WO2023058903A1

WO2023058903A1 - Automized micro combinatorial chemical reaction system and optimized combinatorial chemical synthesis method using same

Info

Publication number: WO2023058903A1
Application number: PCT/KR2022/012803
Authority: WO
Inventors: 김동표; 안광노
Original assignee: 포항공과대학교 산학협력단
Priority date: 2021-10-08
Filing date: 2022-08-26
Publication date: 2023-04-13

Abstract

Disclosed are an automized micro combinatorial chemical reaction system and an optimized combinatorial chemical synthesis method using same. The automized micro combinatorial chemical reaction system comprises: a raw material supply unit (100); an intermediate reaction unit (200); an intermediate reaction control unit (300); and a first product reaction unit (400), and has the effect of producing plural types of products rapidly and at high yields.

Description

Automated micro combinatorial chemical reactor and optimized combinatorial chemical synthesis method using the same

The present invention relates to an automated micro combinatorial chemical reactor and an optimized combinatorial chemical synthesis method using the same.

Flow technologies and micro-reactors for chemical synthesis are becoming key tools for organic synthesis as well as pharmaceuticals. Micro-reactor devices can maximize the reaction efficiency of general organic synthesis based on fast mass and heat transfer due to high surface-to-volume ratios. While thermothermally stable compounds can be synthesized with conventional batch reaction methods, reaction kinetics can be controlled with microreactors. In particular, it is possible to control unstable and short-lived highly reactive organolithium intermediates through precise residence time control, which is of great interest because it plays an important role in organic synthesis including Active Pharmaceutical Ingredients (API) by ultra-fast synthetic chemical intermediates. is dragging

Nevertheless, due to trial and error in the process of exploring various reaction parameters, including very short reaction times, ultrafast chemistry methodologies based on microreactors have not been widely used. Reaction intermediates produced in ultrafast chemistry have different chemical reactivity and life time due to their inherent instability, so optimizing selectivity and productivity by examining the effects of reaction residence time and temperature in consideration of this is not only synthetic chemistry but also flow chemistry reaction systems It requires an engineering understanding of In addition, highly reactive ultrafast synthetic chemistry is generally difficult to perform appropriate reactions even for highly skilled researchers due to ignitability and vulnerability to oxygen or moisture. In addition, it is time-consuming and costly to find optimal synthesis conditions as precise individual performance of various reaction parameter combinations is required in a micro-reactor.

Therefore, there is a need for research on combinatorial chemistry that can quickly find optimal synthesis conditions and rapidly produce various compounds under the optimal synthesis conditions.

An object of the present invention is to solve the above problems, a combinational chemical reaction apparatus capable of quickly finding optimal synthesis conditions (high yield) and rapidly producing various compounds under the optimal synthesis conditions, and It is to provide an optimized combinatorial chemical synthesis method using the same.

Another object of the present invention is to provide a combinatorial chemical reaction apparatus having a high yield while rapidly producing a plurality of types of products, and an optimized combinatorial chemical synthesis method using the same.

According to one aspect of the present invention, raw materials including one or a plurality of first raw materials, one or a plurality of second raw materials, and one or a plurality of third raw materials are supplied, respectively, and the flow rates of the raw materials are respectively A raw material supply unit 100 including a plurality of flow rate regulators for controlling; A plurality of intermediate micro mixers (M1, M2, M3, M4) generating a first mixture by mixing the first raw material and the second raw material supplied from the raw material supply unit 100 and the intermediate by reacting the first mixture An intermediate reaction unit 200 comprising a plurality of tubular intermediate reactors to generate; An intermediate reaction control unit 300 including an intermediate reaction control valve member for controlling at least one of the length of the tubular intermediate reactor and the type of the second raw material to be supplied; And a first product micro mixer (M5) for generating a second mixture by mixing the intermediate supplied from the intermediate reaction unit 200 and the third raw material supplied from the raw material supply unit 100, An automated micro combinatorial chemical reactor 10 including a first product reaction unit 400 for producing a product is provided.

In addition, the reaction time of the first mixture is controlled by the flow rate of the first raw material and the second raw material controlled by the flow rate controller and the reaction volume of the tubular intermediate reactor controlled by the intermediate reaction control valve member. it may be

In addition, the plurality of intermediate micro-mixers include a first intermediate micro-mixer, a second intermediate micro-mixer, . . . , ith intermediate micromixer, . . . , And an n-th intermediate micro-mixer (n is a natural number, i is a natural number, 1≤i≤n), wherein a plurality of the tubular intermediate reactors include a first tubular intermediate reactor, a second tubular intermediate reactor, ... , the ith tubular intermediate reactor, ... , And an nth tubular intermediate reactor (n is a natural number, i is a natural number, 1≤i≤n), wherein the n intermediate micromixers and the n tubular intermediate reactors may be connected in series alternately in order. there is.

In addition, the reaction volume of the tubular intermediate reactor may be controlled by arbitrarily selecting the i-th intermediate micro-mixer supplying the second raw material.

In addition, any one of a plurality of the second raw materials is supplied to the i-th intermediate micro-mixer, and any one of the supplied second raw materials is mixed with the first raw material in the i-th intermediate micro-mixer to form the first mixture It may form, and the first mixture reacts while passing through the reaction volume to produce the intermediate.

In addition, the reaction volume is the volume of the ith tubular intermediate reactor, . . . , and the volume of the nth tubular intermediate reactor.

In addition, the flow rate controller controls the flow rate of the singular or plural number of the first raw material, the singular or plural number of the second raw material, and the singular or plural number of the third raw material, respectively. It may include a raw material flow rate regulator, one or more second raw material flow rate regulators, and one or more third raw material flow rate regulators.

In addition, the intermediate reaction control valve member is a first intermediate reaction control valve, ... , ith intermediate reaction control valve, ... , And an n th intermediate reaction control valve (n is a natural number, i is a natural number, 1≤i≤n), wherein the n intermediate reaction control valves are connected in parallel to each other, and the n intermediate reaction control valves are each In order, the first intermediate micromixer, . . . , ith intermediate micromixer, . . . , And connected in series with the nth intermediate micromixer, the n intermediate reaction control valves are connected in series with the second raw material flow rate controller, respectively, and the n intermediate reaction control valves are each independently opened (open ) or closing, the second raw material may be supplied to or blocked from each of the n intermediate micromixers.

In addition, the raw material supply unit 100 further includes a second raw material supply valve member, and the second raw material is a 2-1 raw material, . . . , 2-j raw material, . . . , And a 2-m raw material (m is a natural number, j is a natural number, 1≤j≤m), wherein the m second raw materials are different from each other, and the second raw material flow rate controller is the m second raw material A 2-1 raw material flow rate controller for controlling the flow rate of raw materials, respectively... , 2-j raw material flow rate controller, . . . , and a 2-m raw material flow rate controller (m is a natural number, j is a natural number, 1≤j≤m), wherein the second raw material supply valve member is a 2-1 raw material supply valve, . , 2-j raw material supply valve, . . . , and 2-m raw material supply valves (j is a natural number, m is a natural number, 1≤j≤m), wherein the m second raw material supply valves are sequentially configured as a 2-1 raw material flow rate controller, . . . , 2-j raw material flow rate controller, . . . , and connected in series with the 2-m raw material flow rate controller, the m second raw material supply valves are connected in parallel with each other, and the m second raw material supply valves are each in series with the intermediate reaction unit 200 It may be connected to, and by opening or closing the m second raw material supply valves independently, respectively, supplying or blocking any one of the m second raw materials to the intermediate micromixer.

In addition, the raw material supply unit 100 further includes a third raw material supply valve member, and the third raw material is a 3-1 raw material, . . . , 3-k raw material, . . . , and 3-p raw materials (p is a natural number, k is a natural number, 1≤k≤p), the p third raw materials are different from each other, and the third raw material supply valve member is the 3-1 raw material supply valve, … , 3-k raw material supply valve, . . . , and 3-p raw material supply valves (k is a natural number, p is a natural number, 1≤k≤p), wherein the p third raw material supply valves are connected in parallel to each other, and the p third raw material supply valves are connected in parallel to each other. Valves are connected in series with the third raw material flow rate controller, respectively, the third raw material flow rate controller is connected in series with the first product reaction unit 400, respectively, and the p number of third raw material supply valves are respectively connected. By independently opening or closing, any one of the p third raw materials may be supplied to or blocked from the first product reaction unit 400 , respectively.

In addition, the raw material further includes a single or a plurality of fourth raw materials, and the raw material supply unit 100 supplies the fourth raw material and controls the flow rate of the fourth raw material, a fourth raw material flow rate regulator, and a fourth raw material supply valve member, wherein the automated micro combinatorial chemical reactor 10 further includes a second product reaction unit 500, wherein the second product reaction unit 500 comprises the second product reaction unit 500. A second product micro mixer (M6) for generating a third mixture by mixing the first product supplied from the first product reaction unit 400 and the fourth raw material supplied from the raw material supply unit 100, A second product is manufactured, and the fourth raw material is the 4-1 raw material, . . . , 4-h raw material, ... , and 4-q raw materials (q is a natural number, h is a natural number, 1≤h≤q), the q number of fourth raw materials are different from each other, and the fourth raw material supply valve member is the 4-1 raw material supply valve, … , 4-h raw material supply valve, . . . , and a 4-q raw material supply valve (h is a natural number, q is a natural number, 1≤h≤q), wherein the q fourth raw material supply valves are connected in parallel to each other, and the q fourth raw material supply valves are connected in parallel to each other. A valve is connected in series with the fourth raw material flow rate controller, respectively, the fourth raw material flow rate controller is connected in series with the second product reaction unit 500, respectively, and the q number of fourth raw material supply valves are respectively connected. By independently opening or closing, any one of the q fourth raw materials may be supplied to or blocked from the second product reaction unit 500 , respectively.

In addition, the intermediate reaction control valve member may include a solenoid valve.

In addition, the lifetime of the intermediate may be 1 millisecond (ms) to 100 seconds (s).

In addition, the intermediate micro mixer may be a T-shaped intermediate micro mixer.

In addition, the micro combinatorial chemical reactor 10 may further include a temperature control unit for adjusting the temperature of the intermediate reaction unit and the first product reaction unit.

In addition, the temperature controller may include a circulating thermostat and a cooling chamber.

In addition, the temperature controller may adjust the temperature of the intermediate reaction unit and the first product reaction unit to any one temperature selected from the range of -80 to 50 °C.

In addition, the automated micro combinatorial chemical reaction apparatus may further include an artificial intelligence unit controlling the raw material supply unit, the intermediate reaction unit, the intermediate reaction control unit, the first product reaction unit, and the temperature control unit. .

In addition, the artificial intelligence unit uses a Bayesian optimization algorithm to derive an optimized value of the reaction volume of the intermediate reaction unit, the flow rate of the raw material, the reaction temperature of the intermediate reaction unit, and the reaction temperature of the first product reaction unit.

In addition, the second raw material is n -butyllithium, sec -butyllithium, n -hexyllithium, n -octyllithium, tert -octyllithium, n -decyllithium, phenyllithium, 1-naphthyllithium, 4-butylphenyl and at least one organolithium compound selected from the group consisting of lithium, p -tolyllithium, 4-phenylbutyllithium, cyclohexyllithium, 4-butylcyclohexyllithium and 4-cyclohexylbutyllithium.

In addition, the automated micro combinatorial chemical reactor may further include an analysis unit including an analyzer for analyzing a product generated from any one selected from the group consisting of the first product reaction unit and the second product reaction unit. can

In addition, the analysis unit Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC-MS), liquid chromatography mass spectrometry (LC-MS), and ultraviolet-visible spectroscopy It may include any one device selected from the group consisting of analysis methods (UV-Vis).

According to another aspect of the present invention, an automated micro combination chemical reactor comprising a raw material supply unit 100, an intermediate reaction unit 200, an intermediate reaction control unit 300 and a first product reaction unit 400 (a) supplying a plurality of raw materials including a first raw material, a second raw material, and a third raw material by adjusting the flow rate, respectively, using a plurality of flow rate controllers of the raw material supply unit, respectively; doing; (b) mixing the first raw material and the second raw material supplied from the raw material supply unit in any one of a plurality of intermediate micro-mixers of the intermediate reaction unit to produce a first mixture, and one of a plurality of the tubular intermediate reactors Generating an intermediate by reacting the first mixture in the above; And (c) mixing the intermediate supplied from the intermediate reaction unit and the third raw material supplied from the raw material supply unit in a first product micro mixer of the first product reaction unit to produce a second mixture and prepare a first product. Including, the valve member of the intermediate reaction control unit is provided with an optimized combinatorial chemical synthesis method that controls the length of the tubular intermediate reactor.

In addition, the raw material further includes a single or a plurality of fourth raw materials, and the raw material supply unit 100 supplies the fourth raw material and controls the flow rate of the fourth raw material, a fourth raw material flow rate regulator, and a fourth raw material supply valve member, and the automated micro combinational chemical reactor 10 may further include a second product reaction unit 500 .

In addition, the optimized combinatorial chemical synthesis method, after step (c), (d) the first product supplied from the first product reaction unit 400 and the fourth raw material supplied from the raw material supply unit 100 mixing in the second product micro mixer of the second product reaction unit 500 to create a third mixture and to prepare a second product; may further include.

In addition, the optimized combinatorial chemical synthesis method uses the flow rate of the first raw material and the second raw material controlled by the flow rate controller and the reaction volume of the tubular intermediate reactor controlled by the valve member to determine the first mixture. It may be to control the reaction time of

In addition, the automated micro combinatorial chemical reaction device may include a temperature control unit for controlling the temperature of the intermediate reaction unit and the first product reaction unit; and an artificial intelligence unit controlling the raw material supply unit, the intermediate reaction unit, the intermediate reaction control unit, the first product reaction unit, and the temperature control unit.

The automated micro combinatorial chemical reactor and the optimized combinatorial chemical synthesis method using the same of the present invention can quickly find optimal synthesis conditions (high yield), and can rapidly produce various compounds under the optimal synthetic conditions. there is.

In addition, the automated micro combinatorial chemical reactor and the optimized combinatorial chemical synthesis method using the same of the present invention have the effect of having high yields while rapidly producing a plurality of types of products.

Since these drawings are for reference in explaining exemplary embodiments of the present invention, the technical spirit of the present invention should not be construed as being limited to the accompanying drawings.

1 shows a schematic diagram of an automated micro combinatorial chemical reactor according to one embodiment of the present invention.

Figure 2a is a schematic diagram of an autocollector used in an automated micro combinatorial chemical reactor according to an embodiment of the present invention.

Figure 2b is a schematic diagram showing the operation of the autocollector used in the automated micro combinatorial chemical reactor according to one embodiment of the present invention.

Figure 3a shows the results when an optimization reaction experiment was performed 15 times to secure a high yield of the first product by additionally using a Bayesian optimization algorithm in the automated micro combinatorial chemical reactor of Example 1.

Figure 3b shows the yield when the optimization reaction experiment of Figure 3a was performed 15 times.

Figure 4 shows the ¹ H NMR results of the 4e compound prepared using the automated micro combinatorial chemical reactor of Example 2.

5 shows the ¹³ C NMR results of the 4e compound prepared using the automated micro combinatorial chemical reactor of Example 2.

Figure 6 shows the ¹ H NMR results of the 4f compound prepared using the automated micro combinatorial chemical reactor of Example 2.

7 shows the ¹³ C NMR results of the 4f compound prepared using the automated micro combinatorial chemical reactor of Example 2.

Figure 8 shows the ¹ H NMR results of the 4h compound prepared using the automated micro combinatorial chemical reactor of Example 2.

Figure 9 shows the ¹³ C NMR results of the 4h compound prepared using the automated micro combinatorial chemical reactor of Example 2.

FIG. 10 shows the ¹ H NMR results of the 4i compound prepared using the automated micro combinatorial chemical reactor of Example 2. FIG.

11 shows the ¹³ C NMR results of the 4i compound prepared using the automated micro combinatorial chemical reactor of Example 2.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention.

However, the following description is not intended to limit the present invention to specific embodiments, and in describing the present invention, if it is determined that the detailed description of related known technologies may obscure the gist of the present invention, the detailed description will be omitted. .

Terms used herein are only used to describe specific embodiments, and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this application, the terms "comprise" or "having" are intended to indicate that there is a feature, number, step, operation, component, or combination thereof described in the specification, but one or more other features or It should be understood that the presence or addition of numbers, steps, operations, components, or combinations thereof is not precluded.

Also, terms including ordinal numbers such as first and second to be used below may be used to describe various components, but the components are not limited by the terms. These terms are only used for the purpose of distinguishing one component from another. For example, a first element may be termed a second element, and similarly, a second element may be termed a first element, without departing from the scope of the present invention.

In addition, when a component is referred to as being “formed” or “layered” on another component, it may be formed or laminated directly on the front or one side of the surface of the other component, but intermediate It should be understood that other components may be further present.

Hereinafter, an automated micro combinatorial chemical reactor and an optimized combinatorial chemical synthesis method using the same will be described in detail. However, this is presented as an example, and the present invention is not limited thereby, and the present invention is only defined by the scope of the claims to be described later.

Referring to FIG. 1, the present invention supplies raw materials including one or a plurality of first raw materials, one or a plurality of second raw materials, and one or a plurality of third raw materials, respectively, and the flow rate of the raw materials A raw material supply unit 100 including a plurality of flow rate regulators for controlling each; A plurality of intermediate micro mixers (M1, M2, M3, M4) generating a first mixture by mixing the first raw material and the second raw material supplied from the raw material supply unit 100 and the intermediate by reacting the first mixture An intermediate reaction unit 200 comprising a plurality of tubular intermediate reactors to generate; An intermediate reaction control unit 300 including an intermediate reaction control valve member for controlling at least one of the length of the tubular intermediate reactor and the type of the second raw material to be supplied; And a first product micro mixer (M5) for generating a second mixture by mixing the intermediate supplied from the intermediate reaction unit 200 and the third raw material supplied from the raw material supply unit 100, Provides an automated micro-combination chemical reactor 10 including a first product reaction unit 400 for producing a product.

In addition, the temperature controller may adjust the temperature of the intermediate reaction unit and the first product reaction unit to any one temperature selected from the range of -80 to 50 °C. When the temperature is less than -80 ° C., it is not preferable because it is difficult to manufacture intermediates and first products in the intermediate reaction part and the first product reaction part, respectively, and when it exceeds 50 ° C., the intermediate reaction part and the first product In the product reaction unit, by-products other than the target material may be produced, which is undesirable.

The present invention is an optimized combination using an automated micro combination chemical reactor 10 including a raw material supply unit 100, an intermediate reaction unit 200, an intermediate reaction control unit 300 and a first product reaction unit 400 A chemical synthesis method, (a) supplying a plurality of raw materials including a first raw material, a second raw material, and a third raw material by adjusting the flow rate, respectively, using a plurality of flow rate controllers of the raw material supply unit 100, respectively step; (b) mixing the first raw material and the second raw material supplied from the raw material supply unit 100 in any one of a plurality of intermediate micro mixers of the intermediate reaction unit 200 to produce a first mixture, and generating an intermediate by reacting the first mixture in at least one of the tubular intermediate reactors; and (c) mixing the intermediate supplied from the intermediate reaction unit 200 and the third raw material supplied from the raw material supply unit 100 in a first product micromixer of the first product reaction unit 400. 2, generating a mixture and preparing a first product; and providing an optimized combinatorial chemical synthesis method in which the valve member of the intermediate reaction control unit 300 controls the length of the tubular intermediate reactor.

[Example]

Hereinafter, a preferred embodiment of the present invention will be described. However, this is for illustrative purposes and the scope of the present invention is not limited thereby.

1 shows a schematic diagram of an automated micro combinatorial chemical reactor according to one embodiment of the present invention. Referring to FIG. 1, an automated micro combinatorial chemical reactor of Examples 1 and 2 was prepared.

Example 1: When using the first raw material, the second raw material, and the third raw material

Raw material supply unit 100

The first raw material, 2-bromophenyl isothiocyanate (Alfa Aesar) and the second raw material, n- butyllithium, n - BuLi, Sigma-Aldrich, phenyllithium, Airtight syringe (syringe) (50 mL, inner diameter: 27.6 mm) purchased from SGE Analytical Science, which supplies PhLi, Sigma-Aldrich) and sec -butyllithium, s -BuLi, Sigma-Aldrich, respectively. ) equipped with a PHD Ultra syringe pump (Harvard Apparatus) (p1, p2, p3, p4), wherein the syringe pump can stop, start and flow through a MATLAB program in serial communication through an RS-232 interface. set to control.

Supplied n- butyllithium ( n - BuLi, Sigma-Aldrich), phenyllithium (PhLi, Sigma-Aldrich) and sec -butyllithium ( sec -butyllithium, s -BuLi, Sigma-Aldrich) respectively Syringe pumps (p2, p3, p4) using high-purity PTFE tubes (1/16" od, 0.03" id) and polyethylene ether ketone 1/4-28 nuts (IDEX HEALTH & SCIENCE) each supply the second raw material It was connected in series with the valve solenoid valve (LVM15R3HY-6C1U, SMC Korea) (v5, v6, v7). At this time, the three solenoid valves (v5, v6, v7) are connected in parallel to each other to form a second raw material supply valve member.

Three types of third raw materials were used, and phenyl- (2a), p -anisyl- (2b) and p -nitrophenyl- (2c) isocyanate solutions (solvent: THF) were used, respectively.

The three types of the third raw material are solenoid valves, each of which is a third raw material supply valve, using a high purity PTFE tube (1/16" od, 0.03" id) and a polyethylene ether ketone 1/4-28 nut (IDEX HEALTH & SCIENCE) (LVM15R3HY-6C1U, SMC Korea) (v8, v9, v10) was connected in series, and the three solenoid valves (v8, v9, v10) were connected in parallel to each other to form a third raw material supply valve member.

The third raw material supply valve member (v8, v9, v10) is connected in series with a high-performance isocratic pump (hp1), which is a third raw material injector, and the fourth raw material supply valve member (v11, v12, v13) is 4 It was connected in series with a high-performance isocratic pump (hp2), which is a raw material injector.

Each solenoid valve in the second raw material supply valve member and the third raw material supply valve member is connected to a control box self-manufactured based on a microcontroller (Arduino Uno) of Interaction Design Institutelvera (Italy), and the microcontroller and MathWorks (MA, USA) The opening and closing were controlled by serial communication using a PC MATLAB program.

Intermediate reaction unit 200

The intermediate reaction unit mixes the first raw material and the second raw material supplied from the raw material supply unit 100 to generate a first mixture, a plurality of intermediate micro mixers M1, M2, M3, M4 and the first mixture It includes a plurality of tubular intermediate reactors for reacting to produce intermediates.

In this case, the intermediate is a compound represented by Structural Formula 1 below.

[Structural Formula 1]

The intermediate micromixer was prepared as four stainless steel (SUS304) micromixers (Sanko Seiki Co.) (M1, M2, M3, M4) with a T-shape and an inner diameter of 250 μm.

As the tubular intermediate reactor, a stainless steel (SUS304) tube having an inner diameter of 250 μm and a stainless steel (SUS304) tube having an inner diameter of 1000 μm were purchased from GL Science and used. The stainless steel (SUS304) tube having an inner diameter of 250 μm was cut to 4 cm and used, and the stainless steel (SUS304) tube with an inner diameter of 1000 μm was cut to 70, 26 and 4 cm.

The stainless steel (SUS304) tube having an inner diameter of 1000 μm was also used as a cooling unit, and in this case, it was cut to 50 cm and used.

The intermediate micromixer and the tubular intermediate reactor were alternately connected in series using stainless steel fittings (GL Science, 1/16" OUW) to form an intermediate reaction unit.

Intermediate reaction controller 300

The second raw material supply valve member (v5, v6, v7) of the raw material supply unit uses a high-purity PTFE tube (1/16" od, 0.03" id) and a polyethylene ether ketone 1/4-28 nut (IDEX HEALTH & SCIENCE) and connected in series with four solenoid valves (v1, v2, v3, v4), which are intermediate reaction control valves, and the four solenoid valves (v1, v2, v3, v4) are respectively the intermediate micro mixers (M1, M2, M3, M4) and high-purity PTFE tubes (1/16" od, 0.03" id) and polyethylene ether ketone 1/4-28 nuts (IDEX HEALTH & SCIENCE) were connected in series.

The intermediate reaction control valve member including the four solenoid valves (v1, v2, v3, v4) is a first raw material (2-bromophenyl isothiocyanate) Br and a second raw material ( n- BuLi, PhLi and It is for controlling the reaction volume (V _R ) in which the exchange reaction of Li occurs in any one selected from s -BuLi).

In the intermediate reaction control valve member including the above, the solenoid valve is connected to a control box self-manufactured based on a microcontroller (Arduino Uno) of Interaction Design Institutelvera (Italy), and a PC MATLAB program of the microcontroller and MathWorks (MA, USA). Opening/closing was controlled by serial communication using .

First product reaction unit 400

The first product micromixer of the first product reaction unit mixes the intermediate supplied from the intermediate reaction unit 200 and the third raw material supplied from the raw material supply unit 100 to generate a second mixture. It includes a mixer (M5), and is to prepare the first product.

In this case, the first product may be a compound represented by Structural Formula 2 below.

[Structural Formula 2]

In Structural Formula 2,

R ¹ is a hydrogen atom as the third raw material is selected from the group consisting of phenyl- (2a), p -anisyl- (2b) and p -nitrophenyl- (2c) isocyanate solution (solvent: THF) , a methoxy group (-O-CH ₃ ), or a nitric acid group (-NO ₂ ).

By mixing the first product represented by Structural Formula 2 with a saturated aqueous solution of ammonium chloride, quenching is induced to finally obtain the first product represented by Structural Formula 3 below.

[Structural Formula 3]

In Structural Formula 3,

The first product micromixer was a T-shaped stainless steel (SUS304) micromixer (Sanko Seiki Co.) (M5) having an inner diameter of 250 μm.

The intermediate reaction unit 200 and the first product reaction unit 400 are disposed in a specially designed cooling chamber connected to a circulating thermostat to control temperature T. The circulation thermostat (RW3-2035, 20L, -35 ~ 150℃) of Jeio Tech (Korea) is connected to a computer through RS-232 method and communicates with the PC through Modbus protocol. You can control speed, etc.

A typical FT-IR spectrometer (Jasco FT/IR-4600 spectrometer) includes a sealed flow cell accessory based on an IR light source/laser transmissive ZnSe window (path length 0.1 mm) to build a flow-based in-line IR system. (Specac®) is installed. The sealed flow cell accessory aligns to the FT-IR spectrometer unit through a dedicated holder and connects to the AMR through a 1/16" Swagelok fitting connected to the flow cell. Flow-based monitoring is maintained continuously, with spectral data 8 scans per sample. was set to be collected at 20 second intervals.

Acquired data can be processed in real time through the MACRO program developed in-house based on MATLAB and Python languages, and is expressed as yield or conversion data.

After reaching steady state, the product solution was collected for 30 seconds after the reactor or in-line analyzer unless otherwise specified.

Example 2: When using the first raw material, the second raw material, the third raw material, and the fourth raw material

Raw material supply unit 100

The raw material supply unit was prepared in the same manner as the raw material supply unit of Example 1, except that a fourth raw material additionally included and a fourth raw material supply valve member including a fourth raw material supply valve was further included.

Three types of the fourth raw material were used, and benzyl- (3a), p -chloro benzyl- (3b), and p -trifluoromethoxy benzyl- (3c) bromide solutions (solvent: THF) were used, respectively.

The three types of fourth raw materials are solenoid valves, each of which is a fourth raw material supply valve, using a high purity PTFE tube (1/16" od, 0.03" id) and a polyethylene ether ketone 1/4-28 nut (IDEX HEALTH & SCIENCE) (LVM15R3HY-6C1U, SMC Korea) (v11, v12, v13) and connected in series, and the three solenoid valves (v11, v12, v13) were connected in parallel to each other to form a fourth raw material supply valve member.

The fourth raw material supply valve member (v11, v12, v13) is connected in series with a high-performance isocratic pump (hp2), which is a fourth raw material flow rate controller.

In the fourth raw material supply valve member, each solenoid valve is connected to a control box self-manufactured based on a microcontroller (Arduino Uno) of Interaction Design Institutelvera (Italy), and a microcontroller and PC MATLAB of MathWorks (MA, USA) Opening/closing was controlled by serial communication using a program.

Intermediate reaction unit 200

The intermediate reaction part was prepared in the same way as the intermediate reaction part of Example 1.

Intermediate reaction controller 300

The intermediate reaction control unit was prepared in the same manner as the intermediate reaction control unit of Example 1.

First product reaction unit 400

[Structural Formula 2]

In Structural Formula 2,

Second product reaction unit 500

The second product reaction unit includes a second product micromixer configured to generate a third mixture by mixing the first product supplied from the first product reaction unit and the fourth raw material supplied from the raw material supply unit, and to make a product.

At this time, the residence time of the first product (time until the first product reaches the second micro mixer) may be 1 to 3 seconds. When the retention time of the first product is less than 1 second, the yield of the second product is not high, which is not preferable, and when it exceeds 3 seconds, -SLi in Structural Formula 2 is changed to =S or decomposed to react with the fourth raw material. Not desirable due to difficulty.

Specifically, when the residence time of the first product exceeds 3 seconds, -SLi in Structural Formula 2 is changed or decomposed to =S, but the rate is slow, so the yield of the second product does not change. It can be confirmed that it does not (see Test Example 2 below). On the other hand, when the residence time of the first product exceeds 3 seconds, since the decomposition and termination of the first product represented by Structural Formula 2 has almost progressed, it is difficult to react with the fourth raw material, which is not preferable.

The second product micro mixer was a T-shaped stainless steel (SUS304) micro mixer (Sanko Seiki Co.) (M6) having an inner diameter of 250 μm.

Figure 2a is a schematic diagram of the autocollector used in the automated micro combinatorial chemical reactor of one embodiment of the present invention, Figure 2b is a schematic diagram showing the operation of the autocollector used in the automated micro combinatorial chemical reactor of one embodiment of the present invention.

According to Figures 2a and 2b, the autocollector was fabricated using CNC milling with a rotary plate capable of loading 10 vials (30 mL, 1 for waste, 9 for samples) to enable sequential sample collection. In order to finely control the rotation, the rotation plate was connected to the rotation axis of a stepper motor (23HS5623-P4-8, HandsOnTech, Malaysia). In addition, the stepper motor was connected to a microstep driver (TB6600, DFRobot, China) to precisely control the rotation angle and speed. The connection between the central computer with MATLAB installed and the motor was made through an open source based microcontroller Arduino R3 DIP board (Arduino, Italy). The rotation information of the stepper motor was determined according to the commands of the central computer through serial communication with the Arduino board, and sample collection, reactor stabilization, and cleaning processes were possible in each situation.

[Test Example]

Test Example 1: Confirmation of optimal conditions for securing high yield of the first product

Type of second raw material (organolithium), flow rate (Q), reaction volume (V _R and optimized values of the reaction temperature (T) were derived.

Specifically, the flow rate (Q) of each raw material is 6 to 24 mL/min, the reaction temperature (T) of the intermediate reaction part and the first product reaction part is continuously controlled in the range of -20 to 20 ° C, respectively, The types of the second raw material (organolithium) were n- butyllithium ( n - BuLi), phenyllithium (PhLi), and sec -butyllithium ( s -BuLi), and the reaction volumes ( _VR ) were 787, 237, 33 and It was controlled discontinuously with 2 μL.

At this time, the flow rate (Q) is the flow rate (Q ₁ ) of 2-bromophenyl isothiocyanate as the first raw material, and the second raw material (organolithium) (from the group consisting of n-BuLi, PhLi and s-BuLi It is the sum of the flow rate (Q ₂ ) and the flow rate (Q ₃ ) of the third raw material (4-nitrophenyl isocyanate), and each ratio (Q ₁ : Q ₂ : Q ₃ ) is 4: It was adjusted to 1:3.

The reaction volumes (V _R ) of 787, 237, 33, and 2 μL were set by adjusting the injection position of n -butyllithium, specifically, in series with four intermediate micro mixers (M1, M2, M3, and M4), respectively. The reaction volume was controlled by supplying n -butyllithium to any one of the above four intermediate micromixers by independently opening or closing the connected valves (v1, v2, v3, v4).

In addition, the reaction conditions for the initial experiments were randomly selected within a range of parameters and the reaction results were automatically analyzed by inline FT-IR. A total of 15 experiments were repeated to derive optimized values for the type of organolithium, flow rate (Q), reaction volume ( _VR ), and reaction temperature (T).

Figure 3a shows the results when an optimization reaction experiment was performed 15 times to secure a high yield of the first product by additionally using a Bayesian optimization algorithm in the automated micro combinatorial chemical reactor of Example 1, and Figure 3b shows the result. The yield is summarized and shown when the optimization reaction experiment of FIG. 3a is performed 15 times.

3a and 3b, phenyllithium (PhLi) is used as the second raw material (organolithium), the flow rate (Q) is 17 mL/min, the reaction volume ( _VR ) is 2 µL, and the reaction temperature (T) is 19 °C In one case, it can be confirmed that the yield of the first product reaches 90% within 1 hour and 30 minutes.

Test Example 2: Confirmation of the second product yield according to the reaction volume of the first product

In the automated micro combinatorial chemical reactor of Example 2, the tubular reactor connecting the first product reaction unit 400 and the second product reaction unit 500 has an inner diameter of 250 purchased from GL Science and cut to 4 cm. At least one selected from the group consisting of μm stainless steel (SUS304) tubes and stainless steel (SUS304) tubes having an inner diameter of 1000 μm cut into 70, 26, and 4 cm, respectively, was used.

In detail, the reaction volume of the first product is set to 393, 785, 1,571 and 3,142 μL by using various tubular reactors connecting the first product reaction unit 400 and the second product reaction unit 500. Accordingly, the residence time of the first product and the yield of the second product in the tubular reactor are summarized in Table 1 below.

제1 생산물 반응부피 (μL)First product reaction volume (μL)	제1 생산물 체류 시간 (s)First product residence time (s)	제2 생산물 수율 (%)Second product yield (%)
393393	2.22.2	8080
785785	4.54.5	8080
1,5711,571	9.09.0	8080
3,1423,142	18.018.0	8080

According to Table 1, the yield of the second product is not significantly affected by the change in residence time of the first product represented by Structural Formula 2 below, because the first product represented by Structural Formula 2 is relatively stable .

[Structural Formula 2]

In Structural Formula 2,

Specifically, when the residence time of the first product exceeds 3 seconds, -SLi in Structural Formula 2 is changed or decomposed to =S, but the rate is slow, so the yield of the second product does not change. can confirm that it is not.

Therefore, since the yield of the second product was not greatly affected by the change in residence time of the first product, the reaction volume of the first product was fixed at 393 μL.

Test Example 3: Preparation of 9 products according to the types of the third raw material and the fourth raw material

The type of the second raw material (organolithium) confirmed in Test Example 1, phenyllithium (PhLi), which is the optimized value of the flow rate (Q ), reaction volume ( _VR ), and reaction temperature (T) of each raw material, 17 mL/min, The conditions of the automated micro combinatorial chemical synthesizer of Example 2 were set to 2 μL and 19 ° C.

In detail, the first raw material was prepared with 0.10 M 2-bromophenyl isothiocyanate in THF, and the flow rate of the first raw material was set to 17/2 mL/min (Q ₁ = Q/2 mL/min). The second raw material was prepared with 0.42 M phenyl lithium in hexane or Et ₂ O, and the flow rate of the second raw material was set to 17/8 mL/min (Q ₂ = Q/8 mL/min). The third raw material was prepared as a solution (solvent THF) with a concentration of 0.22 M and the flow rate was set to 17/4 mL/min (Q ₃ = Q/4 mL/min). The fourth raw material was prepared as a solution (solvent THF) with a concentration of 1.2 M and the flow rate was set to 17/8 mL/min (Q ₄ = Q/8 mL/min).

In the case of using the automated micro combinatorial chemical synthesizer of Example 2, a combination of a first raw material, a second raw material, three third

raw materials

2a, 2b, and 2c, and three fourth

raw materials

3a, 3b, and 3c According to this, nine types of products (4a to 4i) were produced, and at this time, the third raw material and the fourth raw material used respectively and the results are summarized in Table 2 below.

생산물product	제3 원료3rd raw material	제4 원료4th raw material
구분 division	제3 원료3rd raw material	제4 원료4th raw material	화학식chemical formula
4a4a	Phenyl isocyanatePhenyl isocyanate	Benzyl bromideBenzyl bromide
4b4b	Phenyl isocyanatePhenyl isocyanate	4-chlorobenezyl bromide4-chlorobenzyl bromide
4c4c	Phenyl isocyanatePhenyl isocyanate	4-(trifluoromethoxy)benzyl bromide4-(trifluoromethoxy)benzyl bromide
4d4d	4-methoxyphenyl isocyanate4-methoxyphenyl isocyanate	Benzyl bromideBenzyl bromide
4e4e	4-methoxyphenyl isocyanate4-methoxyphenyl isocyanate	4-chlorobenezyl bromide4-chlorobenzyl bromide
4f4f	4-methoxyphenyl isocyanate4-methoxyphenyl isocyanate	4-(trifluoromethoxy)benzyl bromide4-(trifluoromethoxy)benzyl bromide
4g4g	4-nitrophenyl isocyanate4-nitrophenyl isocyanate	Benzyl bromideBenzyl bromide
4h4h	4-nitrophenyl isocyanate4-nitrophenyl isocyanate	4-chlorobenezyl bromide4-chlorobenzyl bromide
4i4i	4-nitrophenyl isocyanate4-nitrophenyl isocyanate	4-(trifluoromethoxy)benzyl bromide4-(trifluoromethoxy)benzyl bromide

Test Example 3-1: Confirmation of Product Synthesis

The 9 types of products prepared using the automated micro-combination chemical synthesizer of Example 2 were extracted and purified by recrystallization with hexane, respectively. ¹ H NMR and ¹³ C NMR analysis of the nine products, respectively, confirmed that the target compounds were synthesized. shown in

In detail, FIG. 4 shows the ¹ H NMR results of the 4e compound prepared using the automated micro combinatorial reactor of Example 2, and FIG. It shows the ¹³ C NMR result of the 4e compound prepared by

4 and 5, ^{the 1} H NMR and ¹³ C NMR values of the 4e compound were shown below, and one of the targeted products, 2-((4-chlorobenzyl)thio)-3-(4-methoxyphenyl ) It can be confirmed that the quinazolin-4(3H)-one compound was well synthesized.

^1H NMR (500 MHz, CDCl ₃ ) δ 8.24 (dd, J = 4.5 Hz, 1H), 7.75 (td, J = 8.4 Hz, 1H), 7.65 (d, J = 4.0 Hz, 1H), 7.41 (td , J = 8.0 Hz, 1H), 7.34–7.24 (m, 4H), 7.20 (dt, J = 7.6 Hz, 2H), 7.01 (dt, J = 7.5 Hz, 2H), 4.36 (s, 2H), 3.86 (s, 3H) ppm; ¹³ C NMR (125 MHz, CDCl ₃ ) δ 162.2, 160.7, 157.4, 147.8, 135.5, 134.8, 133.4, 130.8, 130.4, 128.8, 128.2, 127.5, 126.3, 126.0, 125.1, 125.1 ppm; HRMS (EI) (m/z) cald. for C ₂₂ H ₁₇ ClN ₂ O ₂ S ⁺ [M] ⁺ : 408.0699; found: 408.0697.

6 shows the ¹ H NMR results of the 4f compound prepared using the automated micro combinatorial reactor of Example 2, and FIG. 7 shows the 4f compound prepared using the automated micro combinatorial reactor of Example 2. It shows the ¹³ C NMR result of the compound.

6 and 7, the ¹ H NMR and ¹³ C NMR values of the 4f compound were shown as follows, and one of the targeted products, 3-(4-methoxyphenyl)-2-((4-trifluoromethoxy)benzyl It can be confirmed that )thio)quinazolin-4(3H)-one compound was well synthesized.

^1H NMR (500 MHz, CDCl ₃ ) δ 8.25 (dd, J = 4.6 Hz, 1H), 7.75 (td, J = 8.5 Hz, 1H), 7.65 (d, J = 4.4 Hz, 1H), 7.43-7.00 (m, 9H), 4.39 (s, 2H), 3.86 (s, 3H) ppm; ¹³ C NMR (125 MHz, CDCL ₃ ) Δ 162.2, 160.8, 157.4, 148.6, 147.8, 134.8, 130.9, 130.4, 128.9, 128.2, 127.5, 126.3, 126.1, 121.1, 120.1, 115.1, 55.6, 36.3 ppm; HRMS (EI) (m/z) cald. for C ₂₃ H ₁₇ F ₃ N ₂ O ₃ S ⁺ [M] ⁺ : 458.0912; found: 458.0914.

8 shows the ¹ H NMR results of the 4h compound prepared using the automated micro combinatorial reactor of Example 2, and FIG. 9 shows the 4h compound prepared using the automated micro combinatorial reactor of Example 2. It shows the ¹³ C NMR result of the compound.

8 and 9, ^{the 1} H NMR and ¹³ C NMR values of the 4h compound were shown below, and one of the targeted products, 2-((4-chlorobenzyl)thio)-3-(4-nitrophenyl ) It can be confirmed that the quinazolin-4(3H)-one compound was well synthesized.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.38 (dt, J = 7.2 Hz, 2H), 8.23 (dd, J = 4.7 Hz, 1H), 7.80 (td, J = 8.5 Hz, 1H), 7.68 (d , J = 4.0 Hz, 1H), 7.51 (dt, J = 7.2 Hz, 2H), 7.45 (td, J = 8.1 Hz, 1H), 7.33–7.25 (m, 4H), 4.40 (s, 2H) ppm; ¹³ C NMR (125 MHz, CDCl ₃ ) δ 161.5, 155.1, 148.7, 147.6, 141.4, 135.4, 134.8, 133.7, 130.8 (2C), 128.9, 127.5, 126.6, 126.5, 125.1, 119.48 ppm; HRMS (EI) (m/z) cald. for C ₂₁ H ₁₄ ClN ₃ O ₃ S ⁺ [M] ⁺ : 423.0444; found: 423.0448.

10 shows the ¹ H NMR results of the 4i compound prepared using the automated micro combinatorial reactor of Example 2, and FIG. 11 shows the 4i prepared using the automated micro combinatorial reactor of Example 2. It shows the ¹³ C NMR result of the compound.

10 and 11, ^{the 1} H NMR and ¹³ C NMR values of the 4i compound were shown as follows, and one of the targeted products, 3-(4-nitrophenyl)-2-((4-trifluoromethoxy)benzyl It can be confirmed that )thio)quinazolin-4(3H)-one compound was well synthesized.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.39 (dt, J = 7.2 Hz, 2H), 8.24 (dd, J = 4.6 Hz, 1H), 7.80 (td, J = 8.5 Hz, 1H), 7.69 (dd , J = 4.4 Hz, 1H), 7.52 (dt, J = 7.2 Hz, 2H), 7.46 (td, J = 8.2 Hz, 1H), 7.41 (dt, J = 7.1 Hz, 2H), 7.14 (d, J = 4.0 Hz, 2H), 4.43 (s, 2H) ppm; ¹³ C NMR (125 MHz, CDCl ₃ ) δ 161.5, 155.0, 148.8, 148.7, 147.6, 141.4, 135.4, 135.1, 130.9 (2C), 127.5, 126.6, 126.5, 125.1, 121.6, 121.6, 121.6, ppm; HRMS (EI) (m/z) cald. for C ₂₂ H ₁₄ F ₃ N ₃ O ₄ S ⁺ [M] ⁺ : 473.0657; found: 473.0655.

Experimental Example 3-2: Yield of 9 types of products prepared using an automated micro combinatorial chemical reactor

Table 3 below summarizes the yields of 9 types of products prepared using the automated micro combinatorial chemical reactor of Example 2, respectively.

구분division	생산물 수율 (%)Product yield (%)
4a4a	8181
4b4b	9898
4c4c	9090
4d4d	9393
4e4e	7979
4f4f	6565
4g4g	9696
4h4h	8686
4i4i	7777

Specifically, the yield is an isolated yield of a product separated through crystallization and column chromatography.

According to Table 3, the automated micro combinatorial chemical reactor of Example 1 produces 9 types of products in high yield (65 to 98%) without human intervention within 20 minutes of operating time from the injection of the first and second raw materials. production can be verified.

In addition, it can be seen that the individual products automatically collected by the autocollector are easily separated through a simple recrystallization process and exhibit excellent yields (65 to 98%).

The scope of the present invention is indicated by the following claims rather than the detailed description above, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention. do.

[Description of code]

10: Automated Micro Combination Chemical Reactor

100: raw material supply unit

200: intermediate reaction unit

300: intermediate reaction controller

400: first product reaction unit

500: second product reaction unit

p1: first raw material flow rate controller

p2, p3, p4: second raw material flow rate controller

hp1: 3rd raw material flow rate regulator

hp2: 4th raw material flow rate regulator

M1, M2, M3, M4: intermediate micromixers

M5: first product micromixer

M6: second product micromixer

v1, v2, v3, v4: intermediate reaction control valve

v5, v6, v7: 2nd raw material supply valve

v8, v9, v10: 3rd raw material supply valve

v11, v12, v13: 4th raw material supply valve

Claims

A plurality of flow rate controllers for supplying raw materials including a single or plural first raw material, a single or plural second raw material, and a single or plural third raw material, respectively, and controlling the flow rate of the raw material, respectively A raw material supply unit comprising;

An intermediate comprising a plurality of intermediate micro-mixers generating a first mixture by mixing the first raw material and the second raw material supplied from the raw material supply unit and a plurality of tubular intermediate reactors generating an intermediate by reacting the first mixture reaction part;

An intermediate reaction control unit including an intermediate reaction control valve member for controlling at least one of the length of the tubular intermediate reactor and the type of the second raw material to be supplied; and

A first product reaction unit comprising a first product micromixer mixing the intermediate supplied from the intermediate reaction unit and the third raw material supplied from the raw material supply unit to generate a second mixture, and producing a first product; cast

An automated micro combinatorial chemical reactor comprising:
According to claim 1,

Controlling the reaction time of the first mixture by the flow rate of the first raw material and the second raw material controlled by the flow rate controller and the reaction volume of the tubular intermediate reactor controlled by the intermediate reaction control valve member Automated micro combinatorial chemical reactor characterized by.
According to claim 1,

The plurality of intermediate micro-mixers include a first intermediate micro-mixer, a second intermediate micro-mixer, ... , ith intermediate micromixer, . . . , And an nth intermediate micromixer (n is a natural number, i is a natural number, 1≤i≤n),

The plurality of tubular intermediate reactors are a first tubular intermediate reactor, a second tubular intermediate reactor, ... , the ith tubular intermediate reactor, ... , and an nth tubular intermediate reactor (n is a natural number, i is a natural number, 1≤i≤n),

The n intermediate micromixers and the n tubular intermediate reactors are automated micro combinatorial chemical reactors, characterized in that connected in series alternately in order.
According to claim 3,

An automated micro combinatorial chemical reactor, characterized in that the reaction volume of the tubular intermediate reactor is controlled by arbitrarily selecting the i-th intermediate micro mixer for supplying the second raw material.
According to claim 3,

Any one of the plurality of second raw materials is supplied to the i-th intermediate micro-mixer,

Any one of the supplied second raw materials is mixed with the first raw material in the i-th intermediate micro mixer to form the first mixture;

An automated micro combinatorial chemical reactor, characterized in that the first mixture passes through the reaction volume and reacts to generate the intermediate.
According to claim 5,

The reaction volume is the volume of the ith tubular intermediate reactor, . . . , and the volume of the n-th tubular intermediate reactor.
According to claim 1,

The flow rate controller controls the flow rate of the singular or plural number of the first raw material, the singular or plural number of the second raw material, and the singular or plural number of the third raw material, respectively. An automated micro combinatorial chemical reactor comprising a speed controller, a single or plurality of second raw material flow rate regulators and a single or plurality of third raw material flow rate regulators.
According to claim 7,

The intermediate reaction control valve member is a first intermediate reaction control valve, ... , ith intermediate reaction control valve, ... , And an nth intermediate reaction control valve (n is a natural number, i is a natural number, 1≤i≤n),

The n intermediate reaction control valves are connected in parallel to each other,

The n intermediate reaction control valves are sequentially connected to the first intermediate micromixer, ... , ith intermediate micromixer, . . . , and connected in series with the nth intermediate micromixer,

The n intermediate reaction control valves are each connected in series with the second raw material flow rate controller,

An automated micro combinatorial chemical reactor characterized in that the n intermediate reaction control valves independently open or close to supply or block the second raw material to the n intermediate micro mixers, respectively. .
According to claim 7,

The raw material supply unit further comprises a second raw material supply valve member,

The second raw material is the 2-1 raw material, . . . , 2-j raw material, . . . , and the 2-m raw material (m is a natural number, j is a natural number, 1≤j≤m), respectively,

The m second raw materials are different from each other,

A 2-1 raw material flow rate controller for controlling the flow rates of the m second raw materials, respectively, by the second raw material flow rate controller, . . . , 2-j raw material flow rate controller, . . . , and a 2-m raw material flow rate controller (m is a natural number, j is a natural number, 1≤j≤m),

The second raw material supply valve member is a 2-1 raw material supply valve, . . . , 2-j raw material supply valve, . . . , and a 2-m raw material supply valve (j is a natural number, m is a natural number, 1≤j≤m),

The m number of second raw material supply valves are sequentially configured as a 2-1 raw material flow rate controller, . . . , 2-j raw material flow rate controller, . . . , And connected in series with the 2-m raw material flow rate controller,

The m second raw material supply valves are connected in parallel to each other,

The m second raw material supply valves are each connected in series with the intermediate reaction unit,

Automated micro combination, characterized in that for supplying or blocking any one of the m second raw materials to the intermediate micro mixer, respectively, by independently opening or closing the m second raw material supply valves. chemical reactor.
According to claim 7,

The raw material supply unit further comprises a third raw material supply valve member,

The third raw material is the 3-1 raw material, . . . , 3-k raw material, . . . , and a 3-p raw material (p is a natural number, k is a natural number, 1≤k≤p), respectively,

The p third raw materials are different from each other,

The third raw material supply valve member is a 3-1 raw material supply valve, . . . , 3-k raw material supply valve, . . . , and a 3-p raw material supply valve (k is a natural number, p is a natural number, 1≤k≤p),

The p third raw material supply valves are connected in parallel to each other,

The p number of third raw material supply valves are connected in series with the third raw material flow rate controller, respectively;

The third raw material flow rate controller is connected in series with the first product reaction unit, respectively,

By opening or closing the p third raw material supply valves independently, respectively, supplying or blocking any one of the p third raw materials to the first product reaction unit, characterized in that Micro Combination Chemical Reactor.
According to claim 7,

The raw material further includes a single or a plurality of fourth raw materials,

The raw material supply unit further comprises a fourth raw material flow rate regulator supplying the fourth raw material and adjusting a flow rate of the fourth raw material, and a fourth raw material supply valve member,

The automated micro combinatorial chemical reactor further includes a second product reaction unit,

The second product reaction unit includes a second product micromixer configured to generate a third mixture by mixing the first product supplied from the first product reaction unit and the fourth raw material supplied from the raw material supply unit, to produce products,

The fourth raw material is the 4-1 raw material, . . . , 4-h raw material, ... , and the 4-q raw material (q is a natural number, h is a natural number, 1≤h≤q), respectively,

The q fourth raw materials are different from each other,

The fourth raw material supply valve member is a 4-1 raw material supply valve, . . . , 4-h raw material supply valve, . . . , and a 4-q raw material supply valve (h is a natural number, q is a natural number, 1≤h≤q),

The q number of fourth raw material supply valves are connected in parallel to each other,

The q number of fourth raw material supply valves are connected in series with the fourth raw material flow rate controller, respectively;

The fourth raw material flow rate controller is connected in series with the second product reaction unit, respectively,

By independently opening or closing the q fourth raw material supply valves, respectively, supplying or blocking any one of the q fourth raw materials to the second product reaction unit, characterized in that Micro Combination Chemical Reactor.
According to claim 1,

An automated micro combinatorial chemical reactor, characterized in that the intermediate reaction control valve member comprises a solenoid valve.
According to claim 1,

An automated micro combinatorial chemical reactor, characterized in that the lifetime of the intermediate is 1 millisecond (ms) to 100 seconds (s).
According to claim 1,

An automated micro combinatorial chemical reactor, characterized in that the intermediate micro-mixer is a T-shaped intermediate micro-mixer.
According to claim 1,

The automated micro combinatorial chemical reaction apparatus further comprises a temperature control unit for controlling the temperature of the intermediate reaction unit and the first product reaction unit.
According to claim 15,

The automated micro combinatorial chemical reactor

An automated micro combinatorial chemical reactor further comprising: an artificial intelligence unit controlling the raw material supply unit, the intermediate reaction unit, the intermediate reaction control unit, the first product reaction unit, and the temperature control unit.
According to claim 16,

The artificial intelligence unit uses a Bayesian optimization algorithm to derive an optimized value of the reaction volume of the intermediate reaction unit, the flow rate of the raw material, the reaction temperature of the intermediate reaction unit, and the reaction temperature of the first product reaction unit. Micro Combination Chemical Reactor.
According to claim 1,

The second raw material is n -butyllithium, sec -butyllithium, n -hexyllithium, n -octyllithium, tert -octyllithium, n -decyllithium, phenyllithium, 1-naphthyllithium, 4-butylphenyllithium, p -tolyllithium, 4-phenylbutyllithium, cyclohexyllithium, 4-butylcyclohexyllithium and 4-cyclohexylbutyllithium, characterized in that it comprises at least one organolithium compound selected from the group consisting of automated micro-assembly. chemical reactor.
According to claim 1,

The automated micro combinatorial chemical reactor further comprises an analysis unit including an analyzer for analyzing a product generated from any one selected from the group consisting of the first product reaction unit and the second product reaction unit. Automated micro combinatorial chemical reactor.
An optimized combinatorial chemical synthesis method using an automated micro combinatorial chemical reactor including a raw material supply unit, an intermediate reaction unit, an intermediate reaction control unit, and a first product reaction unit,

(a) supplying a plurality of raw materials including a first raw material, a second raw material, and a third raw material by respectively adjusting the flow rate using a plurality of flow rate controllers of the raw material supply unit;

(b) mixing the first raw material and the second raw material supplied from the raw material supply unit in any one of a plurality of intermediate micro-mixers of the intermediate reaction unit to produce a first mixture, and one of a plurality of the tubular intermediate reactors Generating an intermediate by reacting the first mixture in the above; and

(c) mixing the intermediate supplied from the intermediate reaction unit and the third raw material supplied from the raw material supply unit in the first product micro mixer of the first product reaction unit to produce a second mixture and to prepare a first product Step; including,

Optimized combinatorial chemical synthesis method wherein the valve member of the intermediate reaction control unit controls the length of the tubular intermediate reactor.
According to claim 20,

The raw material further includes a single or a plurality of fourth raw materials,

The raw material supply unit further comprises a fourth raw material flow rate regulator supplying the fourth raw material and adjusting a flow rate of the fourth raw material, and a fourth raw material supply valve member,

Optimized combinatorial chemical synthesis method, characterized in that the automated micro combinatorial chemical reactor further comprises a second product reaction unit.
According to claim 21,

The optimized combinatorial chemical synthesis method is after the step (c),

(d) mixing the first product supplied from the first product reaction unit and the fourth raw material supplied from the raw material supply unit in a second product micro mixer of the second product reaction unit to generate a third mixture; Optimized combinatorial chemical synthesis method, characterized in that it further comprises the step of preparing a product.
According to claim 20,

The optimized combinatorial chemical synthesis method reacts the first mixture by the flow rate of the first raw material and the second raw material controlled by the flow rate controller and the reaction volume of the tubular intermediate reactor controlled by the valve member. An optimized combinatorial chemical synthesis method characterized by controlling time.
According to claim 20,

a temperature control unit for controlling the temperatures of the intermediate reaction unit and the first product reaction unit in the automated micro combinatorial chemical reaction unit; and

The optimized combination chemical synthesis method further comprising: an artificial intelligence unit controlling the raw material supply unit, the intermediate reaction unit, the intermediate reaction control unit, the first product reaction unit, and the temperature control unit.
According to claim 24,

Optimization combination, characterized in that the artificial intelligence unit derives an optimized value of the reaction volume of the intermediate reaction unit, the flow rate of the raw material, the reaction temperature of the intermediate reaction unit and the reaction temperature of the first product reaction unit using a Bayesian optimization algorithm chemical synthesis method.