WO2023106361A1 - Method for producing boronic acid compound - Google Patents

Method for producing boronic acid compound Download PDF

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Publication number
WO2023106361A1
WO2023106361A1 PCT/JP2022/045261 JP2022045261W WO2023106361A1 WO 2023106361 A1 WO2023106361 A1 WO 2023106361A1 JP 2022045261 W JP2022045261 W JP 2022045261W WO 2023106361 A1 WO2023106361 A1 WO 2023106361A1
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boronic acid
flow path
acid compound
appropriately selected
particularly limited
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PCT/JP2022/045261
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French (fr)
Japanese (ja)
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愛一郎 永木
洋祐 芦刈
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株式会社altFlow
株式会社中化学日本総合研究所
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Publication of WO2023106361A1 publication Critical patent/WO2023106361A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to a method for producing a boronic acid compound.
  • Patent Document 1 A method for synthesizing a boronic acid compound from an o-dihaloaromatic compound is known (Patent Document 1), but this method requires a reaction at an extremely low temperature of -80°C to -50°C and is simple. It cannot be said that it is a good method.
  • an object of the present invention is to solve the above-mentioned problems in the past and to achieve the following objects. That is, an object of the present invention is to provide a method for efficiently and easily producing a boronic acid compound from p-bromobenzonitrile.
  • step 1 of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into the first micromixer and Step 2 of introducing the compound obtained in Step 1 and the boronic acid ester compound into a second micromixer.
  • step 2 of introducing the compound obtained in Step 1 and the boronic acid ester compound into a second micromixer.
  • p-bromobenzonitrile to provide a method for producing a boronic acid compound.
  • Step 1 of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into a first micromixer, the compound obtained in step 1, and a boronate ester compound. and a step 2 of introducing into a second micromixer.
  • FIG. 1 is a schematic diagram of a flow microreactor used in one example of the production method of the present invention.
  • 2 is a schematic diagram of the microreactor system used in Example 1.
  • FIG. 3 is a schematic diagram of the microreactor system used in Example 2.
  • FIG. 4 is a schematic diagram of the microreactor system used in Example 3.
  • FIG. 1 is a schematic diagram of a flow microreactor used in one example of the production method of the present invention.
  • 2 is a schematic diagram of the microreactor system used in Example 1.
  • FIG. 3 is a schematic diagram of the microreactor system used in Example 2.
  • FIG. 4 is a schematic diagram of the microreactor system used in Example 3.
  • the method for producing the boronic acid compound includes steps 1 and 2, and may further include other steps.
  • the step 1 is a step of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into the first micromixer.
  • p-bromobenzonitrile The p-bromobenzonitrile is also referred to as 4-bromobenzonitrile.
  • the lower limit of the concentration of the p-bromobenzonitrile is not particularly limited as long as it is 0.30 M or more, and can be appropriately selected according to the purpose. 0.35M or more is preferable, and 0.38M or more is more preferable from the point of manufacturing a compound.
  • the upper limit of the concentration of p-bromobenzonitrile is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of suppressing side reactions, it is preferably 0.5 M or less.
  • nBuLi is also referred to as n-butyllithium or normal butyllithium.
  • the lower limit of the concentration of nBuLi is not particularly limited as long as it is 1.6M or more, and can be appropriately selected according to the purpose.
  • the upper limit of the concentration of nBuLi is not particularly limited and can be appropriately selected depending on the intended purpose.
  • the first micromixer is not particularly limited as long as it is a mixing means in a microreactor (hereinafter sometimes referred to as "flow microreactor” or “flow reactor”), and is appropriately selected according to the purpose. It may be a substrate-type micromixer or a pipe joint-type micromixer in the microreactor described below.
  • the microreactor is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include a microreactor provided with mixing means, a flow path, and other means as necessary. .
  • the mixing means and the flow path may be integrated or separated.
  • the mixing means is a means capable of mixing two or more liquids.
  • the flow path is a tube through which liquid can flow.
  • the flow passage is connected with at least one of the mixing means.
  • the flow microreactor By using the flow microreactor, it is possible to shorten the residence time from the generation to the next reaction of a compound with low stability, thereby suppressing side reactions. In addition, since the flow microreactor has excellent cooling efficiency, it is possible to suppress side reactions caused by heat generation in an exothermic reaction.
  • Examples of the mixing means and the flow path of the integrated flow microreactor include a substrate-type micromixer.
  • the substrate-type micromixer is composed of a substrate having passages formed therein or on its surface, and is sometimes referred to as a microchannel.
  • the substrate-type micromixer is not particularly limited and can be appropriately selected according to the purpose. ; the mixer described in the document ““Microreactors” Chapter 3, W. Ehrfeld, V. Hessel, H. Lowe, published by Wiley-VCH Co.”, and the like.
  • the mixing means and the flow path are composed of minute flow paths capable of mixing a plurality of liquids.
  • the substrate-type micromixer has an introduction path other than the flow path, which communicates with the flow path and introduces a plurality of liquids into the flow path. That is, it is preferable that the upstream side of the flow path is branched according to the number of the introduction paths.
  • the number of the introduction channels is not particularly limited and can be appropriately selected according to the purpose. is preferred. It should be noted that a configuration may be adopted in which one liquid is charged in advance into the flow path and another liquid is introduced through the introduction path.
  • the mixing means is not particularly limited as long as it can mix two or more liquids, and can be appropriately selected according to the purpose. Examples thereof include a pipe joint type micromixer.
  • the pipe joint type micromixer has a channel formed inside and, if necessary, a connection member that connects the channel formed inside and the flow channel.
  • the connection method of the connection member is not particularly limited, and can be appropriately selected from known connection methods according to the purpose. Welding type, flange type, bite type, flare type, mechanical type, and the like are included.
  • an introduction path communicating with the flow path and introducing a plurality of liquids into the flow path is formed inside the pipe joint type micromixer. That is, it is preferable that the upstream side of the flow path is branched according to the number of the introduction paths.
  • the number of the introduction paths is two, for example, a T-shape or Y-shape can be used as the pipe joint type micromixer, and when the number of the introduction paths is three, can use, for example, a cross shape. It should be noted that a configuration may be adopted in which one liquid is charged in advance into the flow path and another liquid is introduced through the introduction path.
  • the material of the pipe joint type micromixer is not particularly limited, and can be appropriately selected according to requirements such as heat resistance, pressure resistance, solvent resistance, and ease of processing. Titanium, copper, nickel, aluminum, silicon, fluorine resins such as Teflon (registered trademark), PFA (perfluoroalkoxy resin), TFAA (trifluoroacetamide), and the like.
  • YM-1 type mixer and YM-2 type mixer manufactured by Azbil Corporation; mixing tees and tees (T-shaped connector) manufactured by Shimadzu GLC Co., Ltd.
  • Micro High Mixer developed by Toray Engineering; Union Tee manufactured by Swagelok, T-shaped Micro Mixer manufactured by Sanko Seiki Kogyo Co., Ltd.;
  • the method of mixing two or more raw materials in the mixing means is not particularly limited and can be appropriately selected according to the purpose.
  • Examples thereof include laminar flow mixing and turbulent mixing.
  • laminar flow mixing static mixing
  • laminar flow mixing is preferable in terms of more efficient reaction control and heat removal.
  • the flow path in the mixing means is minute, the plurality of liquids introduced into the mixing means naturally tend to flow laminarly, and are diffused and mixed in the direction perpendicular to the flow.
  • a configuration may be adopted in which branch points and confluence points are further provided in the flow path to divide the laminar cross section of the flowing liquid, thereby increasing the mixing speed.
  • the flow rate and the shape of the channel can be changed from laminar to turbulent.
  • the turbulent mixing has the advantage of high mixing efficiency and high mixing speed compared to the laminar mixing.
  • the smaller the inner diameter of the flow path in the mixing means the shorter the diffusion distance of molecules, so the time required for mixing can be shortened and the mixing efficiency can be improved. Furthermore, the smaller the inner diameter of the flow channel, the larger the ratio of the surface area to the volume, making it easier to control the temperature of the liquid, for example, to remove the heat of reaction. On the other hand, if the inner diameter of the flow path is too small, the pressure loss increases when the liquid flows, and the pump used for liquid transfer needs to have a special high pressure resistance, which increases the manufacturing cost. There is in addition, the structure of the micromixer may also be limited due to the limitation of the flow rate of liquid transfer.
  • the lower limit of the average inner diameter of the flow path in the mixing means is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of effectively removing heat of reaction and reducing pressure loss during liquid feeding, the thickness is preferably 50 ⁇ m or more, more preferably 100 ⁇ m or more, even more preferably 250 ⁇ m or more, even more preferably 500 ⁇ m or more, and particularly preferably 1000 ⁇ m or more. 1300 ⁇ m or more is most preferable.
  • the upper limit of the average inner diameter of the channel in the mixing means is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 4 mm or less, more preferably 3 mm or less. Preferably, 2.5 mm or less is more preferable.
  • the average inner diameter When the average inner diameter is less than 50 ⁇ m, pressure loss may increase. If the average inner diameter exceeds 4 mm, the surface area per unit volume becomes small, and as a result, rapid mixing and removal of reaction heat may become difficult.
  • the cross-sectional area of the flow channel is not particularly limited and can be appropriately selected according to the purpose . ⁇ 2.1 mm 2 is more preferred, and 190,000 ⁇ m 2 to 1 mm 2 is particularly preferred.
  • the cross-sectional shape of the flow path is not particularly limited, and can be appropriately selected according to the purpose. Examples include circular, rectangular, semicircular, and triangular shapes.
  • the flow path is not particularly limited as long as it is a tube that is connected to at least one of the mixing means and can circulate the liquid, and can be appropriately selected according to the purpose.
  • the configuration such as the material can be appropriately selected according to the desired reaction.
  • the flow path is used, for example, when supplying raw materials to the mixing means. Further, the flow path is used, for example, when supplying the reaction product of two or more substances mixed by the mixing means to the next mixing means. At this time, the reaction may continue to occur within the flow path.
  • a stainless steel tube manufactured by GL Sciences Co., Ltd. (outer diameter 1/16 inch (1.58 mm), inner diameter 250 ⁇ m, 500 ⁇ m and 1,000 ⁇ m can be selected, The tube length can be adjusted by the user).
  • the material of the flow path is not particularly limited, and those exemplified as the material of the mixing means can be suitably used.
  • the lower limit of the average inner diameter of the flow passage (tube precooling unit: cooling line average inner diameter) connected upstream of the mixing means is not particularly limited and can be appropriately selected according to the purpose.
  • the thickness is preferably 50 ⁇ m or more, more preferably 100 ⁇ m or more, still more preferably 250 ⁇ m or more, even more preferably 500 ⁇ m or more, particularly preferably 1000 ⁇ m or more, and most preferably 2000 ⁇ m or more.
  • the upper limit of the average inner diameter of the flow passage (tube precooling unit: cooling line average inner diameter) connected upstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The following is preferable, 3 mm or less is more preferable, and 2.5 mm or less is even more preferable.
  • the lower limit of the average inner diameter of the flow passage connected downstream of the mixing means is not particularly limited and can be appropriately selected according to the purpose. From the viewpoint of reducing pressure loss, it is preferably 50 ⁇ m or more, more preferably 100 ⁇ m or more, still more preferably 250 ⁇ m or more, even more preferably 500 ⁇ m or more, and particularly preferably 1000 ⁇ m or more.
  • the upper limit of the average inner diameter of the flow path (the average inner diameter of the microtube reactor) connected downstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 4 mm or less. , 3 mm or less, and more preferably 2.5 mm or less.
  • the lower limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (p-bromobenzonitrile) is not particularly limited, and is appropriately selected according to the purpose. However, from the viewpoint of efficiently producing a boronic acid compound from p-bromobenzonitrile, it is preferably 5 mL / min or more, more preferably 10 mL / min or more, further preferably 20 mL / min or more, and 30 mL / min or more. is more preferable, 50 mL/min or more is particularly preferable, and 60 mL/min or more is particularly preferable.
  • the upper limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (p-bromobenzonitrile) is not particularly limited, and is appropriately selected according to the purpose. but preferably 300 mL/min or less.
  • the lower limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (nBuLi) is not particularly limited, and can be appropriately selected according to the purpose. , From the viewpoint of efficiently producing a boronic acid compound from p-bromobenzonitrile, it is preferably 1.25 mL / min or more, more preferably 2.5 mL / min or more, even more preferably 5 mL / min or more, 7.5 mL / minutes or more is even more preferable, 12.5 mL/minute or more is particularly preferable, and 15 mL/minute or more is particularly preferable.
  • the upper limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (nBuLi) is not particularly limited, and can be appropriately selected according to the purpose. , 75 mL/min or less is preferred.
  • the lower limit of the retention time of the reaction liquid in the flow path through which the reaction liquid in step 1 flows is not particularly limited and can be appropriately selected according to the purpose. 0.01 second or more is preferable, and 0.1 second or more is more preferable.
  • the upper limit of the retention time of the reaction solution in the flow path through which the reaction solution flows in step 1 is not particularly limited, and can be appropriately selected according to the purpose. From the viewpoint of producing a boronic acid compound from p-bromobenzonitrile, the time is preferably 10 seconds or less, more preferably 5 seconds or less, even more preferably 2 seconds or less, even more preferably 1 second or less, and particularly 0.5 seconds or less. preferable.
  • the residence time can be set within the above range by adjusting the length and average inner diameter of the microtube reactor.
  • the lower limit of the length of the flow path connected upstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. 100 cm or more is more preferable, and 100 cm or more is particularly preferable.
  • the upper limit of the length of the flow path connected upstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The following is more preferable, and 230 cm or less is particularly preferable.
  • the lower limit of the length of the flow path connected downstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The above is more preferable, 20 cm or more is even more preferable, and 50 cm or more is particularly preferable.
  • the upper limit of the length of the flow path connected downstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The following is more preferable, and 230 cm or less is particularly preferable.
  • the other means are not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include liquid feeding means, temperature control means and the like.
  • the liquid sending means is not particularly limited as long as it can supply various raw materials to the flow path of the flow microreactor, and can be appropriately selected according to the purpose. Examples include a pump.
  • the pump is not particularly limited and can be appropriately selected from those that can be used industrially, but those that do not cause pulsation during liquid transfer are preferable, and examples include plunger pumps, gear pumps, rotary pumps, and diaphragm pumps. etc.
  • the temperature control means is not particularly limited as long as the temperature of the mixing means and the channel of the flow microreactor can be controlled, and can be appropriately selected according to the purpose.
  • the lower limit of the reaction temperature in step 1 is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of reducing the cooling load, -20 ° C. or higher is preferable, and -15 ° C. or higher is more preferable. -10°C or higher is more preferred, -5°C or higher is even more preferred, and 0°C or higher is particularly preferred.
  • the upper limit of the reaction temperature in step 1 is not particularly limited and can be appropriately selected according to the purpose. 10° C. or lower is more preferable, and 5° C. or lower is particularly preferable.
  • the lower limit of the amount of nBuLi with respect to the p-bromobenzonitrile is not particularly limited and can be appropriately selected depending on the purpose. It is preferably 1.0 molar equivalents or more, more preferably 1.1 molar equivalents or more.
  • the upper limit of the amount of nBuLi with respect to the p-bromobenzonitrile is not particularly limited and can be appropriately selected depending on the purpose, but from the viewpoint of saving reagents, it is preferably 2.5 molar equivalents or less. , is more preferably 2.0 molar equivalents or less, and more preferably 1.5 molar equivalents or less.
  • the step 2 is a step of introducing the compound obtained in the step 1 and the boronic acid ester compound into a second micromixer.
  • the compound obtained in step 1 is a compound obtained by mixing the p-bromobenzonitrile and the nBuLi with a first micromixer.
  • Examples of the compound obtained by mixing the p-bromobenzonitrile and the nBuLi in the first micromixer include p-cyanophenyllithium.
  • the boronate ester compound is not particularly limited and can be appropriately selected depending on the intended purpose. From the viewpoint of suppressing side reactions, isopropoxyboronic acid pinacol ester or triisopropyl borate is preferable.
  • Second Micro Mixer The second micromixer is as described for the first micromixer above.
  • the lower limit of the retention time of the reaction solution in the flow path through which the reaction solution in step 2 flows is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound, the time is preferably 0.01 seconds or longer, more preferably 0.1 seconds or longer, even more preferably 2 seconds or longer, and particularly preferably 5 seconds or longer.
  • the upper limit of the residence time of the reaction solution in the flow path through which the reaction solution in step 2 flows is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound, the time is preferably 30 seconds or less, more preferably 20 seconds or less, and even more preferably 10 seconds or less.
  • the residence time can be set within the above range by adjusting the length and average inner diameter of the microtube reactor.
  • the lower limit of the reaction temperature in step 2 is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of reducing the cooling load, -20 ° C. or higher is preferable, and -15 ° C. or higher is more preferable. -10°C or higher is more preferred, -5°C or higher is even more preferred, and 0°C or higher is particularly preferred.
  • the upper limit of the reaction temperature in step 2 is not particularly limited and can be appropriately selected according to the purpose. 10° C. or lower is more preferable, and 5° C. or lower is particularly preferable.
  • the lower limit of the amount of the boronate compound relative to the compound obtained in the step 1 is not particularly limited and can be appropriately selected depending on the purpose. 0 molar equivalent or more is preferable, 1.1 molar equivalent or more is more preferable, and 1.2 molar equivalent or more is still more preferable.
  • the upper limit of the amount of the boronic acid ester compound relative to the compound obtained in the step 1 is not particularly limited and can be appropriately selected depending on the purpose.
  • the molar equivalent or less is preferable, 2.0 molar equivalent or less is more preferable, and 1.5 molar equivalent or less is even more preferable.
  • the yield of the boronic acid compound in the method for producing the boronic acid compound is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 50% or more, more preferably 60% or more, and 70%. 80% or more is more preferable, 85% or more is particularly preferable, and 90% or more is most preferable.
  • the yield is determined by GC analysis or HPLC analysis as follows.
  • the quenching step after step 2 is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include a method of adding methanol or hydrochloric acid.
  • the boronic acid compound is produced by the method for producing a boronic acid compound described above.
  • FIG. 1 is a schematic diagram showing an example of a flow microreactor.
  • the flow microreactor shown in FIG. 1 comprises two mixing means and five flow channels.
  • the flow path P1 is connected to the mixing means M1.
  • the flow path P2 is connected to the mixing means M1.
  • the flow path P3 is connected to the mixing means M2.
  • the flow path R1 is connected to the mixing means M1 and the mixing means M2.
  • the flow path R1 is also a reaction section.
  • the flow path R2 is connected to the mixing means M2.
  • the flow path R2 is also a reaction section.
  • the p-bromobenzonitrile is supplied from the flow path P1 to the mixing means M1.
  • nBuLi is supplied from the flow path P2 to the mixing means M1.
  • the p-bromobenzonitrile and the nBuLi are mixed in the mixing means M1, and p-bromobenzonitrile is lithiated in the resulting liquid to produce p-cyanophenyllithium.
  • the p-cyanophenyllithium-containing liquid flowing through the flow path R1 is introduced into the mixing means M2.
  • the liquid is mixed with the boronic acid ester compound supplied from the flow path P3 to produce a boronic acid compound after quenching.
  • Example 1 Reaction in flow reactor: examination of temperature and inner diameter of micromixer
  • Two T-shaped micromixers M1 and M2 Sanko Seiki Kogyo Co., Ltd.
  • two microtube reactors R1 and R2 GL Sciences
  • the flow microreactor system was placed in a cooling bath at T° C., and 4-bromobenzonitrile solution (0.38 M, THF solution, flow rate: 6.0 mL/min, Tokyo Chemical Industry Co., Ltd.) and n-butyllithium solution (1. 6 M, hexane solution, flow rate: 1.5 mL/min (Kanto Kagaku Co., Ltd.) was introduced into M1 (250 ⁇ m or 500 ⁇ m) by a syringe pump.
  • Example 2 Reaction in flow reactor: study of flow rate and temperature
  • Two T-shaped micromixers M1 and M2 Sanko Seiki Kogyo Co., Ltd.
  • two microtube reactors R1 and R2 GL Sciences
  • Example 3 Reaction at high concentration in a flow reactor: examination of the inner diameter of the cooling line and the inner diameter of the micromixer
  • two T-shaped micromixers M1 and M2 Sanko Seiki Kogyo Co., Ltd.
  • two microtube reactors R1 and R2 GL Sciences
  • Embodiments of the present invention include, for example, the following.
  • Step 1 of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into a first micromixer, the compound obtained in step 1, and a boronate ester compound. and a step 2 of introducing into a second micromixer.
  • ⁇ 2> The method for producing a boronic acid compound according to ⁇ 1>, wherein the step 1 is performed at -20°C or higher.
  • step 3> The method for producing a boronic acid compound according to ⁇ 1> or ⁇ 2>, wherein step 2 is carried out at -20°C or higher.
  • ⁇ 4> The method for producing a boronic acid compound according to any one of ⁇ 1> to ⁇ 3>, wherein in step 1, the p-bromobenzonitrile is introduced at a rate of 10 mL/min or more.
  • ⁇ 5> The method for producing a boronic acid compound according to any one of ⁇ 1> to ⁇ 3>, wherein in step 1, the p-bromobenzonitrile is introduced at a rate of 60 mL/min or more.
  • ⁇ 6> The method for producing a boronic acid compound according to any one of ⁇ 1> to ⁇ 5>, wherein the first micromixer has an average inner diameter of 250 ⁇ m or more.
  • ⁇ 7> The method for producing a boronic acid compound according to any one of ⁇ 1> to ⁇ 6>, wherein the second micromixer has an average inner diameter of 250 ⁇ m or more.
  • ⁇ 8> The method for producing a boronic acid compound according to any one of ⁇ 1> to ⁇ 7>, wherein the yield of the boronic acid compound is 50% or more.

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Abstract

Provided is a method for producing a boronic acid compound characterized by including: a first step of introducing in a first micromixer p-bromobenzonitrile at 0.30M or more and nBuLi at 1.6M or more; and a second step of introducing in a second micromixer the compound obtained in the first step and a boronic acid ester compound.

Description

ボロン酸化合物の製造方法Method for producing boronic acid compound
　本発明は、ボロン酸化合物の製造方法に関する。 The present invention relates to a method for producing a boronic acid compound.
　鈴木カップリング反応の基質などとして使用されるボロン酸化合物は、近年、その需要が高まっている。
　ｏ－ジハロ芳香族化合物からボロン酸化合物を合成する方法は知られているが（特許文献１）、この方法は、－８０℃～－５０℃の極低温で反応させることが必要であり、簡易な方法であるとはいえない。 Demands for boronic acid compounds used as substrates for Suzuki coupling reactions have increased in recent years.
A method for synthesizing a boronic acid compound from an o-dihaloaromatic compound is known (Patent Document 1), but this method requires a reaction at an extremely low temperature of -80°C to -50°C and is simple. It cannot be said that it is a good method.
　したがって、効率よく簡易に、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する方法は未だ提供されておらず、その速やかな提供が強く求められている。 Therefore, a method for efficiently and simply producing a boronic acid compound from p-bromobenzonitrile has not yet been provided, and there is a strong demand for its prompt provision.
特開２００８－１９５６３９号公報JP 2008-195639 A
　本発明は、従来における前記諸問題を解決し、以下の目的を達成することを課題とする。即ち、本発明は、効率よく簡易に、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する方法を提供することを目的とする。 The object of the present invention is to solve the above-mentioned problems in the past and to achieve the following objects. That is, an object of the present invention is to provide a method for efficiently and easily producing a boronic acid compound from p-bromobenzonitrile.
　本発明者らが、前記目的を達成すべく鋭意研究を重ねた結果、０．３０Ｍ以上のｐ－ブロモベンゾニトリルと、１．６Ｍ以上のｎＢｕＬｉと、を第１のマイクロミキサーに導入する工程１と、前記工程１で得られた化合物と、ボロン酸エステル化合物と、を第２のマイクロミキサーに導入する工程２と、を含むことを特徴とするボロン酸化合物の製造方法により、効率よく簡易に、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する方法が提供できることを知見した。 As a result of extensive research by the present inventors to achieve the above object, step 1 of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into the first micromixer and Step 2 of introducing the compound obtained in Step 1 and the boronic acid ester compound into a second micromixer. , p-bromobenzonitrile to provide a method for producing a boronic acid compound.
　本発明は、本発明者らによる前記知見に基づくものであり、前記課題を解決するための手段としては以下のとおりである。即ち、
　＜１＞　０．３０Ｍ以上のｐ－ブロモベンゾニトリルと、１．６Ｍ以上のｎＢｕＬｉと、を第１のマイクロミキサーに導入する工程１と、前記工程１で得られた化合物と、ボロン酸エステル化合物と、を第２のマイクロミキサーに導入する工程２と、を含むことを特徴とするボロン酸化合物の製造方法である。 The present invention is based on the above findings by the present inventors, and the means for solving the above problems are as follows. Namely
<1> Step 1 of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into a first micromixer, the compound obtained in step 1, and a boronate ester compound. and a step 2 of introducing into a second micromixer.
　本発明によると、効率よく簡易に、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する方法を提供することができる。 According to the present invention, it is possible to provide a method for efficiently and easily producing a boronic acid compound from p-bromobenzonitrile.
図１は、本発明の製造方法の一例に用いるフローマイクロリアクターの概略図である。FIG. 1 is a schematic diagram of a flow microreactor used in one example of the production method of the present invention. 図２は、実施例１で使用したマイクロリアクターシステムの概略図である。2 is a schematic diagram of the microreactor system used in Example 1. FIG. 図３は、実施例２で使用したマイクロリアクターシステムの概略図である。3 is a schematic diagram of the microreactor system used in Example 2. FIG. 図４は、実施例３で使用したマイクロリアクターシステムの概略図である。4 is a schematic diagram of the microreactor system used in Example 3. FIG.
　（ボロン酸化合物の製造方法）
　前記ボロン酸化合物の製造方法は、工程１と、工程２と、を含み、さらに、その他の工程を含むことができる。 (Method for producing boronic acid compound)
The method for producing the boronic acid compound includes steps 1 and 2, and may further include other steps.
＜工程１＞
　前記工程１は、０．３０Ｍ以上のｐ－ブロモベンゾニトリルと、１．６Ｍ以上のｎＢｕＬｉと、を第１のマイクロミキサーに導入する工程である。 <Step 1>
The step 1 is a step of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into the first micromixer.
－ｐ－ブロモベンゾニトリル－
　前記ｐ－ブロモベンゾニトリルは、４－ブロモベンゾニトリルとも表記する。 -p-bromobenzonitrile-
The p-bromobenzonitrile is also referred to as 4-bromobenzonitrile.
　前記ｐ－ブロモベンゾニトリルの濃度の下限値としては、０．３０Ｍ以上である限り、特に制限はなく、目的に応じて適宜選択することができるが、効率よく、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する点から、０．３５Ｍ以上が好ましく、０．３８Ｍ以上がより好ましい。 The lower limit of the concentration of the p-bromobenzonitrile is not particularly limited as long as it is 0.30 M or more, and can be appropriately selected according to the purpose. 0.35M or more is preferable, and 0.38M or more is more preferable from the point of manufacturing a compound.
　前記ｐ－ブロモベンゾニトリルの濃度の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、副反応を抑制する点から、０．５Ｍ以下が好ましい。 The upper limit of the concentration of p-bromobenzonitrile is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of suppressing side reactions, it is preferably 0.5 M or less.
－ｎＢｕＬｉ－
　前記ｎＢｕＬｉは、ｎ－ブチルリチウム、又はノルマルブチルリチウムとも表記する。 -nBuLi-
The nBuLi is also referred to as n-butyllithium or normal butyllithium.
　前記ｎＢｕＬｉの濃度の下限値としては、１．６Ｍ以上である限り、特に制限はなく、目的に応じて適宜選択することができる。
　前記ｎＢｕＬｉの濃度の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、副反応を抑制する点から、２．８Ｍ以下が好ましい。 The lower limit of the concentration of nBuLi is not particularly limited as long as it is 1.6M or more, and can be appropriately selected according to the purpose.
The upper limit of the concentration of nBuLi is not particularly limited and can be appropriately selected depending on the intended purpose.
－第１のマイクロミキサー－
　前記第１のマイクロミキサーとしては、マイクロリアクター（以下、「フローマイクロリアクター」又は「フロー反応器」と称することがある）における混合手段である限り、特に制限はなく、目的に応じて適宜選択することができ、下記のマイクロリアクターにおける、基板型のマイクロミキサー、又は管継手型のマイクロミキサーであってもよい。 -The first micro mixer-
The first micromixer is not particularly limited as long as it is a mixing means in a microreactor (hereinafter sometimes referred to as "flow microreactor" or "flow reactor"), and is appropriately selected according to the purpose. It may be a substrate-type micromixer or a pipe joint-type micromixer in the microreactor described below.
－マイクロリアクター－
　前記マイクロリアクターとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、混合手段と、流通路とを備え、更に必要に応じてその他の手段を備えるマイクロリアクターなどが挙げられる。
　前記混合手段と前記流通路とは、一体型であってもよいし、別体型であってもよい。 －Micro Reactor－
The microreactor is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include a microreactor provided with mixing means, a flow path, and other means as necessary. .
The mixing means and the flow path may be integrated or separated.
　前記混合手段は、２種以上の液体を混合可能な手段である。
　前記流通路は、液体を流通可能な管である。前記流通路は、少なくとも１つの前記混合手段と接続される。 The mixing means is a means capable of mixing two or more liquids.
The flow path is a tube through which liquid can flow. The flow passage is connected with at least one of the mixing means.
　前記フローマイクロリアクターを用いることで、安定性の低い化合物について、生成から次の反応までの滞留時間を短時間にし、副反応を抑制することができる。
　また、前記フローマイクロリアクターは、冷却効率が優れるため、発熱反応における発熱による副反応を抑制することができる。 By using the flow microreactor, it is possible to shorten the residence time from the generation to the next reaction of a compound with low stability, thereby suppressing side reactions.
In addition, since the flow microreactor has excellent cooling efficiency, it is possible to suppress side reactions caused by heat generation in an exothermic reaction.
－－一体型のフローマイクロリアクター－－
　前記一体型のフローマイクロリアクターの前記混合手段及び前記流通路としては、基板型のマイクロミキサーなどが挙げられる。 --Integrated flow microreactor--
Examples of the mixing means and the flow path of the integrated flow microreactor include a substrate-type micromixer.
　前記基板型のマイクロミキサーは、内部又は表面に通路が形成された基板からなり、マイクロチャンネルと称される場合がある。
　前記基板型のマイクロミキサーとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、国際公開第９６／３０１１３号パンフレットに記載される混合のための微細な流路を有するミキサー；文献「“マイクロリアクターズ”三章、Ｗ．Ｅｈｒｆｅｌｄ、Ｖ．Ｈｅｓｓｅｌ、Ｈ．Ｌｏｗｅ著、Ｗｉｌｅｙ－ＶＣＨ社刊」に記載されるミキサーなどが挙げられる。 The substrate-type micromixer is composed of a substrate having passages formed therein or on its surface, and is sometimes referred to as a microchannel.
The substrate-type micromixer is not particularly limited and can be appropriately selected according to the purpose. ; the mixer described in the document ““Microreactors” Chapter 3, W. Ehrfeld, V. Hessel, H. Lowe, published by Wiley-VCH Co.”, and the like.
　前記基板型のマイクロミキサーは、前記混合手段及び前記流通路が、複数の液体を混合可能な微小な流路により構成されている。 In the substrate-type micromixer, the mixing means and the flow path are composed of minute flow paths capable of mixing a plurality of liquids.
　前記基板型のマイクロミキサーには、前記流路以外に、前記流路に連通し、前記流路に複数の液体を導入する導入路が形成されていることが好ましい。即ち、前記導入路の数に応じて、前記流路の上流側が分岐した構成が好ましい。 It is preferable that the substrate-type micromixer has an introduction path other than the flow path, which communicates with the flow path and introduces a plurality of liquids into the flow path. That is, it is preferable that the upstream side of the flow path is branched according to the number of the introduction paths.
　前記導入路の数としては、特に制限はなく、目的に応じて適宜選択することができるが、混合を所望する複数の液体を別々の導入路から導入し、流路で合流させて混合することが好ましい。なお、１つの液体を予め流路に仕込んでおき、それ以外の液体を導入路により導入する構成としてもよい。 The number of the introduction channels is not particularly limited and can be appropriately selected according to the purpose. is preferred. It should be noted that a configuration may be adopted in which one liquid is charged in advance into the flow path and another liquid is introduced through the introduction path.
－－別体型のフローマイクロリアクター－－
　前記別体型のフローマイクロリアクターは、混合手段と、流通路とが接続してなる。 --Separate flow microreactor--
In the separate flow microreactor, the mixing means and the flow path are connected.
　前記混合手段としては、２種以上の液体を混合可能な限り、特に制限はなく、目的に応じて適宜選択することができ、例えば、管継手型のマイクロミキサーなどが挙げられる。 The mixing means is not particularly limited as long as it can mix two or more liquids, and can be appropriately selected according to the purpose. Examples thereof include a pipe joint type micromixer.
　前記管継手型のマイクロミキサーは、内部に形成された流路を備え、必要に応じて前記内部に形成された流路と、前記流通路とを接続する接続部材を備える。前記接続部材における接続方式としては、特に制限はなく、公知の接続方式の中から目的に応じて適宜選択することができ、例えば、ねじ込み式、ユニオン式、突合わせ溶接式、差込み溶接式、ソケット溶接式、フランジ式、食込み式、フレア式、メカニカル式などが挙げられる。 The pipe joint type micromixer has a channel formed inside and, if necessary, a connection member that connects the channel formed inside and the flow channel. The connection method of the connection member is not particularly limited, and can be appropriately selected from known connection methods according to the purpose. Welding type, flange type, bite type, flare type, mechanical type, and the like are included.
　前記管継手型のマイクロミキサーの内部には、前記流路以外に、前記流路に連通し、前記流路に複数の液体を導入する導入路が形成されていることが好ましい。即ち、前記導入路の数に応じて、前記流路の上流側が分岐された構成が好ましい。前記導入路の数が２つである場合には、前記管継手型のマイクロミキサーとして、例えば、Ｔ字型やＹ字型を用いることができ、前記導入路の数が３つである場合には、例えば、十字型を用いることができる。なお、１つの液体を予め流路に仕込んでおき、それ以外の液体を導入路により導入する構成としてもよい。 It is preferable that, in addition to the flow path, an introduction path communicating with the flow path and introducing a plurality of liquids into the flow path is formed inside the pipe joint type micromixer. That is, it is preferable that the upstream side of the flow path is branched according to the number of the introduction paths. When the number of the introduction paths is two, for example, a T-shape or Y-shape can be used as the pipe joint type micromixer, and when the number of the introduction paths is three, can use, for example, a cross shape. It should be noted that a configuration may be adopted in which one liquid is charged in advance into the flow path and another liquid is introduced through the introduction path.
　前記管継手型のマイクロミキサーの材質としては、特に制限はなく、耐熱性、耐圧性、耐溶剤性、及び加工容易性などの要求に応じて、適宜選択することができ、例えば、ステンレス鋼、チタン、銅、ニッケル、アルミニウム、シリコン、及びテフロン（登録商標）、ＰＦＡ（パーフルオロアルコキシ樹脂）などのフッ素樹脂、ＴＦＡＡ（トリフルオロアセトアミド）などが挙げられる。 The material of the pipe joint type micromixer is not particularly limited, and can be appropriately selected according to requirements such as heat resistance, pressure resistance, solvent resistance, and ease of processing. Titanium, copper, nickel, aluminum, silicon, fluorine resins such as Teflon (registered trademark), PFA (perfluoroalkoxy resin), TFAA (trifluoroacetamide), and the like.
　前記管継手型のマイクロミキサーとしては、市販品を利用することができ、例えば、アズビル株式会社製ＹＭ－１型ミキサー、ＹＭ－２型ミキサー；島津ＧＬＣ社製ミキシングティー及びティー（Ｔ字コネクタ）；東レエンジニアリング開発品マイクロ・ハイ・ミキサー；スウェージロック社製ユニオンティー、株式会社三幸精機工業製Ｔ字型マイクロミキサーなどが挙げられる。 Commercially available products can be used as the pipe joint type micromixer. For example, YM-1 type mixer and YM-2 type mixer manufactured by Azbil Corporation; mixing tees and tees (T-shaped connector) manufactured by Shimadzu GLC Co., Ltd. Micro High Mixer developed by Toray Engineering; Union Tee manufactured by Swagelok, T-shaped Micro Mixer manufactured by Sanko Seiki Kogyo Co., Ltd.;
　前記混合手段内での２以上の原料物質の混合方式としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、層流による混合、乱流による混合などが挙げられる。中でも、より効率的に反応制御や除熱を行える点で、層流による混合（静的混合）が好ましい。 The method of mixing two or more raw materials in the mixing means is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include laminar flow mixing and turbulent mixing. Among them, laminar flow mixing (static mixing) is preferable in terms of more efficient reaction control and heat removal.
　なお、前記混合手段内の流路は微小であるため、混合手段に導入された複数の液体同士はおのずと層流支配の流れとなりやすく、流れに直交する方向に拡散して混合される。層流による混合において、さらに、流路内に分岐点及び合流点を設けることで、流れる液体の層流断面を分割するような構成とし、混合速度を高める構成としてもよい。
　また、前記混合手段の流路において、乱流による混合（動的混合）を行う場合には、流量や流路の形状（接液部分の３次元形状や流路の屈曲などの形状、壁面の粗さ、など）を調整することによって、層流から乱流へと変化させることができる。前記乱流による混合は、前記層流による混合と比べて、混合効率がよく混合速度が速いという利点を有する。 Since the flow path in the mixing means is minute, the plurality of liquids introduced into the mixing means naturally tend to flow laminarly, and are diffused and mixed in the direction perpendicular to the flow. In mixing by laminar flow, a configuration may be adopted in which branch points and confluence points are further provided in the flow path to divide the laminar cross section of the flowing liquid, thereby increasing the mixing speed.
In addition, when performing mixing (dynamic mixing) by turbulent flow in the channel of the mixing means, the flow rate and the shape of the channel (three-dimensional shape of the wetted part, shape such as bending of the channel, wall surface roughness, etc.) can be changed from laminar to turbulent. The turbulent mixing has the advantage of high mixing efficiency and high mixing speed compared to the laminar mixing.
　ここで、前記混合手段内の前記流路の内径が小さい方が、分子の拡散距離を短くできるので、混合に要する時間を短縮させて混合効率を向上させることができる。さらに、前記流路の内径が小さい方が、体積に対する表面積の比が大きくなり、例えば、反応熱の除熱などの、液体の温度制御を容易に行うことができる。
　一方で、前記流路の内径が小さ過ぎると、液体を流す時の圧力損失が増加するとともに、送液に使用するポンプとして特別な高耐圧のものが必要となるため、製造コストが高くなることがある。また、送液流量が制限されることにより、前記マイクロミキサーの構造も制限されることがある。 Here, the smaller the inner diameter of the flow path in the mixing means, the shorter the diffusion distance of molecules, so the time required for mixing can be shortened and the mixing efficiency can be improved. Furthermore, the smaller the inner diameter of the flow channel, the larger the ratio of the surface area to the volume, making it easier to control the temperature of the liquid, for example, to remove the heat of reaction.
On the other hand, if the inner diameter of the flow path is too small, the pressure loss increases when the liquid flows, and the pump used for liquid transfer needs to have a special high pressure resistance, which increases the manufacturing cost. There is In addition, the structure of the micromixer may also be limited due to the limitation of the flow rate of liquid transfer.
　前記混合手段内の前記流路の平均内径（前記マイクロミキサーの平均内径）の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、より迅速に混合でき、より効率的に反応熱を除熱でき、送液時の圧力損失を低減する点から、５０μｍ以上が好ましく、１００μｍ以上がより好ましく、２５０μｍ以上がさらに好ましく、５００μｍがよりさらに好ましく、１０００μｍ以上が特に好ましく、１３００μｍ以上が最も好ましい。 The lower limit of the average inner diameter of the flow path in the mixing means (the average inner diameter of the micromixer) is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of effectively removing heat of reaction and reducing pressure loss during liquid feeding, the thickness is preferably 50 μm or more, more preferably 100 μm or more, even more preferably 250 μm or more, even more preferably 500 μm or more, and particularly preferably 1000 μm or more. 1300 μm or more is most preferable.
　前記混合手段内の前記流路の平均内径（マイクロミキサーの平均内径）の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、４ｍｍ以下が好ましく、３ｍｍ以下がより好ましく、２．５ｍｍ以下がさらに好ましい。 The upper limit of the average inner diameter of the channel in the mixing means (the average inner diameter of the micromixer) is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 4 mm or less, more preferably 3 mm or less. Preferably, 2.5 mm or less is more preferable.
　前記平均内径が５０μｍ未満であると、圧力損失が増大することがある。前記平均内径が４ｍｍを超えると、単位体積当たりの表面積が小さくなり、その結果、迅速な混合や反応熱の除熱が困難になることがある。 When the average inner diameter is less than 50 μm, pressure loss may increase. If the average inner diameter exceeds 4 mm, the surface area per unit volume becomes small, and as a result, rapid mixing and removal of reaction heat may become difficult.
　前記流路の断面積としては、特に制限はなく、目的に応じて適宜選択することができ、１００μｍ２～１６ｍｍ２が好ましく、１，０００μｍ２～４．０ｍｍ２がより好ましく、１０，０００μｍ２～２．１ｍｍ２が更に好ましく、１９０，０００μｍ２～１ｍｍ２が特に好ましい。 The cross-sectional area of the flow channel is not particularly limited and can be appropriately selected according to the purpose . ~2.1 mm 2 is more preferred, and 190,000 µm 2 to 1 mm 2 is particularly preferred.
　前記流路の断面形状としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、円形、矩形、半円形、三角形などが挙げられる。 The cross-sectional shape of the flow path is not particularly limited, and can be appropriately selected according to the purpose. Examples include circular, rectangular, semicircular, and triangular shapes.
　前記流通路は、少なくとも１つの前記混合手段と接続され、液体を流通可能な管であれば、特に制限はなく、目的に応じて適宜選択することができ、その内径、外径、長さ、材質などの構成は、所望する反応に応じて適宜選択することができる。 The flow path is not particularly limited as long as it is a tube that is connected to at least one of the mixing means and can circulate the liquid, and can be appropriately selected according to the purpose. The configuration such as the material can be appropriately selected according to the desired reaction.
　前記流通路は、例えば、原料物質を混合手段に供給する際に使用される。
　また、前記流通路は、例えば、前記混合手段によって混合された２種以上の物質の反応生成物を、次の混合手段に供給する際に使用される。なお、この際、前記流通路内では反応が継続して起きていてもよい。 The flow path is used, for example, when supplying raw materials to the mixing means.
Further, the flow path is used, for example, when supplying the reaction product of two or more substances mixed by the mixing means to the next mixing means. At this time, the reaction may continue to occur within the flow path.
　前記流通路としては、市販品を利用することができ、例えば、ジーエルサイエンス株式会社製のステンレスチューブ（外径１／１６インチ（１．５８ｍｍ）、内径２５０μｍ、５００μｍ及び１，０００μｍから選択可能、チューブ長さは使用者により調整可能）などが挙げられる。 Commercially available products can be used as the flow path. For example, a stainless steel tube manufactured by GL Sciences Co., Ltd. (outer diameter 1/16 inch (1.58 mm), inner diameter 250 μm, 500 μm and 1,000 μm can be selected, The tube length can be adjusted by the user).
　前記流通路の材質としては、特に制限はなく、前記混合手段の材質として例示したものを、好適に利用することができる。 The material of the flow path is not particularly limited, and those exemplified as the material of the mixing means can be suitably used.
　前記混合手段の上流に連結される前記流通路の平均内径（チューブ予冷ユニット：クーリングラインの平均内径）の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、送液時の圧力損失を低減する点から、５０μｍ以上が好ましく、１００μｍ以上がより好ましく、２５０μｍ以上がさらに好ましく、５００μｍがよりさらに好ましく、１０００μｍ以上が特に好ましく、２０００μｍ以上が最も好ましい。 The lower limit of the average inner diameter of the flow passage (tube precooling unit: cooling line average inner diameter) connected upstream of the mixing means is not particularly limited and can be appropriately selected according to the purpose. From the viewpoint of reducing pressure loss when liquid, the thickness is preferably 50 µm or more, more preferably 100 µm or more, still more preferably 250 µm or more, even more preferably 500 µm or more, particularly preferably 1000 µm or more, and most preferably 2000 µm or more.
　前記混合手段の上流に連結される前記流通路の平均内径（チューブ予冷ユニット：クーリングラインの平均内径）の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、４ｍｍ以下が好ましく、３ｍｍ以下がより好ましく、２．５ｍｍ以下がさらに好ましい。 The upper limit of the average inner diameter of the flow passage (tube precooling unit: cooling line average inner diameter) connected upstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The following is preferable, 3 mm or less is more preferable, and 2.5 mm or less is even more preferable.
　前記混合手段の下流に連結される前記流通路の平均内径（マイクロチューブリアクターの平均内径）の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、送液時の圧力損失を低減する点から、５０μｍ以上が好ましく、１００μｍ以上がより好ましく、２５０μｍ以上がさらに好ましく、５００μｍがよりさらに好ましく、１０００μｍ以上が特に好ましい。 The lower limit of the average inner diameter of the flow passage connected downstream of the mixing means (the average inner diameter of the microtube reactor) is not particularly limited and can be appropriately selected according to the purpose. From the viewpoint of reducing pressure loss, it is preferably 50 µm or more, more preferably 100 µm or more, still more preferably 250 µm or more, even more preferably 500 µm or more, and particularly preferably 1000 µm or more.
　前記混合手段の下流に連結される前記流通路の平均内径（マイクロチューブリアクターの平均内径）の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、４ｍｍ以下が好ましく、３ｍｍ以下がより好ましく、２．５ｍｍ以下がさらに好ましい。 The upper limit of the average inner diameter of the flow path (the average inner diameter of the microtube reactor) connected downstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 4 mm or less. , 3 mm or less, and more preferably 2.5 mm or less.
　原材料（ｐ－ブロモベンゾニトリル）を供給する前記流通路（前記混合手段の上流に連結される前記流通路）における液の流量の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、効率よく、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する点から、５ｍＬ／分以上が好ましく、１０ｍＬ／分以上がより好ましく、２０ｍＬ／分以上がさらに好ましく、３０ｍＬ／分以上がよりさらに好ましく、５０ｍＬ／分以上が特に好ましく、６０ｍＬ／分以上が特に好ましい。 The lower limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (p-bromobenzonitrile) is not particularly limited, and is appropriately selected according to the purpose. However, from the viewpoint of efficiently producing a boronic acid compound from p-bromobenzonitrile, it is preferably 5 mL / min or more, more preferably 10 mL / min or more, further preferably 20 mL / min or more, and 30 mL / min or more. is more preferable, 50 mL/min or more is particularly preferable, and 60 mL/min or more is particularly preferable.
　原材料（ｐ－ブロモベンゾニトリル）を供給する前記流通路（前記混合手段の上流に連結される前記流通路）における液の流量の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、３００ｍＬ／分以下が好ましい。 The upper limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (p-bromobenzonitrile) is not particularly limited, and is appropriately selected according to the purpose. but preferably 300 mL/min or less.
　原材料（ｎＢｕＬｉ）を供給する前記流通路（前記混合手段の上流に連結される前記流通路）における液の流量の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、効率よく、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する点から、１．２５ｍＬ／分以上が好ましく、２．５ｍＬ／分以上がより好ましく、５ｍＬ／分以上がさらに好ましく、７．５ｍＬ／分以上がよりさらに好ましく、１２．５ｍＬ／分以上が特に好ましく、１５ｍＬ／分以上が特に好ましい。 The lower limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (nBuLi) is not particularly limited, and can be appropriately selected according to the purpose. , From the viewpoint of efficiently producing a boronic acid compound from p-bromobenzonitrile, it is preferably 1.25 mL / min or more, more preferably 2.5 mL / min or more, even more preferably 5 mL / min or more, 7.5 mL / minutes or more is even more preferable, 12.5 mL/minute or more is particularly preferable, and 15 mL/minute or more is particularly preferable.
　原材料（ｎＢｕＬｉ）を供給する前記流通路（前記混合手段の上流に連結される前記流通路）における液の流量の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、７５ｍＬ／分以下が好ましい。 The upper limit of the flow rate of the liquid in the flow path (the flow path connected upstream of the mixing means) for supplying the raw material (nBuLi) is not particularly limited, and can be appropriately selected according to the purpose. , 75 mL/min or less is preferred.
　前記工程１の反応液が流通する流通路における前記反応液の滞留時間の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、転化率を高くする点から、０．０１秒以上が好ましく、０．１秒以上がより好ましい。 The lower limit of the retention time of the reaction liquid in the flow path through which the reaction liquid in step 1 flows is not particularly limited and can be appropriately selected according to the purpose. 0.01 second or more is preferable, and 0.1 second or more is more preferable.
　前記工程１の反応液が流通する流通路における前記反応液の滞留時間の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、副反応を抑制し、効率よく、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する点から、１０秒以下が好ましく、５秒以下がより好ましく、２秒以下がさらに好ましく、１秒以下がよりさらに好ましく、０．５秒以下が特に好ましい。 The upper limit of the retention time of the reaction solution in the flow path through which the reaction solution flows in step 1 is not particularly limited, and can be appropriately selected according to the purpose. From the viewpoint of producing a boronic acid compound from p-bromobenzonitrile, the time is preferably 10 seconds or less, more preferably 5 seconds or less, even more preferably 2 seconds or less, even more preferably 1 second or less, and particularly 0.5 seconds or less. preferable.
　前記滞留時間は、前記マイクロチューブリアクターの長さと平均内径を調節することにより、上記範囲とすることができる。 The residence time can be set within the above range by adjusting the length and average inner diameter of the microtube reactor.
　前記混合手段の上流に連結される前記流通路の長さの下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、４０ｃｍ以上が好ましく、６０ｃｍ以上がより好ましく、８０ｃｍ以上がさらに好ましく、１００ｃｍ以上が特に好ましい。 The lower limit of the length of the flow path connected upstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. 100 cm or more is more preferable, and 100 cm or more is particularly preferable.
　前記混合手段の上流に連結される前記流通路の長さの上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、３００ｃｍ以下が好ましく、２８０ｃｍ以下がより好ましく、２５０ｃｍ以下がさらに好ましく、２３０ｃｍ以下が特に好ましい。 The upper limit of the length of the flow path connected upstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The following is more preferable, and 230 cm or less is particularly preferable.
　前記混合手段の下流に連結される前記流通路の長さの下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、５ｃｍ以上が好ましく、１０ｃｍ以上がより好ましく、１５ｃｍ以上がさらに好ましく、２０ｃｍ以上がよりさらに好ましく、５０ｃｍ以上が特に好ましい。 The lower limit of the length of the flow path connected downstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The above is more preferable, 20 cm or more is even more preferable, and 50 cm or more is particularly preferable.
　前記混合手段の下流に連結される前記流通路の長さの上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、３００ｃｍ以下が好ましく、２８０ｃｍ以下がより好ましく、２５０ｃｍ以下がさらに好ましく、２３０ｃｍ以下が特に好ましい。 The upper limit of the length of the flow path connected downstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose. The following is more preferable, and 230 cm or less is particularly preferable.
－－その他の手段－－
　前記その他の手段としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、送液手段、温度調節手段などが挙げられる。 --other means--
The other means are not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include liquid feeding means, temperature control means and the like.
　前記送液手段としては、各種原料物質を、前記フローマイクロリアクターの前記流通路に供給できる限り、特に制限はなく、目的に応じて適宜選択することができ、例えば、ポンプなどが挙げられる。 The liquid sending means is not particularly limited as long as it can supply various raw materials to the flow path of the flow microreactor, and can be appropriately selected according to the purpose. Examples include a pump.
　前記ポンプとしては、特に制限はなく、工業的に使用されうるものから適宜選択することができるが、送液時に脈動を生じないものが好ましく、例えば、プランジャーポンプ、ギアーポンプ、ロータリーポンプ、ダイアフラムポンプなどが挙げられる。 The pump is not particularly limited and can be appropriately selected from those that can be used industrially, but those that do not cause pulsation during liquid transfer are preferable, and examples include plunger pumps, gear pumps, rotary pumps, and diaphragm pumps. etc.
　前記温度調節手段としては、前記フローマイクロリアクターの前記混合手段、及び前記流路の温度を調節できる限り、特に制限はなく、目的に応じて適宜選択することができる。 The temperature control means is not particularly limited as long as the temperature of the mixing means and the channel of the flow microreactor can be controlled, and can be appropriately selected according to the purpose.
　前記工程１の反応温度の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、冷却負荷を軽減する点から、－２０℃以上が好ましく、－１５℃以上がより好ましく、－１０℃以上がさらに好ましく、－５℃以上がよりさらに好ましく、０℃以上が特に好ましい。 The lower limit of the reaction temperature in step 1 is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of reducing the cooling load, -20 ° C. or higher is preferable, and -15 ° C. or higher is more preferable. -10°C or higher is more preferred, -5°C or higher is even more preferred, and 0°C or higher is particularly preferred.
　前記工程１の反応温度の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、副反応を抑制する点から、２０℃以下が好ましく、１５℃以下がより好ましく、１０℃以下がさらに好ましく、５℃以下が特に好ましい。 The upper limit of the reaction temperature in step 1 is not particularly limited and can be appropriately selected according to the purpose. 10° C. or lower is more preferable, and 5° C. or lower is particularly preferable.
　前記ｐ－ブロモベンゾニトリルに対する、前記ｎＢｕＬｉの量の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、転化率を高くする点から、０．９モル当量以上が好ましく、１．０モル当量以上がより好ましく、１．１モル当量以上がさらに好ましい。 The lower limit of the amount of nBuLi with respect to the p-bromobenzonitrile is not particularly limited and can be appropriately selected depending on the purpose. It is preferably 1.0 molar equivalents or more, more preferably 1.1 molar equivalents or more.
　前記ｐ－ブロモベンゾニトリルに対する、前記ｎＢｕＬｉの量の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、試薬を節減する点から、２．５モル当量以下が好ましく、２．０モル当量以下がより好ましく、１．５モル当量以下がさらに好ましい。 The upper limit of the amount of nBuLi with respect to the p-bromobenzonitrile is not particularly limited and can be appropriately selected depending on the purpose, but from the viewpoint of saving reagents, it is preferably 2.5 molar equivalents or less. , is more preferably 2.0 molar equivalents or less, and more preferably 1.5 molar equivalents or less.
＜工程２＞
　前記工程２は、前記工程１で得られた化合物と、ボロン酸エステル化合物と、を第２のマイクロミキサーに導入する工程である。 <Step 2>
The step 2 is a step of introducing the compound obtained in the step 1 and the boronic acid ester compound into a second micromixer.
－工程１で得られた化合物－
　前記工程１で得られた化合物とは、前記ｐ－ブロモベンゾニトリルと、前記ｎＢｕＬｉと、を第１のマイクロミキサーで混合して得られた化合物である。
　前記ｐ－ブロモベンゾニトリルと、前記ｎＢｕＬｉと、を第１のマイクロミキサーで混合して得られた化合物としては、ｐ－シアノフェニルリチウムなどが挙げられる。 -Compound obtained in step 1-
The compound obtained in step 1 is a compound obtained by mixing the p-bromobenzonitrile and the nBuLi with a first micromixer.
Examples of the compound obtained by mixing the p-bromobenzonitrile and the nBuLi in the first micromixer include p-cyanophenyllithium.
－ボロン酸エステル化合物－
　前記ボロン酸エステル化合物としては、特に制限はなく、目的に応じて適宜選択することができるが、副反応を抑制する点から、イソプロポキシボロン酸ピナコールエステル、又はホウ酸トリイソプロピルが好ましい。 - Boronic acid ester compound -
The boronate ester compound is not particularly limited and can be appropriately selected depending on the intended purpose. From the viewpoint of suppressing side reactions, isopropoxyboronic acid pinacol ester or triisopropyl borate is preferable.
－第２のマイクロミキサー－
　前記第２のマイクロミキサーは、前述の第１のマイクロミキサーに記載したとおりである。 - Second Micro Mixer -
The second micromixer is as described for the first micromixer above.
　前記工程２の反応液が流通する流通路における前記反応液の滞留時間の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、効率よく、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する点から、０．０１秒以上が好ましく、０．１秒以上がより好ましく、２秒以上がさらに好ましく、５秒以上が特に好ましい。 The lower limit of the retention time of the reaction solution in the flow path through which the reaction solution in step 2 flows is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound, the time is preferably 0.01 seconds or longer, more preferably 0.1 seconds or longer, even more preferably 2 seconds or longer, and particularly preferably 5 seconds or longer.
　前記工程２の反応液が流通する流通路における前記反応液の滞留時間の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、効率よく、ｐ－ブロモベンゾニトリルからボロン酸化合物を製造する点から、３０秒以下が好ましく、２０秒以下がより好ましく、１０秒以下がさらに好ましい。 The upper limit of the residence time of the reaction solution in the flow path through which the reaction solution in step 2 flows is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound, the time is preferably 30 seconds or less, more preferably 20 seconds or less, and even more preferably 10 seconds or less.
　前記滞留時間は、前記マイクロチューブリアクターの長さと平均内径を調節することにより、上記範囲とすることができる。 The residence time can be set within the above range by adjusting the length and average inner diameter of the microtube reactor.
　前記工程２の反応温度の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、冷却負荷を軽減する点から、－２０℃以上が好ましく、－１５℃以上がより好ましく、－１０℃以上がさらに好ましく、－５℃以上がよりさらに好ましく、０℃以上が特に好ましい。 The lower limit of the reaction temperature in step 2 is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of reducing the cooling load, -20 ° C. or higher is preferable, and -15 ° C. or higher is more preferable. -10°C or higher is more preferred, -5°C or higher is even more preferred, and 0°C or higher is particularly preferred.
　前記工程２の反応温度の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、副反応を抑制する点から、２０℃以下が好ましく、１５℃以下がより好ましく、１０℃以下がさらに好ましく、５℃以下が特に好ましい。 The upper limit of the reaction temperature in step 2 is not particularly limited and can be appropriately selected according to the purpose. 10° C. or lower is more preferable, and 5° C. or lower is particularly preferable.
　前記工程１で得られた化合物に対する、前記ボロン酸エステル化合物の量の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、転化率を高くする点から、１．０モル当量以上が好ましく、１．１モル当量以上がより好ましく、１．２モル当量以上がさらに好ましい。 The lower limit of the amount of the boronate compound relative to the compound obtained in the step 1 is not particularly limited and can be appropriately selected depending on the purpose. 0 molar equivalent or more is preferable, 1.1 molar equivalent or more is more preferable, and 1.2 molar equivalent or more is still more preferable.
　前記工程１で得られた化合物に対する、前記ボロン酸エステル化合物の量の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、試薬を節減する点から、２．５モル当量以下が好ましく、２．０モル当量以下がより好ましく、１．５モル当量以下がさらに好ましい。 The upper limit of the amount of the boronic acid ester compound relative to the compound obtained in the step 1 is not particularly limited and can be appropriately selected depending on the purpose. The molar equivalent or less is preferable, 2.0 molar equivalent or less is more preferable, and 1.5 molar equivalent or less is even more preferable.
　前記ボロン酸化合物の製造方法における、ボロン酸化合物の収率としては、特に制限はなく、目的に応じて適宜選択することができるが、５０％以上が好ましく、６０％以上がより好ましく、７０％以上がさらに好ましく、８０％以上がよりさらに好ましく、８５％以上が特に好ましく、９０％以上が最も好ましい。
　前記収率は、以下のとおり、ＧＣ分析、又はＨＰＬＣ分析により決定する。 The yield of the boronic acid compound in the method for producing the boronic acid compound is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 50% or more, more preferably 60% or more, and 70%. 80% or more is more preferable, 85% or more is particularly preferable, and 90% or more is most preferable.
The yield is determined by GC analysis or HPLC analysis as follows.
　（ＧＣ分析）
　Ｒｅｓｔｅｋ　Ｒｔｘ－２００カラムを搭載したＳＨＩＭＡＺＵ　ＧＣ－２０１４を使用して実施し、化合物はＦＩＤによって検出する。
　収率については、内部標準溶液を分析して作成した検量線を用いて定量後、下記の式１（バッチ反応器の場合）又は式２（フロー反応器の場合）で算出する。
Figure JPOXMLDOC01-appb-M000001
Figure JPOXMLDOC01-appb-M000002
 (GC analysis)
Performed using a SHIMAZU GC-2014 equipped with a Restek Rtx-200 column and compounds detected by FID.
The yield is calculated using the following formula 1 (for batch reactor) or formula 2 (for flow reactor) after quantification using a calibration curve prepared by analyzing an internal standard solution.
Figure JPOXMLDOC01-appb-M000001
Figure JPOXMLDOC01-appb-M000002
　（ＨＰＬＣ分析）
　ＹＭＣ　ＴＡ１２Ｓ０５－２５４６ＷＴカラムを搭載したＳＨＩＭＡＺＵ　ＬＣ－１０Ａを使用し、移動相としてアセトニトリル／水＝９／１（ｖ／ｖ）を１．０ｍＬ／分で送液して実施し、化合物はＵＶ（検出波長２２０ｎｍ）によって検出する。
　収率については、内部標準溶液を分析して作成した検量線を用いて定量後、上記の式１（バッチ反応器の場合）又は式２（フロー反応器の場合）で算出する。 (HPLC analysis)
A Shimazu LC-10A equipped with a YMC TA12S05-2546WT column was used, and acetonitrile/water = 9/1 (v/v) was fed as a mobile phase at 1.0 mL/min. 220 nm wavelength).
The yield is calculated using the above formula 1 (for batch reactor) or formula 2 (for flow reactor) after quantification using a calibration curve prepared by analyzing an internal standard solution.
＜その他の工程＞
　前記その他の工程としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、前記工程２の後のクエンチ工程などが挙げられる。 <Other processes>
The other steps are not particularly limited and can be appropriately selected depending on the intended purpose.
－前記工程２の後のクエンチ工程－
　前記工程２の後のクエンチ工程としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、メタノール、又は塩酸を添加する方法などが挙げられる。 - Quenching step after step 2 -
The quenching step after step 2 is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include a method of adding methanol or hydrochloric acid.
　（ボロン酸化合物）
　前記ボロン酸化合物は、上述のボロン酸化合物の製造方法により製造される。 (boronic acid compound)
The boronic acid compound is produced by the method for producing a boronic acid compound described above.
　ここで、前記ボロン酸化合物の製造方法に好適に使用されるフローマイクロリアクター及びそれを用いたボロン酸化合物の製造方法の一例を図を用いて説明する。 Here, an example of a flow microreactor suitably used in the method for producing a boronic acid compound and a method for producing a boronic acid compound using the flow microreactor will be described with reference to the drawings.
　図１は、フローマイクロリアクターの一例を示す模式図である。
　図１に示すフローマイクロリアクターは、２つの混合手段と、５つの流通路とを備える。
　流通路Ｐ１は、混合手段Ｍ１に接続されている。
　流通路Ｐ２は、混合手段Ｍ１に接続されている。
　流通路Ｐ３は、混合手段Ｍ２に接続されている。
　流通路Ｒ１は、混合手段Ｍ１、及び混合手段Ｍ２に接続されている。流通路Ｒ１は、反応部でもある。
　流通路Ｒ２は、混合手段Ｍ２に接続されている。流通路Ｒ２は、反応部でもある。 FIG. 1 is a schematic diagram showing an example of a flow microreactor.
The flow microreactor shown in FIG. 1 comprises two mixing means and five flow channels.
The flow path P1 is connected to the mixing means M1.
The flow path P2 is connected to the mixing means M1.
The flow path P3 is connected to the mixing means M2.
The flow path R1 is connected to the mixing means M1 and the mixing means M2. The flow path R1 is also a reaction section.
The flow path R2 is connected to the mixing means M2. The flow path R2 is also a reaction section.
　流通路Ｐ１から混合手段Ｍ１に、前記ｐ－ブロモベンゾニトリルが供給される。流通路Ｐ２から混合手段Ｍ１に、ｎＢｕＬｉが供給される。そうすると、混合手段Ｍ１において、前記ｐ－ブロモベンゾニトリルと、前記ｎＢｕＬｉとが混合され、得られた液中では、ｐ－ブロモベンゾニトリルがリチオ化され、ｐ－シアノフェニルリチウムを生成する。
　流通路Ｒ１を流れる、前記ｐ－シアノフェニルリチウムを含有する液は、混合手段Ｍ２に導入される。混合手段Ｍ２において、前記液は、流通路Ｐ３から供給されたボロン酸エステル化合物と混合され、クエンチ後に、ボロン酸化合物を生成する。 The p-bromobenzonitrile is supplied from the flow path P1 to the mixing means M1. nBuLi is supplied from the flow path P2 to the mixing means M1. Then, the p-bromobenzonitrile and the nBuLi are mixed in the mixing means M1, and p-bromobenzonitrile is lithiated in the resulting liquid to produce p-cyanophenyllithium.
The p-cyanophenyllithium-containing liquid flowing through the flow path R1 is introduced into the mixing means M2. In the mixing means M2, the liquid is mixed with the boronic acid ester compound supplied from the flow path P3 to produce a boronic acid compound after quenching.
　以下、本発明の実施例を説明するが、本発明は、これらの実施例に何ら限定されるものではない。 Examples of the present invention will be described below, but the present invention is not limited to these examples.
＜ボロン酸化合物の製造＞
（比較例１：バッチ反応器における反応）
Figure JPOXMLDOC01-appb-C000003
 　真空乾燥した丸底フラスコに、４－ブロモベンゾニトリル溶液（０．４０Ｍ、ＴＨＦ溶液、４ｍＬ　東京化成工業株式会社）を加え、Ｔ℃（－７８℃、－４０℃、又は０℃）で撹拌し、ｎ－ブチルリチウム溶液（１．６０Ｍ、ヘキサン溶液、１ｍＬ、１．０５当量　関東化学株式会社）を滴下して加えた。
　１０分後、得られた混合物に、イソプロポキシボロン酸ピナコールエステル溶液（２．１Ｍ、ＴＨＦ溶液、１ｍＬ、１．３当量　東京化成工業株式会社）を加え、Ｔ℃（－７８℃、－４０℃、又は０℃）で１０分間撹拌した。
　得られた反応混合物に、１Ｍ　ＨＣｌ（２ｍＬ　富士フィルム和光純薬株式会社）及び酢酸エチル（ＥｔＯＡｃ）（４ｍＬ　富士フィルム和光純薬株式会社）を加え、有機相を、内部標準を使用したＧＣにより分析して、生成物の収率を決定した。反応温度が－７８℃のときの生成物の収率は４７％であり、反応温度が－４０℃のときの生成物の収率は１％未満であり、反応温度が０℃のときの生成物の収率は０％であった。 <Production of boronic acid compound>
(Comparative Example 1: Reaction in batch reactor)
Figure JPOXMLDOC01-appb-C000003
 Add 4-bromobenzonitrile solution (0.40 M, THF solution, 4 mL Tokyo Chemical Industry Co., Ltd.) to a vacuum-dried round bottom flask and stir at T ° C. (-78 ° C., -40 ° C., or 0 ° C.). , n-butyllithium solution (1.60 M, hexane solution, 1 mL, 1.05 equivalents, Kanto Kagaku Co., Ltd.) was added dropwise.
After 10 minutes, an isopropoxyboronic acid pinacol ester solution (2.1 M, THF solution, 1 mL, 1.3 equivalents, Tokyo Chemical Industry Co., Ltd.) was added to the resulting mixture, and the mixture was heated to T°C (-78°C, -40°C). , or 0° C.) for 10 minutes.
To the resulting reaction mixture was added 1M HCl (2 mL Fujifilm Wako Pure Chemical Industries, Ltd.) and ethyl acetate (EtOAc) (4 mL Fujifilm Wako Pure Chemical Industries, Ltd.) and the organic phase was analyzed by GC using an internal standard. was used to determine the product yield. The yield of the product when the reaction temperature is −78° C. is 47%, the yield of the product when the reaction temperature is −40° C. is less than 1%, and the yield when the reaction temperature is 0° C. The yield of product was 0%.
　以上より、バッチ反応器における反応では、ボロン酸化合物を得るためには、－７８℃以下の極低温で反応させることが必要であることが分かった。 From the above, it was found that in the reaction in the batch reactor, it was necessary to carry out the reaction at an extremely low temperature of -78°C or lower in order to obtain the boronic acid compound.
　－ＧＣ分析－
　Ｒｅｓｔｅｋ　Ｒｔｘ－２００カラムを搭載したＳＨＩＭＡＺＵ　ＧＣ－２０１４を使用して実施し、化合物はＦＩＤによって検出した。
　収率については、内部標準としてテトラデカンを含む４－シアノフェニルボロン酸ピナコールエステルの標準溶液（３検体：４－シアノフェニルボロン酸ピナコールエステルを約２０ｍｇ、約４０ｍｇ、約８０ｍｇを別々に測り取り、各々にテトラデカン約１５ｍｇを加えた後酢酸エチルに溶解）を分析して作成した検量線を用いて、４－シアノフェニルボロン酸ピナコールエステルを定量後、下記の式３で算出した。
Figure JPOXMLDOC01-appb-M000004
 - GC analysis -
Performed using a SHIMAZU GC-2014 equipped with a Restek Rtx-200 column and compounds detected by FID.
Regarding the yield, a standard solution of 4-cyanophenylboronic acid pinacol ester containing tetradecane as an internal standard (3 samples: about 20 mg, about 40 mg, and about 80 mg of 4-cyanophenylboronic acid pinacol ester were separately weighed and After adding about 15 mg of tetradecane to the solution (dissolved in ethyl acetate), 4-cyanophenylboronic acid pinacol ester was quantified using a calibration curve prepared by analysis, and then calculated by the following equation 3.
Figure JPOXMLDOC01-appb-M000004
（実施例１：フロー反応器における反応：温度、マイクロミキサーの内径の検討）
　図２に示した、２つのＴ字マイクロミキサー（Ｍ１及びＭ２　株式会社三幸精機工業）、２つのマイクロチューブリアクター（Ｒ１及びＲ２　ＧＬ　Ｓｃｉｅｎｃｅｓ社）、並びに３つのチューブ予冷ユニット（Ｐ１（内径φ＝１０００μｍ、長さＬ＝１００ｃｍ）、Ｐ２（φ＝１０００μｍ、Ｌ＝１００ｃｍ）及びＰ３（φ＝１０００μｍ、Ｌ＝１００ｃｍ）　ＧＬ　Ｓｃｉｅｎｃｅｓ社）からなるフローマイクロリアクターシステムを使用した。 (Example 1: Reaction in flow reactor: examination of temperature and inner diameter of micromixer)
Two T-shaped micromixers (M1 and M2 Sanko Seiki Kogyo Co., Ltd.), two microtube reactors (R1 and R2 GL Sciences), and three tube precooling units (P1 (inner diameter φ = 1000 μm) shown in FIG. , length L=100 cm), P2 (φ=1000 μm, L=100 cm) and P3 (φ=1000 μm, L=100 cm GL Sciences) were used.
　前記フローマイクロリアクターシステムをＴ℃の冷却槽に置き、４－ブロモベンゾニトリル溶液（０．３８Ｍ、ＴＨＦ溶液、流速：６．０ｍＬ／分　東京化成工業株式会社）及びｎ－ブチルリチウム溶液（１．６Ｍ、ヘキサン溶液、流速：１．５ｍＬ／分　関東化学株式会社）を、シリンジポンプにより、Ｍ１（２５０μｍ又は５００μｍ）に導入した。 The flow microreactor system was placed in a cooling bath at T° C., and 4-bromobenzonitrile solution (0.38 M, THF solution, flow rate: 6.0 mL/min, Tokyo Chemical Industry Co., Ltd.) and n-butyllithium solution (1. 6 M, hexane solution, flow rate: 1.5 mL/min (Kanto Kagaku Co., Ltd.) was introduced into M1 (250 μm or 500 μm) by a syringe pump.
　得られた溶液をＲ１（φ＝１０００μｍ、Ｌ＝５．０ｃｍ、ｔＲ１＝０．３１秒）に通し、Ｍ２（２５０μｍ）において、ホウ酸トリイソプロピル溶液（１．８２Ｍ、ＴＨＦ溶液、流速：１．５ｍＬ／分　東京化成工業株式会社）と混合した。得られた溶液をＲ２（φ＝１０００μｍ、Ｌ＝１００ｃｍ、ｔＲ２＝５．２秒）に通した。 The resulting solution is passed through R1 (φ=1000 μm, L=5.0 cm, t R1 =0.31 s), and in M2 (250 μm), triisopropyl borate solution (1.82 M, THF solution, flow rate: 1 .5 mL/min (Tokyo Chemical Industry Co., Ltd.). The resulting solution was passed through R2 (φ=1000 μm, L=100 cm, t R2 =5.2 sec).
　定常状態に達した後、Ｒ２から排出される生成物溶液を３０秒間収集し、メタノール（６ｍＬ　富士フィルム和光純薬株式会社）でクエンチした。反応混合物を、内部標準を使用したＨＰＬＣにより分析して、生成物の収率を決定した。結果を表１に示した。 After reaching a steady state, the product solution discharged from R2 was collected for 30 seconds and quenched with methanol (6 mL Fujifilm Wako Pure Chemical Industries, Ltd.). The reaction mixture was analyzed by HPLC using an internal standard to determine product yield. Table 1 shows the results.
　－ＨＰＬＣ分析－
　ＹＭＣ　ＴＡ１２Ｓ０５－２５４６ＷＴカラムを搭載したＳＨＩＭＡＺＵ　ＬＣ－１０Ａを使用し、移動相としてアセトニトリル／水＝９／１（ｖ／ｖ）を１．０ｍＬ／分で送液して実施し、化合物はＵＶ（検出波長２２０ｎｍ）によって検出した。
　収率については、内部標準としてヘプタノフェノンを含む４－シアノフェニルボロン酸の標準溶液（３検体：４－シアノフェニルボロン酸を約１０ｍｇ、約２０ｍｇ、約４０ｍｇを別々に測り取り、各々にヘプタノフェノン約２５ｍｇを加えた後メタノールに溶解）を分析して作成した検量線を用いて、４－シアノフェニルボロン酸を定量後、下記の式４で算出した。
Figure JPOXMLDOC01-appb-M000005
 -HPLC analysis-
A Shimazu LC-10A equipped with a YMC TA12S05-2546WT column was used, and acetonitrile/water = 9/1 (v/v) was fed as a mobile phase at 1.0 mL/min. wavelength 220 nm).
For the yield, a standard solution of 4-cyanophenylboronic acid containing heptanophenone as an internal standard (3 samples: about 10 mg, about 20 mg, and about 40 mg of 4-cyanophenylboronic acid were weighed separately, After adding about 25 mg of nophenone and dissolving in methanol), 4-cyanophenylboronic acid was quantified using a calibration curve prepared by analysis, and then calculated by the following formula 4.
Figure JPOXMLDOC01-appb-M000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　表１の結果より、フロー反応器における高濃度（４－ブロモベンゾニトリル溶液の濃度が０．３０Ｍ以上、ｎ－ブチルリチウム溶液の濃度が１．６Ｍ以上）反応では、反応温度０℃から２０℃においても高収率でボロン酸化合物が得られることが分かった。 From the results in Table 1, in the high-concentration (4-bromobenzonitrile solution concentration of 0.30 M or more, n-butyllithium solution concentration of 1.6 M or more) reaction in the flow reactor, the reaction temperature ranged from 0°C to 20°C. It was also found that a boronic acid compound can be obtained in high yield.
（実施例２：フロー反応器における反応：流速、温度の検討）
　図３に示した、２つのＴ字マイクロミキサー（Ｍ１及びＭ２　株式会社三幸精機工業）、２つのマイクロチューブリアクター（Ｒ１及びＲ２　ＧＬ　Ｓｃｉｅｎｃｅｓ社）、並びに３つのチューブ予冷ユニット（Ｐ１（内径φ＝１０００μｍ、長さＬ＝１００ｃｍ）、Ｐ２（φ＝１０００μｍ、Ｌ＝１００ｃｍ）及びＰ３（φ＝１０００μｍ、Ｌ＝１００ｃｍ）　ＧＬ　Ｓｃｉｅｎｃｅｓ社）からなるフローマイクロリアクターシステムを使用した。 (Example 2: Reaction in flow reactor: study of flow rate and temperature)
Two T-shaped micromixers (M1 and M2 Sanko Seiki Kogyo Co., Ltd.), two microtube reactors (R1 and R2 GL Sciences), and three tube precooling units (P1 (inner diameter φ = 1000 μm) shown in FIG. , length L=100 cm), P2 (φ=1000 μm, L=100 cm) and P3 (φ=1000 μm, L=100 cm GL Sciences) were used.
　前記フローマイクロリアクターシステムをＴ℃の冷却槽に置き、４－ブロモベンゾニトリル溶液（０．３８Ｍ、ＴＨＦ溶液、流速：Ｖ１ｍＬ／分）及びｎ－ブチルリチウム溶液（１．６Ｍ、ヘキサン溶液、流速：Ｖ２ｍＬ／分）を、シリンジポンプにより、Ｍ１（φ＝５００μｍ）に導入した。 The flow microreactor system was placed in a cooling bath at T° C., and 4-bromobenzonitrile solution (0.38 M, THF solution, flow rate: V 1 mL/min) and n-butyllithium solution (1.6 M, hexane solution, Flow rate: V 2 mL/min) was introduced into M1 (φ=500 μm) by syringe pump.
　得られた溶液をＲ１（φ＝１０００μｍ、Ｌ＝５．０－５０ｃｍ、ｔＲ１＝０．３１秒）に通し、Ｍ２（φ＝５００μｍ）において、ホウ酸トリイソプロピル溶液（１．８２Ｍ、ＴＨＦ溶液、流速：Ｖ３ｍＬ／分）と混合した。得られた溶液をＲ２（φ＝１０００μｍ、Ｌ＝１００ｃｍ、ｔＲ２＝０．５２－５．２秒）に通した。 The resulting solution was passed through R1 (φ=1000 μm, L=5.0-50 cm, t R1 =0.31 s) and passed through M2 (φ=500 μm) in triisopropyl borate solution (1.82 M, THF solution , flow rate: V 3 mL/min). The resulting solution was passed through R2 (φ=1000 μm, L=100 cm, t R2 =0.52-5.2 sec).
　定常状態に達した後、Ｒ２から排出される生成物溶液を２０－３０秒間収集し、メタノール（６－４０ｍＬ）でクエンチした。実施例１と同様にして、反応混合物を、内部標準を使用したＨＰＬＣにより分析して、生成物の収率を決定した。結果を表２に示した。 After reaching steady state, the product solution exiting R2 was collected for 20-30 seconds and quenched with methanol (6-40 mL). As in Example 1, the reaction mixture was analyzed by HPLC using an internal standard to determine product yield. Table 2 shows the results.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　表２の結果より、フロー反応器における高濃度（４－ブロモベンゾニトリル溶液の濃度が０．３０Ｍ以上、ｎ－ブチルリチウム溶液の濃度が１．６Ｍ以上）反応では、４－ブロモベンゾニトリル、ｎ－ブチルリチウム、又はボロン酸エステル化合物の、マイクロミキサーへの導入速度を上げることにより、より高収率でボロン酸化合物が得られることが分かった。 From the results in Table 2, in the high-concentration (4-bromobenzonitrile solution concentration of 0.30 M or more, n-butyllithium solution concentration of 1.6 M or more) reaction in the flow reactor, 4-bromobenzonitrile, n It was found that the boronic acid compound can be obtained in a higher yield by increasing the introduction rate of -butyl lithium or the boronic acid ester compound into the micromixer.
（実施例３：フロー反応器における高濃度での反応：クーリングラインの内径、マイクロミキサーの内径の検討）
　図４に示した、２つのＴ字マイクロミキサー（Ｍ１及びＭ２　株式会社三幸精機工業）、２つのマイクロチューブリアクター（Ｒ１及びＲ２　ＧＬ　Ｓｃｉｅｎｃｅｓ社）、並びに３つのチューブ予冷ユニット（Ｐ１（内径φ＝１０００又は２２００ｍｍ、長さＬ＝１００ｃｍ）、Ｐ２（φ＝１０００又は２２００ｍｍ、Ｌ＝１００ｃｍ）及びＰ３（φ１０００又は２２００ｍｍ、Ｌ＝１００ｃｍ）　ＧＬ　Ｓｃｉｅｎｃｅｓ社）からなるフローマイクロリアクターシステムを使用した。 (Example 3: Reaction at high concentration in a flow reactor: examination of the inner diameter of the cooling line and the inner diameter of the micromixer)
4, two T-shaped micromixers (M1 and M2 Sanko Seiki Kogyo Co., Ltd.), two microtube reactors (R1 and R2 GL Sciences), and three tube precooling units (P1 (inner diameter φ=1000 or 2200 mm, length L=100 cm), P2 (φ=1000 or 2200 mm, L=100 cm) and P3 (φ1000 or 2200 mm, L=100 cm from GL Sciences).
　前記フローマイクロリアクターシステムをＴ℃の冷却槽に置き、４－ブロモベンゾニトリル溶液（０．３８Ｍ、ＴＨＦ溶液、流速：６０ｍＬ／分）及びｎ－ブチルリチウム溶液（１．６Ｍ、ヘキサン溶液、流速：１５ｍＬ／分）を、シリンジポンプにより、Ｍ１（φ＝５００μｍ又は１３００μｍ）に導入した。 The flow microreactor system was placed in a cooling bath at T° C., and 4-bromobenzonitrile solution (0.38 M, THF solution, flow rate: 60 mL/min) and n-butyllithium solution (1.6 M, hexane solution, flow rate: 15 mL/min) was introduced into M1 (φ=500 μm or 1300 μm) by syringe pump.
　得られた溶液をＲ１（φ＝１０００μｍ、Ｌ＝５０ｃｍ、ｔＲ１＝０．３１秒）に通し、Ｍ２（φ＝５００μｍ又は１３００μｍ）において、ホウ酸トリイソプロピル溶液（１．８２Ｍ、ＴＨＦ溶液、流速：１５ｍＬ／分）と混合した。得られた溶液をＲ２（φ＝１０００μｍ、Ｌ＝１００ｃｍ、ｔＲ２＝０．５２秒）に通した。 The resulting solution is passed through R1 (φ=1000 μm, L=50 cm, t R1 =0.31 s) and in M2 (φ=500 μm or 1300 μm) in triisopropyl borate solution (1.82 M, THF solution, flow rate : 15 mL/min). The resulting solution was passed through R2 (φ=1000 μm, L=100 cm, t R2 =0.52 sec).
　定常状態に達した後、Ｒ２から排出される生成物溶液を２０秒間収集し、メタノール（４０ｍＬ）でクエンチした。実施例１と同様にして、反応混合物を、内部標準を使用したＨＰＬＣにより分析して、生成物の収率を決定した。結果を表３に示した。 After reaching steady state, the product solution exiting R2 was collected for 20 seconds and quenched with methanol (40 mL). As in Example 1, the reaction mixture was analyzed by HPLC using an internal standard to determine product yield. Table 3 shows the results.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　表３の結果より、フロー反応器における高濃度（４－ブロモベンゾニトリル溶液の濃度が０．３０Ｍ以上、ｎ－ブチルリチウム溶液の濃度が１．６Ｍ以上）反応では、流路拡大した場合においても、高収率でボロン酸化合物が得られることが分かった。 From the results in Table 3, in the high-concentration (4-bromobenzonitrile solution concentration of 0.30 M or more, n-butyllithium solution concentration of 1.6 M or more) reaction in the flow reactor, even when the flow path was expanded , the boronic acid compound was obtained in high yield.
　本発明の態様としては、例えば、以下のものなどが挙げられる。
　＜１＞　０．３０Ｍ以上のｐ－ブロモベンゾニトリルと、１．６Ｍ以上のｎＢｕＬｉと、を第１のマイクロミキサーに導入する工程１と、前記工程１で得られた化合物と、ボロン酸エステル化合物と、を第２のマイクロミキサーに導入する工程２と、を含むことを特徴とするボロン酸化合物の製造方法である。
　＜２＞　前記工程１が－２０℃以上で行われる、前記＜１＞に記載のボロン酸化合物の製造方法である。
　＜３＞　前記工程２が－２０℃以上で行われる、前記＜１＞又は＜２＞に記載のボロン酸化合物の製造方法である。
　＜４＞　前記工程１において、前記ｐ－ブロモベンゾニトリルの導入速度が１０ｍＬ／分以上である、前記＜１＞から＜３＞のいずれかに記載のボロン酸化合物の製造方法である。
　＜５＞　前記工程１において、前記ｐ－ブロモベンゾニトリルの導入速度が６０ｍＬ／分以上である、前記＜１＞から＜３＞のいずれかに記載のボロン酸化合物の製造方法である。
　＜６＞　前記第１のマイクロミキサーの平均内径が２５０μｍ以上である、前記＜１＞から＜５＞のいずれかに記載のボロン酸化合物の製造方法である。
　＜７＞　前記第２のマイクロミキサーの平均内径が２５０μｍ以上である、前記＜１＞から＜６＞のいずれかに記載のボロン酸化合物の製造方法である。
　＜８＞　前記ボロン酸化合物の収率が５０％以上である、前記＜１＞から＜７＞のいずれかに記載のボロン酸化合物の製造方法である。 Embodiments of the present invention include, for example, the following.
<1> Step 1 of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into a first micromixer, the compound obtained in step 1, and a boronate ester compound. and a step 2 of introducing into a second micromixer.
<2> The method for producing a boronic acid compound according to <1>, wherein the step 1 is performed at -20°C or higher.
<3> The method for producing a boronic acid compound according to <1> or <2>, wherein step 2 is carried out at -20°C or higher.
<4> The method for producing a boronic acid compound according to any one of <1> to <3>, wherein in step 1, the p-bromobenzonitrile is introduced at a rate of 10 mL/min or more.
<5> The method for producing a boronic acid compound according to any one of <1> to <3>, wherein in step 1, the p-bromobenzonitrile is introduced at a rate of 60 mL/min or more.
<6> The method for producing a boronic acid compound according to any one of <1> to <5>, wherein the first micromixer has an average inner diameter of 250 μm or more.
<7> The method for producing a boronic acid compound according to any one of <1> to <6>, wherein the second micromixer has an average inner diameter of 250 μm or more.
<8> The method for producing a boronic acid compound according to any one of <1> to <7>, wherein the yield of the boronic acid compound is 50% or more.
　本国際出願は２０２１年１２月９日に出願した日本国特許出願２０２１－１９９８０８号に基づく優先権を主張するものであり、日本国特許出願２０２１－１９９８０８号の全内容を本国際出願に援用する。 This international application claims priority based on Japanese Patent Application No. 2021-199808 filed on December 9, 2021, and the entire contents of Japanese Patent Application No. 2021-199808 are incorporated into this international application. .

Claims (8)

  1. 　０．３０Ｍ以上のｐ－ブロモベンゾニトリルと、１．６Ｍ以上のｎＢｕＬｉと、を第１のマイクロミキサーに導入する工程１と、
    　前記工程１で得られた化合物と、ボロン酸エステル化合物と、を第２のマイクロミキサーに導入する工程２と、を含むことを特徴とするボロン酸化合物の製造方法。     Step 1 of introducing 0.30 M or more of p-bromobenzonitrile and 1.6 M or more of nBuLi into a first micromixer;
    A method for producing a boronic acid compound, comprising a step 2 of introducing the compound obtained in step 1 and a boronic acid ester compound into a second micromixer.
  2. 　前記工程１が－２０℃以上で行われる、請求項１に記載のボロン酸化合物の製造方法。 The method for producing a boronic acid compound according to claim 1, wherein the step 1 is performed at -20°C or higher.
  3. 　前記工程２が－２０℃以上で行われる、請求項１又は２に記載のボロン酸化合物の製造方法。 The method for producing a boronic acid compound according to claim 1 or 2, wherein the step 2 is carried out at -20°C or higher.
  4. 　前記工程１において、前記ｐ－ブロモベンゾニトリルの導入速度が１０ｍＬ／分以上である、請求項１から３のいずれかに記載のボロン酸化合物の製造方法。 The method for producing a boronic acid compound according to any one of claims 1 to 3, wherein in the step 1, the introduction rate of the p-bromobenzonitrile is 10 mL/min or more.
  5. 　前記工程１において、前記ｐ－ブロモベンゾニトリルの導入速度が６０ｍＬ／分以上である、請求項１から３のいずれかに記載のボロン酸化合物の製造方法。 The method for producing a boronic acid compound according to any one of claims 1 to 3, wherein in the step 1, the introduction rate of the p-bromobenzonitrile is 60 mL/min or more.
  6. 　前記第１のマイクロミキサーの平均内径が２５０μｍ以上である、請求項１から５のいずれかに記載のボロン酸化合物の製造方法。 The method for producing a boronic acid compound according to any one of claims 1 to 5, wherein the first micromixer has an average inner diameter of 250 µm or more.
  7. 　前記第２のマイクロミキサーの平均内径が２５０μｍ以上である、請求項１から６のいずれかに記載のボロン酸化合物の製造方法。 The method for producing a boronic acid compound according to any one of claims 1 to 6, wherein the second micromixer has an average inner diameter of 250 µm or more.
  8. 　前記ボロン酸化合物の収率が５０％以上である、請求項１から７のいずれかに記載のボロン酸化合物の製造方法。 The method for producing a boronic acid compound according to any one of claims 1 to 7, wherein the yield of the boronic acid compound is 50% or more.
PCT/JP2022/045261 2021-12-09 2022-12-08 Method for producing boronic acid compound WO2023106361A1 (en)

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Publication number Priority date Publication date Assignee Title
JP2008195639A (en) * 2007-02-09 2008-08-28 Fujifilm Finechemicals Co Ltd METHOD FOR PRODUCING o-DISUBSTITUTED AROMATIC COMPOUND

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008195639A (en) * 2007-02-09 2008-08-28 Fujifilm Finechemicals Co Ltd METHOD FOR PRODUCING o-DISUBSTITUTED AROMATIC COMPOUND

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NAGAKI AIICHIRO, KIM HEEJIN, USUTANI HIROTSUGU, MATSUO CHIKA, YOSHIDA JUN-ICHI: "Generation and reaction of cyano-substituted aryllithium compounds using microreactors", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, vol. 8, no. 5, 1 January 2010 (2010-01-01), pages 1212 - 1217, XP093070080, ISSN: 1477-0520, DOI: 10.1039/b919325c *
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