WO2023112820A1 - Production method for boronic acid compound - Google Patents

Production method for boronic acid compound Download PDF

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Publication number
WO2023112820A1
WO2023112820A1 PCT/JP2022/045263 JP2022045263W WO2023112820A1 WO 2023112820 A1 WO2023112820 A1 WO 2023112820A1 JP 2022045263 W JP2022045263 W JP 2022045263W WO 2023112820 A1 WO2023112820 A1 WO 2023112820A1
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Prior art keywords
boronic acid
acid compound
particularly limited
appropriately selected
flow path
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PCT/JP2022/045263
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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 WO2023112820A1 publication Critical patent/WO2023112820A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • 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

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  • 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 simply producing a boronic acid compound from t-butyl-p-bromobenzoate.
  • 0.3 M or more of t-butyl-p-bromobenzoate and 0.4 M or more of BuLi are introduced into the first micromixer. and a step 2 of introducing the compound obtained in the step 1 and the boronic acid ester compound into a second micromixer. It has been found that a method for producing a boronic acid compound from t-butyl-p-bromobenzoate can be provided in a very simple manner.
  • Step 1 of introducing 0.3 M or more t-butyl-p-bromobenzoate and 0.4 M or more BuLi into a first micromixer, the compound obtained in step 1, and boron and step 2 of introducing the acid ester compound 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 0.3 M or more of t-butyl-p-bromobenzoate and 0.4 M or more of BuLi into the first micromixer.
  • t-butyl-p-bromobenzoate The t-butyl-p-bromobenzoate is also referred to as t-butyl-4-bromobenzoate, tert-butyl-p-bromobenzoate, or tert-butyl-4-bromobenzoate.
  • the lower limit of the concentration of t-butyl-p-bromobenzoate is not particularly limited as long as it is 0.3M or more, and can be appropriately selected according to the purpose.
  • the upper limit of the concentration of t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose, but from the viewpoint of suppressing side reactions, it is preferably 0.5M or less.
  • the BuLi is not particularly limited and can be appropriately selected depending on the intended purpose. , or t-BuLi is preferred, n-BuLi or sec-BuLi is more preferred, and sec-BuLi is even more preferred.
  • the nBuLi is also referred to as n-butyllithium or normal butyllithium.
  • the sec-BuLi is also referred to as sec-butyllithium or secondary butyllithium.
  • the t-BuLi is also referred to as t-butyllithium or tertiary-butyllithium.
  • the lower limit of the concentration of BuLi is not particularly limited as long as it is 0.4 M or more, and can be appropriately selected according to the purpose. 0.7M or more is preferable from the point of manufacturing.
  • the upper limit of the BuLi concentration is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of suppressing side reactions, it is preferably 2.8 M or less.
  • the lower limit of the concentration of n-BuLi is not particularly limited as long as it is 0.4 M or more, and can be appropriately selected according to the purpose. From the viewpoint of producing an acid compound, it is preferably 1.0M or more, more preferably 1.5M or more, and even more preferably 1.6M or more.
  • the upper limit of the n-BuLi concentration is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of suppressing side reactions, it is preferably 2.8 M or less.
  • the lower limit of the concentration of sec-BuLi is not particularly limited as long as it is 0.4 M or more, and can be appropriately selected according to the purpose. 0.7M or more is preferable from the point of manufacturing an acid compound.
  • the upper limit of the concentration of sec-BuLi is not particularly limited and can be appropriately selected depending on the intended purpose.
  • the lower limit of the concentration of the t-butyl-p-bromobenzoate is not particularly limited as long as it is 0.3 M or more, and is appropriately selected according to the purpose. However, from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, it is preferably 0.35M or more, more preferably 0.38M or more.
  • the upper limit of the concentration of the t-butyl-p-bromobenzoate when n-BuLi is used as the BuLi is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of suppression, 0.5 M or less is preferable.
  • the lower limit of the concentration of the t-butyl-p-bromobenzoate is not particularly limited as long as it is 0.3 M or more, and is appropriately selected according to the purpose. be able to.
  • the upper limit of the concentration of the t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of suppression, 0.5 M or less is preferable.
  • 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 a 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 channel in the mixing means is not particularly limited and can be appropriately selected depending on the purpose. It is preferably 50 ⁇ m or more, more preferably 100 ⁇ m or more, and even more preferably 250 ⁇ m or more, from the viewpoint of removing the heat of reaction and reducing the pressure loss during liquid transfer.
  • 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. More preferably, it is 2.5 mm or less.
  • 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, even 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 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, and even more preferably 250 ⁇ 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 (t-butyl-p-bromobenzoate) is not particularly limited, depending on the purpose. Although it can be selected as appropriate, from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, it is preferably 1 mL/min or more, more preferably 2.5 mL/min or more, and 5 mL/min or more. is more preferred, and 6 mL/min or more is particularly preferred.
  • 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 (t-butyl-p-bromobenzoate) is not particularly limited, depending on the purpose. Although it can be selected as appropriate, it is preferably 100 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 (BuLi) is not particularly limited, and can be appropriately selected according to the purpose. , from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, it is preferably 0.2 mL / min or more, more preferably 0.5 mL / min or more, and further preferably 1 mL / min or more. 0.5 mL/min or more is even more preferred, and 2.5 mL/min or more is particularly preferred.
  • 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 (BuLi) is not particularly limited, and can be appropriately selected according to the purpose. , preferably 25 mL/min or less.
  • 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. 0.001 second or more is preferable, and 0.01 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 t-butyl-p-bromobenzoate, it is preferably 10 seconds or less, and further in the following order, 5 seconds or less, 2 seconds or less, 1.5 seconds or less, 1 second or less, 0.5 seconds or less. 5 seconds or less, 0.2 seconds or less, 0.1 seconds or less, 0.05 seconds or less, or 0.02 seconds or less are more 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, -40 ° C. or higher is preferable, and -30 ° C. or higher is more preferable. -20°C or higher is more preferred, and -10°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 BuLi with respect to the t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. Equivalents or more are preferred, 1.0 molar equivalents or more are more preferred, and 1.1 molar equivalents or more are even more preferred.
  • the upper limit of the amount of BuLi relative to the t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. The following is preferable, 2.0 molar equivalents or less is more preferable, and 1.5 molar equivalents or less is even more preferable.
  • 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 t-butyl-p-bromobenzoate and the BuLi with a first micromixer.
  • Examples of the compound obtained by mixing the t-butyl-p-bromobenzoate and the BuLi in the first micromixer include 4-(t-butoxycarbonyl)phenyllithium.
  • 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 residence time of the reaction solution in the flow path through which the reaction solution flows in step 2 is not particularly limited, and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound from bromobenzoate, the time is preferably 0.001 seconds or longer, more preferably 0.01 seconds or longer, even more preferably 0.1 seconds or longer, particularly preferably 2 seconds or longer, and most preferably 5 seconds or longer. preferable.
  • the upper limit of the residence time of the reaction solution in the flow path through which the reaction solution flows in step 2 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound from bromobenzoate, 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, -40 ° C. or higher is preferable, and -30 ° C. or higher is more preferable. -20°C or higher is more preferred, and -10°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 20% or more, more preferably 30% or more, and 40%. 50% or more is more preferable, 60% or more is particularly preferable, and 70% or more is most preferable.
  • the yield is determined by 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 t-butyl-p-bromobenzoate is supplied from the flow path P1 to the mixing means M1. BuLi is supplied from the flow path P2 to the mixing means M1. Then, in the mixing means M1, the t-butyl-p-bromobenzoate and the BuLi are mixed, and in the resulting liquid, t-butyl-p-bromobenzoate is lithiated and 4-(t- butoxycarbonyl)phenyllithium.
  • the liquid containing 4-(t-butoxycarbonyl)phenyllithium 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.
  • Example 1 Reaction in a flow reactor: consideration of temperature
  • 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 t-butyl-p-bromobenzoate solution (0.38 M, THF solution, flow rate: 6.0 mL/min, Combi-Blocks) and n-butyllithium solution ( A 1.6 M, hexane solution, flow rate: 1.5 mL/min (Kanto Kagaku Co., Ltd.) was introduced into M1 (250 ⁇ m) with a syringe pump.
  • Example 2 Reaction in flow reactor: study of residence time
  • 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 t-butyl-p-bromobenzoate solution (0.38 M, THF solution, flow rate: 6.0 mL/min, Combi-Blocks) and n-butyllithium solution ( A 1.6 M, hexane solution, flow rate: 1.5 mL/min (Kanto Kagaku Co., Ltd.) was introduced into M1 (250 ⁇ m) with a syringe pump.
  • the resulting solution is passed through R1 ( ⁇ 1 ⁇ m, L 1 cm, t R1 sec), and at M2 (250 ⁇ m), triisopropyl borate solution (1.82 M, THF solution, flow rate: 1.5 mL / min Tokyo Kasei Kogyo Co., Ltd.).
  • microtube reactor (R1) It was found that the yield of the boronic acid compound can be improved even at -20°C or higher by shortening the residence time at .
  • the flow microreactor system was placed in a ⁇ 20° C. cooling bath, and t-butyl-p-bromobenzoate solution (C 1 M, THF solution, flow rate: 6.0 mL/min, Combi-Blocks) and sec-butyllithium solution were added.
  • C 1 M t-butyl-p-bromobenzoate solution
  • sec-butyllithium solution t-butyl-p-bromobenzoate solution
  • C 2 M hexane solution, flow rate: V 2 mL/min, Kanto Kagaku Co., Ltd.
  • Embodiments of the present invention include, for example, the following.
  • Step 1 of introducing 0.3 M or more t-butyl-p-bromobenzoate and 0.4 M or more BuLi into a first micromixer, the compound obtained in step 1, and boron and step 2 of introducing the acid ester compound 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 introduction rate of the t-butyl-p-bromobenzoate is 6 mL/min or more. be.
  • ⁇ 5> The method for producing a boronic acid compound according to any one of ⁇ 1> to ⁇ 4>, wherein the BuLi is sec-BuLi.
  • ⁇ 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 20% or more.

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Abstract

The present invention is a production method for a boronic acid compound, said method being characterized by including: a step 1 in which at least 0.3 M of t-butyl-p-bromobenzoate and at least 0.4 M of BuLi are introduced into a first micromixer; and a step 2 in which the compound obtained in step 1 and a boronic ester compound are introduced into a second micromixer.

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、ｔ－ブチル－ｐ－ブロモベンゾエート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 t-butyl-p-bromobenzoate has not yet been provided, and there is a strong demand for its prompt provision.
特開２００８－１９５６３９号公報JP-A-2008-195639
　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、ｔ－ブチル－ｐ－ブロモベンゾエート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 simply producing a boronic acid compound from t-butyl-p-bromobenzoate.
　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、０．３Ｍ以上のｔ－ブチル－ｐ－ブロモベンゾエートと、０．４Ｍ以上のＢｕＬｉ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、ｔ－ブチル－ｐ－ブロモベンゾエート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, 0.3 M or more of t-butyl-p-bromobenzoate and 0.4 M or more of BuLi are introduced into the first micromixer. and a step 2 of introducing the compound obtained in the step 1 and the boronic acid ester compound into a second micromixer. It has been found that a method for producing a boronic acid compound from t-butyl-p-bromobenzoate can be provided in a very simple manner.
　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＞　０．３Ｍ以上のｔ－ブチル－ｐ－ブロモベンゾエートと、０．４Ｍ以上のＢｕＬｉ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 0.3 M or more t-butyl-p-bromobenzoate and 0.4 M or more BuLi into a first micromixer, the compound obtained in step 1, and boron and step 2 of introducing the acid ester compound into a second micromixer.
　本発明によると、効率よく簡易に、ｔ－ブチル－ｐ－ブロモベンゾエート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 simply producing a boronic acid compound from t-butyl-p-bromobenzoate.
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、０．３Ｍ以上のｔ－ブチル－ｐ－ブロモベンゾエートと、０．４Ｍ以上のＢｕＬｉ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 0.3 M or more of t-butyl-p-bromobenzoate and 0.4 M or more of BuLi into the first micromixer.
－ｔ－ブチル－ｐ－ブロモベンゾエート－
　前記ｔ－ブチル－ｐ－ブロモベンゾエートは、ｔ－ブチル－４－ブロモベンゾエート、ｔｅｒｔ－ブチル－ｐ－ブロモベンゾエート、又はｔｅｒｔ－ブチル－４－ブロモベンゾエートとも表記する。 -t-butyl-p-bromobenzoate-
The t-butyl-p-bromobenzoate is also referred to as t-butyl-4-bromobenzoate, tert-butyl-p-bromobenzoate, or tert-butyl-4-bromobenzoate.
　前記ｔ－ブチル－ｐ－ブロモベンゾエートの濃度の下限値としては、０．３Ｍ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ｔ－ブチル－ｐ－ブロモベンゾエート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 lower limit of the concentration of t-butyl-p-bromobenzoate is not particularly limited as long as it is 0.3M or more, and can be appropriately selected according to the purpose.
The upper limit of the concentration of t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose, but from the viewpoint of suppressing side reactions, it is preferably 0.5M or less.
－ＢｕＬｉ－
　前記ＢｕＬｉ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、ｔ－ブチル－ｐ－ブロモベンゾエートからボロン酸化合物を製造する点から、ｎ－ＢｕＬｉ、ｓｅｃ－ＢｕＬｉ、又はｔ－ＢｕＬｉが好ましく、ｎ－ＢｕＬｉ又はｓｅｃ－ＢｕＬｉがより好ましく、ｓｅｃ－ＢｕＬｉがさらに好ましい。
　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。
　前記ｓｅｃ－ＢｕＬｉは、ｓｅｃ－ブチルリチウム、又はセカンダリーブチルリチウムとも表記する。
　前記ｔ－ＢｕＬｉは、ｔ－ブチルリチウム、又はターシャリー－ブチルリチウムとも表記する。 -BuLi-
The BuLi is not particularly limited and can be appropriately selected depending on the intended purpose. , or t-BuLi is preferred, n-BuLi or sec-BuLi is more preferred, and sec-BuLi is even more preferred.
The nBuLi is also referred to as n-butyllithium or normal butyllithium.
The sec-BuLi is also referred to as sec-butyllithium or secondary butyllithium.
The t-BuLi is also referred to as t-butyllithium or tertiary-butyllithium.
　前記ＢｕＬｉの濃度の下限値としては、０．４Ｍ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、ｔ－ブチル－ｐ－ブロモベンゾエートからボロン酸化合物を製造する点から、０．７Ｍ以上が好ましい。
　前記ＢｕＬｉ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 BuLi is not particularly limited as long as it is 0.4 M or more, and can be appropriately selected according to the purpose. 0.7M or more is preferable from the point of manufacturing.
The upper limit of the BuLi concentration is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of suppressing side reactions, it is preferably 2.8 M or less.
　前記ｎ－ＢｕＬｉの濃度の下限値としては、０．４Ｍ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、ｔ－ブチル－ｐ－ブロモベンゾエートからボロン酸化合物を製造する点から、１．０Ｍ以上が好ましく、１．５Ｍ以上がより好ましく、１．６Ｍ以上がさらに好ましい。
　前記ｎ－ＢｕＬｉ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 n-BuLi is not particularly limited as long as it is 0.4 M or more, and can be appropriately selected according to the purpose. From the viewpoint of producing an acid compound, it is preferably 1.0M or more, more preferably 1.5M or more, and even more preferably 1.6M or more.
The upper limit of the n-BuLi concentration is not particularly limited and can be appropriately selected according to the purpose, but from the viewpoint of suppressing side reactions, it is preferably 2.8 M or less.
　前記ｓｅｃ－ＢｕＬｉの濃度の下限値としては、０．４Ｍ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、ｔ－ブチル－ｐ－ブロモベンゾエートからボロン酸化合物を製造する点から、０．７Ｍ以上が好ましい。
　前記ｓｅｃ－ＢｕＬｉ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 sec-BuLi is not particularly limited as long as it is 0.4 M or more, and can be appropriately selected according to the purpose. 0.7M or more is preferable from the point of manufacturing an acid compound.
The upper limit of the concentration of sec-BuLi is not particularly limited and can be appropriately selected depending on the intended purpose.
　前記ＢｕＬｉとして、ｎ－ＢｕＬｉを用いたときの、前記ｔ－ブチル－ｐ－ブロモベンゾエートの濃度の下限値としては、０．３Ｍ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、ｔ－ブチル－ｐ－ブロモベンゾエート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。
　前記ＢｕＬｉとして、ｎ－ＢｕＬｉを用いたときの、前記ｔ－ブチル－ｐ－ブロモベンゾエート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。 When n-BuLi is used as the BuLi, the lower limit of the concentration of the t-butyl-p-bromobenzoate is not particularly limited as long as it is 0.3 M or more, and is appropriately selected according to the purpose. However, from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, it is preferably 0.35M or more, more preferably 0.38M or more.
The upper limit of the concentration of the t-butyl-p-bromobenzoate when n-BuLi is used as the BuLi is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of suppression, 0.5 M or less is preferable.
　前記ＢｕＬｉとして、ｓｅｃ－ＢｕＬｉを用いたときの、前記ｔ－ブチル－ｐ－ブロモベンゾエートの濃度の下限値としては、０．３Ｍ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ＢｕＬｉとして、ｓｅｃ－ＢｕＬｉを用いたときの、前記ｔ－ブチル－ｐ－ブロモベンゾエート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。 When sec-BuLi is used as the BuLi, the lower limit of the concentration of the t-butyl-p-bromobenzoate is not particularly limited as long as it is 0.3 M or more, and is appropriately selected according to the purpose. be able to.
When sec-BuLi is used as the BuLi, the upper limit of the concentration of the t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of suppression, 0.5 M or less is preferable.
－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 a 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（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い。 The lower 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. It is preferably 50 μm or more, more preferably 100 μm or more, and even more preferably 250 μm or more, from the viewpoint of removing the heat of reaction and reducing the pressure loss during 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. More preferably, it is 2.5 mm or less.
　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, even 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, and even more preferably 250 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（ｔ－ブチル－ｐ－ブロモベンゾエート）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、ｔ－ブチル－ｐ－ブロモベンゾエートからボロン酸化合物を製造する点から、１ｍＬ／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、６ｍＬ／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 (t-butyl-p-bromobenzoate) is not particularly limited, depending on the purpose. Although it can be selected as appropriate, from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, it is preferably 1 mL/min or more, more preferably 2.5 mL/min or more, and 5 mL/min or more. is more preferred, and 6 mL/min or more is particularly preferred.
　原材料（ｔ－ブチル－ｐ－ブロモベンゾエート）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、１００ｍＬ／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 (t-butyl-p-bromobenzoate) is not particularly limited, depending on the purpose. Although it can be selected as appropriate, it is preferably 100 mL/min or less.
　原材料（ＢｕＬｉ）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、ｔ－ブチル－ｐ－ブロモベンゾエートからボロン酸化合物を製造する点から、０．２ｍＬ／分以上が好ましく、０．５ｍＬ／分以上がより好ましく、１ｍＬ／分以上がさらに好ましく、１．５ｍＬ／分以上がよりさらに好ましく、２．５ｍＬ／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 (BuLi) is not particularly limited, and can be appropriately selected according to the purpose. , from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, it is preferably 0.2 mL / min or more, more preferably 0.5 mL / min or more, and further preferably 1 mL / min or more. 0.5 mL/min or more is even more preferred, and 2.5 mL/min or more is particularly preferred.
　原材料（ＢｕＬｉ）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、２５ｍＬ／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 (BuLi) is not particularly limited, and can be appropriately selected according to the purpose. , preferably 25 mL/min or less.
　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、０．００１秒以上が好ましく、０．０１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. 0.001 second or more is preferable, and 0.01 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、ｔ－ブチル－ｐ－ブロモベンゾエート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、さらに次の順で、５秒以下、２秒以下、１．５秒以下、１秒以下、０．５秒以下、０．２秒以下、０．１秒以下、０．０５秒以下、０．０２秒以下、がより好ましい。 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 t-butyl-p-bromobenzoate, it is preferably 10 seconds or less, and further in the following order, 5 seconds or less, 2 seconds or less, 1.5 seconds or less, 1 second or less, 0.5 seconds or less. 5 seconds or less, 0.2 seconds or less, 0.1 seconds or less, 0.05 seconds or less, or 0.02 seconds or less are more 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、－４０℃以上が好ましく、－３０℃以上がより好ましく、－２０℃以上がさらに好ましく、－１０℃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, -40 ° C. or higher is preferable, and -30 ° C. or higher is more preferable. -20°C or higher is more preferred, and -10°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ｔ－ブチル－ｐ－ブロモベンゾエートに対する、前記ＢｕＬｉ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 BuLi with respect to the t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. Equivalents or more are preferred, 1.0 molar equivalents or more are more preferred, and 1.1 molar equivalents or more are even more preferred.
　前記ｔ－ブチル－ｐ－ブロモベンゾエートに対する、前記ＢｕＬｉ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 BuLi relative to the t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. The following is preferable, 2.0 molar equivalents or less is more preferable, and 1.5 molar equivalents or less is even more preferable.
＜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ｔ－ブチル－ｐ－ブロモベンゾエートと、前記ＢｕＬｉ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ｔ－ブチル－ｐ－ブロモベンゾエートと、前記ＢｕＬｉ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、４－（ｔ－ブトキシカルボニル）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 t-butyl-p-bromobenzoate and the BuLi with a first micromixer.
Examples of the compound obtained by mixing the t-butyl-p-bromobenzoate and the BuLi in the first micromixer include 4-(t-butoxycarbonyl)phenyllithium.
－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、ｔ－ブチル－ｐ－ブロモベンゾエートからボロン酸化合物を製造する点から、０．００１秒以上が好ましく、０．０１秒以上がより好ましく、０．１秒以上がさらに好ましく、２秒以上が特に好ましく、５秒以上が最も好ましい。 The lower limit of the residence time of the reaction solution in the flow path through which the reaction solution flows in step 2 is not particularly limited, and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound from bromobenzoate, the time is preferably 0.001 seconds or longer, more preferably 0.01 seconds or longer, even more preferably 0.1 seconds or longer, particularly preferably 2 seconds or longer, and most preferably 5 seconds or longer. preferable.
　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、ｔ－ブチル－ｐ－ブロモベンゾエート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 flows in step 2 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of producing a boronic acid compound from bromobenzoate, 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、－４０℃以上が好ましく、－３０℃以上がより好ましく、－２０℃以上がさらに好ましく、－１０℃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, -40 ° C. or higher is preferable, and -30 ° C. or higher is more preferable. -20°C or higher is more preferred, and -10°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、２０％以上が好ましく、３０％以上がより好ましく、４０％以上がさらに好ましく、５０％以上がよりさらに好ましく、６０％以上が特に好ましく、７０％以上が最も好ましい。
　前記収率は、以下のとおり、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 20% or more, more preferably 30% or more, and 40%. 50% or more is more preferable, 60% or more is particularly preferable, and 70% or more is most preferable.
The yield is determined by HPLC analysis as follows.
　（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、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
 (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 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
＜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ｔ－ブチル－ｐ－ブロモベンゾエートが供給される。流通路Ｐ２から混合手段Ｍ１に、ＢｕＬｉが供給される。そうすると、混合手段Ｍ１において、前記ｔ－ブチル－ｐ－ブロモベンゾエートと、前記ＢｕＬｉとが混合され、得られた液中では、ｔ－ブチル－ｐ－ブロモベンゾエートがリチオ化され、４－（ｔ－ブトキシカルボニル）フェニルリチウムを生成する。
　流通路Ｒ１を流れる、前記４－（ｔ－ブトキシカルボニル）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 t-butyl-p-bromobenzoate is supplied from the flow path P1 to the mixing means M1. BuLi is supplied from the flow path P2 to the mixing means M1. Then, in the mixing means M1, the t-butyl-p-bromobenzoate and the BuLi are mixed, and in the resulting liquid, t-butyl-p-bromobenzoate is lithiated and 4-(t- butoxycarbonyl)phenyllithium.
The liquid containing 4-(t-butoxycarbonyl)phenyllithium 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、ｔ－ブチル－ｐ－ブロモベンゾエート溶液（０．１０Ｍ又は０．３８Ｍ、ＴＨＦ溶液、３．０ｍＬ　Ｃｏｍｂｉ－Ｂｌｏｃｋｓ社）を加え、Ｔ℃で撹拌し、ｎ－ブチルリチウム溶液（０．４２Ｍ又は１．６Ｍ、ヘキサン溶液、１ｍＬ、１．１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、ホウ酸トリイソプロピル溶液（０．４８Ｍ又は１．８２Ｍ、ＴＨＦ溶液、０．７５ｍＬ、１．２当量　東京化成工業株式会社）を加え、Ｔ℃で１０分間撹拌した。
　メタノール（６ｍＬ　富士フィルム和光純薬株式会社）により反応をクエンチした。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。 <Production of boronic acid compound>
(Comparative Example 1: Reaction in batch reactor)
Figure JPOXMLDOC01-appb-C000003
 A t-butyl-p-bromobenzoate solution (0.10 M or 0.38 M, THF solution, 3.0 mL Combi-Blocks) was added to a vacuum-dried round bottom flask, stirred at T° C., and n-butyl lithium A solution (0.42 M or 1.6 M, hexane solution, 1 mL, 1.1 eq Kanto Kagaku Co., Ltd.) was added dropwise.
After 10 minutes, a triisopropyl borate solution (0.48 M or 1.82 M, THF solution, 0.75 mL, 1.2 equivalents, Tokyo Chemical Industry Co., Ltd.) was added to the resulting mixture and stirred at T° C. for 10 minutes. bottom.
The reaction was 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－（ｔ－ブトキシカルボニル）フェニルボロン酸の標準溶液（３検体：４－（ｔ－ブトキシカルボニル）フェニルボロン酸を約５ｍｇ、約２０ｍｇ、約４０ｍｇを別々に測り取り、各々にヘプタノフェノン約２０ｍｇ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－（ｔ－ブトキシカルボニル）フェニルボロン酸を定量後、下記の式３で算出した。
Figure JPOXMLDOC01-appb-M000004
 -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).
Regarding the yield, a standard solution of 4-(t-butoxycarbonyl)phenylboronic acid containing heptanophenone as an internal standard (3 samples: 4-(t-butoxycarbonyl)phenylboronic acid of about 5 mg, about 20 mg, about 40 mg was separately weighed, and about 20 mg of heptanophenone was added to each, and then dissolved in methanol). It was calculated by the formula 3 of.
Figure JPOXMLDOC01-appb-M000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　表１の結果より、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、－７０℃以下の極低温で反応させることが必要であり、さらに、－７０℃以下の極低温化でも低収率でしかボロン酸化合物が得られないことが分かった。 From the results in Table 1, in the reaction in the batch reactor, in order to obtain a boronic acid compound, it is necessary to carry out the reaction at an extremely low temperature of -70 ° C. or lower. It was found that the boronic acid compound was obtained only in yield.
（実施例１：フロー反応器における反応：温度の検討）
　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 a flow reactor: consideration of 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、ｔ－ブチル－ｐ－ブロモベンゾエート溶液（０．３８Ｍ、ＴＨＦ溶液、流速：６．０ｍＬ／分　Ｃｏｍｂｉ－Ｂｌｏｃｋｓ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）に導入した。 The flow microreactor system was placed in a cooling bath at T° C., and t-butyl-p-bromobenzoate solution (0.38 M, THF solution, flow rate: 6.0 mL/min, Combi-Blocks) and n-butyllithium solution ( A 1.6 M, hexane solution, flow rate: 1.5 mL/min (Kanto Kagaku Co., Ltd.) was introduced into M1 (250 μm) with 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。収率を下記の式４で算出した以外は、比較例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。
Figure JPOXMLDOC01-appb-M000006
 After reaching steady state, the product solution exiting 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 the yield of the product in the same manner as in Comparative Example 1, except that the yield was calculated by Equation 4 below. Table 2 shows the results.
Figure JPOXMLDOC01-appb-M000006
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（ｔ－ブチル－ｐ－ブロモベンゾエート溶液の濃度が０．３Ｍ以上、ブチルリチウム溶液の濃度が０．４Ｍ以上）反応では、反応温度－４０℃から－６０℃において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 (t-butyl-p-bromobenzoate solution concentration of 0.3 M or more, butyllithium solution concentration of 0.4 M or more) reaction in the flow reactor, the reaction temperature from -40 ° C. It was found that a boronic acid compound can be obtained in high yield at -60°C.
（実施例２：フロー反応器における反応：滞留時間の検討）
　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 residence time)
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、ｔ－ブチル－ｐ－ブロモベンゾエート溶液（０．３８Ｍ、ＴＨＦ溶液、流速：６．０ｍＬ／分　Ｃｏｍｂｉ－Ｂｌｏｃｋｓ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）に導入した。 The flow microreactor system was placed in a cooling bath at T° C., and t-butyl-p-bromobenzoate solution (0.38 M, THF solution, flow rate: 6.0 mL/min, Combi-Blocks) and n-butyllithium solution ( A 1.6 M, hexane solution, flow rate: 1.5 mL/min (Kanto Kagaku Co., Ltd.) was introduced into M1 (250 μm) with a syringe pump.
　得られた溶液をＲ１（φ１μｍ、Ｌ１ｃｍ、ｔＲ１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 1 μm, L 1 cm, t R1 sec), and at M2 (250 μm), triisopropyl borate solution (1.82 M, THF solution, flow rate: 1.5 mL / min Tokyo Kasei Kogyo 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。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 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.). 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（ｔ－ブチル－ｐ－ブロモベンゾエート溶液の濃度が０．３Ｍ以上、ブチルリチウム溶液の濃度が０．４Ｍ以上）反応では、マイクロチューブリアクター（Ｒ１）における滞留時間を短くすることにより、－２０℃以上においても、ボロン酸化合物の収率向上が可能であることが分かった。 From the results in Table 3, in the high-concentration (t-butyl-p-bromobenzoate solution concentration of 0.3 M or more, butyllithium solution concentration of 0.4 M or more) reaction in the flow reactor, microtube reactor (R1) It was found that the yield of the boronic acid compound can be improved even at -20°C or higher by shortening the residence time at .
（実施例３：フロー反応器における反応：ｓｅｃ－ＢｕＬｉを用いた検討）
　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＝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 3: Reaction in flow reactor: study using sec-BuLi)
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 µm , 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－２０℃の冷却槽に置き、ｔ－ブチル－ｐ－ブロモベンゾエート溶液（Ｃ１Ｍ、ＴＨＦ溶液、流速：６．０ｍＬ／分　Ｃｏｍｂｉ－Ｂｌｏｃｋｓ社）及びｓｅｃ－ブチルリチウム溶液（Ｃ２Ｍ、ヘキサン溶液、流速：Ｖ２ｍＬ／分　関東化学株式会社）を、シリンジポンプにより、Ｍ１（２５０μｍ）に導入した。 The flow microreactor system was placed in a −20° C. cooling bath, and t-butyl-p-bromobenzoate solution (C 1 M, THF solution, flow rate: 6.0 mL/min, Combi-Blocks) and sec-butyllithium solution were added. (C 2 M, hexane solution, flow rate: V 2 mL/min, Kanto Kagaku Co., Ltd.) was introduced into M1 (250 μm) by a syringe pump.
　得られた溶液をＲ１（φ＝１０００μｍ、Ｌ＝３．５ｃｍ、ｔＲ１＝０．０１２－０．０１４秒）に通し、Ｍ２（２５０μｍ）において、ホウ酸トリイソプロピル溶液（Ｃ３Ｍ、ＴＨＦ溶液、流速：Ｖ３ｍＬ／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＝４．４－５．２秒）に通した。 The resulting solution was passed through R1 (φ=1000 μm, L=3.5 cm, t R1 =0.012-0.014 sec), and in M2 (250 μm), triisopropyl borate solution (C 3 M, THF solution , flow rate: V 3 mL/min (Tokyo Chemical Industry Co., Ltd.). The resulting solution was passed through R2 (φ=1000 μm, L=100 cm, t R2 =4.4-5.2 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。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４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.). As in Example 1, the reaction mixture was analyzed by HPLC using an internal standard to determine product yield. Table 4 shows the results.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　表４の結果より、フロー反応器における反応では、ｓｅｃ－ブチルリチウムを用いることにより、－２０℃において、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 4, it was found that in the reaction in the flow reactor, a boronic acid compound was obtained at -20°C with a higher yield by using sec-butyllithium.
　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＞　０．３Ｍ以上のｔ－ブチル－ｐ－ブロモベンゾエートと、０．４Ｍ以上のＢｕＬｉ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ｔ－ブチル－ｐ－ブロモベンゾエートの導入速度が、６ｍＬ／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ＢｕＬｉが、ｓｅｃ－ＢｕＬｉである、前記＜１＞から＜４＞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２０％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 0.3 M or more t-butyl-p-bromobenzoate and 0.4 M or more BuLi into a first micromixer, the compound obtained in step 1, and boron and step 2 of introducing the acid ester compound 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 introduction rate of the t-butyl-p-bromobenzoate is 6 mL/min or more. be.
<5> The method for producing a boronic acid compound according to any one of <1> to <4>, wherein the BuLi is sec-BuLi.
<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 20% or more.
　本国際出願は２０２１年１２月１５日に出願した日本国特許出願２０２１－２０３２７４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２０２１－２０３２７４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. 2021-203274 filed on December 15, 2021, and the entire contents of Japanese Patent Application No. 2021-203274 are incorporated into this international application. .

Claims (8)

  1. 　０．３Ｍ以上のｔ－ブチル－ｐ－ブロモベンゾエートと、０．４Ｍ以上のＢｕＬｉ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 0.3M or more t-butyl-p-bromobenzoate and 0.4M or more BuLi 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ｔ－ブチル－ｐ－ブロモベンゾエートの導入速度が、６ｍＬ／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 said step 1, said t-butyl-p-bromobenzoate is introduced at a rate of 6 mL/min or more.
  5. 　前記ＢｕＬｉが、ｓｅｃ－ＢｕＬｉである、請求項１から４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 4, wherein said BuLi is sec-BuLi.
  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２０％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 20% or more.
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