Mechanochemical reaction method and reaction equipment

Abstract

The present invention provides a mechanochemical reaction method and reaction equipment that allows operations such as adding reagents during a reaction, removing reaction products, and adding a substrate to be used in the next reaction to be performed without removing the lid of the reaction vessel, while preventing a decrease in reaction efficiency and ensuring safety, and that also allows the state inside the reaction vessel to be confirmed, with improved operability and workability, and with shorter (higher speed) reaction steps. [Solution] This is a mechanochemical reaction method using a reaction device comprising a reaction vessel A having an opening and a lid 12 that seals the opening 13 of the reaction vessel in an openable and closable manner, wherein one or more through holes 21 that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in the reaction vessel other than the opening and / or in the lid.

Description

[Technical Field]

[0001] The present invention relates to a mechanochemical reaction method and reaction equipment. [Background technology]

[0002] Mechanochemical reaction methods are organic synthesis methods that involve direct contact between reactants without using organic solvents or with only small amounts of organic solvents. They are of academic and industrial interest as a low-environmental-impact synthesis method. Mechanochemical reaction methods involve the application of mechanical energy to substrates to induce reactions. Mechanical energy can be generated mechanically by means of grinding, shearing, impact, compression, shaking, pressing, dispersion, kneading, or crushing. Applying such mechanical energy to substrates activates them to react. Mechanochemical reaction methods involve the direct contact and mixing of components in the reaction system, eliminating the need for or requiring only very small amounts of organic solvents. They offer high reactivity and high reaction efficiency while maintaining a low environmental impact.

[0003] Mechanochemical reaction methods have been used to develop functional materials using various organic compounds as raw materials, such as pharmaceuticals, pesticides, liquid crystal compounds, organic electroluminescent compounds, organic thin-film solar cells, polymer compounds, oligomers, electrolytes, coloring materials, energy ray absorbing materials, information recording materials, wavelength conversion materials, indicator materials, sensor materials, organic light-emitting diodes (OLEDs), and organic semiconductor materials.

[0004] Patent Document 1 discloses a cross-coupling reaction method that utilizes a mechanochemical reaction method and does not use a solvent, and a method for producing a cross-coupling reaction product using this method. Patent Document 2 discloses a method for producing an organometallic nucleophilic agent using a mechanochemical reaction method, and a reaction method using an organometallic nucleophilic agent. Patent Document 3 relates to a mechanoredox reaction using a piezoelectric material by utilizing a mechanochemical reaction method, and more specifically, discloses a mechanoredox reaction and a method for producing a redox reaction product by using the reaction method. Patent Document 4 discloses a method for producing a monocross-coupled aromatic compound having one less leaving group than an aromatic compound having at least two leaving groups, using a mechanochemical reaction method. Patent Document 5 discloses a method for producing a coupling reaction product and a mechanochemical reaction apparatus that can suppress the production of by-products and easily carry out a coupling reaction with a high yield. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 7023019 [Patent Document 2] Patent No. 7404606 [Patent Document 3] International Publication No. 2021 / 045207 [Patent Document 4] International Publication No. 2021 / 177290 [Patent Document 5] Japanese Patent Application Laid-Open No. 2023-139499 Summary of the Invention [Problem to be solved by the invention]

[0006] Mechanochemical reaction methods are useful synthetic methods that can synthesize target compounds more easily and rapidly than conventional organic synthesis methods. However, mechanochemical reaction methods typically do not impose any particular restrictions on the atmosphere inside the reaction vessel (the atmosphere of the reaction system). Therefore, all reagents are added through the opening of the reaction vessel body under atmospheric conditions. The opening is then closed with a retractable lid under atmospheric conditions, and mechanical energy is applied to the substrate by shaking or stirring for a predetermined period of time using a ball mill or other device to synthesize the target compound. This can lead to various problems, including (i) inactivation or deterioration of the reaction product in an oxygen-containing atmosphere such as air, (ii) risk of fire or explosion of the reaction product in an oxygen-containing atmosphere, (iii) gas generation during the reaction resulting in an increase in internal pressure, and (iv) the need to check the reaction status. Therefore, since the lid of the reaction vessel must be removed during the reaction to add reagents, remove the reaction product, add the substrate for the next reaction, or check the reaction status, improvements are needed to prevent a decrease in reaction efficiency and ensure safety.

[0007] One of the problems that the present invention aims to solve is to provide a mechanochemical reaction method in which, without removing the lid of the reaction vessel, it is possible to perform operations such as adding reagents during the reaction, removing reaction products, and adding a substrate to be used in the next reaction, while preventing a decrease in reaction efficiency and ensuring safety, and it is also possible to check the state inside the reaction vessel, and further, it is easy to operate and work, and the reaction process is shortened (speeded up). One of the problems that the present invention aims to solve is to provide a mechanochemical reaction method that uses a reaction device that includes a reaction vessel having an opening and a lid that seals the opening of the reaction vessel in an openable and closable manner, in which one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in a portion other than the opening of the reaction vessel and / or in the lid. One of the problems that the present invention aims to solve is to provide a mechanochemical reaction device used in a mechanochemical reaction method, which allows operations such as adding reagents during a reaction, removing reaction products, and adding a substrate to be used in the next reaction, without removing the lid of the reaction vessel, while preventing a decrease in reaction efficiency and ensuring safety, and which also allows the state inside the reaction vessel to be confirmed, and which further has improved operability and workability and shortens (speeds up) the reaction process. One of the problems that the present invention aims to solve is to provide a reaction device used in a mechanochemical reaction method, which comprises a reaction vessel having an opening and a lid that seals the opening of the reaction vessel in an openable and closable manner, and in which one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in a part other than the opening of the reaction vessel and / or in the lid. [Means for solving the problem]

[0008] As a result of extensive research, the inventors discovered that the above problems can be solved by a mechanochemical reaction method using a reaction device having a specific structure, or a reaction device having a specific structure used in a mechanochemical reaction method, and thus completed the present invention. That is, the present invention relates to a mechanochemical reaction method and a reaction device according to the following items 1 to 5. [Item 1] A mechanochemical reaction method using a reaction device comprising a reaction vessel having an opening and a lid that can be opened and closed to seal the opening of the reaction vessel, wherein one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in the lid and / or other than the opening of the reaction vessel. [Item 2] The mechanochemical reaction method according to Item 1, wherein the reaction uses Li or a Li compound. [Item 3] The mechanochemical reaction method according to Item 1 or 2, which is a method for producing an organometallic nucleophile, comprises reacting an organic halide with a metal or a metal compound by a mechanochemical reaction method in the presence of 0.5 to 10.0 equivalents of an ether compound per equivalent of the organic halide. [Item 4] A reaction device used in the mechanochemical reaction method according to Item 1 or 2, comprising a reaction vessel having an opening and a lid that seals the opening of the reaction vessel in an openable and closable manner, wherein one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in the lid and / or outside the opening of the reaction vessel. [Item 5] The reaction equipment according to Item 4, wherein the reaction vessel and / or the lid are made of a material containing at least one selected from the group consisting of stainless steel, agate, alumina, tungsten carbide, chromium steel, zirconia, silicon nitride, brass, fluororesin, polyoxymethylene, polyamide, polyimide, polyamideimide, polyether ether ketone, and polypropylene. [Effects of the Invention]

[0009] The present invention provides a mechanochemical reaction method in which, without removing the lid of the reaction vessel, it is possible to perform operations such as adding reagents during the reaction, removing reaction products, and adding substrates to be used in the next reaction, while preventing a decrease in reaction efficiency and ensuring safety, and it is also possible to check the state inside the reaction vessel.Furthermore, it provides a mechanochemical reaction method in which operability and workability are improved and the reaction process is shortened (speeded up). The present invention provides a mechanochemical reaction method using a reaction device comprising a reaction vessel having an opening and a lid that can be opened and closed to seal the opening of the reaction vessel, wherein one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in the reaction vessel other than the opening and / or in the lid. The present invention provides a mechanochemical reaction device used in a mechanochemical reaction method, which allows operations such as adding reagents during a reaction, removing reaction products, and adding a substrate to be used in the next reaction, without removing the lid of the reaction vessel, while preventing a decrease in reaction efficiency and ensuring safety, and which also allows the state inside the reaction vessel to be confirmed.Furthermore, it provides a mechanochemical reaction device with improved operability and workability, and which shortens (speeds up) the reaction process. The present invention provides a reaction device for use in a mechanochemical reaction method, which comprises a reaction vessel having an opening and a lid that seals the opening of the reaction vessel in an openable and closable manner, and in which one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in a part other than the opening of the reaction vessel and / or in the lid.

[0010] The mechanochemical reaction method and reactor of the present invention are applicable to all mechanochemical reactions. It allows for the addition of reagents during a reaction, the addition of reagents for the next reaction, the confirmation of the internal state of the reaction vessel at any time during the reaction, and the removal of gases, reaction products, etc. from the reaction vessel at any time during the reaction, all without removing the lid of the reaction vessel. This prevents the deactivation of reaction products and intermediates, prevents a decrease in reaction efficiency, and allows the confirmation of the internal state of the reaction vessel in real time. This method and reactor are highly safe, easy to operate, and highly useful. The internal state of the reaction vessel can be, for example, one or more selected from the group consisting of internal temperature, internal pressure, the amount of specific components such as moisture, the atmosphere (concentration of various gases), the state of the substrate, the movement of the stirring member, the state of the reaction product, and the state of the inner wall of the reaction vessel. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a diagram showing a reaction device according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] Hereinafter, the mechanochemical reaction method and reaction device according to the present invention will be described in detail with reference to the drawings. It should be understood that the present invention is not limited to the embodiments described below, and includes various modifications that are implemented within the scope that does not change the gist of the present invention.

[0013] [Reaction equipment used in mechanochemical reaction methods] The reaction equipment used in the mechanochemical reaction method is not particularly limited as long as it comprises a reaction vessel with an opening and a lid that seals the opening of the reaction vessel in an openable and closable manner, and one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in the lid and / or outside the opening of the reaction vessel, and can perform a mechanochemical reaction by applying mechanical energy to a substrate in the reaction equipment.

[0014] Examples of devices that can impart mechanical energy to a substrate in a reaction device include: Grinding machines such as ball mills, rod mills, jet mills, SAG mills, etc.; Rotary mills, grinders, etc. Horizontal cylindrical, V-type, double cone type, square cube type, S-type and continuous V-type (horizontal axis rotation) container rotating type mixers; Horizontal cylindrical, V-shaped, double cone and ball mill type (with baffle blades) rotating vessel mixers; (Rotary vibration) container-rotating mixers such as rocking and cross-rotary types; Fixed vessel mixers (horizontal axis rotation) such as ribbon, paddle, single-shaft rotor and bag mill types; Ribbon type, screw type, planetary type, turbine type, high-speed flow type, rotating disk type and Mahler type (vertical axis rotating) stationary vessel type mixers; (vibrating) stationary vessel type mixing equipment such as vibrating mills and sieves; (Fluidization) fluid movement type mixers such as heterogeneous fluidized beds, swirling fluidized beds, types with risers and jot pump types; (gravity) fluid motion type mixing devices such as gravity type and static mixers; Low Frequency Resonant Acoustic Mixer (RAM); Devices that have a reaction vessel and one or more stirring members (balls) placed in the reaction vessel, and generate relative motion by the reciprocating and / or rotating motion of the reaction vessel or any other motion, such as a reciprocating mixer mill in which the reaction vessel and balls reciprocate relative to each other, a planetary ball mill in which the reaction vessel and balls rotate relative to each other, or a rotary ball mill; One or more selected from the group consisting of the above can be used.

[0015] The amount of energy to be applied when carrying out the mechanochemical method is not particularly limited, and can be determined appropriately taking into consideration the types and amounts of the reaction raw materials, the reaction temperature, the treatment time, and the like. For example, when a ball mill is used, the shaking can be carried out at 5 Hz or more, preferably 10 Hz or more, and more preferably 20 Hz or more. The treatment time is not particularly limited. For example, it can be 1 minute or more. The mechanochemical reaction method is particularly advantageous because it allows the reaction to be completed in a short time. The reaction temperature during the mechanochemical reaction is not particularly limited. For example, it can be −100° C. or higher, 0° C. or higher, or 15° C. or higher, and can be, for example, 300° C. or lower, 250° C. or lower, or 200° C. or lower. For heating, a heating tool such as a heater or a heat gun can be used.

[0016] The reaction equipment shown in FIG. 1 shows one embodiment of the reaction equipment used in the mechanochemical reaction method of the present invention. The reaction device A shown in Fig. 1 includes a reaction vessel 11 and a reaction vessel lid 12 that can be opened and closed to seal a reaction vessel opening 13, and the reaction vessel 11 and the reaction vessel lid 12 form a reaction vessel interior 40. In Fig. 1, the reaction vessel 11 is provided with one through-hole 21 that connects the reaction vessel interior 40 to the outside of the reaction vessel. The through-hole 21 can be closed and opened by a through-hole closing member 31.

[0017] There are no particular limitations on the material that constitutes the reaction vessel 11. For example, it is possible to use a material that includes at least one selected from the group consisting of stainless steel, agate, alumina, tungsten carbide, chromium steel, zirconia, silicon nitride, brass, fluororesin, polyoxymethylene, polyamide, polyimide, polyamideimide, polyetheretherketone, and polypropylene.

[0018] There are no particular limitations on the material that constitutes the reaction vessel lid 12. For example, it is possible to use a material that includes at least one selected from the group consisting of stainless steel, agate, alumina, tungsten carbide, chromium steel, zirconia, silicon nitride, brass, fluororesin, polyoxymethylene, polyamide, polyimide, polyamideimide, polyether ether ketone, and polypropylene.

[0019] One or more through-holes 21 that communicate between the inside 40 of the reaction vessel and the outside of the reaction vessel can be provided in the reaction vessel 11 and / or the reaction vessel lid 12. There are no particular limitations on the opening position, size, or shape of the through-hole 21. They can be set as desired depending on the application, mode of use, etc. of the through-hole 21.

[0020] The through-hole 21 can be closed / opened at any timing using the through-hole closing member 31. This allows for the safe addition of reagents during a reaction, addition of reagents for the next reaction after the reaction is completed, collection of the contents during a reaction, collection of reaction products, removal of gas, etc., without deactivating / deteriorating the substances in the reaction vessel. Examples of the through-hole closing member 31 include a stopper, a screw plug, etc., and if necessary, a member such as a packing may be used to improve the sealing performance. For example, a flanged screw plug is advantageous in terms of handling, etc.

[0021] It is also possible to install measuring instruments such as a camera, a thermometer, and lighting in the through-hole 21 to observe the inside 40 of the reaction vessel during the mechanochemical reaction. It is possible to circulate an inert gas by providing a plurality of through-holes 21. In this case, by providing a porous member or the like on the side of the through-holes 21 facing the inside 40 of the reaction vessel, it is possible to prevent substances in the reaction vessel from leaking. A tube is connected to the through-hole 21, and if necessary, connected to a supply means and / or a collection means via a valve and / or valves, and one or more control means for the valve, valve, supply means and collection means can be provided to perform the introduction of reagents, collection of contents (reaction products), removal of gas, replacement of the atmosphere, etc. These controls can also be automatically controlled by a computer program or the like. When there are a plurality of through-holes 21, each of the through-holes 21 can be used for one or more of observing the inside of the reaction vessel, distributing gas, supplying / collecting, and controlling. In this case, the uses of the through-holes 21 may be the same or different from each other.

[0022] The volume of the reaction vessel interior 40 is not particularly limited. It can be a volume from the microliter level to the kiloliter level. The reaction vessel interior 40 may be equipped with a mechanism or member for applying mechanical energy to the substrate. For example, a ball made of a hard material such as a stainless steel ball, a stirrer, an ultrasonic resonance mechanism, etc. can be used. When balls are used, the number of balls to be placed in the reaction vessel interior 40 is not particularly limited. Any number of balls can be placed depending on the mechanical energy to be applied to the reaction, the amount of heat generated during the reaction, etc.

[0023] The material constituting the reaction vessel 11 and / or the reaction vessel lid 12 is not particularly limited. Any appropriate material can be used from the viewpoints of durability, chemical resistance, etc. For example, a material containing at least one selected from the group consisting of stainless steel, agate, alumina, tungsten carbide, chromium steel, zirconia, silicon nitride, brass, fluororesin, polyoxymethylene, polyamide, polyimide, polyamideimide, polyetheretherketone, and polypropylene can be used.

[0024] In addition to the reaction vessel and the lid, the reaction equipment may further include, as necessary, a means for fixing the reaction vessel to a device capable of applying mechanical energy, a heating means for heating the inside of the reaction vessel, a cooling means for cooling the inside of the reaction vessel, and other mechanisms required for carrying out a mechanochemical reaction. Furthermore, the reaction equipment can be used in combination with one or more of the following devices other than the device capable of applying mechanical energy: a heating device for heating the inside of the reaction vessel, a cooling device for cooling the inside of the reaction vessel, a device for adding substrates, etc., a device for irradiating visible light, ultraviolet light, etc., a device for filling the reaction product, various control devices, and other devices required for a mechanochemical reaction.

[0025] [Mechanochemical reaction method] The mechanochemical reaction method of the present invention is a mechanochemical reaction method that uses a reaction device that includes a reaction vessel having an opening and a lid that seals the opening of the reaction vessel in an openable and closable manner, and in which one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in the lid and / or other than the opening of the reaction vessel.

[0026] The mechanochemical reaction method of the present invention can be applied to various chemical reactions, such as various reduction reactions, various coupling reactions, various oxidation reactions, various addition reactions, and various condensation reactions. For example, it can be used in methods that have been established as mechanochemical reaction methods, and in particular, it can be applied to reactions for producing organometallic nucleophiles, such as Grignard reactions. In this case, it can be applied to a method for producing organometallic nucleophiles, in which an organic halide is reacted with a metal or metal compound by a mechanochemical reaction method in the presence of 0.5 to 10.0 equivalents of an ether compound per equivalent of the organic halide.

[0027] The mechanochemical reaction method of the present invention can be applied to reactions using Li or Li compounds. Examples of Li (lithium) or Li compounds (lithium compounds) include at least one selected from the group consisting of metallic lithium in the form of wire (fiber), powder, lump, foil, etc.; lithium salts such as chlorides, bromides, iodides, nitrates, sulfates, and carbonates; and oxides of lithium. The mechanochemical reaction using Li or a Li compound is not particularly limited, and examples thereof include a reaction with an organic halide to form an organometallic nucleophile.

[0028] In reactions using Li or Li compounds, the reaction product / intermediate is likely to be denatured and deactivated in the presence of moisture or oxygen, resulting in a decrease in reaction efficiency. In the mechanochemical reaction method of the present invention, it is possible to inject the substrate or inert gas used in the next reaction into the reaction vessel without opening the lid of the reaction vessel, and further, the reaction product can be easily removed, preventing the denaturation and deactivation of the reaction product / intermediate when the reaction vessel is opened. Furthermore, previous mechanochemical reaction methods using Li or Li compounds required an inert gas atmosphere when the lid of the reaction vessel was opened, which resulted in problems such as the apparatus becoming large-scale and reducing workability. However, the mechanochemical reaction method of the present invention can solve these problems.

[0029] The mechanochemical reaction method of the present invention can be applied to a method for producing an organometallic nucleophile, in which an organic halide is reacted with a metal or a metal compound by a mechanochemical reaction method in the presence of 0.5 to 10.0 equivalents of an ether compound per equivalent of the organic halide.

[0030] The organic halide may be a compound of the following formula (I): A 1 -Xm (I) One or more compounds represented by the following formula can be used. The compound represented by formula (I) may be a commercially available product, which may be used as is or after purification.

[0031] In formula (I), A 1represents any one of an m-valent aromatic hydrocarbon group having 6 to 30 carbon atoms which may have a substituent, an m-valent heterocyclic group which may have a substituent, an m-valent aromatic-aliphatic hydrocarbon group having 7 to 30 carbon atoms which may have a substituent, an m-valent aliphatic hydrocarbon group having 1 to 20 carbon atoms which may have a substituent, or an m-valent unsaturated aliphatic hydrocarbon group having 2 to 20 carbon atoms which may have a substituent. In formula (I), each X independently represents F (fluorine), Cl (chlorine), Br (bromine) or I (iodine). In formula (I), m is the number of X and represents an integer of 1 or more.

[0032] A in formula (I) 1 Examples of the aromatic hydrocarbon group in the formula (I) include a monocyclic aromatic hydrocarbon group, a polycyclic aromatic hydrocarbon group, a fused ring aromatic hydrocarbon group, etc. The aromatic hydrocarbon group may be an aromatic-aliphatic hydrocarbon group formed by bonding an aromatic ring and an aliphatic group. A in formula (I) 1 The heterocyclic group in the formula (I) is, for example, a group containing at least one heteroatom, preferably 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom, or a sulfur atom, and having a 5- to 8-membered aliphatic heterocyclic structure and / or an aromatic heterocyclic structure, and examples thereof include a monocyclic heterocyclic group, a polycyclic heterocyclic group, and a fused ring heterocyclic group. A in formula (I) 1 The aliphatic hydrocarbon group in may be, for example, any of a linear saturated aliphatic hydrocarbon group, a branched saturated aliphatic hydrocarbon group, and a cyclic saturated aliphatic hydrocarbon group. A in formula (I) 1 The unsaturated aliphatic hydrocarbon group in may be, for example, a linear unsaturated aliphatic hydrocarbon group, a branched unsaturated aliphatic hydrocarbon group, or a cyclic unsaturated aliphatic hydrocarbon group. In the unsaturated aliphatic hydrocarbon group, the unsaturated group is a polymerizable carbon-carbon double bond or carbon-carbon triple bond, and it is sufficient that the unsaturated group contains one or more polymerizable carbon-carbon double bonds or carbon-carbon triple bonds. Examples of the substituent include one or more selected from the group consisting of alkyl groups having 1 to 20 carbon atoms, alkoxy groups having 1 to 20 carbon atoms, cycloalkyl groups having 3 to 20 carbon atoms, alkenyl groups having 1 to 24 carbon atoms, alkynyl groups having 1 to 24 carbon atoms, aryl groups having 5 to 24 carbon atoms, arylalkyl groups having 7 to 24 carbon atoms, aryloxy groups having 5 to 24 carbon atoms, heteroaryl groups having 4 to 24 carbon atoms, acyl groups having 1 to 24 carbon atoms, amino groups having 0 to 24 carbon atoms, fluorine, fluorine-containing groups such as fluorine-containing hydrocarbon groups having 1 to 30 carbon atoms, cyano groups, nitro groups, and the like. The substituents may be crosslinked to each other, or may form a cyclic structure as a whole. The substituent may further have another substituent.

[0033] The metal or metal compound is not particularly limited as long as it can react with an organic halide to form an organometallic nucleophile. Examples of metals include one or more selected from the group consisting of alkaline earth metals, alkali metals, transition metals, zinc, aluminum, indium, tin, bismuth, boron, silicon, gallium, germanium, antimony, lead, and rare earth metals. Examples of metal compounds include one or more selected from the group consisting of salts of these metals (chlorides, bromides, iodides, nitrates, sulfates, carbonates, etc.) and oxides of these metals. Among these, one or more selected from the group consisting of magnesium, calcium, strontium, lithium, manganese, palladium, titanium, zinc, aluminum, bismuth, indium, samarium, salts of these metals, oxides of these metals, etc. are preferred.

[0034] The amount of metal or metal compound used is not particularly limited. It is, for example, 0.1 equivalent or more, preferably 0.5 equivalent or more, more preferably 0.7 equivalent or more, relative to 1 equivalent of organic halide, and is, for example, 10.0 equivalents or less, preferably 5.0 equivalents or less, more preferably 3.0 equivalents or less. If the amount is less than 0.1 equivalent, the reaction may not proceed sufficiently, resulting in a reduced yield. If the amount exceeds 10.0 equivalents, it is necessary to remove unreacted metal or metal compound, and the unreacted metal or metal compound may cause a side reaction.

[0035] The ether compound may be a compound having one or more ether bonds (—O—) in the molecule, and is not particularly limited as long as it is a compound that is inactive in the reaction between an organic halide and a metal or metal compound. For example, one or more selected from the group consisting of diethyl ether, diisopropyl ether, dibutyl ether, t-butyl methyl ether, tetrahydrofuran, tetrahydropyran, dimethoxyethane, 1,4-dioxane, anisole, acetoxy-2-ethoxyethane, propylene glycol monomethyl ether acetate, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1-methoxy-1,1,2,2-tetrafluoroethane, 1-ethoxy-1,1,2,2-tetrafluoroethane, and the like can be mentioned.

[0036] The amount of ether compound used is 0.5 to 10.0 equivalents per equivalent of organic halide. It is preferably 0.7 equivalents or more, more preferably 1.0 equivalents or more, even more preferably 1.2 equivalents or more, and even more preferably 1.5 equivalents or more, and is preferably 7.0 equivalents or less, more preferably 5.0 equivalents or less. If the amount is less than 0.5 equivalents, organometallic nucleophiles, particularly Grignard reagents, cannot be efficiently synthesized, and the reaction may not proceed sufficiently when used in subsequent reactions. If the amount exceeds 10.0 equivalents, the ether compound essentially functions as a solvent, making it difficult to apply mechanochemical action to the substrate (reaction component). This makes it difficult to efficiently synthesize organometallic nucleophiles, particularly Grignard reagents, and the reaction may not proceed sufficiently when used in subsequent reactions. [Example]

[0037] The present invention will be specifically and in detail explained below using examples. These examples are merely one embodiment of the present invention, and the present invention is not limited to these examples in any way.

[0038] In the examples, when reactions were carried out using a ball mill, a ball mill MM400 manufactured by Verder Scientific Co., Ltd. (formerly Retsch) was used. The compounds used in the examples were commercially available products and were used without further purification unless otherwise specified.

[0039] The organic halogen compounds (1a) to (1d) and organic carbonyl compounds (2a) to (2e) used in the examples are as follows: [ka]

[0040] [ka]

[0041] The target reaction products (3a) to (3e) produced in the examples are as follows: [ka]

[0042] [Example 1] A 5.0 mL stainless steel ball mill jar (reaction vessel with a through-hole) with a through-hole connecting the inside and outside of the reaction vessel and plugged with a plug was placed in the jar. Two 10 mm diameter stainless steel balls were placed in the jar. Under an argon atmosphere, 209 μL (2.0 mmol, 1.0 equiv.) of bromobenzene (1a) as the substrate organic halide, 30.5 mg (4.4 mmol, 2.2 equiv.) of lithium (wire), and 450 μL (4.4 mmol, 2.2 equiv.) of diethyl ether were added. The ball mill jar was then capped and attached to a ball mill. The mixture was shaken and stirred at room temperature (25 °C) for 5 minutes at a frequency of 30 Hz. After the reaction was completed, the plug blocking the through-hole was removed under an argon atmosphere, and 100.1 mg (1.0 mmol, 1.0 equivalent) of 4-methylpentan-2-one (2a) was added as an organic carbonyl compound to the inside of the reaction vessel through the through-hole, and the plug was then closed under an argon gas atmosphere. The ball mill jar was attached to a ball mill, and the reaction was carried out by shaking and stirring at room temperature (25°C) at a frequency of 30 Hz for 15 minutes. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The collected organic layer was dried over magnesium sulfate and then filtered through pleated filter paper. The ethyl acetate was removed from the resulting organic layer using an evaporator, yielding the desired reaction product (2-phenyl-2-hydroxy-4-methyl-pentane (3a)). 1 The NMR yield of the desired reaction product (3a) was 74% by 1 H NMR.

[0043] [Examples 2 to 5] The same procedures as in Example 1 were carried out except that the organic halide and organic carbonyl compound were changed to the compounds shown in Table 1, to obtain the corresponding reaction products (3b) to (3e). 1 The NMR yields of the target reaction products (3b) to (3e) measured by 1 H NMR were as shown in Table 1.

[0044] [Table 1]

[0045] [About the Examples] For example, when mechanochemical reaction methods are performed using Li or Li compounds, flammable organolithium species are generated during the reaction, so a strict inert atmosphere is required, and it has been difficult to operate safely with previous mechanochemical reaction methods. In the present invention, a mechanochemical reaction method is carried out using a reaction device that includes a reaction vessel having an opening, and a lid that seals the opening of the reaction vessel in an openable and closable manner, and in which one or more through-holes that connect the inside of the reaction vessel to the outside of the reaction vessel are provided in the lid and / or other than the opening of the reaction vessel.This means that, for example, even when a mechanochemical reaction method is carried out using Li or a Li compound, the mechanochemical reaction method can be carried out safely, and a reaction product can be obtained in high yield in a short period of time. From this, it can be seen that the present invention is extremely useful industrially. [Explanation of symbols]

[0046] A Reaction equipment 11 Reaction vessel 12 Reaction vessel lid 13 Reaction vessel opening 21 through hole 31 Through-hole blocking member 40 Inside the reaction vessel

Claims

1. A mechanochemical organic synthesis reaction method using a mechanochemical organic synthesis reaction device including a reaction vessel having an opening and a lid that can open and close the opening of the reaction vessel, comprising: The mechanochemical organic synthesis reaction method, wherein the mechanochemical organic synthesis reaction equipment is provided with one or more through holes that communicate the inside of the reaction vessel with the outside of the reaction vessel and that are provided in a portion other than the opening of the reaction vessel and / or in the lid, and a through hole blocking member that blocks the through hole.

2. A mechanochemical organic synthesis reaction apparatus for use in a mechanochemical organic synthesis reaction method, comprising a reaction vessel having an opening and a lid that can be opened and closed to seal the opening of the reaction vessel; The mechanochemical organic synthesis reaction equipment is provided with one or more through holes that communicate the inside of the reaction vessel with the outside of the reaction vessel and that are provided in a portion other than the opening of the reaction vessel and / or in the lid, and a through hole blocking member that blocks the through hole.

3. A mechanochemical organic synthesis reaction vessel provided in a mechanochemical organic synthesis reaction apparatus used in a mechanochemical organic synthesis reaction method, comprising: An opening; one or more through holes provided in the mechanochemical organic synthesis reaction vessel other than the opening, which communicate the interior of the mechanochemical organic synthesis reaction vessel with the exterior of the mechanochemical organic synthesis reaction vessel; a through-hole closing member that is detachable from the through-hole; The mechanochemical organic synthesis reaction vessel is provided with:

4. A lid for a mechanochemical organic synthesis reaction vessel that is provided in a mechanochemical organic synthesis reaction apparatus used in a mechanochemical organic synthesis reaction method and that seals an opening of the mechanochemical organic synthesis reaction vessel in an openable and closable manner, comprising: one or more through holes provided in a lid of the mechanochemical organic synthesis reaction vessel, which communicate the interior of the mechanochemical organic synthesis reaction vessel with the exterior of the mechanochemical organic synthesis reaction vessel; a through-hole closing member that is detachable from the through-hole; The lid of the mechanochemical organic synthesis reaction vessel is provided with:

5. A reaction device used in a mechanochemical reaction method, comprising a reaction vessel having an opening and a lid that can be opened and closed to seal the opening of the reaction vessel, The reaction device, wherein the reaction vessel has one or more through holes that communicate the inside of the reaction vessel with the outside of the reaction vessel, and a through hole closing member that closes the through hole can be attached.

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