invention, a new numbering microreactor module assembly comprising a stainless steel (s/s) flow divider and a reaction module of 25 copper capillaries manufactured by computerized numerical control (CNC) machining and 3D printing technology. to provide. The dispensing performance was verified with a low maldistribution factor (MF), and reagents were uniformly fed into the numbering up copper capillaries using a T-mixer and an additional static mixer. The scale-up production of the commercial drug lupinamide was carried out using a microreactor assembled in a single step and site-specific reaction manner under pre-optimized conditions, and the productivity (0.53 g/min) was It was found to be about 25 times the yield of a single reactor (73.3%).

Republic of Korea Patent Publication No. 10-2013-0101689

The present invention relates to a microreactor equipped with a plurality of heterogeneous catalytic reaction modules to enable scale-up synthesis, and to a method for producing a pharmaceutical or pharmaceutical raw material compound using the same.

The present invention provides a numbering-up microreactor configured by assembling a raw material injection and mixing module, a flow rate distribution module, a plurality of catalytic reaction modules, and an integrated discharge module.

The raw material injection and mixing module, the flow distribution module, a plurality of catalytic reaction modules, and the integrated discharge module may be sequentially stacked and assembled.

The fluid mixed by the raw material injection and mixing module in the microreactor may be uniformly supplied to a plurality of catalytic reaction modules through a flow rate distribution module.

The mixing module may be composed of a T-mixer and a static mixer.

The T-mixer and static mixer can be arranged in series in the flow path of the fluid.

The flow distribution module may include a baffle disk.

The flow distribution module may exhibit a uniform flow rate distribution irrespective of the clogged reaction module.

The plurality of catalytic reaction modules may be provided in parallel.

The catalytic reaction module may be a heterogeneous catalytic module.

The catalytic reaction module may be a copper capillary tube.

The plurality of catalytic reaction modules may be composed of 2 to 25 modules, more preferably composed of 25 modules.

The microreactor may be provided with a plurality of inlets through which fluid is introduced.

The microreactor may be used for mass production of pharmaceuticals or pharmaceutical raw materials.

In addition, the present invention provides a method for producing a pharmaceutical product or pharmaceutical raw material by supplying a sample to the microreactor.

In addition, the present invention provides a method for producing lupinamide by supplying a 2,6-difluorobenzyl azide solution and a propiolamide solution to the microreactor.

Ascorbic acid may be added to the 2,6-difluorobenzyl azide solution or propiolamide solution.

In addition, the present invention is a method of producing lupinamide using the microreactor, and the 2,6-difluorobenzyl azide solution and the propiolamide solution supplied to the microreactor are mixed by a T-mixer and a static mixer. After that, it provides a method for producing lupinamide comprising the step of performing a reaction by staying in a reaction module.

The reaction may be performed at 80 to 130 °C for 5 to 30 minutes.

If it exceeds the above range, loss of the reactant and evaporation of the solvent may be accelerated, resulting in a decrease in the reaction yield.

The present invention can provide a microreactor equipped with a plurality of catalytic reaction modules and a method for producing pharmaceuticals or pharmaceutical raw materials using the same. The microreactor according to the present invention is stable, has high durability, and can implement a uniform flow rate distribution. In addition, by applying a T-mixer and a static mixer together, a high mixing efficiency of more than 98% can be realized. In addition, it is possible to easily increase the productivity of pharmaceuticals or pharmaceutical raw materials through a microreactor equipped with a plurality of heterogeneous catalyst modules. In addition, the microreactor according to the present invention has a characteristic of having a uniform flow rate distribution regardless of clogging of the catalytic reaction module by a flow distribution module including a baffle.

1 is an optical image of a numbering-up metal microreactor assembled with parallel 25 frog capillaries individually connected to (a) schematic diagram and (b) stainless steel (s/s) flow divider with built-in baffle disk. to be. The body of the flow distributor is manufactured by CNC machining, and the complex baffle disk is manufactured by 3D printing. Reagents are injected through two inlets at the bottom, respectively, and mixed through two mixers: a T-mixer and a static mixer.
2 is a cross-sectional view of a numbering module in (a) an xy plane and (b) an xz plane.
3 shows a numbering-up metal microreactor for a continuous flow heterogeneous catalytic reaction and a module constituting the same. The components of the module consist of the top and bottom of the flow distributor and the top and bottom of the exit junction, baffles, static mixers, connectors, O-rings and copper capillaries.
4 is a cross-sectional view showing the results of a numerical study in the case of having a flow rate of 12 mL/min in the xy-plane centered on the inlet. (a) the contour of the y-direction velocity field, (b) the contour of the concentration field and (c) the pressure drop in the numbering-up module.
5 is a cross-sectional view of the y-direction velocity field contour at each flow rate. (a) 6 mL/min, (b) 12 mL/min and (c) 24 mL/min.
6 is a cross-sectional view of the contour of the concentration field at each flow rate. (a) 6 mL/min, (b) 12 mL/min and (c) 24 mL/min.
7 is a cross-sectional view of a pressure field contour at each flow rate. (a) 6 mL/min, (b) 12 mL/min and (c) 24 mL/min.
Figure 8 is a cross-sectional view of the time change over the concentration field in a device with a flow rate of 12 mL/min. Concentration field at (a) t = 50 s, (b) t = 150 s and (c) t = 250 s.
9 is a result of analyzing the average flow rate of 25 microreactors at a total flow rate of 12 mL/min in a clogging situation.
10 is an xz-plane cross-sectional view of the concentration field at each position of the mixer. (a) Change in mixing efficiency when only T-mixer is used and (b) Change in mixing efficiency when T-mixer and static mixer are used.
11 shows the results of comparing the maldistribution factor (MF) of the results obtained through experiments and numerical analysis at 25 outlets under conditions of total flow rates of 6, 12 and 24 mL/min.
12 is a result of analyzing the flow performance of the flow rate distributor of the numbering up module having 25 capillaries each having a diameter of 1 mm. Ethanol containing red dye was collected from the capillaries at the 25 outlets into 25 containers each. The total flow rate in the experiment was (a) 6 mL/min, (b) 12 mL/min and (c) 24 mL/min.
13 shows the results of experimental verification of the flow rate distribution in a clogging situation. When clogging occurred in one capillary tube, the distribution of the dye-containing fluid was visually evaluated at a total flow rate of 12 mL/min.
14 shows the results of experimental analysis of the performance of the mixing module of the numbering-up reactor. Ethanol containing red dye and blue dye was injected into each of the two inlets of the module. Images of solutions collected from 25 capillary outlets into 25 syringe vessels when (a) only a T-mixer was used and (b) when a T-mixer and static mixer were used. (c) UV-vis spectra of 5 samples obtained from the outlet of a specific location when only the T-mixer was used and (d) when the T-mixer and static mixer were used.
15 relates to a continuous-flow synthesis of rufinamide in a single copper capillary reactor and numbering module for optimization of reaction conditions. ^a The residence time of the fluid. ^b Isolated yield. ^c NMR yield. The copper capillary is 1/16″ od, 0.04″ id and 2 m long.
16 schematically shows the scale-up process of continuous flow synthesis of lupinamide. The reagents contained in each bottle are introduced into a reactor heated by an oven through an HPLC pump, and the product obtained from the reactor is collected in a prepared bottle.
^{17 is a 1} H NMR spectrum of 2,6-difluorobenzyl bromide (1).
Fig. 18 is a ¹ H NMR spectrum of propiolamide (2).
^{19 is a 1} H NMR spectrum of rufinamide (3).

Hereinafter, the present invention will be described with reference to the drawings.

Numbering up module design

As shown in Figure 1, the numbering-up reactor for continuous-flow heterogeneous catalyst is assembled by a number of modules with specific functions: raw material injection and mixing module, flow distribution module, site-specific reaction ( Site-specific reaction) for 25 catalytic reaction modules, integrated discharge module (see Figs. 2 and 3). A three-dimensional (3D) design draft of all components is created using a computer-aided design (CAD) program. The operating process or principle of operation of the reactor is as follows. First, the reagent solution is injected into each inlet located at the bottom of the system. When a large throughput is inflow, in order to obtain a uniformly mixed solution, a T-mixer and a static mixer are arranged in series in the flow path. The reagent injected first is mixed by a T-mixer. Subsequently, the solution passes through an upward flow channel equipped with a bar-type static mixer to improve mixing efficiency. The mixed solution gradually fills the reservoir of the flow distributor and the baffle disk of the top block and is evenly distributed into 25 copper capillaries for a site-specific heterogeneous catalytic reaction. The baffle structure was designed with minor modifications to the baffle design in previous reports (YJ Park, T. Yu, SJ Yim, D. You and DP Kim, LabChip , 2018, 18 , 1250-1258). All parameters of the baffle can maintain a porosity value of 0.5 to create a uniform fluid flow under an acceptable pressure drop. The reaction solution is combined in the integrated discharge module after achieving the synthesis reaction in each copper capillary tube. In particular, the copper capillary can be replaced with other materials for various heterogeneous catalytic reactions.

[Table 1]

Detailed dimensions of the numbering-up microreactor

CFD (computational fluid dynamic) evaluation of numbering-up microreactor

Numerical studies were conducted to evaluate the performance of the numbering up microreactor. First, the module was examined under conditions in which total flow rates of 6, 12, and 24 mL/min and reagents were injected at a ratio of 6.6:1 through the two inlets of the raw material injection module. The uniformity of the flow distribution across 25 capillaries is determined by the maldistribution factor (MF). The definition of MF is as follows.

(1)

(One)

는 마이크로반응기의 평균 질량 유량이다. MF는 질량 유량의 표준 편차를 평균 질량 유량으로 나눈 값이다. 따라서 낮은 MF 값은 마이크로반응기 사이의 유동 분포가 균일하다는 것을 나타낸다.Where n is the number of microreactors, m _i is the mass flow rate of the i-th reactor,

Is the average mass flow rate of the microreactor. MF is the value obtained by dividing the standard deviation of the mass flow rate by the average mass flow rate. Thus, a low MF value indicates that the flow distribution between the microreactors is uniform.

4 shows a contour with a flow rate of 12 mL/min. Fig. 4(a) is a contour of a velocity field in the y-direction. Since the flow rate ratio is 6.6, there is a strong vortex motion on the right side of the mixer. 4(b) shows the concentration field 250 seconds after the start of operation. The two fluids are uniformly mixed as they pass through the mixer. Fig. 4(c) is the pressure distribution of the device. Because the capillary is 2 m long and has a coil structure, most of the pressure drop occurs in the capillary. When comparing the cross-sectional view of each variable according to the flow rate, it shows almost the same distribution (FIGS. 5-7). Since there is a difference in the distance from the mixer to each reaction module (capillary tube), the mixed fluid first reaches the central reaction module (Fig. 8). After sufficient time, the same amount of fluid passes through each reaction module. MF was about 0.35% for all three cases (Table 2). When the numbering up module was used at flow conditions of 6, 12 and 24 mL/min, the two fluids were well mixed and evenly distributed in each microreactor.

[Table 2]

Maldistribution factors (MF), mixing efficiency (η) and pressure drop (ΔP) of the change in total flow

Next, a numerical study was conducted to investigate the effect of a clogged reaction module on a nearby reaction module. In consideration of the symmetry of the system, the following six clogging cases were investigated: clogging occurred in the 13th, 14th, 15th, 19th, 20th and 25th reactors (Fig. 2(b)). In all cases, other conditions such as initial conditions, boundary conditions and material properties are the same in the numerical domain except for the blocked reaction module. In the case of a blocked reaction module, computational meshes were removed and a no-slip condition was applied to the interface. The results of the six cases were compared with the results of the case of having a flow rate of 12 mL/min without clogging. The MF value was less than 0.4% in all six cases (FIG. 9 and Table 3). There is a difference in pressure drop of about 18 pa because the velocity of the fluid increases by about 4% when one reaction module is shut off. However, in the case of the microreactor according to the present invention, a uniform flow rate distribution may be exhibited regardless of a blocked reaction module.

[Table 3]

Maldistribution factors (MF) and pressure drop (ΔP) in case of having a clogged micro-reaction module.

Finally, the performance of the combination of the T-mixer and the static mixer was evaluated in comparison with the case of using the T-mixer alone (total flow rate of 12 mL/min). The degree of mixing of the two fluids is quantified by the mixing efficiency. The mixing efficiency η is defined as follows.

(2)

(2)

(3)

(3)

Where σ represents the standard concentration deviation in the section, N is the number of nodes in the section, c _j is the local concentration at the sample node in section j, c _in is the average concentration at the inlet, and σ _{max is the} concentration of Is the maximum standard deviation. For the flow rate ratio (6.6:1) of the present invention, σ _max is 0.8683.

10 shows the mixing degree of two fluids at each position of the mixer. In FIG. 10(a), it was confirmed that the efficiency gradually increased as the fluid passed through the T-mixer and finally had a value of 88.3%. The T-mixer is not sufficient to mix the two fluids well because laminar flow is formed under the flow conditions of the fluid used in the device. In contrast, in FIG. 10(b), it was confirmed that the two fluids were mixed rapidly as they passed through the T-mixer and the static mixer in sequence, and finally η reached 98.4%. These results show that the mixing module has perfect mixing efficiency (98% or more) when the static mixer is used with the T mixer (Table 4).

[Table 4]

Maldistribution factors (MF), mixing efficiency (η) and pressure drop (ΔP) with T- and static mixers, or only T-mixers

Manufacturing method and experimental evaluation of numbering up module

The design of the numbering-up microreactor module verified through numerical studies is the additive manufacturing (AM) method by 3D printing and the subtractive manufacturing (SM) method by computerized numerical control (CNC). It was made with. In both methods, CAD digital files are used directly, and accordingly, the design, analysis, and manufacturing of modules are integrated into the process. According to the design characteristics of each model, an appropriate manufacturing method may be selected in consideration of the aspects of precision, cost, and time for production of the module system. AM methods, which are generally expensive, have been chosen with limited choices to create complex and small-sized components. A separate baffle disk structure with a complex configuration was manufactured in a form that can be assembled by a 3D printer of the Direct Metal Laser Sintering (DMLS) type. Alternatively, components of relatively complex size, flow distributor body and integrated discharge module parts were manufactured by CNC method with superior accuracy at lower cost than 3D printing. Moreover, flow paths for both types of mixers are built inside the distributor body, which is necessary to mix a large amount of fluid to a sufficient level. In order to securely assemble individually manufactured parts without leakage problems, high-precision built-in screw fittings were made using the SM method, and polymer O-rings were placed between the assembly parts for comprehensive bonding. The inlet/outlet tube and copper capillary are connected to the distribution module body and the integrated discharge module through Swagelok connectors, a fitting solution for commercial fluid systems.

The mixing and dispensing performance of the manufactured numbering up module was experimentally evaluated. A uniform flow rate distribution was confirmed by measuring the average MF values at total flow rates of 6, 12 and 24 mL/min as investigated by numerical studies. In order to measure the change in volume in the experiment, the solution was individually collected for 1 minute by connecting a container made with a syringe to the outlet of 25 capillaries, and an MF in the range of 3.0-4.4 was identified. This is a higher value than the MF (less than 0.4) in numerical studies. This difference in MF values is expected to occur due to inevitable interference in the actual flow due to slight distortion at the end of the coiled capillary tube. However, less than 5% of MF is generally reported to be acceptable in the numbering system. In general, when clogging occurs in the branch structure used in the numbering system, the pressure gradient and flow distribution of the entire channel become non-uniform. It was confirmed that the flow rate distribution behavior was maintained by controlling the flow rate even in the case of clogged with.

In addition, the mixing efficiency was experimentally investigated by visual observation and UV-Vis spectrum under symmetrical flow rate conditions (flow rate ratio = 1:1 and total flow rate 12 mL/min). Ethanol with red dye and blue dye was injected into the two inlets of the raw material injection and mixing module, respectively. As a result, as shown in Fig. 14(a), when only the T-mixer was used, it was confirmed that the color of the fluid coming out of each outlet was different. Meanwhile, as shown in FIG. 14(b), when both the T-mixer and the static mixer are used, the color of the fluid was confirmed to be uniform with high mixing efficiency. In order to quantitatively confirm the mixing efficiency, the Uv-vis spectrum of each fluid was checked. When only the T-mixer is used, the UV-vis spectrum is different from each other as shown in FIG. 14(c), but when both the T-mixer and the static mixer are used, as shown in FIG. 14(d), UV-vis It was confirmed that the spectra were identical to each other.

Continuous-flow synthesis of Rufinamide in a single capillary and numbering module

As an important example of pharmaceutical synthesis using heterogeneous catalysts in microreactors, the production of 1,2,3-triazole structures using commercial copper capillaries has been reported. The 1,2,3-triazole structure is used as a building block in major pharmaceutical manufacturing industries. The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction known as the "click" reaction works effectively under a copper capillary made of metallic copper(0) and 1, 2,3-triazole can be produced with high conversion and selectivity. One of the important drugs, including 1,2,3-triazole, Rufinamide, was approved by the US Food and Drug Administration (FDA) in 2008 to treat Lennox-Gastaut syndrome spasm. The reported productivity of lupinamide in a single copper capillary is 0.00362 g/min (P. Zhang, MG Russell and TF Jamison, Org. Process Res. Dev., 2014, 18, 1567-1570.) However, this is not sufficient for industrial use.

In order to achieve high productivity by using the numbering up module system, we first investigated the optimal conditions. The original two-stage process was changed to a single-stage reaction by performing only the second stage of the CuAAC reaction, and the high purity reactants 2,6-difluorobenzyl azide (1) and propiolamide (2) were a common batch process. Was synthesized. Subsequently, the reaction conditions were newly optimized by carrying out a heterogeneous catalytic reaction in a single copper capillary with reference to the reported conditions such as temperature and residence time. Ionization of Cu(0) to Cu(I) and Cu(II) is induced on the surface of the copper capillary, and ascorbic acid was added as an oxidizing agent harmless to the human body for reduction of Cu(I) of Cu(II).

When reacted at 110° C. as shown in FIG. 15, rufinamide was obtained in a maximum yield of 89.2% under a retention time of 9.75 minutes (entry 5), and a yield of 77.2% under a retention time of 3.25 minutes (entry 1). . It is noteworthy that the catalytic activity was improved by the addition of ascorbic acid, and the productivity was 6 times higher than that of the prior art (3.62 mg/min).

Finally, scale-up production was carried out using the numbering-up module under conditions optimized based on productivity as described above. 2,6-difluorobenzyl azide (1) and propiolamide (2) prepared through a batch process were injected into the two inlets of the module at a total flow rate of 12 mL/min and a 6.6:1 ratio. As a result, as shown in FIG. 15, the synthetic yield was 73.3%, and the productivity was 96% of the predicted one at 0.5306 g/min (25 times the single capillary output = 0.555 g/min). The operation of this module under this condition was carried out for 1 hour.

conclusion

The present invention provides a numbering up microreactor based on two metal materials (stainless steel and copper) and using two precision manufacturing methods (CNC and 3D printing). A uniform flow distribution along the 25 copper capillaries was confirmed in both numerical and experimental studies at total flow rates of 6, 12 and 24 mL/min. The microreactor produced a uniform flow rate distribution irrespective of the clogged reaction module. In addition, according to the results of numerical studies, the combination of the T-mixer and the static mixer showed a high mixing efficiency of more than 98%. In addition, the performance of the mixer was confirmed qualitatively and quantitatively by experiment. The numbering up module was able to perform scale-up synthesis of lupinamide at 0.53 g/min by supplying a reagent at 12 mL/min using optimized conditions. These results show that scale-up can be applied by numbering up. Therefore, the stable and durable s/s and copper-based numbering microreactor module can easily increase the productivity of pharmaceuticals.

The present invention will be described in more detail through the following examples. Objects, features, and advantages of the present invention will be easily understood through the following examples. The present invention is not limited to the embodiments described herein, and may be embodied in other forms. The embodiments introduced herein are provided in order to sufficiently convey the spirit of the present invention to those of ordinary skill in the technical field to which the present invention pertains. Therefore, the present invention should not be limited by the following examples.

General considerations

Unless otherwise specified, components for making flow reactors were purchased from IDEX Health & Science Technologies. Regular flow tubing is 1/16″o.d. And 0.03″i.d. high purity PFA tubing and PEEK 1/4-28 nuts. 1/16″o.d. And 0.04″i.d, were purchased from YMS. Stainless steel Swagelok Tube Fittings, Male Connectors (SS-100-1-1 and SS-600-1-2) were purchased from Swagelok. The static mixer (Sus316L, 5 elements, 5pi, 45mm) was manufactured by Sehwa Hightech. O-rings (SM9-4D, fluorine rubber, heat resistance, 8.5 pi and 1.5 mm thick) were purchased from Misumi Korea. Reagents were delivered by a PhD Ultra syringe pump purchased from Harvard Apparatus equipped with an SGE sealed glass syringe purchased from SGE Analytical Science and a high-flow HPLC pump purchased from Scientific system Inc. The solvent was purchased from Samcheon Chemical, and 2,6-difluorobenzyl bromide and methyl propiolate were purchased from AlfaAesar. CNC machining was carried out using DMX MORI's TX Beta 1250 TC equipment and the material is Sus 316L. Metal 3D printing was performed by Systems Inc.'s DMP type printer, ProX DMP320, and the material was Sus 17-4PH.

Computing setup

An in-house code that discretizes the incompressible Navier-Stokes equation using a numerical analysis technique with second-order accuracy in time and space is used. The number of computing cells is about 4.2 million, and about 86% of the total grid is composed of hexahedral cells. A grid convergence test was performed and numerical analysis was performed using a grid that there was no change in the solution according to the grid. In the case of boundary conditions, Dirichlet boundary conditions for velocity and concentration were applied to each inlet, and convective exit boundary conditions were applied to the outlet. When the total flow rate into the numbering module is 12 mL/min, the velocities at each inlet are 10.42 and 1.58 mL/min, and concentrations are imposed as 1 and 0 at each inlet. No-slip boundary conditions for velocity and concentration were applied to the wall boundaries.

General procedure for the synthesis of 2,6-difluorobenzyl azide (1) in a batch

Sodium azide (3.9 g) was dissolved in 100 mL DMF solvent, and 2,6-difluorobenzyl bromide (10.34 g) was added to the solution. The reaction mixture was stirred at 80° C. for at least 1 hour. The reaction mixture was then cooled to room temperature and stirred at room temperature for at least 2 hours until TLC analysis indicated consumption of starting material. 100 mL of water was added, and the aqueous solution was extracted with diethyl ether (3 x 100 mL). The mixed organic layer was washed with water (2 x 100 mL) and brine (100 mL). After drying over sodium sulfate, the ether was removed under reduced pressure to give pure benzyl azide (1) as a yellow oil in 90% yield. The isolated compound was analyzed by NMR.

General procedure for the synthesis of propionamide (2) in batch

The ammonium hydroxide solution (28 mL) was cooled to -78 °C. Methyl propiolate (8.8 mL) was added to the solution. The reaction mixture was stirred at -78 °C for at least 20 minutes. The reaction mixture was then warmed to room temperature and stirred at room temperature for at least 1 hour until TLC analysis indicated consumption of the starting material. 25 mL of water was added, and the aqueous solution was extracted with diethyl ether (3 x 50 mL). The mixed organic layer was washed with water (50 mL) and brine (50 mL). After drying over sodium sulfate, the ether was removed under reduced pressure to give pure propiolamide (2) as a yellow powder in 90% yield. The isolated compound was analyzed by NMR.

Continuous synthesis of rufinamide (3) in a single copper capillary.

A DMSO solution of 2,6-difluorobenzyl azide [0.29 M] and ascorbic acid (0.384 g) were placed in a 50 mL Hamilton Gastight syringe (Feed A). A DMSO solution of propionamide [2.8 M] was placed in a second 50 mL Hamilton Gastight syringe (Feed B). Two syringes were pumped with a Harvard Apparatus syringe pump. Feed A was pumped at 208.3 μL/min and Feed B was pumped at 31.7 μL/min. Both feeds were connected with a T-mixer and passed through a 1.571 mL copper capillary. The capillary tube was heated at 110° C. by means of an oil bath with a hot plate. The total calculated residence time in the copper capillary was 3.25 minutes. The reaction proceeded for 13 minutes (2-retention time) to reach a steady state, and the reaction was collected for 3 minutes to obtain a brown/red solution. Water (twice the volume of the reaction mixture) was added while stirring to the remaining reaction mixture, and the resulting slurry was allowed to stand for 15 minutes. After filtering and washing with water, the off-white sticky cake was dried in a vacuum oven for 24 hours. Lupinamide was obtained as a dried off-white solid (77% yield). The productivity of this sequence was 22.2 mg/h. The isolated compound was analyzed by NMR.

Continuous synthesis of rufinamide (3) in a numbering-up module with 25 copper capillaries .

A DMSO solution of 2,6-difluorobenzyl azide [0.29 M] and ascorbic acid (3.84 g) were placed in a 500 mL bottle (Feed A). A DMSO solution of propiolamide [2.8 M] was placed in a second 500 mL bottle (Feed B). Two solutions were pumped each with a high flow HPLC pump from Scientific system Inc. Feed A was pumped at 5.2 mL/min and feed B was pumped at 0.8 mL/min. The two feeds were distributed through a mixing module and a flow distribution module and passed through 25 copper capillary reactors. The reactor was heated in an oven at 110°C. The residence time in the copper capillary was 3.25 minutes. The reaction proceeded for 6.5 minutes (twice the residence time) to reach a steady state, and the reaction was collected for 1 minute to obtain a brown/red solution. Water (twice the volume of the reaction mixture) was added while stirring to the remaining reaction mixture, and the resulting slurry was allowed to stand for 15 minutes. After filtering and washing with water, the off-white sticky cake was dried in a vacuum oven for 24 hours. Rufinamide was obtained as a dried off-white solid (73% yield). The productivity of this sequence was 530.6 mg/h. The isolated compound was analyzed by NMR.

Claims (16)

As a microreactor of a structure in which raw material injection and mixing module, flow distribution module, a plurality of catalytic reaction modules and integrated discharge modules are sequentially stacked and assembled,
The catalytic reaction module includes a metal capillary tube,
An assembly type microreactor, characterized in that the fluid mixed by the raw material injection and mixing module is uniformly supplied to a plurality of catalytic reaction modules through a flow rate distribution module.
The method according to claim 1,
The mixing module is assembled microreactor, characterized in that consisting of a T-mixer and a static mixer.
The method according to claim 2,
The assembled microreactor, characterized in that the T-mixer and the static mixer are arranged in series in the flow path of the fluid.
The method according to claim 1,
The assembly type microreactor, characterized in that a baffle disk is embedded in the flow distribution module.
The method according to claim 1,
The flow distribution module is an assembled microreactor, characterized in that the uniform flow rate distribution regardless of the clogged reaction module.
The method according to claim 1,
The assembly type microreactor, characterized in that the plurality of catalytic reaction modules are provided in parallel.
The method according to claim 1,
The catalytic reaction module is an assembled microreactor, characterized in that the heterogeneous catalytic module.
The method of claim 6,
The catalytic reaction module is an assembled microreactor, characterized in that the copper capillary tube.
The method according to claim 1,
The assembly type microreactor, characterized in that the plurality of reaction modules are composed of 2 to 25 modules.
The method according to claim 1,
The microreactor is an assembled microreactor, characterized in that provided with a plurality of inlets through which the fluid is introduced.
The method according to claim 1,
The microreactor is an assembled microreactor, characterized in that used for mass production of pharmaceutical raw materials.
A method for producing pharmaceutical raw materials by supplying a sample to the microreactor of claim 1.
As a method for producing lupinamide using the microreactor of claim 1,
A method for producing lupinamide by supplying a 2,6-difluorobenzyl azide solution and a propiolamide solution to the microreactor.
The method of claim 13,
Method for producing lupinamide, characterized in that ascorbic acid is added to the 2,6-difluorobenzyl azide solution or propiolamide solution.
As a method for producing lupinamide using the microreactor of claim 1,
Luffy comprising the step of mixing the 2,6-difluorobenzyl azide solution and the propiolamide solution supplied to the microreactor by a T-mixer and a static mixer, and then staying in the catalytic reaction module to perform the reaction. How to produce namide.
The method of claim 15.
The reaction is a method for producing lupinamide, characterized in that carried out for 5 to 30 minutes at 80 ~ 130 ℃.

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