JP2005144634A - Washing method for microchemical device and manufacturing method for optically-active epoxide using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To further quickly remove a sample adsorbed by a microchemical device such as a flow passage wall face by washing when reaction is executed by using the microchemical device, to realize quick and highly efficient reaction and analysis, and further, to make an expensive micro device usable for a long period of time. <P>SOLUTION: The washing method for a microchemical device is characterized in that the adsorbed sample is washed by introducing an oxidizer aqueous solution to the microchemical device after reaction. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a cleaning method for efficiently removing unnecessary substances such as samples remaining when performing analysis or synthesis reaction using a microchemical device and obtaining a stable result, and production of an optically active epoxide using the same. Regarding the method.

In recent years, researches using microchemical devices such as microreactors and microchips have been actively conducted in order to increase reaction efficiency, perform rapid and highly sensitive analysis, and perform many reactions and analyzes efficiently.
In addition, research aimed at producing pharmaceuticals and their intermediates with high efficiency by paralleling a large number of microchannels in a microchemical device has been conducted.

However, when a chemical reaction is performed using the microchemical device as described above, the reaction or sample adsorbs and remains in the reaction part, observation part, liquid feeding part, etc. of the microchemical device, resulting in poor reaction efficiency or rapid response. In addition, there is a problem that high-sensitivity analysis cannot be performed. In addition, the flow of the flow path becomes imbalanced due to the accumulation of adsorbate, making it difficult to control the fluid, making it difficult to give stable reaction results and analysis results, and the flow path is blocked by the adsorbate, making it impossible to use the device itself. Therefore, there has been a problem that it is necessary to periodically replace the microchemical device.
In addition, for the purpose of substance production, when the reaction solution is continuously passed through the microchemical device and reacted, the adsorbate is likely to deposit, and the above problem is likely to occur. In particular, in the homogeneous catalytic reaction, the catalyst is adsorbed and deposited. As a result, many problems such as loss of the catalyst to the outside of the reaction system, deactivation of the catalyst, and increase of side reactions due to excessive reaction of the catalyst may occur.

With respect to the above-mentioned problems, conventionally, the following techniques have been devised to modify the surface of the flow channel wall of the microchemical device so that reagents and the like are hardly adsorbed.
In Patent Document 1, the surface of a microchemical device is modified with a fluorine-based polymer such as a fluorine ether-based oligomer silane coupling agent and then used for NOx measurement. It is described that high sensitivity can be achieved.
However, this method is effective when using inexpensive microchemical devices in mild reaction conditions, but the surface treatment may deteriorate quickly depending on the reaction conditions and the solvent or reagent to be passed. Yes, it is not suitable for continuous use of expensive microchemical devices under severe reaction conditions.

  Non-Patent Document 1 discloses that a laminar flow of a protective liquid and a reaction liquid is formed by flowing a protective layer on the wall surface of a coaxial double tube type device at a high speed so that the reaction liquid does not contact the flow path wall surface. It describes that a fine powder of silver chloride is being produced. This device is very good in that the sample does not come into contact with the reactor wall surface, but it has the disadvantage that it is unsuitable for reactions that handle very small amounts because the device is large and requires a flow rate. .

As a method for removing the adsorbate as described above, a method using an organic solvent, an acid, an alkali, or the like as a cleaning agent can be considered, but there is a problem that its use is limited, for example, the cleaning power is weak or the device itself may be deteriorated. There is a point.
Cleaning using an oxidizing agent is effective for reactions that handle organic substances, and adsorbed organic substances are cleaned by oxidative decomposition.

In Patent Document 2, a dry etching gas, a resist, a film to be processed, and the like that cause high resistance of a semiconductor as a part of a semiconductor process are flowed at high speed on the surface of a processing object containing an oxidizing agent, a chelating agent, and a fluorine compound. However, it is not performed as part of the reaction or analysis using a microchemical device, nor is it passed through the flow path.
Further, the cleaning using such an oxidizing agent has a problem that the cleaning liquid is often toxic, corrosive or explosive and is difficult to use.

  Patent Document 3 describes an epoxidation reaction using a microchemical device. Although it is stated that various epoxidation reactions can be carried out safely and highly efficiently by using a microreactor, the case where raw materials are precipitated by mixing or the case where insoluble matter is generated by reaction is described. There is no mention of the cleaning method.

JP 2003-139761 A JP 2002-113431 A JP 2003-532646 A Hideharu Nagasawa and Kazuhiro Mae, Development of Multi-functional Microstructured Device for Inorganic Fine Particle Crystallization, 7Th International Conference on Microreaction Technology, IMRET, 2003/9 / 7-10, p127-129

  The present invention solves the above-mentioned problems in producing a substance efficiently by performing a reaction / analysis in a minute amount using a microchemical device such as a microchip or a microreactor or continuously flowing for a long time. Is an issue. That is, in the present invention, when the reaction is performed using the microchemical device, the sample adsorbed on the microchemical device such as the wall surface of the flow path is quickly removed, and a rapid and highly efficient reaction or analysis is realized. The problem is to make the microdevice usable for a long period of time.

As a result of diligent research to solve the above problems, the present inventor has found that the adsorbate can be efficiently removed with a small amount of cleaning agent by periodically cleaning the inside of the microchemical device with a strong oxidizing agent. It came to complete.
That is, the present invention

(1) A method for cleaning a microchemical device, characterized by passing an aqueous oxidant solution through the microchemical device after reaction,
(2) The cleaning method according to (1), wherein the microchemical device is a glass microchemical device,
(3) The cleaning method according to (1) or (2), wherein the glass microchemical device is quartz or Pyrex (registered trademark).
(4) The cleaning method according to any one of (1) to (3), wherein the oxidizing agent is fuming nitric acid,
(5) The oxidant aqueous solution is introduced by suction, and the suction part has means for capturing gas generated from the oxidant aqueous solution and / or the oxidant, according to any one of (1) to (4). Cleaning method,
(6) A reaction method using a microchemical device, wherein the cleaning method according to (1) to (5) is intermittently performed during the reaction step,
(7) The reaction method according to (6), wherein the reaction method is a homogeneous catalytic reaction,
(8) The method for producing an optically active epoxide characterized by performing an asymmetric epoxidation reaction on an olefin using a salen manganese complex as the homogeneous catalytic reaction according to (7),
(9) A microchemical device having a means for introducing an aqueous oxidant solution by suction and capturing the oxidant aqueous solution and / or gas generated from the oxidant in the suction part;
About.

  According to the present invention, a microchemical device can be efficiently washed, and analysis and production using it can be carried out continuously and stably.

  The method for cleaning a microchemical device of the present invention and the method for producing an optically active epoxide using the same will be described in detail.

  The cleaning method of the present invention is a cleaning method for a microchemical device, characterized in that an oxidizing agent aqueous solution is passed through the microchemical device after reaction.

  In the present invention, the microchemical device is “a three-dimensional structure used for performing a chemical reaction utilizing a microspace, which is produced on a solid substrate or the like by an appropriate process of microtechnology, and , A device having a function such as a microreactor, a heat exchanger, a mixer, a valve, a sensor, etc., which performs an operation such as a reaction in a flow path (microchannel) having an equivalent diameter of 500 μm or less.

  In the present invention, the microreactor is “a three-dimensional structure used to perform mixing including diffusion, or mixing and chemical reaction, and is created on a solid substrate by an appropriate process of microtechnology. And having an equivalent diameter of 500 μm or less ”.

  The material of the microchemical device used in the present invention is, for example, made of glass such as quartz glass, Pyrex (registered trademark), Vycor, Kovar, etc., made of metal such as stainless steel, hastelloy, titanium, or made of fluororesin such as PTFE or ETFE. Although it can be used, it is preferably a microchemical device made of glass, more preferably a microchemical device made of quartz or Pyrex (registered trademark).

  As the oxidizing agent used in the present invention, for example, fuming nitric acid, nitric acid, permanganic acid, dichromic acid, hydrogen peroxide, ozone, hypochlorous acid, persulfuric acid and the like can be used, preferably fuming nitric acid. is there. Moreover, you may use what mixed inorganic acids, such as a sulfuric acid. Further, those obtained by dissolving an inorganic salt in these oxidizing agents are preferred, and those obtained by dissolving a lithium salt and a sodium salt are particularly preferred. The density | concentration which uses an oxidizing agent as aqueous solution is 1-99% (W / W) normally, Preferably it is 70-99% (W / W).

  Moreover, in this invention, you may perform the washing | cleaning which lets water and an organic solvent flow similarly to a washing | cleaning liquid before and behind a washing | cleaning liquid. Water and an organic solvent may be mixed with each other and allowed to pass through. As the organic solvent to be used, an organic solvent known to those skilled in the art can be used. Further, a surfactant known to those skilled in the art as an additive may be dissolved in a cleaning solution that can be used before and after cleaning with an oxidizing agent. The surfactant is preferably an anionic surfactant, a cationic surfactant, a nonionic surfactant, or a zwitterionic surfactant, particularly preferably a fatty acid salt, an α-sulfo fatty acid ester salt, an alkylbenzene sulfonate, an alkyl sulfate. Salt, alkyl ether sulfate ester salt, alkyl sulfate triethanolamine, fatty acid diethanolamide, polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, alkyltrimethylammonium salt, dialkyldimethylammonium chloride, alkylpyridinium chloride, alkylcarboxybetaine . The concentration in the case of adding these is about 0.01 to 10% (W / W) with respect to the cleaning liquid used before and after the cleaning with the oxidizing agent.

  The interval of washing performed in the present invention is within one month, preferably within one week, particularly preferably within 30 minutes, when the reaction is carried out continuously.

  Reactions applicable to the reaction method of the present invention can be applied to all reactions that can be considered by those skilled in the art of synthesis and analysis using microchemical devices, but preferably those that are easily adsorbed on the constituent materials of microchemical devices are handled. It can be applied to pretreatment reactions for synthesis reactions and analyses, and reactions such that side reactions and reaction intermediates are low in solubility during the reaction and adhere to the wall surface as insoluble matter.

  In the present invention, the homogeneous catalytic reaction is one in which the catalyst used for the chemical reaction is solid or not fixed to the solid phase and is uniformly dissolved in the solvent in which the reaction is carried out. Applicable reactions include reactions using an inorganic metal catalyst, an organometallic catalyst, and an organic compound catalyst, preferably a reaction using an organometallic catalyst, and more preferably a reaction using a salen manganese complex.

  The salen manganese complex used in the production method of the present invention is a catalyst having a salen derivative and manganese in the structural formula known for epoxidation reaction, preferably optically active (R, R) -trans 1,2- Bis [(2-hydroxy-3,5-ditertiarybutylbenzylidene) amino] cyclohexane manganese dichloride or optically active (S, S) -trans 1,2-bis [(2-hydroxy-3,5-ditertiary Butylbenzylidene) amino] cyclohexane manganese dichloride (Jacobsen catalyst).

  Any olefin known to those skilled in the art can be used as the olefin used in the production method of the present invention. Preferred are aliphatic, aromatic and heterocyclic aromatic olefins, particularly preferably indene. Aliphatic olefins are linear, branched and cyclic olefins. Also preferred are those in which the olefin is an αβ unsaturated carbonyl compound.

  1, 2, and 3 are schematic configuration diagrams illustrating an example of an embodiment of a chemical reaction apparatus including a cleaning mechanism including an introduction pipe for cleaning liquid or the like for performing cleaning according to the present invention. FIG. 5 shows an example of a flow path pattern of a device having a mechanism for deactivating the cleaning liquid on the microdevice in order to remove adverse effects on the reaction and analysis by the cleaning liquid.

For example, as shown in FIGS. 1, 2, and 3, an example of a system for feeding a reaction solution and a cleaning solution and cleaning a microchemical device includes a microchemical device, a pump for supplying the reaction solution to the device, and a device A pump for supplying cleaning liquid to the tube, a tube connecting the pump and the device, a connector for connecting the tube to the device, a drain for discharging the reaction liquid, a storage tank for the reaction liquid and the cleaning liquid, and a storage tank for storing the mixed solution after the reaction Consists of abatement equipment.

  When performing the reaction using the apparatus shown in FIG. 1, FIG. 2, FIG. 3, the reaction solution is fed from the introduction tube using a pump, mixed and reacted at the mixing site, or reacted at the reaction site for a certain period of time. By intermittently introducing a cleaning solution instead of the reaction solution and cleaning the device every time, the reaction can be carried out under stable conditions, and a certain reaction yield and analysis result can be obtained.

  The cleaning liquid amount may be adjusted by using a metering pump or a quantitative injection valve. However, the cleaning liquid amount may be excessive, and may be adjusted by the valve opening / closing time.

  In addition, as shown in FIG. 4, the cleaning liquid can be toxic, corrosive, or explosive cleaning liquid by deactivating the cleaning liquid in the middle of using the device or by combining the suction port with a wet or dry detoxifying device. Both environment and human body can be handled safely.

  Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1
Asymmetric epoxidation reaction using a micro device Using an organic synthetic chip (KG-01) manufactured by IMT as a micro chemical device, an apparatus as shown in FIG. A sodium hypochlorite aqueous solution having a concentration 1.3 times that of indene is introduced from the inlet 1 at a rate of 10 μL / min. Similarly, the raw material and the catalyst from the inlet 2 are 1.25 mol / L of indene, 0.375 mmol / L of the salen manganese complex shown in FIG. 6, and 1.88 mmol / L of 4-phenylpyridine-N-oxide, respectively. The methylene chloride solution containing was introduced at a rate of 10 μL / min. Further, hexane was introduced as a diluted solution from the inlet 3 at a rate of 10 μL / min. The reaction mixture was introduced into the 1 mol / L sodium thiosulfate aqueous solution and hexane from the drain outlet while stirring vigorously to stop the reaction. After storing for 5 minutes, the conversion efficiency and optical purity were measured by the HPLC method using a reverse phase column and a chiral column. Furthermore, as a control experiment, the reaction was carried out without adding the salen manganese complex and 4-phenylpyridine-N-oxide using an organic synthetic chip that was passed for 60 minutes. The results are shown in Table 1. In addition, when the organic synthesis chip after use was washed by passing about 10 μL of fuming nitric acid by suction and then subjected to the same reaction using a microchip washed with 1 mL of water, it was the same as a new one. Results were obtained.

Table 1
Chip used Presence or absence of salen manganese complex Sampling time Optical purity
% Ee from the start of liquid flow
1 New 3 mol% 0-5 minutes 79.6
2 New 3mol% 30-35min 81.5
3 New 3 mol% 60-65 minutes 22.1
4 After washing 3 mol% 0-5 minutes 80.4

According to the present invention, when a reaction / analysis is performed in a minute amount using an expensive microchemical device, a large number of samples can be processed quickly without a decrease in reaction efficiency or contamination due to the sample adsorbed inside the device. Moreover, since it can be used many times, it has the advantage that the number of discarded chips can be reduced.
This is very useful in terms of work efficiency and waste reduction in the field of exploratory research such as high-throughput screening of pharmaceuticals and agricultural chemicals using microchemical devices, combinatorial chemistry, and high-speed catalyst optimization.
In addition, it enables highly efficient material production methods by continuously using micro chemical devices for a long time, reducing production energy, reducing environmental impact, reducing capital investment costs, reducing equipment maintenance costs, etc. This is very useful in the chemical industry.

It is a schematic block diagram which shows one Embodiment of the chemical reaction apparatus provided with the washing | cleaning mechanism which introduce | transduces a reaction liquid and a washing | cleaning liquid into a microchemical device, respectively by a high pressure liquid feeding method. It is a schematic block diagram which shows one Embodiment of the chemical reaction apparatus provided with the washing | cleaning mechanism which introduce | transduces a reaction liquid and a washing | cleaning liquid into a microchemical device, respectively by the pressure reduction liquid feeding method. It is a schematic block diagram which shows one Embodiment of the chemical reaction apparatus provided with the washing | cleaning mechanism which introduce | transduces a reaction liquid into a microchemical device by a high pressure liquid feeding method and a washing | cleaning liquid by a pressure reduction liquid feeding method. It is the schematic of an example of a microchemical device. It is the schematic of the apparatus structure used in experiment. It is an example of a salen manganese complex.

Explanation of symbols

R1 and R2 are reservoirs for the reaction solution, and P1 and P2 are pumps for feeding the reaction solution. R3 is a cleaning liquid reservoir. P3 is a pump for feeding the cleaning liquid. V is a valve for switching the flow path. C is a connector for connecting the tube and the device, and R4 is a storage tank for storing the reaction mixture after the reaction. MD is a microchemical device. A solid line connecting the devices is a tube for liquid feeding.

Claims (9)

A method for cleaning a microchemical device, comprising passing an aqueous oxidizing agent solution through the microchemical device after the reaction. The cleaning method according to claim 1, wherein the microchemical device is a glass microchemical device. The cleaning method according to claim 1 or 2, wherein the glass microchemical device is quartz or Pyrex (registered trademark). The cleaning method according to any one of claims 1 to 3, wherein the oxidizing agent is fuming nitric acid. The cleaning method according to any one of claims 1 to 4, wherein the oxidizing agent aqueous solution is introduced by suction, and the suction part has means for capturing the oxidizing agent aqueous solution and / or gas generated from the oxidizing agent. 6. A reaction method using a microchemical device, wherein the cleaning method according to claim 1 is carried out intermittently during the reaction step. The reaction method according to claim 6, wherein the reaction method is a homogeneous catalytic reaction. The method for producing an optically active epoxide, wherein the homogeneous catalytic reaction according to claim 7 is carried out by performing an asymmetric epoxidation reaction on an olefin using a salen manganese complex. A microchemical device having a means for introducing an aqueous oxidant solution by suction and capturing the oxidant aqueous solution and / or gas generated from the oxidant in the suction part.

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