Production method for boronic acid compound

Abstract

To provide an efficient and simple method for producing a boronic acid compound from t-butyl-p-bromobenzoate.SOLUTION: The present invention is a production method for a boronic acid compound, the method 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 the step 1 and a boronic ester compound are introduced into a second micromixer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a boronic acid compound. [Background technology]

[0002] In recent years, there has been an increasing demand for boronic acid compounds, which are used as substrates in Suzuki coupling reactions, etc. A method for synthesizing a boronic acid compound from an o-dihaloaromatic compound is known (Patent Document 1), but this method requires the reaction to be carried out at extremely low temperatures of -80°C to -50°C, and therefore cannot be considered a simple method.

[0003] 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 the prompt provision of such a method. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2008-195639 A Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention aims to solve the above-mentioned problems in the prior art and to achieve the following object: That is, the present invention aims to provide a method for efficiently and simply producing a boronic acid compound from t-butyl-p-bromobenzoate. [Means for solving the problem]

[0006] As a result of intensive research by the present inventors to achieve the above-mentioned object, it has been found that a method for efficiently and simply producing a boronic acid compound from t-butyl-p-bromobenzoate can be provided by a method for producing a boronic acid compound, the method comprising: step 1 of introducing 0.3 M or more of t-butyl-p-bromobenzoate and 0.4 M or more of BuLi into a first micro mixer; and step 2 of introducing the compound obtained in step 1 and a boronic acid ester compound into a second micro mixer.

[0007] The present invention is based on the above findings by the present inventors, and the means for solving the above problems are as follows. <1> The method for producing a boronic acid compound includes step 1 of introducing 0.3 M or more of t-butyl-p-bromobenzoate and 0.4 M or more of BuLi into a first micro mixer, and step 2 of introducing the compound obtained in step 1 and a boronic acid ester compound into a second micro mixer. Effect of the Invention

[0008] According to the present invention, there is provided a method for efficiently and simply producing a boronic acid compound from t-butyl-p-bromobenzoate. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 is a schematic diagram of a flow microreactor used in one example of the production method of the present invention. [Diagram 2] FIG. 2 is a schematic diagram of the microreactor system used in Example 1. [Diagram 3] FIG. 3 is a schematic diagram of the microreactor system used in Example 2. [Figure 4] FIG. 4 is a schematic diagram of the microreactor system used in Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] (Method of Producing Boronic Acid Compound) The method for producing a boronic acid compound includes step 1 and step 2, and may further include other steps.

[0011] <Process 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 a first micro mixer.

[0012] -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.

[0013] 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 can be appropriately selected depending on the purpose. 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, but is preferably 0.5 M or less in terms of suppressing side reactions.

[0014] -BuLi- The BuLi is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, however, n-BuLi, sec-BuLi, or t-BuLi is preferable, n-BuLi or sec-BuLi is more preferable, and sec-BuLi is even more preferable. The nBuLi is also written as n-butyllithium or normal butyllithium. The sec-BuLi is also referred to as sec-butyllithium or secondary butyllithium. The t-BuLi is also written as t-butyl lithium or tertiary butyl lithium.

[0015] The lower limit of the BuLi concentration is not particularly limited as long as it is 0.4 M or more and can be appropriately selected depending on the purpose. However, from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, it is preferably 0.7 M or more. The upper limit of the BuLi concentration is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 2.8 M or less from the viewpoint of suppressing side reactions.

[0016] The lower limit of the concentration of the n-BuLi is not particularly limited as long as it is 0.4 M or more and can be appropriately selected depending on the purpose. From the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, however, the concentration is preferably 1.0 M or more, more preferably 1.5 M or more, and even more preferably 1.6 M or more. The upper limit of the concentration of n-BuLi is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 2.8 M or less in terms of suppressing side reactions.

[0017] 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 depending on the purpose. However, from the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, a concentration of 0.7 M or more is preferable. The upper limit of the concentration of sec-BuLi is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 2.8 M or less in terms of suppressing side reactions.

[0018] 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 can be appropriately selected depending on the purpose. From the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, however, the concentration is preferably 0.35 M or more, and more preferably 0.38 M or more. When n-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. However, from the viewpoint of suppressing side reactions, the upper limit is preferably 0.5 M or less.

[0019] 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 can be appropriately selected depending on the purpose. 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. However, from the viewpoint of suppressing side reactions, it is preferably 0.5 M or less.

[0020] -The first micro mixer- The first micromixer is not particularly limited as long as it is a mixing means in a microreactor (hereinafter, may be referred to as a "flow microreactor" or a "flow reactor") and may be appropriately selected depending on the purpose, and may be a substrate-type micromixer or a pipe joint-type micromixer in the microreactor described below.

[0021] -Microreactor- The microreactor is not particularly limited and can be appropriately selected depending on the purpose. For example, a microreactor equipped with a mixing means and a flow path and further equipped with other means as necessary can be mentioned. The mixing means and the flow passage may be of an integral type or of a separate type.

[0022] The mixing means is a means capable of mixing two or more kinds of liquids. The flow passage is a pipe through which a liquid can flow, and is connected to at least one of the mixing means.

[0023] By using the flow microreactor, it is possible to shorten the residence time from the production to the next reaction of a less stable compound, thereby suppressing side reactions. In addition, the flow microreactor has excellent cooling efficiency, and therefore can suppress side reactions caused by heat generated in an exothermic reaction.

[0024] --Integrated flow microreactor-- The mixing means and the flow passage of the integrated flow microreactor may be a substrate-type micromixer.

[0025] The substrate-type micromixer is made of a substrate having a passage formed therein or on its surface, and may be called a microchannel. The substrate-type micromixer is not particularly limited and may be appropriately selected depending on the purpose. Examples of the substrate-type micromixer include the mixer having fine flow paths for mixing described in International Publication No. 96 / 30113; and the mixer described in the literature "Microreactors, Chapter 3, by W. Ehrfeld, V. Hessel, and H. Lowe, published by Wiley-VCH."

[0026] In the substrate-type micromixer, the mixing means and the flow passage are formed of minute flow passages capable of mixing a plurality of liquids.

[0027] In addition to the flow paths, the substrate-type micromixer is preferably provided with inlet paths that communicate with the flow paths and introduce a plurality of liquids into the flow paths. That is, it is preferable that the upstream side of the flow paths is branched according to the number of the inlet paths.

[0028] The number of the introduction paths is not particularly limited and can be appropriately selected depending on the purpose, but it is preferable to introduce multiple liquids to be mixed from separate introduction paths and merge them in the flow path to mix them. Note that a configuration in which one liquid is preliminarily charged in the flow path and the other liquids are introduced through the introduction paths may also be used.

[0029] --Separate flow microreactor-- The separate type flow microreactor is configured by connecting a mixing means and a flow passage.

[0030] The mixing means is not particularly limited as long as it can mix two or more liquids, and can be appropriately selected depending on the purpose. For example, a pipe joint type micromixer can be mentioned.

[0031] The pipe joint type micromixer includes a flow path formed therein, and if necessary, a connecting member that connects the flow path formed therein and the flow passage. The connection method of the connecting member is not particularly limited and can be appropriately selected from known connection methods depending on the purpose, and examples thereof include a screw type, a union type, a butt welding type, a plug welding type, a socket welding type, a flange type, a bite type, a flare type, and a mechanical type.

[0032] In addition to the flow paths, it is preferable that an inlet path is formed inside the pipe joint type micromixer, which is connected to the flow paths and introduces a plurality of liquids into the flow paths. That is, it is preferable that the upstream side of the flow paths is branched depending on the number of the inlet paths. When the number of the inlet 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 inlet paths is three, for example, a cross shape can be used. Note that it is also possible to use a configuration in which one liquid is charged in the flow paths in advance and the other liquids are introduced through the inlet paths.

[0033] The material of the pipe joint type micromixer is not particularly limited and can be appropriately selected depending on requirements such as heat resistance, pressure resistance, solvent resistance, and ease of processing. Examples of the material include stainless steel, titanium, copper, nickel, aluminum, silicon, Teflon (registered trademark), fluororesins such as PFA (perfluoroalkoxy resin), and TFAA (trifluoroacetamide).

[0034] As the pipe joint type micro mixer, commercially available products can be used, such as YM-1 type mixer and YM-2 type mixer manufactured by Azbil Corporation; mixing tee and tee (T-shaped connector) manufactured by Shimadzu GLC Corporation; micro-high mixer developed by Toray Engineering; union tee manufactured by Swagelok Corporation, and T-shaped micro mixer manufactured by Sanko Seiki Kogyo Co., Ltd.

[0035] The method of mixing two or more raw materials in the mixing means is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include mixing by laminar flow, mixing by turbulent flow, etc. Among them, mixing by laminar flow (static mixing) is preferred in terms of more efficient reaction control and heat removal.

[0036] In addition, since the flow path in the mixing means is minute, the liquids introduced into the mixing means tend to naturally flow in a laminar manner, and are mixed by diffusing in a direction perpendicular to the flow. In the mixing by laminar flow, a branch point and a junction point may be provided in the flow path to divide the laminar cross section of the flowing liquid, thereby increasing the mixing speed. Furthermore, when turbulent mixing (dynamic mixing) is performed in the flow path of the mixing means, the laminar flow can be changed to a turbulent flow by adjusting the flow rate and the shape of the flow path (the three-dimensional shape of the liquid-contacting portion, the shape of the flow path such as bending, the roughness of the wall surface, etc.). The mixing by the turbulent flow has the advantages of better mixing efficiency and faster mixing speed than the mixing by the laminar flow.

[0037] Here, the smaller the inner diameter of the flow passage in the mixing means, the shorter the diffusion distance of the molecules, and therefore the shorter the time required for mixing and the higher the mixing efficiency.Furthermore, the smaller the inner diameter of the flow passage, the larger the ratio of the surface area to the volume, and therefore the easier it is 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 during the flow of the liquid increases, and a special high-pressure pump is required for the liquid delivery, which may increase the manufacturing cost. In addition, the liquid delivery flow rate is limited, which may limit the structure of the micromixer.

[0038] The lower limit of the average inner diameter of the flow path in the mixing means (average inner diameter of the micromixer) is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoints of enabling more rapid mixing, more efficient removal of reaction heat, and reducing pressure loss during liquid transfer, the lower limit is preferably 50 μm or more, more preferably 100 μm or more, and even more preferably 250 μm or more.

[0039] The upper 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, but is preferably 4 mm or less, more preferably 3 mm or less, and even more preferably 2.5 mm or less.

[0040] If the average inner diameter is less than 50 μm, the pressure loss may increase, and if the average inner diameter is more than 4 mm, the surface area per unit volume becomes small, which may result in rapid mixing and removal of reaction heat becoming difficult.

[0041] The cross-sectional area of ​​the flow channel is not particularly limited and can be appropriately selected depending on the purpose. 2 ~16mm 2 is preferable, and 1,000 μm 2 ~4.0mm 2 More preferably, 10,000 μm 2 ~2.1mm 2 More preferably, 190,000 μm 2 ~1mm 2 is particularly preferred.

[0042] The cross-sectional shape of the flow channel is not particularly limited and can be appropriately selected depending on the purpose. Examples of the cross-sectional shape include a circle, a rectangle, a semicircle, and a triangle.

[0043] The flow passage is not particularly limited as long as it is a tube that is connected to at least one of the mixing means and can flow a liquid, and can be appropriately selected depending on the purpose. The configuration of the flow passage, such as its inner diameter, outer diameter, length, material, etc., can be appropriately selected depending on the desired reaction.

[0044] The flow passage is used, for example, when supplying raw materials to the mixing means. The flow passage is used, for example, when supplying a reaction product of two or more kinds of substances mixed by the mixing means to a subsequent mixing means. Note that, at this time, the reaction may continue to occur in the flow passage.

[0045] The flow passage may be a commercially available product, such as a stainless steel tube manufactured by GL Sciences Inc. (outer diameter 1 / 16 inch (1.58 mm), inner diameter selectable from 250 μm, 500 μm, and 1,000 μm, tube length adjustable by the user).

[0046] The material of the flow passage is not particularly limited, and the materials exemplified as the materials of the mixing means can be suitably used.

[0047] The lower limit of the average inner diameter of the flow passage connected upstream of the mixing means (the average inner diameter of the tube pre-cooling unit: cooling line) is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of reducing pressure loss during liquid delivery, however, it 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.

[0048] The upper limit of the average inner diameter of the flow passage connected upstream of the mixing means (the average inner diameter of the tube pre-cooling unit: cooling line) 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, and even more preferably 2.5 mm or less.

[0049] The lower limit of the average inner diameter of the flow passage connected downstream of the mixing means (average inner diameter of the microtube reactor) is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of reducing pressure loss during liquid transfer, however, it is preferably 50 μm or more, more preferably 100 μm or more, and even more preferably 250 μm or more.

[0050] The upper limit of the average inner diameter of the flow passage connected downstream of the mixing means (average inner diameter of the microtube reactor) 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, and even more preferably 2.5 mm or less.

[0051] The lower limit of the liquid flow rate in the flow passage (the flow passage connected upstream of the mixing means) for supplying the raw material (t-butyl-p-bromobenzoate) is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, however, the lower limit is preferably 1 mL / min or more, more preferably 2.5 mL / min or more, even more preferably 5 mL / min or more, and particularly preferably 6 mL / min or more.

[0052] The upper limit of the liquid flow rate in the flow passage (the flow passage connected upstream of the mixing means) through which the raw material (t-butyl-p-bromobenzoate) is supplied is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 100 mL / min or less.

[0053] The lower limit of the liquid flow rate in the flow passage (the flow passage connected upstream of the mixing means) for supplying the raw material (BuLi) is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, however, it is preferably 0.2 mL / min or more, more preferably 0.5 mL / min or more, even more preferably 1 mL / min or more, even more preferably 1.5 mL / min or more, and particularly preferably 2.5 mL / min or more.

[0054] The upper limit of the liquid flow rate in the flow passage (the flow passage connected upstream of the mixing means) through which the raw material (BuLi) is supplied is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 25 mL / min or less.

[0055] The lower limit of the residence time of the reaction liquid in the flow passage through which the reaction liquid flows is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of increasing the conversion rate, however, it is preferably 0.001 seconds or more, and more preferably 0.01 seconds or more.

[0056] The upper limit of the residence time of the reaction liquid in the flow channel through which the reaction liquid flows is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of suppressing side reactions and efficiently producing a boronic acid compound from t-butyl-p-bromobenzoate, however, 10 seconds or less is preferable, and further, 5 seconds or less, 2 seconds or less, 1.5 seconds or less, 1 second or less, 0.5 seconds or less, 0.2 seconds or less, 0.1 seconds or less, 0.05 seconds or less, and 0.02 seconds or less are more preferable in the following order.

[0057] The residence time can be set within the above range by adjusting the length and average inner diameter of the microtube reactor.

[0058] The lower limit of the length of the flow passage connected upstream of the mixing means is not particularly limited and may be appropriately selected depending on the purpose, but is preferably 40 cm or more, more preferably 60 cm or more, even more preferably 80 cm or more, and particularly preferably 100 cm or more.

[0059] The upper limit of the length of the flow passage connected upstream of the mixing means is not particularly limited and may be appropriately selected depending on the purpose, but is preferably 300 cm or less, more preferably 280 cm or less, even more preferably 250 cm or less, and particularly preferably 230 cm or less.

[0060] The lower limit of the length of the flow passage connected downstream of the mixing means is not particularly limited and may be appropriately selected depending on the purpose, but is preferably 5 cm or more, more preferably 10 cm or more, even more preferably 15 cm or more, even more preferably 20 cm or more, and particularly preferably 50 cm or more.

[0061] The upper limit of the length of the flow passage connected downstream of the mixing means is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 300 cm or less, more preferably 280 cm or less, even more preferably 250 cm or less, and particularly preferably 230 cm or less.

[0062] --Other methods-- The other means are not particularly limited and can be appropriately selected depending on the purpose. Examples of the other means include a liquid delivery means and a temperature adjustment means.

[0063] The liquid delivery means is not particularly limited as long as it can supply various raw materials to the flow passage of the flow microreactor, and can be appropriately selected depending on the purpose. For example, a pump can be used.

[0064] The pump is not particularly limited and can be appropriately selected from those that can be used industrially. Preferably, the pump does not generate pulsation during liquid transfer. Examples of the pump include a plunger pump, a gear pump, a rotary pump, and a diaphragm pump.

[0065] The temperature control means is not particularly limited as long as it can control the temperature of the mixing means and the flow path of the flow microreactor, and can be appropriately selected depending on the purpose.

[0066] The lower limit of the reaction temperature in step 1 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of reducing the cooling load, however, it is preferably -40°C or higher, more preferably -30°C or higher, even more preferably -20°C or higher, and particularly preferably -10°C or higher.

[0067] The upper limit of the reaction temperature in step 1 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of suppressing side reactions, however, the upper limit is preferably 20° C. or lower, more preferably 15° C. or lower, even more preferably 10° C. or lower, and particularly preferably 5° C. or lower.

[0068] The lower limit of the amount of BuLi relative to the amount of t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of increasing the conversion rate, however, the amount is preferably 0.9 molar equivalents or more, more preferably 1.0 molar equivalents or more, and even more preferably 1.1 molar equivalents or more.

[0069] The upper limit of the amount of BuLi relative to the amount of t-butyl-p-bromobenzoate is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of saving reagents, however, the upper limit is preferably 2.5 molar equivalents or less, more preferably 2.0 molar equivalents or less, and even more preferably 1.5 molar equivalents or less.

[0070] <Process 2> The step 2 is a step of introducing the compound obtained in the step 1 and a boronic acid ester compound into a second micro mixer.

[0071] -Compound obtained in step 1- The compound obtained in the step 1 is a compound obtained by mixing the t-butyl-p-bromobenzoate and the BuLi in a first micromixer. An example of the compound obtained by mixing the t-butyl-p-bromobenzoate and the BuLi in the first micromixer is 4-(t-butoxycarbonyl)phenyllithium.

[0072] -Boronate ester compounds- The boronic acid ester compound is not particularly limited and can be appropriately selected depending on the purpose, but isopropoxyboronic acid pinacol ester or triisopropyl borate is preferred from the viewpoint of suppressing side reactions.

[0073] -The second micro mixer- The second micro-mixer is as described above for the first micro-mixer.

[0074] The lower limit of the reaction temperature in step 2 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of reducing the cooling load, however, it is preferably -40°C or higher, more preferably -30°C or higher, even more preferably -20°C or higher, and particularly preferably -10°C or higher.

[0075] The upper limit of the reaction temperature in step 2 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of suppressing side reactions, however, the upper limit is preferably 20° C. or lower, more preferably 15° C. or lower, even more preferably 10° C. or lower, and particularly preferably 5° C. or lower.

[0076] The lower limit of the amount of the boronic acid ester compound relative to the compound obtained in step 1 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of increasing the conversion rate, however, the amount is preferably 1.0 molar equivalent or more, more preferably 1.1 molar equivalent or more, and even more preferably 1.2 molar equivalent or more.

[0077] The upper limit of the amount of the boronic acid ester compound relative to the compound obtained in step 1 is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of saving reagents, however, the amount is preferably 2.5 molar equivalents or less, more preferably 2.0 molar equivalents or less, and even more preferably 1.5 molar equivalents or less.

[0078] The yield of the boronic acid compound in the method for producing a boronic acid compound is not particularly limited and may be appropriately selected depending on the purpose, but is preferably 20% or more, more preferably 30% or more, even more preferably 40% or more, even more preferably 50% or more, particularly preferably 60% or more, and most preferably 70% or more. The yield is determined by HPLC analysis as follows.

[0079] (HPLC analysis) The analysis was performed using a SHIMAZU LC-10A equipped with a YMC TA12S05-2546WT column, with a mobile phase of acetonitrile / water = 9 / 1 (v / v) delivered at 1.0 mL / min, and the compounds were detected by UV (detection wavelength 220 nm). The yield is quantified using a calibration curve prepared by analyzing the internal standard solution, and then calculated using the following formula 1 (for a batch reactor) or formula 2 (for a flow reactor).

number

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[0080] <Other processes> The other steps are not particularly limited and can be appropriately selected depending on the purpose. For example, a quenching step following step 2 can be included.

[0081] -Quenching step after step 2- The quenching step subsequent to the step 2 is not particularly limited and can be appropriately selected depending on the purpose. For example, a method of adding methanol or hydrochloric acid can be mentioned.

[0082] (Boronic acid compounds) The boronic acid compound is produced by the above-mentioned method for producing a boronic acid compound.

[0083] Here, an example of a flow microreactor that can be suitably used in the method for producing a boronic acid compound and a method for producing a boronic acid compound using the same will be described with reference to the drawings.

[0084] FIG. 1 is a schematic diagram showing an example of a flow microreactor. The flow microreactor shown in FIG. 1 includes two mixing means and five flow paths. The flow passage P1 is connected to a mixing means M1. The flow passage P2 is connected to the mixing means M1. The flow passage P3 is connected to the mixing means M2. The flow passage R1 is connected to the mixing means M1 and the mixing means M2. The flow passage R1 also serves as a reaction section. The flow passage R2 is connected to the mixing means M2. The flow passage R2 also serves as a reaction section.

[0085] The t-butyl-p-bromobenzoate is supplied to the mixing means M1 through a flow path P1. BuLi is supplied to the mixing means M1 through a flow path P2. Then, the t-butyl-p-bromobenzoate and the BuLi are mixed in the mixing means M1, and in the resulting liquid, the t-butyl-p-bromobenzoate is lithiated to produce 4-(t-butoxycarbonyl)phenyllithium. The liquid containing 4-(t-butoxycarbonyl)phenyllithium flowing through the flow passage R1 is introduced into the mixing means M2. In the mixing means M2, the liquid is mixed with the boronate compound supplied from the flow passage P3 to produce a boronate compound after quenching. EXAMPLES

[0086] Examples of the present invention will be described below, but the present invention is not limited to these examples.

[0087] <Production of boronic acid compounds> (Comparative Example 1: Reaction in a batch reactor) [ka] 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-butyllithium solution (0.42 M or 1.6 M, hexane solution, 1 mL, 1.1 equivalents, Kanto Chemical 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 the mixture was stirred at T° C. for 10 minutes. 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 the product yield. The results are shown in Table 1.

[0088] -HPLC analysis- The analysis was performed using a SHIMAZU LC-10A equipped with a YMC TA12S05-2546WT column, with the mobile phase being acetonitrile / water = 9 / 1 (v / v) delivered at 1.0 mL / min, and the compounds were detected by UV (detection wavelength 220 nm). The yield was calculated using the following formula 3 after quantifying 4-(t-butoxycarbonyl)phenylboronic acid using a calibration curve prepared by analyzing a standard solution of 4-(t-butoxycarbonyl)phenylboronic acid containing heptanophenone as an internal standard (three samples: approximately 5 mg, approximately 20 mg, and approximately 40 mg of 4-(t-butoxycarbonyl)phenylboronic acid were weighed out separately, and approximately 20 mg of heptanophenone was added to each sample and then dissolved in methanol).

number

[0089] [Table 1]

[0090] The results in Table 1 show that in order to obtain a boronic acid compound in a batch reactor, the reaction must be carried out at extremely low temperatures of -70°C or lower, and furthermore, even at extremely low temperatures of -70°C or lower, the boronic acid compound can only be obtained in low yield.

[0091] Example 1: Reactions in a flow reactor: Temperature studies As shown in Figure 2, a flow microreactor system was used, which consisted of two T-shaped micromixers (M1 and M2, Sanko Seiki Kogyo Co., Ltd.), two microtube reactors (R1 and R2, GL Sciences Co., Ltd.), and three tube pre-cooling 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 Co., Ltd.).

[0092] The flow microreactor system was placed in a cooling bath at T°C, and a t-butyl-p-bromobenzoate solution (0.38 M, THF solution, flow rate: 6.0 mL / min, Combi-Blocks) and an n-butyllithium solution (1.6 M, hexane solution, flow rate: 1.5 mL / min, Kanto Chemical Co., Ltd.) were introduced into M1 (250 μm) using a syringe pump.

[0093] The obtained solution was placed in a container with R1 (φ = 1000 μm, L = 5.0 cm, t R1 =0.31 s) and mixed with triisopropyl borate solution (1.82 M, THF solution, flow rate: 1.5 mL / min, Tokyo Chemical Industry Co., Ltd.) in M2 (250 μm). The resulting solution was passed through R2 (φ=1000 μm, L=100 cm, t R2 = 5.2 seconds).

[0094] 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 the product yield in the same manner as in Comparative Example 1, except that the yield was calculated using the following formula 4. The results are shown in Table 2.

number

[0095] [Table 2]

[0096] The results in Table 2 show that in high-concentration reactions in a flow reactor (t-butyl-p-bromobenzoate solution with a concentration of 0.3 M or more, and butyllithium solution with a concentration of 0.4 M or more), boronic acid compounds can be obtained in high yields at reaction temperatures of -40°C to -60°C.

[0097] (Example 2: Reaction in a flow reactor: residence time study) A flow microreactor system was used, which is shown in FIG. 3 and consists of two T-shaped micromixers (M1 and M2, Sanko Seiki Kogyo Co., Ltd.), two microtube reactors (R1 and R2, GL Sciences Co., Ltd.), and three tube pre-cooling 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 Co., Ltd.).

[0098] The flow microreactor system was placed in a cooling bath at T°C, and a t-butyl-p-bromobenzoate solution (0.38 M, THF solution, flow rate: 6.0 mL / min, Combi-Blocks) and an n-butyllithium solution (1.6 M, hexane solution, flow rate: 1.5 mL / min, Kanto Chemical Co., Ltd.) were introduced into M1 (250 μm) using a syringe pump.

[0099] The obtained solution was placed in a container with R1 (φ1 μm, L1 cm, t R1 The resulting solution was passed through R2 (φ=1000 μm, L=100 cm, t R2 = 5.2 seconds).

[0100] After reaching a steady state, the product solution exiting 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 the product yield. The results are shown in Table 3.

[0101] [Table 3]

[0102] The results in Table 3 show that in high-concentration reactions in a flow reactor (t-butyl-p-bromobenzoate solution with a concentration of 0.3 M or more, and butyllithium solution with a concentration of 0.4 M or more), the yield of boronic acid compounds can be improved even at temperatures of -20°C or higher by shortening the residence time in the microtube reactor (R1).

[0103] (Example 3: Reaction in a flow reactor: Study using sec-BuLi) As shown in FIG. 4, a flow microreactor system was used, which consisted of two T-shaped micromixers (M1 and M2, Sanko Seiki Kogyo Co., Ltd.), two microtube reactors (R1 and R2, GL Sciences Co., Ltd.), and three tube pre-cooling 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 Co., Ltd.).

[0104] The flow microreactor system was placed in a cooling bath at -20°C, and a t-butyl-p-bromobenzoate solution (C1M, THF solution, flow rate: 6.0 mL / min, Combi-Blocks) and a sec-butyllithium solution (C2M, hexane solution, flow rate: V2 mL / min, Kanto Chemical Co., Ltd.) were introduced into M1 (250 µm) using a syringe pump.

[0105] The obtained solution was placed in a container with R1 (φ = 1000 μm, L = 3.5 cm, t R1 =0.012-0.014 sec) and mixed with triisopropyl borate solution (C3M, THF solution, flow rate: V3 mL / min, Tokyo Chemical Industry Co., Ltd.) in M2 (250 μm). The resulting solution was mixed with triisopropyl borate solution (C3M, THF solution, flow rate: V3 mL / min, Tokyo Chemical Industry Co., Ltd.) in R2 (φ=1000 μm, L=100 cm, t R2 =4.4-5.2 seconds).

[0106] After reaching a steady state, the product solution exiting 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 the product yield. The results are shown in Table 4.

[0107] [Table 4]

[0108] The results in Table 4 show that in the reaction in a flow reactor, the use of sec-butyllithium allows the production of a boronic acid compound in higher yield at -20°C.

[0109] Examples of aspects of the present invention include the following. <1> The method for producing a boronic acid compound includes step 1 of introducing 0.3 M or more of t-butyl-p-bromobenzoate and 0.4 M or more of BuLi into a first micro mixer, and step 2 of introducing the compound obtained in step 1 and a boronic acid ester compound into a second micro mixer. <2> The step 1 is carried out at −20° C. or higher. <1> The present invention relates to a method for producing a boronic acid compound according to the present invention. <3> The step 2 is carried out at −20° C. or higher. <1> or <2> The present invention relates to a method for producing a boronic acid compound according to the present invention. <4> In the step 1, the introduction rate of the t-butyl-p-bromobenzoate is 6 mL / min or more. <1> from <3> 1. A method for producing a boronic acid compound according to any one of claims 1 to 9. <5> The BuLi is sec-BuLi. <1> from <4> 1. A method for producing a boronic acid compound according to any one of claims 1 to 9. <6> The first micromixer has an average inner diameter of 250 μm or more. <1> from <5> 1. A method for producing a boronic acid compound according to any one of claims 1 to 9. <7> The second micromixer has an average inner diameter of 250 μm or more. <1> from <6> 1. A method for producing a boronic acid compound according to any one of claims 1 to 9. <8> The yield of the boronic acid compound is 20% or more. <1> from <7> 1. A method for producing a boronic acid compound according to any one of claims 1 to 9.

Claims

1. Step 1 of introducing 0.3M or more of t-butyl-p-bromobenzoate and 0.4M or more of BuLi into a first micro mixer; A process for producing a boronic acid compound, comprising: a process 2 for introducing the compound obtained in the process 1 and a boronic acid ester compound into a second micromixer.

2. The method for producing a boronic acid compound according to claim 1, wherein the step 1 is carried out at -20°C or higher.

3. 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. The method for producing a boronic acid compound according to any one of claims 1 to 3, wherein in the step 1, an introduction rate of the t-butyl-p-bromobenzoate is 6 mL / min or more.

5. The method for producing a boronic acid compound according to any one of claims 1 to 4, wherein the BuLi is sec-BuLi.

6. The method for producing a boronic acid compound according to claim 1 , 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 claim 1 , 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 claim 1 , wherein the yield of the boronic acid compound is 20% or more.

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