JP5216954B2 - Method for producing diarylethene compound - Google Patents

Description

  The present invention relates to a method for producing a diarylethene compound and a diarylethene compound obtained by the production method, and more particularly to a method for producing a diarylethene compound suitable as a functional dye having photochromism, and a diarylethene compound obtained by the production method.

A diarylethene compound is known as a compound having a photochromic reaction characteristic in which a chemical bond state is changed without changing the molecular weight by light irradiation, and two isomers having an absorption spectrum and a refractive index are reversibly generated.
An essential structure for a diarylethene compound to exhibit a photochromism that causes a reversible change in the absorption spectrum of the compound by radiation at a given light wavelength is a hexatriene skeleton, and the formation of the hexatriene skeleton is This is achieved by introducing two aryl groups to the olefinic moiety of octafluorocyclopentene. The introduction of the aryl group is performed by a cross-coupling reaction using aryl lithium (lithium compound), and the aryl lithium (lithium compound) is usually prepared by a halogen-lithium exchange reaction between an aryl halide and an organolithium reagent. (For example, refer to Patent Documents 1 to 3).

Since the organolithium reagent has high reactivity and a wide range of substrate application, the halogen-lithium exchange reaction is highly useful as a synthesis scheme on a laboratory scale such as sample synthesis. However, since the generated lithium compound has high reactivity and low thermal stability, it must be cooled to reduce the reaction rate, or it can be brought into a crystalline state to reduce the reactivity to suppress side reactions.
In addition, since the halogen-lithium exchange reaction and the cross-coupling reaction with octafluorocyclopentene using the lithium compound generated by the halogen-lithium exchange reaction are both exothermic reactions, the diarylethene compound is generally produced in a batch system. When manufacturing, it carries out by the semibatch type process of dripping another raw material little by little, cooling one raw material from -70 degreeC to -100 degreeC. In this case, when dripping the raw material, a long dripping time is required to remove the heat of reaction, and the side reaction occurs due to the deterioration of the lithium compound and the occurrence of local heat storage during the dripping. There are problems such as a decrease in rate.

Furthermore, when manufacturing a diarylethene compound on an industrial scale, a cooling low-temperature reaction production plant for performing a reaction in a low temperature range of −70 to −100 ° C. has equipment construction costs and maintenance costs as compared with a general-purpose production plant. In addition to the problem of high, local heat storage caused by dripping the raw material for a long time, localization of the raw material concentration during the dropping reaction, different liquid composition changes due to the dropping progress, etc. There are problems such as fluctuations in reaction yield due to changes.
In addition, when producing a large amount of diarylethene compounds on an industrial scale, the use of a large amount of the lithium compound, which is a water-inhibiting dangerous material, as a raw material, there is a risk of uncontrollable reaction runaway, etc. There is also a large risk (see Non-Patent Document 1, for example).

As a method for solving the above-mentioned safety risks, a continuous production method using a flow reaction apparatus has been proposed (see, for example, Patent Documents 4 and 5).
Since the flow reactor has a small volume in the reactor, the concentration distribution and temperature distribution of the raw materials in the reactor can be made uniform. Further, since the lithium compound having low thermal stability is continuously moved to the next step without storing a large amount, the risk of thermal decomposition of the intermediate is reduced.
Patent Document 4 mentions a production method using a continuous reaction apparatus, and it seems that the merit of this method is great. However, since a static mixer is used as a stirrer, the heat removal capability is not sufficient. There's a problem. The existing static mixer is the smallest and has a large pipe inner diameter of about 1/4 inch. Therefore, it is necessary to take measures to avoid thermal decomposition of the lithium compound by reaction heat. It is necessary to carry out under low temperature conditions such as −50 ° C. and −35 ° C. Therefore, a special cooling device is required.

  On the other hand, recently, in the field of chemical synthesis, chemical reactions using a micro container called a microreactor or a micromixer have been studied (for example, see Non-Patent Documents 2 and 3). In the reaction using a microreactor, it is thought that accurate flow control of reaction solution, temperature control, and rapid mixing are possible. Improvement is expected, and it is attracting attention as a highly efficient production method. The German IMM and FZK laboratories are developing microreactors for mixing, heat exchange, catalytic reactions, and electrochemical reactions, and are proposing the construction of mini-plants using these reactor components.

As described above, in the production of the diarylethene compound by the batch method, the lithium compound is a dangerous substance, a cooling device is necessary to realize a low temperature environment during the reaction, and further, the electrophilic compound octafluorocyclopentene. Has a problem that it is difficult to handle, such as loss due to volatilization due to low boiling point, and water mixing as a result of condensation due to cooling.
Therefore, by using a novel technique for synthesizing the diarylethene compound with high efficiency, for example, a method using the microreactor, the diarylethene compound can be produced safely and efficiently at a high yield without using a special cooling device. Although there is a demand for a method that can produce the above, no satisfactory method has yet been provided.

JP-A-3-135777 Japanese Patent Laid-Open No. 3-261762 JP-A-3-261788 JP 2000-229981 A JP 2000-239282 A “The Journal of Medicinal Chemistry”, vol. 42, 1999, p. 1088-1099 “Chimia”, 2002, volume 56, p. 636 “Tetrahedron”, vol. 58, p. 4735-4757

An object of the present invention is to solve the conventional problems and achieve the following objects.
That is, an object of the present invention is to provide a method capable of producing a diarylethene compound safely and efficiently in a high yield without using a special cooling device or the like, and a diarylethene compound produced by the method. .

  As a result of intensive studies by the present inventors in order to solve the above problems, the following knowledge has been obtained. That is, when producing a diarylethene compound by reacting a lithium compound and an alkene compound, using a microreactor, optimizing the reaction time (retention time) and the reaction temperature, without using a special cooling device, A diarylethene compound can be produced efficiently and in high yield under relatively mild cooling conditions of −10 to 10 ° C., in particular, by using a continuous reaction apparatus connected with a plurality of microreactors, synthesis of a lithium compound, and This is a finding that a diarylethene compound can be produced very efficiently and in a high yield by continuously performing the reaction between the lithium compound and the alkene compound.

This invention is based on the said knowledge by the present inventors, and the means for solving the said subject are as follows. That is,
<1> A lithium compound solution and an alkene compound solution,
Introducing into a microreactor with a flow path that can mix multiple liquids,
A method for producing a diarylethene compound, wherein the lithium compound and the alkene compound are subjected to a cross-coupling reaction in the microreactor. In the method for producing a diarylethene compound according to <1>, the lithium compound solution and the alkene compound solution are introduced into a microreactor having a flow channel capable of mixing a plurality of liquids, and the Since the lithium compound and the alkene compound are subjected to a cross-coupling reaction, the reaction time (residence time) and the reaction temperature can be optimized, and as a result, the diarylethene compound can be efficiently produced at a high yield. .
<2> The lithium compound is represented by the following structural formula (I) obtained by introducing a halogen compound solution and an organolithium reagent solution into a microreactor and reacting the halogen compound and the organolithium reagent in the microreactor. It is a manufacturing method of the diarylethene compound as described in said <1> which is a compound made.
However, in the structural formula (I), the ring represented by A represents an aromatic ring, a saturated ring, a partially saturated ring, or a heterocyclic ring.
<3> Performed using a continuous reaction apparatus in which a first microreactor and a second microreactor are connected,
A lithium compound is synthesized in the first microreactor;
The method for producing a diarylethene compound according to any one of <1> to <2>, wherein a cross-coupling reaction between the lithium compound and the alkene compound is performed in the second microreactor. In the method for producing a diarylethene compound according to <3>, the process is performed using the continuous reaction apparatus in which the first microreactor and the second microreactor are connected, and the lithium compound is Since the cross-coupling reaction between the lithium compound and the alkene compound is performed in the second microreactor, the lithium compound, which is a water-inhibiting hazardous substance, can be handled in a closed system. As a result, safety is ensured, and even when the lithium compound is unstable, by continuously reacting with the alkene compound, loss can be suppressed, and the diarylethene compound can be produced extremely efficiently and in a high yield. Can be manufactured.
<4> Performed using a continuous reaction apparatus to which the first to fourth microreactors are connected,
A first lithium compound is synthesized in a first microreactor;
A cross-coupling reaction between the first lithium compound and the alkene compound is performed in a second microreactor;
A second lithium compound is synthesized in a third microreactor;
The diarylethene compound according to any one of <1> to <2>, wherein a cross-coupling reaction between the second lithium compound and the compound synthesized in the second microreactor is performed in a fourth microreactor. It is a manufacturing method. In the method for producing a diarylethene compound according to <4>, the diarylethene compound is produced by using the continuous reaction apparatus to which the first to fourth microreactors are connected, and the lithium compound is contained in the first and third microreactors. Since the cross-coupling reaction between the lithium compound and the alkene compound is performed in the second and fourth microreactors, which are synthesized in a reactor, the lithium compound that is a water-inhibiting hazardous material is handled in a closed system. Therefore, even when the lithium compound is unstable, the reaction with the alkene compound continuously prevents the loss, and the diarylethene compound can be produced extremely efficiently and at a high yield. Can be manufactured.

<5> The method for producing a diarylethene compound according to any one of <1> to <4>, which is performed within a temperature range of −20 to 20 ° C.
<6> The method for producing a diarylethene compound according to any one of <1> to <5>, wherein the microreactor is installed in a thermostat adjusted to -20 to 20 ° C.
<7> Any of <3> to <6>, wherein the residence time in the first microreactor is 0.0005 seconds to 40 seconds and the residence time in the second microreactor is 0.001 seconds to 10 minutes. A process for producing the diarylethene compound according to claim 1.

<8> The method for producing a diarylethene compound according to any one of <2> to <7>, wherein the organolithium reagent is any one of alkyllithium, alkenyllithium, and alkynyllithium.
<9> The method for producing a diarylethene compound according to any one of <2> to <8>, wherein the organolithium reagent is n-butyllithium.
<10> The method for producing a diarylethene compound according to any one of <2> to <9>, wherein the halogen compound is any one of a chlorine compound, a bromine compound, and an iodine compound.
<11> The halogen compound is bromobenzene, iodobenzene, 4-bromotoluene, 4-bromoanisole, 4-bromo-dimethylaniline, 1,4-dibromobenzene, 2-bromothiophene, 3-bromothiophene, 3-bromo. Any one of <2> to <10>, which is any one of 2-methyl-5-phenylthiophene, 4-bromo-5-methyl-2-phenylthiazole, and 3-bromo-2-methylbenzothiophene It is a manufacturing method of the described diarylethene compound.

<12> The method for producing a diarylethene compound according to any one of <1> to <11>, wherein the alkene compound is a cycloalkene compound represented by the following structural formula (II).
However, in said structural formula (II), n represents the integer of 2-5, X represents either hydrogen, chlorine, and a fluorine, and Y represents a halogen atom.
<13> The method for producing a diarylethene compound according to any one of <1> to <12>, wherein the alkene compound is octafluorocyclopentene.

<14> A diarylethene compound produced by the method for producing a diarylethene compound according to any one of <1> to <13>.
<15> The diarylethene compound according to <14>, which is represented by the following structural formula (III).
However, in said structural formula (III), n represents the integer of 2-5, X represents either hydrogen, chlorine, and fluorine, The ring represented by A and A 'is an aromatic ring, It represents any of a saturated ring, a partially saturated ring, and a heterocyclic ring, and A and A ′ may be the same as or different from each other.

<16> The diarylethene compound according to any one of <14> to <15> represented by the following structural formula (1).
However, in the structural formula (1), Me represents a methyl group.
<17> The diarylethene compound according to any one of <14> to <15>, which is represented by the following structural formula (2).
However, in the structural formula (2), Me represents a methyl group.
<18> The diarylethene compound according to any one of <14> to <15>, which is represented by the following structural formula (3).
However, in the structural formula (3), Me represents a methyl group.
<19> The diarylethene compound according to any one of <14> to <15>, which is represented by the following structural formula (4).
However, in said structural formula (4), Me represents a methyl group and Ph represents a phenyl group.
<20> The diarylethene compound according to any one of <14> to <19>, which has photochromic properties.

  According to the present invention, the conventional problems can be solved, and a diarylethene compound can be produced safely and efficiently in a high yield without using a special cooling device, and the diarylethene produced by the method. A compound can be provided.

FIG. 1 is an example of a conceptual diagram showing a reaction flow in the method for producing a diarylethene compound of the present invention. FIG. 2 is an explanatory diagram showing each reaction condition in the method for producing a diarylethene compound of Examples 1 to 23. FIG. 3 is an explanatory diagram showing the reaction of the method for producing diarylethene compounds of Examples 24 to 40. FIG. 4 is an explanatory diagram showing each reaction condition in the method for producing diarylethene compounds of Examples 24 to 40. FIG. 5 shows the spectra of the diarylethene compound synthesized in Example 1 before and after irradiation with ultraviolet light. 6 is a spectrum of the diarylethene compound synthesized in Example 31 before and after ultraviolet irradiation. FIG. 7 is an example of a conceptual diagram showing a reaction flow in the method for producing an asymmetric diarylethene compound of the present invention. FIG. 8 is an explanatory view showing each reaction condition in the method for producing an asymmetric diarylethene compound of Example 33. FIG. 9 is an explanatory diagram showing each reaction condition in the method for producing a diarylethene compound of Comparative Examples 3 to 6 (macroflow system).

(Method for producing diarylethene compound)
In the method for producing a diarylethene compound of the present invention, a lithium compound solution and an alkene compound solution are introduced into a microreactor having a flow channel capable of mixing a plurality of liquids, and the lithium compound and the alkene are contained in the microreactor. This is a method of cross-coupling reaction with a compound.

  The lithium compound is also preferably synthesized in a microreactor. The lithium compound is a halogen compound solution and an organolithium reagent solution introduced into the microreactor, and the halogen compound and the organolithium reagent in the microreactor. It is preferable that it is a compound represented by following structural formula (I) obtained by making this react.

However, in the structural formula (I), the ring represented by A represents an aromatic ring, a saturated ring, a partially saturated ring, or a heterocyclic ring.

The method for producing the diarylethene compound is carried out, for example, using a continuous reaction apparatus in which a first microreactor and a second microreactor are connected,
A lithium compound is synthesized in the first microreactor;
It is preferable that the cross-coupling reaction between the lithium compound and the alkene compound is performed in the second microreactor.

In addition, the said lithium compound may be single 1 type, or 2 types may be sufficient as it. By using two lithium compounds, an asymmetric diarylethene compound can be obtained.
The method for producing the asymmetric diarylethene compound is carried out, for example, using a continuous reaction apparatus to which first to fourth microreactors are connected,
A first lithium compound is synthesized in a first microreactor;
A cross-coupling reaction between the first lithium compound and the alkene compound is performed in a second microreactor;
A second lithium compound is synthesized in a third microreactor;
It is preferable that a cross-coupling reaction between the second lithium compound and the compound synthesized in the second microreactor is performed in the fourth microreactor.

The microreactor (microflow reactor) is a micro flow reactor including a liquid introduction path, a mixing unit (micromixer) capable of mixing a plurality of liquids, and a reaction unit connected to the mixing unit, The minimum diameter of the cross section of the flow path of the part and the reaction part is typically from several μm to several thousand μm. A plurality of liquids (a raw material compound solution or a liquid raw material compound) supplied through the liquid introduction path of the microreactor are mixed together in the mixing unit, and a reaction occurs in the reaction unit.
Here, the mixture of the plurality of liquids is referred to as the micromixer, and the one used for mixing involving a chemical reaction is sometimes referred to as a microreactor. The micromixer constitutes the microreactor together with the reaction unit. And included in the microreactor.

  The lithium compound and alkene compound used in the method for producing the diarylethene compound of the present invention, and the halogen compound and organolithium reagent (hereinafter sometimes referred to as “raw compound”) used in the synthesis of the lithium compound are liquids in the microreactor. Need to be supplied as. For this reason, when the raw material compound is not liquid, it is necessary to prepare a raw material compound solution using a solvent and supply it to the microreactor.

There is no restriction | limiting in particular as a solvent used in order to prepare the said raw material compound solution, Although it can select suitably according to the objective, For example, the solvent etc. which are used by a well-known halogen-metal exchange reaction are mentioned. .
The solvent used in the halogen-metal exchange reaction may be any of a polar solvent and a nonpolar solvent. Specifically, benzene, toluene, xylene, mesitylene, durene, ethylbenzene, diethylbenzene, isopropylbenzene, Aromatic hydrocarbon compounds such as diisopropylbenzene, diphenylmethane, chlorobenzene, 1,2-dichlorobenzene, 1,2,4-trichlorobenzene; pyridine, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N -Polar solvents such as methylpyrrolidone; acetates such as methyl acetate, ethyl acetate, butyl acetate; alkanes such as n-pentane, n-hexane, n-heptane, cyclohexane, and perfluoroalkanes; dimethyl ether, diethyl ether Le, dibutyl ether, dimethoxyethane, petroleum ether, tetrahydrofuran, dioxane, ethers such as cyclopentyl methyl ether; methylene chloride, halogenated alkanes dichloroethane and the like.
Among these, tetrahydrofuran, diethyl ether, dibutyl ether, cyclopentyl methyl ether, dimethoxyethane, toluene, and xylene are preferred, tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, dimethoxyethane, dibutyl ether, toluene, and xylene are more preferred, tetrahydrofuran , Diethyl ether and cyclopentyl methyl ether are particularly preferred.

  The said solvent can be used individually or in mixture of 2 or more types, The mixing ratio in the case of mixing use can be defined arbitrarily. The solvent is used in an amount of 1 to 15,000 mL, preferably 150 to 8,000 mL, more preferably 300 to 4,000 mL, and particularly preferably 600 to 2,000 mL with respect to 1 mol of the raw material compound.

A chelating agent such as a tertiary amine can be added to activate the organolithium reagent and the lithium compound.
The amount of the chelating agent added is preferably 0.01 to 10 mol, more preferably 0.1 to 2 mol, and 0.9 to 1.1 mol, relative to 1 mol of the organolithium reagent and the lithium compound. Is particularly preferred.

<Microreactor>
The microreactor used in the method for producing a diarylethene compound of the present invention is not particularly limited as long as it is a micro container equipped with a flow channel (the mixing unit) capable of mixing a plurality of liquids, and is appropriately selected according to the purpose. It may be a commercially available product or a product that has been newly designed and manufactured for the intended reaction.
A plurality of the microreactors may be connected to each other, or an integrated device incorporating a plurality of the microreactors may be used. In these cases, a multistage reaction can be performed.
Examples of the microreactor include a static micromixer represented by a small flow reactor, a mixer having a fine flow path for mixing, as described in WO 96/30113 ( This is a reaction device for conducting the reaction in a steady state using a "static micromixer", "" Microreactors "Chapter 3, W. Ehrfeld, V. Hessel, H. Lowe, published by Wiley-VCH. And a mixer (mixer) described in the above.

  Examples of the commercially available microreactor include a microreactor having an interdigital channel structure, a single mixer and a caterpillar mixer manufactured by Institute Hugh Microtechnique Mainz (IMM), a microglass reactor manufactured by Microglass, and a CPC system. Cytos manufactured by Susu; YM-1 type mixer, YM-2 type mixer manufactured by Yamatake Corporation; Mixing tee and tee (T-shaped connector) manufactured by Shimadzu GLC; IMT chip reactor manufactured by Micro Chemical Engineering Co., Ltd .; -Mixer; Swagelok union tea etc. are mentioned.

The mixing of the raw material compound solution in the microreactor proceeds by molecular diffusion, and since the scale in the flow path is small, the raw material compound solutions become a laminar flow dominant flow and diffuse in a direction perpendicular to the flow. Mixed.
In order to promote the reaction of the raw material compound in the microreactor, vibration energy or the like may be added from the outside.
The raw material compound solution may be mixed by turbulent flow or laminar flow. The flow velocity, the flow velocity and the shape of the reactor (the three-dimensional shape of the wetted part, the shape of the flow path, etc., the wall surface) Depending on the relationship of roughness, etc., it can be changed from static mixing (laminar flow) to dynamic mixing (turbulent flow). The turbulent mixing has better mixing efficiency and faster mixing speed than laminar mixing, but is inferior to laminar mixing in reaction control and exothermic heat removal.

The continuous reaction apparatus used in the embodiment in which the lithium compound is synthesized in the first microreactor and the cross-coupling reaction between the lithium compound and the alkene compound is performed in the second microreactor, The first microreactor and the second microreactor are not particularly limited as long as the first microreactor and the second microreactor are connected in series, and can be appropriately selected according to the purpose. For example, a series two-stage microreactor And a device constructed by connecting two microreactors called a so-called micromixer / tube reactor or mixer-and-loop reactor in series.
In the continuous reaction apparatus, the halogen compound and the organolithium reagent start mixing in the first microreactor and react while mixing on the way to the second microreactor, and then the second microreactor. The reaction is performed while being mixed with the alkene compound in a microreactor and mixing in a reaction part (for example, in a tube) connected to the outlet of the second microreactor.

  Further, the structure of one microreactor may have a plurality of mixer structures for mixing and a plurality of flow channel structures for adjusting reaction time. Such a microreactor has a structure optimized so as to increase the yield of the product obtained according to the reactivity of the raw material compound, and further has a mixing section (micrometer) having an optimized size. A microreactor having a mixer) and a reaction part (for example, a tube) is preferred. By using the microreactor having the optimized structure, the raw material compound solution can be quickly mixed, the flow can be controlled, the reaction temperature can be precisely controlled, and the residence time can be precisely controlled. Since it is stabilized, a stable manufacturing process can be realized.

The microreactor is a micro container having a flow channel capable of mixing a plurality of liquids, and the flow channel is a simple T-shaped flow channel tee where two introduction channels (substreams) merge. However, sufficient mixing and reaction performance can be obtained by utilizing the contraction effect and the flow turbulence at a high flow rate.
Inside the structure of the microreactor, the reaction is started by mixing the raw material compound solution, and at the same time, heat is generated by the reaction.

  If the minimum diameter of the microreactor channel cross section is small, the molecular diffusion distance in the cross-sectional direction is small, mass transfer takes place in a short time, high-speed mixing is possible, and the time during which the liquid stays inside the microreactor (retention) Time) distribution can be reduced, and heat transfer through the flow path wall can be performed at high speed. However, if the minimum diameter is too small, the pressure loss when the solution flows is increased, so there is a problem that the liquid flow rate is limited, a higher pressure pump is required, and the device cost is increased. May occur. For this reason, it is preferable that the minimum diameter of the flow path cross section of the microreactor is appropriately set according to the purpose.

The diameter of the flow path of the microreactor that performs the reaction by mixing the two introduction paths (substreams) is particularly preferably 0.8 to 2.3 mm.
As the cross-sectional area of the flow path, a 100μm ² ~16mm ^2, preferably 1,000μm ² ~4.0mm ^2, more preferably 10,000μm ² ~2.1mm ^2, 190,000μm ² ~1mm ² is particularly preferred.
If the minimum diameter of the flow path is larger than 5 mm, for example, it corresponds to a so-called conventional kenic type static mixer, and sufficient mixing performance cannot be obtained in the mixing reaction. Since the heat removal capability is insufficient, it is distinguished from the micromixer used in the method for producing a diarylethene compound of the present invention.

The shape of the channel cross section of the microreactor is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include a circle, a rectangle, a semicircle, and a triangle.
The length, shape, etc. in the flow direction of the reaction part of the microreactor are not particularly limited and can be appropriately selected according to the type of reaction, reaction time, and the like.

The microreactor (micromixer) is preferably manufactured by a fine processing technique.
The fine processing technique is not particularly limited and can be appropriately selected depending on the purpose. For example, (a) LIGA technique combining X-ray lithography and electroplating, (b) high aspect ratio using EPON SU8 Specific photolithography method, (c) Mechanical micro cutting (micro drilling that rotates high-speed drill with micro-order drill diameter), (d) High aspect ratio processing method of silicon by Deep RIE, (e) Hot Emboss Examples thereof include a processing method, (f) stereolithography, (g) laser processing, and (e) ion beam method.

  The material of the microreactor can be appropriately selected according to demands such as heat resistance, pressure resistance, solvent resistance, and processability. For example, stainless steel, titanium, copper, nickel, aluminum, silicon , And fluororesins such as Teflon (registered trademark) and PFA (perfluoroalkoxy resin), TFAA (trifluoroacetamide), and the like.

The tube connected to the rear part of the microreactor has functions of diffusion mixing of the raw material compound solution, mixing reaction, and heat removal from the reaction heat.
The smaller the inner diameter of the tube, the shorter the molecular diffusion distance, the higher the reaction rate, and the reaction time can be shortened to improve the efficiency. In addition, the smaller the tube inner diameter, the greater the heat exchange capability, which is effective for use in reactions involving a large exotherm. However, if the tube inner diameter is too small, the pressure loss when flowing the raw material compound solution increases, and a pump with a special high pressure resistance is required as a pump used for liquid feeding, resulting in an increase in manufacturing cost and equipment cost. There is. In addition, the structure of the micromixer may be limited by limiting the flow rate of the liquid.
Therefore, the inner diameter of the tube is usually 50 μm to 4 mm, preferably 100 μm to 3 mm, more preferably 250 μm to 2 mm, and particularly preferably 500 μm to 1 mm.
Moreover, the said tube length does not have a restriction | limiting in particular, Although it adjusts suitably according to optimal reaction time, 0.1-3 m is preferable and 1-2 m is more preferable.

The flow rate (liquid feeding speed) of the raw material compound solution fed to the microreactor is the mixing method, structure, type of reaction, temperature, minimum diameter of the channel, cross-sectional shape, length, etc. in the microreactor. Is appropriately selected.
For example, as a commercially available product of the microreactor, when the reaction is performed using a Swagelok union tee (inner diameter: 2.3 mm) and a tube having an inner diameter of 0.8 mm connected thereto, the flow rate (liquid feeding speed) Is usually 10 μL / min to 100 mL / min, preferably 0.1 mL / min to 50 mL / min, more preferably 0.5 mL / min to 20 mL / min, and particularly preferably 1 mL / min to 10 mL / min. . When a plurality of microreactors are used, the flow rate of the raw material compound solution supplied to each microreactor may be the same or different.

  The pump used for feeding the raw material compound solution is not particularly limited and may be appropriately selected from those that can be used industrially. However, pumps that do not cause pulsation during feeding are preferable. A jar pump, a gear pump, a rotary pump, a diaphragm pump, etc. are mentioned.

-Reaction temperature-
The temperature range of the cross-coupling reaction between the lithium compound and the alkene compound in the method for producing a diarylethene compound of the present invention may be a range in which the lithium compound is not decomposed, and is preferably in the range of −20 to 20 ° C., − The range of 10-10 degreeC is more preferable.
The temperature range of the halogen-lithium exchange reaction between the halogen compound for synthesizing the lithium compound and the organic lithium reagent is preferably in the range of -20 to 20 ° C, more preferably in the range of -10 to 10 ° C.

The reaction temperature is determined by a method of adding a heat exchanger to the microreactor, a method of installing the entire microreactor or a part of the microreactor in a thermostat, and a heating medium ( For example, the microreactor is installed in a thermostatic chamber adjusted to -20 to 20 ° C. The method is preferred. As the thermostatic bath, the heat medium is preferably a liquid, and a liquid-phase thermostatic cooling water bath is preferable.
Conventional batch production methods and production methods of diarylethene compounds using macro-sized static mixers require ultra-low temperature cooling equipment, and technical barriers are high for mass production, making industrial use difficult. It was. However, according to the method for producing a diarylethene compound of the present invention, it can be produced with equipment using a general-purpose thermostat, etc., and equipment costs can be reduced, power consumption used for cooling can be suppressed, and production costs can be reduced. .

-Reaction time (residence time)-
In the method for producing a diarylethene compound of the present invention, the reaction time means that the raw material compound solution is supplied into the microreactor and mixed in the mixing unit (micromixer) and then connected to the rear part of the micromixer. It is represented by the residence time until it is discharged from the end of the tube through the reaction part (for example, a tube).
In the aspect in which the lithium compound is synthesized in the first microreactor and the cross-coupling reaction between the lithium compound and the alkene compound is performed in the second microreactor, the reaction time (residence time) ) Is the residence time (first reaction section) until the halogen compound solution and the organolithium reagent solution are mixed in the first microreactor and the lithium compound is mixed with the alkene compound in the second microreactor. In the second micromixer, the mixing of the lithium compound and the alkene compound starts and passes through the tube connected to the back of the micromixer and is discharged from the end portion (the second reaction section). expressed.

The reaction time can be adjusted by the amount of the raw material compound solution supplied to the microreactor, but in the reaction using the microreactor, an appropriate flow rate range of the supplied liquid is often set. Therefore, the reaction time is preferably adjusted by changing the length of the microreactor and the equivalent diameter of the flow path.
The appropriate residence time in the microreactor varies depending on parameters such as the reactivity of the raw material compound, the concentration of the raw material compound solution, the reaction temperature, and the stability of the lithium compound, so these parameters are optimized. By doing so, it is preferable to optimize the manufacturing conditions.

  As the reaction time, in the aspect in which the lithium compound is synthesized in the first microreactor, and the cross-coupling reaction between the lithium compound and the alkene compound is performed in the second microreactor, for example, It is preferable that the residence time in the first microreactor is 0.0005 to 40 seconds, and the residence time in the second microreactor is 0.001 seconds to 10 minutes.

The residence time in the first microreactor is a reaction in which the halogen-lithium exchange reaction between the halogen compound and the organolithium reagent is extremely fast, and the resulting lithium compound has low thermal stability at high temperatures, so the residence time is Optimized for a short time, 0.001 to 20 seconds is more preferable, 0.05 to 10 seconds is particularly preferable, and 0.1 to 5 seconds is most preferable.
The residence time in the second microreactor is such that the reaction rate between the lithium compound and the alkene compound is slower than the halogen-lithium exchange reaction in the first microreactor, but the thermal stability of the lithium compound is low. The residence time is optimized for a time equivalent to or slightly longer than the halogen-lithium exchange reaction, more preferably 0.005 seconds to 5 minutes, particularly preferably 0.01 seconds to 1 minute, and most preferably 0.1 seconds to 30 seconds. preferable.
Furthermore, the necessary residence time as a whole is represented by the sum of the residence times, more preferably 0.002 seconds to 10 minutes, particularly preferably 0.005 seconds to 5 minutes, and most preferably 0.01 seconds to 1 minute. preferable.

<Lithium compound>
Examples of the lithium compound include a method of treating ether or thioether with metal lithium or a lithium salt of a radical anion, an organic halogen-lithium exchange reaction, an organic lithium-organic metal exchange reaction, an organic lithium-hydrogen exchange reaction (metalation). Among them, a compound synthesized by a halogen-lithium exchange reaction or the like can be mentioned. Among these, an organic halogen-lithium exchange reaction is preferable from the viewpoint of excellent yield and selectivity.

  The lithium compound is prepared by introducing the halogen compound solution and the organolithium reagent solution into the microreactor, and reacting the halogen compound and the organolithium reagent in the microreactor (halogen-lithium exchange reaction). For example, the lithium compound synthesized in the first microreactor is continuously subjected to a cross-coupling reaction with the alkene compound in the second microreactor. Is preferred.

In addition, in the aspect made to react continuously, even if the said halogen-lithium exchange reaction has not reached | attained, you may use for reaction with the following alkene compound. In the state where the alkene compound coexists, the organolithium reagent becomes a competitive reaction between the halogen compound and the alkene compound, but if the by-product generated by the reaction with the alkene compound is a small amount, Separable in the process.
Since it is difficult to determine the exact end point of the halogen-lithium exchange reaction, the residence time required for the halogen-lithium exchange reaction in the first microreactor depends on the final yield of the diarylethene compound. Can be evaluated and adjusted.

-Halogen compounds-
Examples of the halogen compound include a chlorine compound, a bromine compound, and an iodine compound. Among these, from the viewpoint of reactivity, a bromine compound and an iodine compound are preferable. Examples of the bromine compound and the iodine compound include: The following compounds are mentioned.

  Among these, 3-bromo-2-methyl-5-phenylthiophene, 4-bromo-5-methyl-2-phenylthiazole, and 3-bromo-2-methylbenzothiophene are more preferable.

-Organic lithium reagent-
The organolithium reagent is not particularly limited and can be appropriately selected from conventionally known organolithium compounds. For example, methyllithium, ethyllithium, propyllithium, butyllithium, pentyllithium, hexyllithium, methoxymethyllithium, Alkyl lithium such as ethoxymethyl lithium; alkenyl lithium such as vinyl lithium, allyl lithium, propenyl lithium, butenyl lithium; alkynyl lithium such as ethynyl lithium, butynyl lithium, pentynyl lithium, hexynyl lithium; benzyl lithium, phenylethyl lithium Aralkyl lithium such as phenyl lithium, aryl lithium such as naphthyl lithium; heterocycle such as 2-thienyl lithium, 4-pyridyl lithium and 2-quinolyl lithium Lithium; tri (n- butyl) magnesium lithium, alkyl lithium magnesium complex such as trimethyl magnesium lithium.
Among these, methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, s-butyl lithium, iso-butyl lithium, t-butyl lithium, n-hexyl lithium, n-octyl lithium, n-decyl lithium, vinyl lithium Allyl lithium, methoxymethyl lithium, benzyl lithium, phenyl lithium, 2-thienyl lithium and tri (n-butyl) magnesium lithium are preferable, and n-butyl lithium is more preferable.

  The amount of the organolithium reagent used can be appropriately selected according to the type of the halogen compound, but is usually 0.01 to 20 mol per mol of the halogen compound, and 0.1 to 2. 0 mol is preferable, 0.5 to 1.3 mol is more preferable, and 0.95 to 1.05 mol is particularly preferable.

The lithium compound is preferably a compound represented by the following structural formula (I).
However, in the structural formula (I), the ring represented by A represents an aromatic ring, a saturated ring, a partially saturated ring, or a heterocyclic ring.

  In the lithium compound represented by the structural formula (I), examples of the ring represented by A include monocyclic or polycyclic 6 to 10 membered aromatic rings such as benzene, naphthalene, anthracene, and phenanthrene; Monocyclic or polycyclic 3- to 10-membered partially saturated rings such as cyclopentene, cyclohexene, cyclooctene, and indane; thiophene, furan, pyran, pyridine, pyrrole, pyrazine, azepine, azocine, azonin, azecine, oxazole, thiazole , Pyrimidine, pyridazine, triazine, triazole, tetrazole, imidazole, pyrazole, quinoline, isoquinoline, indole, isoindole, quinoxaline, phthalazine, quinolidine, quinazoline, quinoxaline, naphthyridine, chromene, benzofuran, benzothiophene, etc. 5-10 membered monocyclic or polycyclic nitrogen heteroaromatic ring can be cited containing 1 to 4 atoms selected from nitrogen, oxygen and sulfur. Among these, a monocyclic polycyclic heteroaromatic ring is preferable, and specifically, thiophene, thiazole, benzothiophene, and indole are preferable.

  Further, the ring represented by A may further have a substituent P, and the number and type of the substituent P are not particularly limited. Examples of the substituent P include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, cyclo Linear, branched or cyclic alkyl groups having 1 to 20 carbon atoms (including alkyl substituted by cycloalkyl) such as propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; vinyl, allyl, Propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, hep Linear, branched or cyclic alkenyl groups having 2 to 20 carbon atoms such as decenyl, octadecenyl, nonadecenyl, icocenyl, hexadienyl, dodecatrienyl; ethynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, cyclooctynyl, cyclononynyl, Linear, branched or cyclic C2-C20 alkynyl groups such as cyclodecynyl; 5- to 10-membered monocyclic or bicyclic aryl groups such as phenyl, naphthyl, anthranyl; methoxy, ethoxy, propoxy, butoxy, pentyl Alkoxy groups having 1 to 20 carbon atoms such as oxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, dodecyloxy, hexadecyloxy, octadecyloxy; aryloxy such as phenoxy, naphthyloxy, etc. An alkylthio group having 1 to 20 carbon atoms such as methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, dodecylthio, hexadecylthio, octadecylthio; arylthio groups such as phenylthio, naphthylthio; acetyl, C2-C20 acyl such as propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, and substituted carbonyl groups such as benzoyl, naphthoyl; methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, n-decyloxycarbonyl, phenoxycarbonyl, etc. Substituted oxycarbonyl group; acetyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoylo C2-C20 acyloxy such as xy and substituted carbonyloxy groups such as benzoyloxy and naphthoyloxy; methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, phenyl Substituted sulfonyl groups such as sulfonyl and naphthylsulfonyl; carbamoyl groups substituted by one or two groups selected from alkyl, alkenyl and aryl such as N-methylcarbamoyl and N, N-diphenylcarbamoyl; N-phenylsulfa A sulfamoyl group substituted by two groups selected from alkyl, alkenyl and aryl such as moyl, N, N-diethylcarbamoyl; acetylamino, t-butylcarbonylamino, -C2-C20 acylamino such as hexylcarbonylamino, and substituted carbonylamino groups such as benzoylamino and naphthoylamino; selected from alkyl, alkenyl and aryl such as N-methylureido and N, N-diethylureido Ureido group substituted by 1 or 2 groups; C1-C20 sulfonylamino such as methylsulfonylamino, t-butylsulfonylamino, n-octylsulfonylamino, and substitution such as phenylsulfonylamino, naphthylsulfonylamino, etc. Sulfonylamino group; disubstituted amino groups such as N, N-dimethylamino group, N, N-diethylamino group, N, N-diphenylamino group, N-methyl-N-phenylamino group; t-butoxycarbonyl group, pivaloyl Group, benzyl group, phthaloyl group, etc. Amino group substituted with a protecting group; nitro group; cyano group; substituted silyl group such as trimethylsilyl and triethylsilyl; halogen atom such as fluorine atom, bromine atom, chlorine atom and iodine atom; thiophene, furan, pyran, pyridine, pyrrole , Pyrazine, azepine, azocine, azonin, azecine, oxazole, thiazole, pyrimidine, pyridazine, triazine, triazole, tetrazole, imidazole, pyrazole, morpholine, thiomorpholine, piperidine, piperazine, quinoline, isoquinoline, indole, isoindole, quinoxaline, phthalazine 1 selected from 5- to 10-membered monocyclic or bicyclic nitrogen, oxygen and sulfur such as quinolidine, quinazoline, quinoxaline, naphthyridine, chromene, benzofuran, benzothiophene, etc. And heterocyclic groups containing 4 atoms. Preferably, a C1-C12 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an aryl group, a lower alkoxy group, a phenoxy group, a fluorine atom, and a chlorine atom are mentioned.

The substituent P may further have a substituent Q, and the substituent Q is not particularly limited as long as it does not participate in the reaction.
Examples of the substituent Q include lower alkyl groups such as methyl, ethyl, propyl, and butyl, aryl groups such as phenyl and naphthyl, and halogen atoms such as chlorine and fluorine.

<Alkene compound>
Examples of the alkene compound include cycloalkene compounds represented by the following structural formula (II).
However, in said structural formula (II), n represents the integer of 2-5, X represents either hydrogen, chlorine, and a fluorine, and Y represents a halogen atom.
As the halogen atom represented by Y, for example, chlorine and fluorine are preferable.

  As the cycloalkene compound, for example, octafluorocyclopentene is preferable.

The amount of the alkene compound used is 0.005 to 10 mol, preferably 0.05 to 1.0 mol, more preferably 0.25 to 0.65 mol, per mol of the halogen compound, 0 .475 to 0.525 mole is particularly preferred.
In addition, by using the said alkene compound as a solution, handleability improves and the reproducibility at the time of manufacture improves.

  The diarylethene compound of the present invention using 3-bromo-2-methyl-5-phenylthiophene as the halogen compound, n-butyllithium as the organolithium reagent, and octafluorocyclopentene as the alkene compound An example of the reaction formula in the production method is given.

However, in said formula, Me represents a methyl group and Ph represents a phenyl group.

In the method for producing a diarylethene compound of the present invention, the progress of the cross-coupling reaction between the lithium compound and the alkene compound, and the halogen-lithium exchange reaction between the halogen compound and the organolithium reagent can be performed by various known analytical instruments. Can be used to monitor.
The reaction rate of the reaction can be confirmed by high performance liquid chromatography, capillary gas chromatography or the like.
Furthermore, the reaction can be monitored online by using an online FT-IR spectrometer or an online NIR spectrometer to track the change in absorbance.

  The method for isolating the diarylethene compound obtained by cross-coupling reaction between the lithium compound and the alkene compound is not particularly limited and can be appropriately selected from known methods. For example, an organic solvent is used. Extraction methods, distillation methods, reprecipitation methods using organic solvents, water, or a mixture of organic solvents and water, column chromatography, etc., can be used alone or in combination as appropriate.

(Diarylethene compound)
The diarylethene compound of the present invention is a compound produced by the method for producing a diarylethene compound of the present invention, and is represented, for example, by the following structural formula (III).

However, in said structural formula (III), n represents the integer of 2-5, X represents either hydrogen, chlorine, and fluorine, The ring represented by A and A 'is an aromatic ring, It represents any of a saturated ring, a partially saturated ring, and a heterocyclic ring, and A and A ′ may be the same as or different from each other.

  Examples of the diarylethene compound represented by the structural formula (III) include the following.

However, in said formula, Me represents a methyl group and Ph represents a phenyl group.

  Among the diarylethene compounds, for example, compounds represented by the following structural formulas (1) to (4) may be mentioned as novel compounds.

However, in the structural formula (1), Me represents a methyl group.

However, in the structural formula (2), Me represents a methyl group.

However, in the structural formula (3), Me represents a methyl group.

However, in said structural formula (4), Me represents a methyl group and Ph represents a phenyl group.

  As an example of the diarylethene compound, 1,2-bis (2-methyl-5-phenylthiophen-3-yl) hexafluorocyclopentene will be described. When irradiated with ultraviolet rays, the structure changes as shown below. As a ring-closed body, it exhibits a blue color, and when the ring-closed body is irradiated with visible light, it exhibits a photochromic property that becomes a ring-opened body and disappears.

Hereinafter, although the Example of this invention is described, this invention is not limited to this Example at all.
In addition, the structure of the obtained product was identified by ¹ H NMR, ¹³ C NMR, ¹⁹ F NMR, and the yield was isolated and determined by silica gel column chromatography. The optimization of the conditions was conducted by using ¹⁹ F NMR for comparison using trifluoromethylbenzene as an internal standard substance.

Example 1
<Synthesis of 1,2-Bis (2-methyl-5-phenylthiophene-3-yl) hexafluorocyclopentene>
A halogen-lithium exchange reaction between 3-bromo-2-methyl-5-phenylthiophene as the halogen compound and n-butyllithium as the organolithium reagent is performed in a first microreactor, Cross coupling of lithium compound (3-lithio-2-methyl-5-phenylthiophene) obtained by the halogen-lithium exchange reaction and octafluorocyclopentene as the alkene compound in a connected second microreactor Reaction was performed. The reaction formula is shown below. A conceptual diagram of the reaction is shown in FIG. 1, and reaction conditions based on FIG. 1 are shown in FIG.

However, in said formula, Me represents a methyl group and Ph represents a phenyl group.

For the micromixer M1 of the first microreactor, a union tee (manufactured by Swagelok, channel diameter (a in FIG. 2, a) 2.3 mm, cross-sectional area 4.15 mm ² ) is used. For the micromixer M2, union tee (manufactured by Swagelok, flow path diameter (b in FIG. 2, b) 1.3 mm, cross-sectional area 1.33 mm ² ) was used.
In FIG. 1, a tube having an inner diameter of 0.8 mm (outer diameter 1/16 inch) is used for the first reaction section indicated by sections 5 to 6 and the second reaction section indicated by sections 9 to 10. The setting of the residence time was adjusted by changing the length of the tube (x (m) and y (m) in FIG. 2) without changing the flow rate (z (mL / min in FIG. 2)).

  The reaction temperature was set by installing the entire microreactor in a constant temperature cooling water bath set at 0 ° C.

As the halogen compound solution, 3-bromo-2-methyl-5-phenylthiophene was diluted in a tetrahydrofuran solution to prepare a 3-bromo-2-methyl-5-phenylthiophene solution having a concentration of 0.298 mol / L.
As the organolithium reagent solution, 1.49 mol / L n-butyllithium (n-hexane solution) of a commercially available reagent was used, and the content was determined by titration.
As the alkene compound solution, octafluorocyclopentene was diluted in a tetrahydrofuran solution to prepare a 0.69 mol / L octafluorocyclopentene solution.
The halogen compound solution (3-bromo-2-methyl-5-phenylthiophene solution), the organolithium solution (n-butyllithium solution), and the alkene compound solution (octafluorocyclopentene solution) are each made of a gas-tight syringe made of glass. After sucking up (made by Hamilton), it was sent to the microreactor using a syringe pump (made by Harvard).

The flow rate of the halogen compound solution (3-bromo-2-methyl-5-phenylthiophene solution) (5z in FIG. 2) is 7.5 mL / min, and the flow rate of the organolithium solution (n-butyllithium solution) (figure 2). 2), z) is set to 1.5 mL / min, and the flow rate of the alkene compound solution (octafluorocyclopentene solution) (in FIG. 2, z) is set to 1.5 mL / min. Was discarded and recovered from the microreactor within a few minutes until the reaction was stabilized, and the subsequent reaction solution was collected in an eggplant flask containing 10 mL of ethyl acetate.
26 mL of the solution in the eggplant flask was accurately weighed using a syringe, the salt was removed with a short column, and then the solvent was distilled off with a rotary evaporator to obtain a crude product.
The obtained crude product was isolated and purified by silica gel column chromatography to obtain 572.8 mg of white crystals of diarylethene compound. The yield was 70%. The results are shown in Table 1.

(Examples 2 to 21)
In Example 1, the same procedure as in Example 1 was performed except that the flow path diameter, tube length, flow rate (liquid feeding speed), reaction temperature, and solvent of the microreactor (micromixer) were changed to the conditions shown in Table 1. Thus, a diarylethene compound was produced. The results are shown in Table 1.

(Example 22)
In Example 1, a diarylethene compound was produced in the same manner as in Example 1 except that an IMM microreactor was used as the microreactor (micromixer) and the conditions shown in Table 1 were used. The results are shown in Table 1.

(Example 23)
In Example 1, a diarylethene compound was produced in the same manner as in Example 1 except that Yamatake Microreactor YM-1 was used as the microreactor (micromixer) and the conditions shown in Table 1 were used. The results are shown in Table 1.

(Comparative Example 1)
<Synthesis of 1,2-Bis (2-methyl-5-phenylthiophene-3-yl) hexafluorocyclopentene by batch>
To 10 mL Schlenk substituted with argon gas, 377.2 mg of 3-bromo-2-methyl-5-phenylthiophene was added, 5 mL of tetrahydrofuran was added, and the mixture was cooled to 0 ° C. While stirring with a magnetic stirrer, 1.49 mol / L of n-hexane solution of n-butyllithium was taken into a gas tight syringe and 1.1 ml / min was used at a rate of 0.1 mL / min using a syringe pump (Harvard). 1 mL was added dropwise, and the mixture was stirred at 0 ° C. for 15 minutes after the completion of the addition.
Next, a tetrahydrofuran solution of octafluorocyclopentene having a concentration of 0.69 mol / L was placed in the gas tight syringe, and 1.1 mL was dropped at a rate of 0.1 mL / min using a syringe pump (Harvard).
After stirring at 0 ° C. for 1 hour, the temperature was gradually raised to room temperature over 30 minutes.
As a result of analyzing the obtained reaction solution, it was a complex mixture and almost no diarylethene compound could be confirmed. The results are shown in Table 1.

(Comparative Example 2)
20 g of 3-bromo-2-methyl-5-phenylthiophene and 600 mL of tetrahydrofuran were charged and purged with nitrogen. This was cooled to −70 ° C., and 54 mL of a 1.6 mol / L n-butyllithium n-hexane solution was added dropwise and stirred for 1 hour, followed by dropwise addition of 5.2 mL of octafluorocyclopentene and stirring for 2 hours. And then drained into water and extracted with ether. The organic layer was washed with dilute hydrochloric acid, washed with water three times, dried and concentrated. The obtained composition product was purified by a silica gel column and purified by recrystallization to obtain a diarylethene compound. The yield was 10.7 g, and the yield was 55%. The results are shown in Table 1.

* 1: A to F represent the following solvents.
A ... THF (tetrahydrofuran)
B ... Diethyl ether C ... Toluene D ... CPME (Cyclopentyl methyl ether)
E ... n-butyl ether F ... 1,4-dioxane G ... t-butyl methyl ether * 2: isolated yield

From the results of Table 1, in Comparative Example 1 in which the reaction temperature was 0 ° C. in the batch method, a diarylethene compound could not be obtained, whereas an example by the production method using the microreactor of the present invention was used. In 1-4 and 7-23, it turned out that the target diarylethene compound can be manufactured even if the reaction temperature is 0 degreeC or more. On the other hand, in Example 6 where the reaction temperature is −46 ° C., Example 19 where the tube length is as short as 0.1 m, and Example 23 using a microreactor whose channel diameter is 0.1 mm, the diarylethene compound is 40% or less. The yield was low.
According to the production method of the present invention, the diarylethene compound can be produced efficiently in a short time, compared to Comparative Example 2 in which the reaction is performed at a reaction temperature of −70 ° C. as a conventional method, and the reaction temperature, solvent, It was revealed that diarylethene compounds can be produced in extremely high yields by appropriately optimizing the microreactor channel diameter and tube length.

(Example 24)
A halogen-lithium exchange reaction of bromobenzene as the halogen compound and n-butyl lithium as the organolithium reagent is performed in a first microreactor, and in a second microreactor connected to the first microreactor, A cross-coupling reaction was performed between the lithium compound (phenyllithium) obtained by the halogen-lithium exchange reaction and octafluorocyclopentene as the alkene compound. The reaction formula is shown in FIG. The conceptual diagram of the reaction is as shown in FIG. 1, and the reaction conditions and the like based on FIG. 1 are shown in FIG.

For the micromixer M1 of the first microreactor, union tee (manufactured by Swagelok, flow path diameter (a in FIG. 4, a) 2.3 mm, cross-sectional area 4.15 mm ² ) was used. For the micromixer M2, a union tee (manufactured by Swagelok, flow path diameter (b in FIG. 4, b) 1.3 mm, cross-sectional area 1.33 mm ² ) was used.
In FIG. 1, the first reaction section indicated by sections 5 to 6 includes a tube having an inner diameter (P in FIG. 4) of 0.8 mm and a length (x in FIG. 4) of 1 m, and sections 9 to 10. For the two reaction parts, tubes having an inner diameter (Q in FIG. 4) of 0.8 mm and a length (y in FIG. 4) of 1 m were used.
The residence time of the first microreactor was 3.3 seconds, and the residence time of the second microreactor was 2.9 seconds.

  The reaction temperature was set by installing the entire microreactor in a constant temperature cooling water bath set at 0 ° C.

As the halogen compound solution, 701.8 mg of bromobenzene was diluted in a tetrahydrofuran solution to prepare a bromobenzene solution having a concentration of 0.298 mol / L.
As the organolithium reagent solution, 1.49 mol / L of n-butyllithium (n-hexane solution) as a commercially available reagent was purchased, and the content was determined by titration.
As the alkene compound solution, octafluorocyclopentene was diluted in a tetrahydrofuran solution to prepare a 0.69 mol / L octafluorocyclopentene solution.
The halogen compound solution (bromobenzene solution), the organolithium solution (n-butyllithium solution), and the alkene compound solution (octafluorocyclopentene solution) were each sucked into a glass gas tight syringe, and then syringe pump (Harvard) Liquid was sent to the microreactor.

The flow rate of the halogen compound solution (bromobenzene solution) (5z in FIG. 4) is 7.5 mL / min, and the flow rate of the organolithium solution (n-butyllithium solution) (z in FIG. 4) is 1.5 mL / min. Minutes, the flow rate of the alkene compound solution (octafluorocyclopentene solution) bromobenzene solution (z in FIG. 4) is set to 1.5 mL / min, and after the start of liquid feeding, the reaction of the produced reaction liquid is stabilized. What was discharged | emitted from the said microreactor and collect | recovered for several minutes until it was discarded, and the subsequent reaction liquids were extract | collected to the eggplant flask containing 10 mL of ethyl acetate.
The solution in the eggplant flask was accurately weighed 23.2 mL using a syringe, the salt was removed using a short column, and then the solvent was distilled off using a rotary evaporator to obtain a crude product.
The obtained crude product was isolated and purified by silica gel column chromatography to obtain 370 mg of diarylethene compound white crystals. The yield was 87%. The results are shown in Table 2.

(Examples 25 to 40)
As the halogen compound, except that the bromobenzene of Example 24 was replaced with the compound shown in Table 2, the reaction conditions were changed to the conditions shown in Table 2, and the concentration of the raw material compound solution was changed to the concentration shown in Table 3, the implementation was performed. A diarylethene compound was produced in the same manner as in Example 24. The obtained diarylethene compound and the yield are shown together in Table 4.

* 3: Halogen compounds A to I represent compounds A to I represented by the following structural formula.

*: Isolated yield In the compounds of Table 4, Me represents a methyl group, and Ph represents a phenyl group.

In addition, 1,2-Bis (4-methoxyphenyl) hexafluorocyclopentene represented by the following structural formula (1) obtained in Examples 25 and 35, and represented by the following structural formula (2) obtained in Example 26. 1,2-Bis (4-N, N-dimethylaminophenyl) hexafluorocyclopentene, 1,2-Bis (4-methylphenyl) hexafluorocyclopentene represented by the following structural formula (3) obtained in Examples 27 and 36 is the present invention. And a novel diarylethene compound produced by the method for producing a diarylethene compound.
The spectral data of these novel diarylethene compounds are shown below.

1,2-Bis (4-methoxyphenyl) hexafluorocyclopentene: 78% yield from 4-bromoanisol and octafluorocyclopentene, ¹ H NMR (400MHz) δ 3.82 (s, 6H), 6.91 (d, J = 8.4Hz, 4H), 7.39 ( d, J = 8.8Hz, 4H); ¹³ C NMR (75 MHz) δ 55.0, 107.4-115.2 (m), 113.1-120.5 (m), 114.4, 120.2, 130.9, 137.5-138.1 (m), 161.1; HRMS ( EI) m / z calcd for C ₁₉ H ₁₄ F ₆ O ₂ : 388.0898, found: 388.0898.

1,2-Bis (4-N, N-dimethylaminophenyl) hexafluorocyclopentene: 51% yield from 4-bromo-N, N-dimethylaniline and octafluorocyclopentene, ¹ H NMR (300 MHz) δ 3.00 (s, 12H), 6.63 (d, J = 9.0Hz, 4H), 7.34 (d, J = 9.0Hz, 4H); ^13C NMR (75MHz) δ 39.9,107.4-115.2 (m), 111.7,113.5-120.9 (m), 115.6,130.4,135.7 (m), 150.9; HRMS (EI) m / z calcd for C ₂₁ H ₂₀ F ₆ N ₂ : 414.1513, found: 414.1531.

1,2-Bis (4-methylphenyl) hexafluorocyclopentene: 71% yield from 4-bromotoluene and octafluorocyclopentene, ¹ H NMR (300 MHz) δ 2.42 (s, 6H), 7.22 (d, J = 8.4Hz, 4H), 7.35 ( d, J = 8.4Hz, 4H); ^13C NMR (75MHz) δ 21.2,107.7-115.2 (m), 113.0-120.4 (m), 125.1,129.2,129.6,139.1 (m), 140.6; HRMS (EI) m / z calcd for C ₁₉ H ₁₄ F ₆ : 356.1000, found: 356.0998.

<Evaluation of photochromic characteristics>
1,2-bis (2-methyl-5-phenylthiophen-3-yl) hexafluoropentene synthesized in Example 1 and 1,2-bis (5-methyl-2-phenylthiazole synthesized in Example 31 A hexane solution of -4-yl) hexafluoropentene was prepared, and spectra before and after UV irradiation were measured. The results are shown in FIGS. 5 and 6, respectively.

(Example 34)
-Synthesis of asymmetric diarylethene compounds-
<Synthesis of 1- (2-methyl-5-phenylthiophene-3-yl) -2- (5-methyl-2-phenylthiazo-4-yl) hexafluorocyclopentene>
Synthesis of 4-lithio-5-methyl-2-phenylthiazole by halogen-lithium exchange reaction of n-butyllithium with 4-bromo-5-methyl-2-phenylthiazole, followed by reaction with octafluorocyclopentene. Synthesis of-(5-methyl-2-phenylthiazol-4-yl) heptafluorocyclopentene, followed by halogen-lithium exchange reaction of n-butyllithium and 3-bromo-2-methyl-5-phenylthiophene 1- (2-Methyl-5-phenylthiophen-3-yl) -2- (5-methyl-2-phenylthiazol-4-yl) by reaction with the obtained 3-lithio-2-methyl-5-phenylthiophene ) Hexafluorocyclopentene was synthesized. A conceptual diagram of the reaction is shown in FIG. 7, and reaction conditions based on FIG. 7 are shown in FIG.

For the micromixers (M1 and M3 in FIG. 7) of the first and third microreactors, union tees (manufactured by Swagelok, channel diameter 2.3 mm, cross-sectional area 4.15 mm ² ) were used. For the micromixer (M2 and M4 in FIG. 7) of the fourth microreactor, a union tee (manufactured by Swagelok, channel diameter 1.3 mm, cross-sectional area 1.33 mm ² ) was used.

  The reaction temperature was set by installing the entire microreactor in a constant temperature cooling water bath set at 0 ° C.

  4-Bromo-5-methyl-2-phenylthiazole is diluted in a tetrahydrofuran solution, diluted to a concentration of 0.25 mol / L, 3-bromo-2-methyl-5-phenylthiophene is diluted in a tetrahydrofuran solution, The solution was adjusted to 0.274 mol / L. For n-butyllithium, a commercial reagent 1.37 mol / L n-butyllithium (n-hexane solution) was purchased, and the content was determined by titration. Octafluorocyclopentene was diluted in a tetrahydrofuran solution to prepare a 0.63 mol / L solution. 4-Bromo-5-methyl-2-phenylthiazole solution, 3-bromo-2-methyl-5-phenylthiophene solution, n-butyllithium solution, and octafluorocyclopentene solution were manufactured by Hamilton and SGE, respectively. The solution was sucked into a gas tight syringe and then sent to the microreactor using a Harvard syringe pump. The feeding speeds of 4-bromo-5-methyl-2-phenylthiazole solution, n-butyllithium solution, octafluorocyclopentene solution 3-bromo-2-methyl-5-phenylthiophene solution, and n-butyllithium solution are respectively It was set to 5 mL / min, 1 mL / min, 2.4 mL / min, 5.8 mL / min, and 1.16 mL / min. The mixed reaction solution was discarded for the first few seconds until the reaction was stabilized, then collected in an eggplant flask and stirred at 0 ° C. for 30 minutes, and then 10 mL of ethyl acetate was added. 32.5 mL of the obtained solution was accurately weighed using a syringe, the salt was removed with a short column, and then the solvent was distilled off with a rotary evaporator to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography to obtain 506.4 mg of white crystals (yield 53%). The structural formula and spectrum data of the obtained compound are shown below.

1- (2-methyl-5-phenylthiophene-3-yl) -2- (4-methyl-5-phenylthiazol-2-yl) hexafluorocyclopentene: 53% yield from 3-bromo-2-methyl-5-phenylthiopnene and 4 -bromo-5-methyl-2-phenylthiazol and octafluorocyclopentene, ¹ H NMR (400MHz) δ 2.06 (s, 3H), 2.09 (s, 3H), 7.33-7.46 (m, 7H), 7.60 (d, J = 12Hz , 2H), 7.90-7.93 (m, 2H); ¹³ C NMR (100 MHz) δ 12.3, 14.4, 108.3-114.1 (m), 113.2-118.6 (m), 122.5, 125.4, 125.7, 126.3, 127.8, 128.80 , 128.84, 130.2, 132.8, 133.2, 135.1-135.6 (m), 136.7, 140.2, 141.2, 142.1, 165.5; HRMS (EI) m / z calcd for C ₁₉ H ₁₄ F ₆ O ₂ : 521.0707, found: 521.0707.

(Comparative Examples 3-6)
<Synthesis of 1,2-Bis (2-methyl-5-phenylthiophene-3-yl) hexafluorocyclopentene by macroflow system>
In Example 1, the diarylethene compound was produced in the same manner as in Example 1 except that the reaction conditions were changed to those shown in Table 5 and the experiment was conducted in a macro flow system according to the reaction flow shown in FIG. did. The yield of the obtained diarylethene compound is shown together in Table 5.
The structure of the obtained product was identified by ¹⁹ F NMR and confirmed to be 1,2-Bis (2-methyl-5-phenylthiophene-3-yl) hexafluorocyclopentene.

  From the results shown in Table 5, when a diarylethene compound is synthesized in a flow system that is not microscale, that is, in a macroflow system, the target product is obtained, but it is synthesized in a microflow system (the production method of the present invention using a microreactor). The yield was found to be very low compared to Examples 1 to 23).

According to the method for producing a diarylethene compound of the present invention, the diarylethene compound can be produced under a mild condition of 0 ° C. without requiring ultra-low temperature cooling by a continuous reaction using a microreactor, and in a high yield. It was found that the compound can be obtained.
In addition, it has been clarified that a halogen compound can be appropriately selected and a novel compound can be produced efficiently and easily, and can be applied to development of a photochromic material having a novel function.

  The method for producing a diarylethene compound of the present invention is suitable for producing a diarylethene compound on an industrial scale because a diarylethene compound can be produced safely and efficiently in a high yield without using a special cooling device or the like. In particular, it is suitable for the production of novel compounds having photochromic properties.

Claims (11)

Lithium compound solution and alkene compound solution,
Introducing into a microreactor with a flow path that can mix multiple liquids,
A method for producing a diarylethene compound in which a lithium compound and an alkene compound are cross-coupled in the microreactor ,
The lithium compound is represented by the following structural formula (I) obtained by introducing a halogen compound solution and an organolithium reagent solution into a microreactor and reacting the halogen compound and the organolithium reagent in the microreactor. A compound,
The alkene compound is a cycloalkene compound represented by the following structural formula (II):
The method for producing a diarylethene compound , wherein the diarylethene compound is represented by the following structural formula (III) :
However, in the structural formula (I), the ring represented by A represents an aromatic ring, a saturated ring, a partially saturated ring, or a heterocyclic ring.
However, in said structural formula (II), n represents the integer of 2-5, X represents either hydrogen, chlorine, and fluorine, and Y represents a halogen atom.
However, in said structural formula (III), n represents the integer of 2-5, X represents either hydrogen, chlorine, and fluorine, and the ring represented by A and A 'is an aromatic ring, It represents any of a saturated ring, a partially saturated ring, and a heterocyclic ring, and A and A ′ may be the same as or different from each other. Carried out using a continuous reaction apparatus in which a first microreactor and a second microreactor are connected,
A lithium compound is synthesized in the first microreactor;
The method for producing a diarylethene compound according to claim 1, wherein a cross-coupling reaction between the lithium compound and the alkene compound is performed in the second microreactor. Carried out using a continuous reactor connected with the first to fourth microreactors,
A first lithium compound is synthesized in a first microreactor;
A cross-coupling reaction between the first lithium compound and the alkene compound is performed in a second microreactor;
A second lithium compound is synthesized in a third microreactor;
The method for producing a diarylethene compound according to claim 1, wherein a cross-coupling reaction between the second lithium compound and the compound synthesized in the second microreactor is performed in a fourth microreactor. The method for producing a diarylethene compound according to any one of claims 1 to 3, which is performed within a temperature range of -20 to 20 ° C. The method for producing a diarylethene compound according to any one of claims 1 to 4, wherein the microreactor is installed in a thermostat adjusted to -20 to 20 ° C. The residence time in the first microreactor is 0.0005 to 40 seconds, and the residence time in the second microreactor is 0.001 seconds to 10 minutes. The manufacturing method of the diarylethene compound of description. The method for producing a diarylethene compound according to any one of claims 1 to 6, wherein the organolithium reagent is any one of alkyllithium, alkenyllithium, and alkynyllithium. The method for producing a diarylethene compound according to any one of claims 1 to 7, wherein the organolithium reagent is n-butyllithium. The method for producing a diarylethene compound according to any one of claims 1 to 8, wherein the halogen compound is any one of a chlorine compound, a bromine compound, and an iodine compound. Halogen compounds are bromobenzene, iodobenzene, 4-bromotoluene, 4-bromoanisole, 4-bromo-dimethylaniline, 1,4-dibromobenzene, 2-bromothiophene, 3-bromothiophene, 3-bromo-2- 10. The method according to any one of claims 1 to 9, which is any of methyl-5-phenylthiophene, 4-bromo-5-methyl-2-phenylthiazole, and 3-bromo-2-methylbenzothiophene. A process for producing a diarylethene compound. The method for producing a diarylethene compound according to any one of claims 1 to 10, wherein the alkene compound is octafluorocyclopentene.