WO2020231017A1 - Polyimide film-based synthesis module, method for preparing same and method for mass-producing organic phosphate compound using same - Google Patents

Abstract

The present invention relates to a polyimide film-based synthesis module, a method for preparing same and a method for mass-producing an organic phosphate compound using same, the polyimide film-based synthesis module comprising: a first metal plate having a first inlet, for supplying a first material, and a plurality of outlets for separating products; a second metal plate having a second inlet and a third inlet for supplying a second material and a third material; and a polyimide film adhesive body positioned between the first and second metal plates. The polyimide film adhesive body has therein: distribution channels connected to the first to third inlets and for separately distributing the first to third materials; a mixing channel connected to the distribution channels and for mixing the first to third materials; and a plurality of microreactor channels connected to the mixing channel and for reacting a mixture and then transferring products to the plurality of outlets.

Description

Synthesis module based on polyimide film, manufacturing method thereof, and mass production method of organic phosphate compound using the same

The present invention relates to a polyimide-based film-based synthesis-module for producing an organophosphate-based compound as a drug scaffold through continuous-flow, a method for producing the same, and a mass production method of an organophosphate-based compound using the same.

Continuous-flow microreactors offer many advantages over conventional processes for the synthesis of compounds, particularly in the pharmaceutical and fine chemical industries. Moreover, microfluidic systems offer unique advantages including fast mass- and heat-transfer due to high surface area to volume ratio, improved process safety, simple feasibility studies for scale-up and a cost-effective manner. The problem is how to take advantage of microreactor-specific transmission rates while increasing throughput for production applications.

The modular functionality of the microreactors makes the scale-up somewhat simpler because it increases throughput by simply numbering-up parallel microreactor units with appropriate channel sizes and operating at high flow rates. Moreover, unlike conventional batch processes, scale-up testing and design are not required, so only the same operating conditions are required from a single optimized microreactor. In general, even admitting the promising prospects, there are many problems associated with the numbering-up approach. The multiple parallelization approach of stacking reaction units in metal and glass implements an expensive fabrication cost, auxiliary heat exchange embedding configuration with additional heating/cooling channels. Complex control systems are required to ensure identical operating conditions in each unit for complete and predictable overall reactor performance. In addition, high levels of mixing in short-length channels often require static mixers in each parallel reactor, complicating the fabrication process. These difficulties with the expansion of microreactors have been studied with limited research on high throughput production of expensive chemicals on demand. Therefore, a breakthrough solution is needed to solve this problem. In particular, using a small number of pumps or flow regulators is desirable in order to make the system compact and to avoid problems during operation.

Accordingly, the present inventors have developed a'pad-type small synthesis-module' (CRP, 170 x 170 x 1.2 mm) for high throughput production of organophosphate-based drug precursors in continuous-flow. Two approaches were used to package a micro-flow path sufficient to deliver 1/6 tonnes of drug precursor per year in a small footprint: three-dimensional (3D) integration of the micro-flow circuit and highly reactive reagents. With a choice of fast synthesis methods. Tablet-sized CRP is designed as a simple and economical lamination method of 9 patterned polyimide (PI) films, 16 sets of numbering-up microreactors that ensure uniform flow distribution and ultra-fast mixing efficiency under various conditions. Consists of To demonstrate the scale-up production of major drug precursors, α-phosphonyloxy ketones, which can serve as key motifs and key structures for synthetic drugs in the synthesis of phospholipids, oligonucleotides, sugar analogs and multi-purpose major intermediates of natural products. I chose The approach demonstrated in the present invention should in principle be applicable to other drug precursors. Along with similar modules for control, CRP enables commercial production of drugs within deadlines, providing a paradigm shift in pharmaceutical manufacturing.

The present invention comprises: a first metal plate having a first inlet for supplying a first raw material and a plurality of outlets for separating a product; A second metal plate having a second inlet and a third inlet for supplying the second raw material and the third raw material; And a polyimide-based film bonded body disposed between the first and second metal plates, wherein the polyimide-based film bonded body is connected to the first to third inlets to independently distribute first to third raw materials. A distribution channel connected to the distribution channel, a mixing channel connected to the distribution channel to mix the first to third raw materials, and a plurality of microreaction channels connected to the mixing channel to react a mixture and then deliver the product to a plurality of outlets. It is characterized in that formed, to provide a polyimide-based film-based synthesis-module.

The polyimide-based film bonded body may be bonded using a polyimide film coated with fluoroethylene propylene (FEP).

The distribution channel may be divided into a plurality of distribution channels by branch point flow division, and the width of the distribution channel may decrease as the branch point passes.

The mixing channel may first mix the first and second raw materials, and then mix the third raw materials.

Two or more layers of the microreaction channels may be stacked.

The first raw material is a compound represented by the following formula (1), the second raw material is triethyl phosphite, the third raw material is formic acid, and the product may include a compound represented by the following formula (2):

[Formula 1]

,

,

[Formula 2]

In Formula 1 or Formula 2, R ₁ is a C6˜C20 aryl group unsubstituted or substituted with a C1˜C20 alkoxy group, and R ₂ is hydrogen or an unsubstituted C6˜C20 aryl group.

The reaction of the mixture in the microreaction channel may be performed at a temperature of 20°C to 90°C in an organic solvent.

The polyimide film-based synthesis-module may have a thickness of 0.1 mm to 10 mm.

In one embodiment of the present invention, (a) preparing a polyimide-based film bonding precursor; (b) disposing the polyimide-based film bonding precursor prepared in step (a) between the first and second metal plates; And (c) thermal bonding, wherein the preparation of the polyimide-based film bonding precursor in step (a) includes the steps of (a-1) preparing the first and second polyimide-based films, and (a-2) ) Comprising the step of disposing a patterned polyimide-based film to form a distribution channel, a mixing channel, and a plurality of microreaction channels between the prepared first and second polyimide-based films. It provides a method of manufacturing a mid-based film-based synthesis-module.

In step (c), the thermal bonding may be performed under a temperature of 300°C to 350°C and 1kPa to 50 kPa.

In another embodiment of the present invention, there is provided a method of producing a compound represented by the following Formula 2 using a polyimide film-based synthesis-module:

[Formula 2]

In Formula 2, R ₁ is a C6 to C20 aryl group unsubstituted or substituted with a C1 to C20 alkoxy group, and R ₂ is hydrogen or an unsubstituted C6 to C20 aryl group.

The polyimide-based film-based synthesis-module according to the present invention includes a polyimide-based film bonded body disposed between metal plates, and the polyimide-based film bonded body is manufactured in the form of a pad through thermal bonding, requiring a small installation space. There is an advantage to be, and has the advantage that the raw materials supplied from the inside of the polyimide-based film assembly are uniformly distributed to a plurality of microreaction channels. Therefore, by using the polyimide film-based synthesis-module according to the present invention, it is possible to commercially mass-produce organophosphate-based compounds as a drug scaffold with high separation yield and productivity through continuous-flow.

1A shows the structure and fabrication of a'pad-type compact synthesis-module (CRP)'. a) Structure of CRP, b) Alignment of 9 patterned polyimide films through 4 metal pins and thermal bonding at 320°C. c) Photo of a miniature composite-module. d) CRP sandwiched with two metal frame plates to connect to inlet tubes for 3 reagents ((1), (2) and (3)) and 16 outlet tubes for product.

Figure 1b is a schematic diagram of the fabrication of a "Pad-shaped Small Synthesis-Module" (CRP) device by arranging the patterned PI layers using four metal pins and then laminating a multilayer bonding process at 320°C for 5 hours. Is shown.

FIG. 1C shows an actual image of a laser-abstained patterned polyimide film cut into 9 pieces to be stacked in precise alignment for a 3D microchannel structure designed in CRP. The image on the right shows the stacking numbers in the order of the PI film.

Figure 1d shows a) an actual image of a manufactured CRP (left) and a metal-equipped reactor (right) having three inlets and 16 outlets, and b) a setup for an actual reaction experiment.

Figure 2 shows a computational fluid dynamics (CFD) simulation of CRP for comparing the anomalous distribution factor between experimental and simulated mass output values at 16 outlets.

3A shows a CFD simulation of the volume fraction contour of the reagent 1 according to the channel sections (A), (B) and (C) for calculation of the mixing efficiency.

Figure 3b shows a CFD simulation of the volume fraction contours of a) reagents (2) and b) reagents (3) according to channel cross-sections (A), (B) and (C) for calculation of mixing efficiency at different total flow rates. Is shown.

4 shows a flow distribution test by CFD and an actual experiment for measuring the average MF value of CRP. a) CFD simulation of CRP, b) 16 vials of toluene collected for 150 seconds at a total flow rate of 20.82 ml/min.

Figure 5 shows the synthesis of α-phosphonyloxy ketones (4 and 8) using CRP.

6 shows the thermal stability test of CRP under different solvents at high temperature. a) Burst pressure bar graph of each device and b) SEM images of the FEP coated polyimide microchannel surface exposed to high temperatures in different organic solvents (toluene and DMSO) for 5 days.

Continuous pharmaceutical manufacturing attracts great attention as an alternative method of meeting flexible market demands while ensuring higher safety and quality control. Accordingly, the present inventors manufactured a small synthesis-module (CRP, 170 x 170 x 1.2 mm) in the form of a pad for scale-up production of drug precursors in a continuous-flow. The CRP system was devised by laminating nine patterned polyimide films to integrate the micro-flow circuit, combine the function of even distribution of the feed, and mix perfectly in less than milliseconds. The method of using highly reactive species for single-step synthesis of the drug scaffold α-phosphonyloxy ketone required synthesis time for several seconds in microfluidics. The rapid response in a single CRP enabled the production of 19.2 g/h of drug precursor, suggesting a solid step towards kilogram-scale pharmaceutical manufacturing in a small, desktop-sized footprint.

Hereinafter, the present invention will be described in detail.

Synthesis-module based on polyimide film

The present invention comprises: a first metal plate having a first inlet for supplying a first raw material and a plurality of outlets for separating a product; A second metal plate having a second inlet and a third inlet for supplying the second raw material and the third raw material; And a polyimide-based film bonded body disposed between the first and second metal plates, wherein the polyimide-based film bonded body is connected to the first to third inlets to independently distribute first to third raw materials. A distribution channel connected to the distribution channel, a mixing channel connected to the distribution channel to mix the first to third raw materials, and a plurality of microreaction channels connected to the mixing channel to react a mixture and then deliver the product to a plurality of outlets. It is characterized in that formed, to provide a polyimide-based film-based synthesis-module.

Specifically, the first metal plate is located under the polyimide film assembly, and the first metal plate has drilled holes (preferably, a plurality of holes), which is a first inlet for supplying a first raw material and It becomes a plurality of outlets for separating products.

The first inlet may be formed in a vertical direction (lower → upper) in which a polyimide-based film to be described later is stacked, which is connected to a distribution channel to be described later. In one embodiment of the present invention, the first raw material is preferably a compound represented by Formula 1, but is not limited thereto:

[Formula 1]

In Formula 1, R ₁ is a C6 to C20 aryl group unsubstituted or substituted with a C1 to C20 alkoxy group, and R ₂ is hydrogen or an unsubstituted C6 to C20 aryl group.

In addition, the outlet may be formed in a vertical direction (lower → upper) in which a polyimide-based film to be described later is stacked, which is connected to a microreaction channel to be described later. In one embodiment of the present invention, the product is preferably a compound represented by Formula 2, but is not limited thereto:

[Formula 2]

In Formula 2, R ₁ is a C6 to C20 aryl group unsubstituted or substituted with a C1 to C20 alkoxy group, and R ₂ is hydrogen or an unsubstituted C6 to C20 aryl group.

In addition, the second metal plate is positioned above the polyimide film assembly, and the second metal plate also has drilled holes (preferably, two holes), which are used to supply the second raw material and the third raw material. It becomes the second inlet and the third inlet for.

The second and third inlets may be formed in a vertical direction (top → bottom) in which a polyimide-based film to be described later is stacked, and are connected to a distribution channel to be described later. In one embodiment of the present invention, the second raw material may be triethyl phosphite, and the third raw material may be formic acid, but is not limited thereto.

The polyimide-based film bonded body is disposed between the first and second metal plates, and refers to a state in which the polyimide-based film is laminated in multiple layers and then thermally bonded, and the polyimide-based film bonded body is toluene, DMF Or even when exposed to an organic solvent such as DMSO, it is characterized by excellent durability. At this time, the polyimide-based film bonded body may be bonded using a polyimide film coated with fluoroethylene propylene (FEP), in which case, the FEP is softened by thermal adhesion to be described later, thereby increasing the reliability of sealing. have.

More specifically, a distribution channel connected to the first to third inlets to independently distribute the first to third raw materials in the interior of the polyimide film assembly, and the first to third raw materials connected to the distribution channel A mixing channel for mixing the mixture and a plurality of microreaction channels connected to the mixing channel to react the mixture and then deliver the product to the plurality of outlets are formed.

The distribution channel is connected to the first to the third inlet and serves to independently distribute the first to third raw materials, and is divided into a plurality of branch points (preferably, a plurality of branch points) by flow division, and the As the branch point passes, the width of the distribution channel may decrease. Accordingly, the raw materials supplied from the inside of the polyimide-based film assembly can be uniformly distributed to a plurality of microreaction channels. After passing through the final branch, the width may be 0.1 mm to 0.5 mm, preferably 0.1 mm to 0.3 mm, but is not limited thereto. Meanwhile, the distribution channel is preferably stacked in three or more layers so that the first to third raw materials can be independently distributed.

In addition, the mixing channel is connected to the distribution channel to serve to mix the first to third raw materials, and the mixing channel may mix the first and second raw materials first and then mix the third raw materials. have. The width may be 0.5 mm to 10 mm, preferably 1 mm to 5 mm, but is not limited thereto.

In addition, the micro-reaction channel is a plurality, and is connected to the mixing channel to react a mixture and then to deliver a product to a plurality of outlets.The reaction of the mixture in the micro-reaction channel is carried out in an organic solvent. It can be carried out at a temperature of ℃ to 90 ℃, it is preferable to use toluene, DMF or DMSO as the organic solvent, but is not limited thereto. In this case, the organic solvent may be supplied through the first or second inlet, and the concentration of the organic solvent may be 0.001 M to 0.1 M, preferably 0.001 M to 0.01 M, but is not limited thereto. When the concentration of the organic solvent becomes too high, there is a problem that the separation yield of the organic phosphate-based compound decreases. In addition, the flow rate of the organic solvent may be 1.0 mL/min to 30 mL/min. On the other hand, the distribution channel is good in terms of high separation yield and productivity to stack two or more layers, preferably four or more layers.

The polyimide film-based synthesis-module may have a thickness of 0.1 mm to 10 mm. As a result, it is possible to implement a small synthesis-module, and commercially mass-produce organic phosphate compounds with a small installation space.

Polyimide film-based synthesis-module manufacturing method

In addition, the present invention (a) preparing a polyimide-based film bonding precursor; (b) disposing the polyimide-based film bonding precursor prepared in step (a) between the first and second metal plates; And (c) thermal bonding, wherein the preparation of the polyimide-based film bonding precursor in step (a) includes the steps of (a-1) preparing the first and second polyimide-based films, and (a-2) ) Comprising the step of disposing a patterned polyimide-based film to form a distribution channel, a mixing channel, and a plurality of microreaction channels between the prepared first and second polyimide-based films. It provides a method of manufacturing a mid-based film-based synthesis-module.

Specifically, in the step (a), an unpatterned polyimide-based film and a patterned polyimide-based film are prepared to prepare a polyimide-based film bonding precursor. In the patterned polyimide-based film, holes for forming a distribution channel, a mixing channel, and a plurality of micro-reaction channels may be formed between the prepared first and second polyimide-based films.

More specifically, the patterned polyimide-based film may be disposed between the unpatterned polyimide-based film. By repeating this arrangement two times, preferably four or more times, the microreaction channel Two layers, preferably four or more layers can be laminated. Further, by repeating this arrangement three or more times, three or more layers of the distribution channels can be laminated.

Thereafter, the polyimide-based film bonding precursor is disposed between the first and second metal plates in step (b), and then thermally bonded in step (c), whereby the channels can be sealed. At this time, the thermal bonding is performed under a temperature of 300° C. to 350° C. and 1 kPa to 50 kPa, thereby effectively softening the FEP.

Polyimide film-based synthesis method for producing organic phosphate-based compounds using modules

In addition, the present invention provides a method of producing a compound represented by the following formula (2) using the polyimide film-based synthesis-module:

[Formula 2]

In Formula 2, R ₁ is a C6 to C20 aryl group unsubstituted or substituted with a C1 to C20 alkoxy group, and R ₂ is hydrogen or an unsubstituted C6 to C20 aryl group.

The polyimide-based film-based synthesis-module according to the present invention includes a polyimide-based film bonded body disposed between metal plates, and the polyimide-based film bonded body is manufactured in the form of a pad through thermal bonding, requiring a small installation space. There is an advantage to be, and has the advantage that the raw materials supplied from the inside of the polyimide-based film assembly are uniformly distributed to a plurality of microreaction channels. Therefore, by using the polyimide film-based synthesis-module according to the present invention, it is possible to commercially mass-produce organophosphate-based compounds as a drug scaffold with high separation yield and productivity through continuous-flow.

Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

<Example>

General considerations

All reactions were carried out under a nitrogen environment. Most of the starting materials, reagents and solvents used from commercial sources were purchased and used as such. All spectra were recorded in CDCl ₃ . 1H, 13C and 31P (proton decoupled) spectra were recorded in CDCl ₃ (600, 150 and 242 MHz, respectively) on a Bruker AVANCE 600 spectrometer at room temperature in CDCl ₃ solvent. Chemical shifts (δ ppm) are reported in parts per million for TMS (δH = 0.00 ppm) or CHCl ₃ (δH = 7.25 ppm). Cross-junction and perfluoroalkoxy alkane (PFA) tubing was purchased from IDEX HEALTH & SCIENCE WA, USA), and a syringe pump (Harvard device, PHD 22/2000 Hpsi, PHD Ultra) was used. All reactions were monitored by thin layer chromatography (TLC) using Merck silica gel aluminum plate 60 F254; Visualized with short-wave UV light (254 nm). Column chromatography was performed through silica gel (100-200 mesh) using EtOAc/hexane as an eluent.

Production of "Pad-type compact synthesis-module (CRP)"

A set of 16 microreactors were designed numbered on a single pad by AutoCAD software. 1b and c, each PI film (170 x 170 mm, 125 μm thick) was removed with a UV laser (355 nm) to create a desired patterned fine channel (width range 150 μm to 1.2 mm, height 125 μm). Formed. The inlet channel for supplying reagents had a width of 1.2 mm and was divided into two opposite sides and evenly distributed by branch point flow division. Thus, by switching to 2, 4, 8 and 16 fine channels, the channel width gradually decreased to 0.6 mm, 0.3 mm and 0.15 mm. As previously reported, 9 pieces of patterned PI film were laminated. Typically, the PI films were bonded on the patterned side by spin coating with fluoroethylene propylene (FEP, softening point 260-280° C.) having a thickness of 3 μm. The film, which was sandwiched with a flat metal plate and accurately aligned, was thermally bonded at 320° C. under 10 kPa for 5 hours to strongly seal the channel of CRP. For the close connection between the CRP and the flow tube, a CNC-made aluminum metal frame was used as a sphere with drilled holes for 16 outlets and 3 inlets (triethyl phosphite (2) and HCOOH (3)). 2 inlets at the top for) and 1 inlet at the bottom-center for benzyl (1)). When samples were collected individually, 16 glass vials were placed under CRP with extended tubing (FIG. 1D ).

As shown in FIG. 1B, the numbering-up of 16 sets of microreactors in a single pad was designed and manufactured to enable high throughput chemical production by maintaining a constant fluid flow state in each reactor. The adhesion between the patterned PI films is a kind of fluoropolymer with 1.5 nm particles, in an aqueous dispersion of fluoroethylene propylene (FEP, ND-110, Neoflon, DAIKIN, Japan, 60% solid fluorothermoplastic aqueous dispersion). Manufactured by FEP having a softening point at 260 to 280°C was spin-coated at a speed of 3000 rpm for 30 seconds to form a uniform thickness of 3 μm on the patterned surface of the PI film. In order to convert the 2D patterned PI film into 3D microchannels, the film pattern was passed through a metal pin (diameter: 1.5 mm, length: 6 cm) through four corners of each polyimide film perforated with a 1.5 mm diameter. Aligned. The accurately aligned PI film was placed between flat metal plates and thermally bonded at 320° C. under 10 kPa for 5 hours. Under these conditions, the FEP layer softened between the PI films improved the reliability of hermetic sealing at 320°C by controlling the pressure applied to the interface (10 kPa), and sealing the patterned channels without leakage by slow cooling for 12 hours. There was a tendency. When annealed at 320° C., the microchannels retained their designed shape due to the inherent rigidity of the PI film, such as a high glass transition temperature (Tg) above 400° C. and a low heat shrinkage of about 1%.

Figure 1c showed a PI film patterned by UV laser ablation technique with a CAD design for CRP. Patterned films were carefully cut and laminated in a sequence of 1 to 9, as shown to form the distribution channels, mixing and 16 microreaction pathways designed in CRP. To securely connect the CRP and flow tube without leakage at high flow rates, the aluminum metal frame used for CRP clapping is made by CNC manufacturing, with 1 inlet at the bottom-center, 2 inlets at the top and 16 at the bottom. Drilled for tubing (diameter: 1/4 inch) at the same location on all inlets and outlets installed on a CRP with outlet. Two inlets at the top are for supplying triethyl phosphite (2) and HCOOH (3) to the syringe pump, and one inlet at the bottom is for benzyl (1). In addition, 16 outlets were located under the metal frame by connecting with the extended tube. The CRP and tube were closely connected by screw fittings using a super flangeless ferrule w/SST Ring (1/4-28 flat-bottom, for 1/16" OD) provided by XPEX-202 and IDEX. 16 glass vials (50 ml) were placed under CRP with elongated tubes in order to individually confirm uniform flow distribution with the appropriate MR values.

Computational fluid dynamics simulation setup

In addition to the mass conservation equation, the incompressible Navier-stokes equation can describe the fluid flow inside the microchannel. Assuming a steady state, we can simplify the governing equation for fluid flow.

: Navier-Stokes 식

: Navier-Stokes equation

: 질량 보존식

: Mass conservation formula

Where ρ is the fluid density, ν is the fluid linear velocity, p is the pressure, μ is the fluid dynamic viscosity, and g is the gravitational acceleration. The governing equation was solved with appropriate boundary conditions (no slip boundary conditions on the channel walls, mass flow rates for the inlet and outflow conditions for the outlet, as defined by zero normal slope for all flow variables except pressure). The equation was discretized based on the finite volume method and commercialized numerical software FLUENT 2019 R2 (ANSYS, INC.) was used for numerical simulation. Physical properties of toluene (867 kg m ^-3 , 0.00056 kg m ^-1 s ^-1 ) at 25°C were used as a carrier solvent.

For homogeneous flow distribution analysis, we simulated microchannel structures designed with computational fluid dynamics (CFD). Three reagents injected at the same flow rate (6.94 ml/min, total: 20.82 ml/min) through individual inlets in the center are divided into two opposite sides and distributed evenly by a branch point flow split. The theoretical MF value for the mass flow rate from the 16 outlets is 0.46%, which is much lower than the generally acceptable MF value (4%). To experimentally verify the uniform flow distribution, the inventors stabilize the CRP by flowing toluene at a low flow rate (0.5 ml/min) for 15 minutes by sonication to remove the air inside the CRP. When air is trapped in microchannels, these compressible fluids can impair the flow distribution. After stabilization of CRP, the solutions were individually collected from 16 outlets for 150 seconds, and the average MF value was measured at a flow rate of 20.82 ml/min. The experimental MF 0.55% agreed well with the MF value calculated by CFD (0.46%), indicating the same residence time of the mixed reagents in the 16 reaction channels.

Flow synthesis of α-phosphonyloxy ketone in a capillary reactor

Benzyl (1) (1 mmol), triethyl phosphite (2) (1.2 mmol) and formic acid (3) at room temperature (23-26° C.) in an oven-dried 10 mL snap vial equipped with a magnetic stir bar under N ₂ atmosphere. ) (5 mmol) were individually well mixed in dry toluene (3 x 5 = 15 mL). After properly mixing the three reagents individually (approximately 1 min), all three solutions were transferred to a 6 mL NORM-JECT plastic syringe and introduced into a single PFA coiled capillary (0.5 mm diameter, 1 m long) via two syringe pumps. . The flow rate of each pump was set to 1 mL min ^-1 resulting in a 3.93 second residence time. After reaching steady state, the product sample was taken from the vial collection to the aq. It was quenched with NaHCO ₃ solution. After measuring the collected volume, the sample was extracted with ethyl acetate (40 mL) (diethyl ether was used for the reaction in DMF). The aqueous layer was washed 3 times with ethyl acetate or diethyl ether (3x15 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. Then, the produced residue was purified by column chromatography over silica gel (100-200 mesh) using petroleum ether/ethyl acetate as eluent (by variable ratio). The isolated compound was analyzed by NMR. After completion of the reaction, the capillary was washed with acetone, water and acetone (twice), respectively, and dried for the next reaction.

Experimental procedure for the synthesis of α-phosphonyloxy ketones (4 and 8) using CRP for scale-up

(1) Synthesis of α-phosphonyloxy ketone using CRP at room temperature

Benzyl (1) (1.26 g, 6 mmol), triethyl phosphite (2) (1.24 mL) in an oven-dried round bottom flask equipped with a magnetic stir bar, at room temperature (23-26° C.), under N ₂ atmosphere , 7.2 mmol) and formic acid (3) (1.13 mL, 30 mmol) were individually dissolved in dry toluene (3 x 30 = 90 mL). After properly mixing the three reagents individually (about 2 minutes), all three solutions were transferred to a 30 mL NORM-JECT plastic syringe and introduced into the CRP via two syringe pumps. The total flow rate was set to 20.82 mL min ^-1 resulting in a residence time of 3.93 seconds. After reaching steady state, the product sample was taken from the vial collection to the aq. It was quenched with NaHCO ₃ solution. After measuring the collected volume, the sample was extracted with ethyl acetate (150 mL). The aqueous layer was washed 3 times with ethyl acetate (3x50 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. Then, the produced residue was purified by column chromatography over silica gel (100-200 mesh) using ethyl acetate as an eluent.

At this time, diethyl (2-oxo-1,2-diphenylethyl) phosphate (4) is a colorless oil, obtained in 67% separation yield, and its properties are as follows: ¹ H-NMR (600 MHz, CDCl ₃ ): δ 7.93 (d, J = 7.2 Hz, 2H), 7.51-7.50 (m, 3H), 7.41-7.33 (m, 5H), 6.65 (d, J = 7.9 Hz, 1H), 4.21-4.17 ( m, 2H), 3.94-3.89 (m, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H). ppm. ¹³ C-NMR (150 MHz, CDCl ₃ ): δ 193.71 (d, J = 4.5 Hz), 135.00, 134.95, 134.44, 133.58, 129.38, 128.04, 128.69, 128.13, 80.16 (d, J = 4.5 Hz), 64.37 (d, J = 5.4 Hz), 64.02 (d, J = 6.4 Hz), 16.07 (d, J = 7.3 Hz), 15.87 (d, J = 7.3 Hz). ppm. ³¹ P-NMR (242 MHz, CDCl ₃ ): δ 1.88. ppm.

In addition, 2-hydroxy-1,2-diphenylethanone (5) is a white solid, obtained in 5% separation yield, its properties are as follows: ¹ H-NMR (600 MHz, CDCl ₃ ): δ 7.93-7.90 (m, 2H), 7.54-7.50 (m, 1H), 7.42-7.25 (m, 7H), 5.96 (s, 1H). ppm. ¹³ C-NMR (150 MHz, CDCl ₃ ): δ 190.08, 139.15, 134.02, 133.65, 129.27, 129.25, 128.80, 128.70, 127.9, 76.35. ppm.

In addition, 2-oxo-1,2-diphenylethyl formate (6) is a colorless oil, obtained in 21% separation yield, and its properties are as follows: ¹ H-NMR (600 MHz, CDCl ₃ ): δ 8.22 (s, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.54-7.47 (m, 3H), 7.42-7.34 (m, 5H), 7.01 (s, 1H). ppm. ¹³ C-NMR (150 MHz, CDCl ₃ ): δ 192.85, 160.12, 134.45, 133.80, 133.24, 130.31, 129.69, 129.36, 128.96, 128.83, 128.60, 77.22. ppm.

(2) Synthesis of α-phosphonyloxy ketone using CRP at 80°C

At 80° C., under N ₂ atmosphere, α-dicarbonyl compound (7) (985 mg, 6 mmol), triethyl phosphite (2) (1.24 ml, in an oven-dried round bottom flask equipped with a magnetic stir bar) 7.2 mmol), and formic acid (3) (1.13 ml, 30 mmol) were individually dissolved in dry DMF (90 ml, each reagent in 30 ml). After properly mixing the three reagents individually (approximately 2 minutes), transfer all three solutions to a 30 mL NORM-JECT plastic syringe and hold at 80°C in an oven (set temperature; 80°C±2) via two syringe pumps. Introduced into the CRP. The total flow rate was set to 20.82 mL min ^-1 resulting in a residence time of 3.93 seconds. After reaching steady state, the product sample was taken from the vial collection to the aq. It was quenched with NaHCO ₃ solution. After measuring the collected volume, the sample was extracted with ethyl acetate (150 mL). The aqueous layer was washed 3 times with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. Then, the produced residue was purified by column chromatography over silica gel (100-200 mesh) using petroleum ether/ethyl acetate (variable ratio) as an eluent.

At this time, diethyl (2- (4-methoxyphenyl) -2-oxoethyl) phosphate (8) is a colorless oil, obtained in 50% separation yield, its properties are as follows: ¹ H-NMR (600 MHz, CDCl ₃ ): δ 7.78 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.15 (d, J = 10.2 Hz, 2H), 4.11 (quin, J = 7.3 Hz, 4H), 3.76 (s, 3H), 1.26 (t, J = 7.2 Hz, 6H). ppm. ¹³ C-NMR (150 MHz, CDCl ₃ ): δ 190.58 (d, J = 4.4 Hz), 164.01, 129.96, 126.89, 113.98, 68.34 (d, J = 5.5 Hz), 64.15 (d, J = 6.6 Hz) , 55.41, 15.95 (d, J = 6.6 Hz). ppm. ³¹ P-NMR (242 MHz, CDCl ₃ ): δ 0.45. ppm.

In addition, 2-hydroxy-1-(4-methoxyphenyl)ethanone (9) is a colorless oil, obtained in 5% separation yield, and its properties are as follows: ¹ H-NMR (600 MHz, CDCl ₃ ): δ 7.90 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 4.82 (d, J = 4.6 Hz, 2H), 3.89 (s, 3H), 3.57-3.56 (m, 1H). ppm. ¹³ C-NMR (150 MHz, CDCl ₃ ): δ 196.84, 164.53, 130.15, 126.53, 114.34, 65.13, 55.71. ppm.

In addition, 2-(4-methoxyphenyl)-2-oxoethyl formate (10) is a white solid, obtained in 7% separation yield, and its properties are as follows: ¹ H-NMR (600 MHz, CDCl ₃ ): δ 8.25 (s, 1H), 7.90 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 5.40 (s, 2H) 3.88 (s, 3H). ppm. ¹³ C-NMR (150 MHz, CDCl ₃ ): δ 189.66, 164.35, 160.25, 130.25, 127.13, 114.28, 65.20, 55.69. ppm.

Durability test of polyimide (PI) based microreactor

High chemical resistance and thermal stability are essential requirements for the development of organic microreactors. For thermal stability and durability tests, a simple linear microchannel (width: 300 μm, height: 125 μm, length: 25 cm) device based on polyimide was fabricated. Then, different solvents (toluene and DMSO) were introduced into the prepared PI apparatus using an HPLC pump at a flow rate of 210 μl/min for 5 days at 100° C. and 150° C. to investigate reactor durability. After a long continuous-flow test, we measured the burst pressure of the PI-based microfluidic device exposed under different conditions by means of an HPLC pump capable of reading the pressure at the inlet of the device.

Results and discussion

Methods of synthesizing various organophosphates are useful for a wide range of applications from pesticides to biologically active phosphate medicines. However, α-phosphonyloxy ketones are less prevalent with unsatisfactory selectivity, and are mainly synthesized in a two-step approach involving an extra synthetic step of intermediates. Moreover, the single-step and fast synthetic route to α-phosphonyloxy ketones is highly desirable for efficient scale-up production. However, the reported route requires tens of hours even at elevated temperatures with large amounts of by-products. In the present invention, benzyl (1) as a highly reactive species has been adopted to readily bind triethyl phosphite (2), but this approach still produces significant amounts of undesirable by-products. Continuous-flow chemistry was performed by injecting reagents in toluene as solvent at room temperature into simple perfluoro alkoxy alkanes (PFA) capillaries (0.50 mm diameter, 1 m length) at different concentrations and flow rates through a cross mixer (Table 1). Items 1-5 and 6a)).

Item toluene (Concentration (M)) Flow rate Residence time[s] (4) separation yield (%) One 0.2 3 mL/min 3.93 30 2 0.14 3 mL/min 3.93 44 3 0.067 3 mL/min 3.93 67 4 0.067 1.5 mL/min 7.85 67 5 0.067 4.5 mL/min 2.62 40

* Reaction conditions: Perfluoroalkoxy alkane (PFA) capillary (0.50 mm diameter, 1 m length) was used at 0.067M (1 mmol size) in the solvent (1). For (1), in (2) 1.2 equivalents and 5.0 equivalents of (5) were identified for optimization. RT = 23-26 °C.

As shown in Table 1, the presence of formic acid (3) significantly accelerated the reaction, with the by-products benzoin (5) and oxy-formylated product (6) in 5% and 21% yields, respectively, 3 mL. It was found to give the desired α-phosphonyloxy ketone (4) in 67% yield in a very short time (3.93 sec) at a total flow rate of /min.

On the other hand, α-phosphonyloxy ketone product (4) was obtained in 66% yield, and by-products (5) and (6) were obtained in 5% and 22% yield, respectively. After completion of the reaction, CRP was washed with ethanol (twice) and dried for the next reaction. In order to confirm the reliability of the reaction performance and reactor stability, the same reaction was repeated several times according to the same procedure (items 1-4 in Table 2 and a) in FIG. 6).

Item Flow rate Residence time[s] Separation yield (%) (4:5:6) One 21 mL/min 3.93 60.0:5:22 2 21 mL/min 3.93 65.6:6:21 3 21 mL/min 3.93 65.9:6:21 4 21 mL/min 3.93 65.5:5:21

* Reaction conditions: α-dicarbonyl compound (1) (1.26 gram size, 6 mmol), triethyl phosphite (2) (1.24 mL, 7.2 mmol), and formic acid (3) (1.13 mL, 30 mmol); Total flow rate = 20.82 ml/min (retention time: 3.93 s, total reactor volume: 1.38 mL), RT: 25°C.

In all cases, the yield of product (4) was maintained relatively well with little variation, as shown in Table 2. With the fast synthetic chemistry established for α-phosphonyloxy ketones, the challenge remains for microfluidic structures to produce as many desired drug precursors as possible within as small a region as possible. In order to obtain a high yield of organophosphate by simply numbering-up, PFA tubes are not suitable because they use many cross-junctions to carry out the reaction. This increases the number of infrastructure for operation such as pumps, resulting in very large filling spaces and difficulties in accurate process control. Accordingly, the present inventors have developed an innovative numbering-up microreactor by designing a series flow path with various functions of a uniform flow distributor, an efficient mixer and a fast reaction in a small installation space. The basic structure of CRP is a channel for the micro-flow circuit integrated between the two banks of reactors (Fig. 1a a)), and each bank contains a number of microreactors. For the CRP tested here, there are 8 microreactors in each slot. Thus, there are 16 feed inlets to the microreactor, each inlet line taking a flow of 3 lines for 3 different reagents. The reactor for a large-scale system designed by the present inventors consists of an integrated array of tube lines arranged in a specific manner, to operate as a flow distributor, mixer and reactor. These flow lines were vertically wound and aligned whenever possible, to minimize the footprint of the CRP. Each of the 16 reactors is a 1.6 m long micro-flow line, wound upward and three turns vertically. The width of the CRP pad is 170 mm, the length is 170 mm, the thickness is 1.2 mm, and the total internal volume as a flow-assisted reaction space is 1.38 mL. In particular, the thin panel module ensures excellent heat conduction for a uniform temperature when heated. The CRP was fabricated by aligning nine films, each patterned by laser ablation using four metal pins and coated with a binder, and by thermally bonding the aligned layers. The produced CRP is shown in Figure 1a c). The CRP was screwed into a metal frame of 2 plates, the plate connected to 3 inlets for the introduction of 3 reactants (1, 2 and 3) and 16 outlets for the collection of products (Fig. 1a d)) . The material we selected for fabrication was a fluoroethylene propylene (FEP)-polyimide (PI) film hybrid, which led to a polymer-based microreactor.

The hybrid offers excellent physical rigidity, withstands pressures up to ~ 160 bar, and a chemically inert boost to various organic media except strong bases or chlorinated solvents. Thus, a designed CRP platform was fabricated by laminating a PI layer patterned by laser ablation and coated with FEP as a thermal adhesive. The aligned 9 PI film layers were thermally bonded at 320°C for 5 hours at 10 kPa in step 1 (FIG. 1B). In this three-dimensionally integrated micro-flow circuit, branch point flow division was used to evenly distribute the accompanying flow. For homogeneous flow distribution analysis, we simulated microchannel structures designed with computational fluid dynamics (CFD). The three reagents injected at the same flow rate (6.94 mL/min, total: 20.82 mL/min) through individual inlets in the center were divided into two opposite sides and distributed evenly by branch point flow division. The uniformity of the flow distribution into the 16 reactors was determined by the ideal distribution factor (MF) as widely used. The MF value is defined as follows.

Where n is the number of outlet channels, m _i is the mass of the i-th outlet channel, and m _a is the average mass of the outlet channels. MF is the ratio of the standard deviation to the average mass at the outlet. Thus, a low MF value means that the distribution of flow velocity between the outlet channels is uniform. The theoretical MF value for mass flow from 16 outlets is 0.46%, much lower than the generally acceptable MF value (4%). In order to experimentally verify the uniform flow rate distribution, solutions were collected individually for 150 seconds from 16 outlets to determine the average MF value. The experimental MF 0.55% matched well with the MF value calculated by CFD (0.46%), indicating the same residence time of the mixed reagents in the 16 reaction channels. In addition to the uniform flow rate distribution, considering that the total reaction time is 3.93 seconds, a very short time is required for complete mixing for the two reagents combined at the front of each reactor (Fig. 3b). The three reactants (benzyl (1), triethyl phosphite (2) and formic acid (3)) are independently distributed in 16 microchannels, and are combined in a T-type microchannel structure that causes chaos in the front of each microreactor. Lost (Fig. 1a a)).

Advection with rapid distortion and elongation of fluid interfaces is well known. For rapid mixing, a side impact type of serpentinely structured channel was constructed to generate large advection between the reactants. Evenly distributed reagents (1) and (2) are first mixed at the first T-type mixing point, then meet the reagent (3) at the second T-type mixing point, and all reagents begin to be mixed (Fig. 3A). . In order to quantify the degree of mixing of the three different fluids according to the channel structure, the volume fraction of the reagent 1 in toluene was considered according to the flow. The mixing degree of the three fluids was quantified by the mixing efficiency.

이고, σ는 단면적에서 농도의 표준 편차이고, N은 채널 단면에서 노드의 수이고, c_i는 채널 단면 i의 샘플 노드에서 국소 농도이고, c_in는 입구에서 평균 농도이며, σ_max는 농도의 최대 표준 편차이다. 3 개 반응물의 부피 분율이 동일하게 0.33에 도달할 때, 완전한 혼합 효율이 달성되는 것으로 가정될 수 있다. 결과적으로, 합류 구역으로부터 2.71 mm 채널을 유동할 때 총 유속 21 mL/분으로 2.32 ms만을 취함으로써 3 개 시약의 완전한 혼합을 달성하였다. 추가적으로, 3 mL/min로 낮은 유속에서 혼합 효율은 도 3a에 나타난 바와 같이, 98% 이상의 유사한 효율로 확인되었다. 시약(2) 및(3)의 부피 분율에서 계산된 혼합 효율 역시 동일한 결과를 보였다(도 3b). 도 3b에 나타난 바와 같이, 3개 시약의 완전한 혼합은 합류 구역으로부터 2.71 mm 채널을 유동할 때 상이한 유속(21 ml/min ~ 3 ml/min)에서 2.32 ms 내지 16.3 ms로 짧은 체류 시간을 취함으로써 달성된다. 따라서, 제작된 CRP의 성능을 테스트하였다. 공급은 포름산((3), 5.0 당량), 트리에틸 포스파이트((2), 1.2 당량) 및 벤질((1), 1.0 당량, 1.26 g 크기)로 구성되었다. 용매에 용해된 시약((1), (2) 및 (3))을 7 mL/min의 유속으로 CRP의 중앙에 위치한 3개 개별 입구 내로 개별적으로 도입하였고, 총 유속은 21 mL/분이다. 3.93 초의 체류 시간으로 반응이 완료된 후, 예상된 생성물(4)를 66% 수율로 분리하였고, 부산물(4) 및(5)를 5% 및 22% 수율로 형성하였다. 이러한 수율은 모세관 반응기의 수율과 거의 동일하다. 놀랍게도, 합성을 위한 높은 반응성 시약의 사용은 종종 부산물을 생산하는 것을 수반한다. CRP 플랫폼은 실온에서 19.2 g/h의 생성물(4)를 생산하였으며, 이는 1/6 톤의 약물 전구체의 연간 생산에 해당한다. here,

, Σ is the standard deviation of the concentration in the cross-sectional area, N is the number of nodes in the channel cross-section, c _i is the local concentration at the sample node in the channel cross-section i, c _in is the average concentration at the inlet, and σ _max is the concentration of Is the maximum standard deviation. When the volume fractions of the three reactants equally reach 0.33, it can be assumed that complete mixing efficiency is achieved. As a result, complete mixing of the three reagents was achieved by taking only 2.32 ms with a total flow rate of 21 mL/min when flowing a 2.71 mm channel from the confluence zone. Additionally, the mixing efficiency at a flow rate as low as 3 mL/min was confirmed as a similar efficiency of 98% or more, as shown in FIG. 3A. The mixing efficiency calculated from the volume fraction of reagents (2) and (3) also showed the same result (Fig. 3b). As shown in Figure 3b, complete mixing of the three reagents is achieved by taking a short residence time of 2.32 ms to 16.3 ms at different flow rates (21 ml/min to 3 ml/min) when flowing through a 2.71 mm channel from the confluence zone. Is achieved. Therefore, the performance of the produced CRP was tested. The feed consisted of formic acid ((3), 5.0 eq), triethyl phosphite ((2), 1.2 eq) and benzyl ((1), 1.0 eq, 1.26 g size). Reagents ((1), (2) and (3)) dissolved in the solvent were individually introduced into three separate inlets located in the center of the CRP at a flow rate of 7 mL/min, with a total flow rate of 21 mL/min. After the reaction was completed with a residence time of 3.93 seconds, the expected product (4) was separated in 66% yield, and by-products (4) and (5) were formed in 5% and 22% yield. This yield is almost the same as that of the capillary reactor. Surprisingly, the use of highly reactive reagents for synthesis often entails producing by-products. The CRP platform produced 19.2 g/h of product (4) at room temperature, which corresponds to an annual production of 1/6 ton of drug precursor.

Item Temperature (℃) Concentration (M) Residence time[s] Separation yield (%) productivity (g/h) One RT 0.067 3.93 66 19.2 2 RT 0.067 3.93 65 18.9 3 RT 0.067 3.93 65 18.9 4 RT 0.067 3.93 65 18.9 5 80 0.067 3.93 60 15

* Items 1-4: reaction conditions; Benzyl (1) (1.26 gram size, 6 mmol) in toluene, triethyl phosphite (2) (1.24 mL, 7.2 mmol), and formic acid (3) (1.13 mL, 30 mmol); Total flow rate = 20.82 ml/min (retention time: 3.93 s, total reactor volume: 1.38 mL), RT: 25°C. Item 5: α-dicarbonyl compound (7) (985 mg, 6 mmol) in DMF, triethyl phosphite (2) (1.24 mL, 7.2 mmol), and formic acid (3) (1.13 mL, 30 mmol).

As shown in items 1-5 of Table 3 and a)-b) of FIG. 6, the reliability of CRP was monitored by performing the reaction repeated several times. The yield of product (4) remained relatively good with little change (65-66% yield). To test the performance of CRP at elevated temperature, another α-phosphonyloxy ketone (8) from compound (7) was synthesized at 80° C. in 60% yield (item 5 in Table 3). On the other hand, α-phosphonyloxy ketone product (8) was obtained in 60% yield, and by-products (9) and (10) were obtained in 4% and 14% yields, respectively (Table 3). After completion of the reaction, CRP was washed with ethanol (twice) and dried for the next reaction.

In addition, by testing the durability of CRP, two organic solvents (toluene, dimethyl sulfoxide) were continuously injected at a high temperature of 100° C. and 150° C. for 5 days (FIG. 6). The exposed microchannels withstand the burst pressure of 157 ~ 161 bar and maintain the original bond strength while maintaining a smooth surface shape without defects. Specifically, in a reactor prepared without organic solvent testing, the burst pressure was approximately 16.3 MPa. After exposing the PI-based microdevices to toluene at 100° C. and DMSO at 150° C., the burst pressures were about 15.7 MPa and 16.1 MPa, respectively. This shows that the performance of CRP is maintained even when the device is exposed to high temperatures in organic solvents. In addition, the present inventors confirmed the shape of the FEP-coated polyimide film after exposure to an organic solvent at high temperature using SEM images of the channel surface of the PI microreactor. The shape of the surface of the FEP-coated polyimide microchannel did not change even after exposure to high temperature in an organic solvent (FIG. 6).

By embedding 16 sets of microreactors into a small pad, a small numbering-up microreactor system composed of polyimide film was fabricated in a cost-effective manner. By laminating 9 patterned film layers, the modular structure of the pad-type synthesis-module was flexibly constructed. The integrated micro-flow circuit achieves uniform flow distribution to all 16 reactors along the branch line, perfect mixing in milliseconds, and the desired synthesis in seconds. The fabricated'pad-type compact synthesis-module' (CRP, 170 x 170 x 1.2 mm) system has successfully demonstrated high throughput production of organophosphates in a fast (retention time 3.93 seconds) single-step method. Under the pre-optimized operating conditions set by a single capillary reactor, α-phosphonyloxy ketone was obtained at room temperature with a yield of ∼19 g/h in 66%, while other derivatives at an elevated 80°C with a yield of ∼15 at 60%. g/h was synthesized. A simple stacking of micro-flow layouts placed on the CRP can simply increase the throughput by multiplying the reaction volume. Therefore, such a small installation space and a high-capacity, flat, large-capacity platform enable the emergence of portable desktop factories for pharmacies when necessary, and provide a paradigm shift in pharmaceutical manufacturing.

The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting.

Claims (11)

A first metal plate having a first inlet for supplying a first raw material and a plurality of outlets for separating a product; A second metal plate having a second inlet and a third inlet for supplying the second raw material and the third raw material; And Including a polyimide-based film bonded body disposed between the first and second metal plates, In the interior of the polyimide film assembly, a distribution channel is connected to the first to third inlets to independently distribute the first to third raw materials, and the distribution channel is connected to the distribution channel to mix the first to third raw materials A mixing channel and a plurality of micro-reaction channels connected to the mixing channel to react the mixture and then deliver the product to the plurality of outlets are formed. The method of claim 1, The polyimide-based film bonded body is characterized in that the bonded using a polyimide film coated with fluoroethylene propylene (FEP), a polyimide-based film-based synthesis module. The method of claim 1, The distribution channel is divided into a plurality by branch point flow dividing, characterized in that the width of the distribution channel decreases as the branch point passes, polyimide film-based synthesis-module. The method of claim 1, The mixing channel is characterized in that after first mixing the first and second raw materials, and then mixing the third raw material, polyimide-based film-based synthesis module. The method of claim 1, The micro-reaction channel is characterized in that two or more layers are stacked, polyimide-based film-based synthesis-module. The method of claim 1, The first raw material is a compound represented by the following formula (1), the second raw material is triethyl phosphite, the third raw material is formic acid, and the product comprises a compound represented by the following formula (2). , Polyimide film-based synthesis-module: [Formula 1]

, [Formula 2]

In Formula 1 or Formula 2, R ₁ is a C6˜C20 aryl group unsubstituted or substituted with a C1˜C20 alkoxy group, and R ₂ is hydrogen or an unsubstituted C6˜C20 aryl group. The method of claim 1, The reaction of the mixture in the microreaction channel is characterized in that it is carried out at a temperature of 20 ℃ to 90 ℃ in an organic solvent, polyimide-based film-based synthesis module. The method of claim 1, The polyimide-based film-based synthesis-module, characterized in that the thickness of the module is 0.1 mm to 10 mm, polyimide-based film-based synthesis-module. (a) preparing a polyimide-based film bonding precursor; (b) disposing the polyimide-based film bonding precursor prepared in step (a) between the first and second metal plates; And (c) thermal bonding, Preparation of the polyimide film bonding precursor in step (a) (a-1) preparing the first and second polyimide-based films, and (a-2) comprising the step of disposing a patterned polyimide-based film to form a distribution channel, a mixing channel, and a plurality of microreaction channels between the prepared first and second polyimide-based films. To, the polyimide-based film-based synthesis method according to claim 1-the manufacturing method of the module. The method of claim 9, In the step (c), the thermal bonding is characterized in that performed under a temperature of 300°C to 350°C and 1kPa to 50 kPa, a polyimide film-based synthesis-module manufacturing method. A method for producing a compound represented by the following Formula 2 using the polyimide film-based synthesis-module according to claim 1: [Formula 2]

In Formula 2, R ₁ is a C6 to C20 aryl group unsubstituted or substituted with a C1 to C20 alkoxy group, and R ₂ is hydrogen or an unsubstituted C6 to C20 aryl group.

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