Mechanochemical reaction method and reaction apparatus

Abstract

The present invention addresses the problem of providing: a mechanochemical reaction method with which it is possible to perform operations such as adding a reagent in the middle of a reaction, taking out a reaction product, and charging a substrate to be used in the next reaction, while preventing a decrease in reaction efficiency and ensuring safety without removing a lid of a reaction container, and with which it is possible to see the state of the inside of the reaction container, wherein operability and workability are improved, and the reaction process is shortened (speeded up); and a reaction apparatus which is used for this mechanochemical reaction method. As a solution, the present invention provides a mechanochemical reaction method that uses a reaction apparatus which is provided with a reaction container having an opening and a lid that seals the opening of the reaction container in an openable and closable manner, wherein one or more through-holes that bring the inside of the reaction container and the outside of the reaction container into communication with each other are provided in a portion other than the opening of the reaction container and / or in the lid.

Description

Mechanochemical reaction method and reaction equipment

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

[0002] Mechanochemical reaction methods are organic synthesis methods that involve direct contact between reactant materials without using organic solvents or using 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 cause a reaction. Mechanical energy can be generated mechanically by means of grinding, shearing, impact, compression, shaking, pressing, dispersion, kneading, crushing, and the like. By applying such mechanical energy to substrates, they can be activated and reacted. Mechanochemical reaction methods are organic synthesis reaction methods that involve direct contact and mixing of the components contained in the reaction system, eliminating the need for organic solvents or requiring only very small amounts. They are highly reactive and highly efficient, while also having 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, agricultural chemicals, 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 Literature 1 discloses a solvent-free cross-coupling reaction method using a mechanochemical reaction method and a method for producing a cross-coupling reaction product using the method. Patent Literature 2 discloses a method for producing an organometallic nucleophile using a mechanochemical reaction method and a reaction method using an organometallic nucleophile. Patent Literature 3 relates to a mechanoredox reaction using a piezoelectric material using a mechanochemical reaction method, and more specifically, a mechanoredox reaction and a method for producing a redox reaction product using the reaction method. Patent Literature 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 Literature 5 discloses a method for producing a coupling reaction product and a mechanochemical reaction apparatus that suppress the generation of by-products and enable a coupling reaction to be carried out easily and with high yield.

[0005] Japanese Patent No. 7023019 Japanese Patent No. 7404606 International Publication No. 2021 / 045207 International Publication No. 2021 / 177290 Japanese Patent Application Laid-Open No. 2023-139499

[0006] Mechanochemical reaction methods are useful synthesis methods that can synthesize target compounds more easily and quickly 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). For this reason, 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, stirring, or the like using a ball mill or similar device for a predetermined period of time to synthesize the target compound. This can lead to the following problems: (i) the reaction product is deactivated or altered in an oxygen-containing atmosphere such as air; (ii) the reaction product may ignite or explode in an oxygen-containing atmosphere; (iii) gas is generated during the reaction, causing an increase in internal pressure; and (iv) the reaction status needs to be checked. Therefore, since the lid of the reaction vessel must be removed during the reaction to add reagents, remove the reaction product, add the substrate to be used in the next reaction, check the reaction status, and so on, improvements have been sought in terms of preventing a decrease in reaction efficiency and ensuring safety.

[0007] One of the problems to be solved by the present invention 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, operability and workability are improved, and the reaction process is shortened (speeded up).One of the problems to be solved by the present invention is to provide a mechanochemical reaction method that uses a reaction device equipped with a reaction vessel having an opening and a lid that can open and close and seal the opening of the reaction vessel, in which one or more through-holes that communicate between the inside of the reaction vessel and the outside of the reaction vessel are provided in the part other than the opening of the reaction vessel and / or in the lid. One of the problems to be solved by the present invention 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 to be performed 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 improves operability and workability and shortens (speeds up) the reaction process.One of the problems to be solved by the present invention is to provide a reaction device used in a mechanochemical reaction method, which comprises a reaction vessel having an opening and a lid that can open and close and seal the opening of the reaction vessel, and in which one or more through-holes are provided in the part of the reaction vessel other than the opening and / or in the lid, connecting the inside of the reaction vessel with the outside of the reaction vessel.

[0008] After extensive research, the present inventors discovered that the above-mentioned problems can be solved by a mechanochemical reaction method using a reaction device with a specific structure, or a reaction device with a specific structure used in a mechanochemical reaction method, and thus completed the present invention. Specifically, the present invention relates to mechanochemical reaction methods and reaction devices according to the following items 1 to 5. [Item 1] A mechanochemical reaction method using a reaction device including a reaction vessel having an opening and a lid that can open and close the opening of the reaction vessel, wherein one or more through-holes communicating the inside of the reaction vessel with the outside of the reaction vessel are provided in a portion other than the opening of the reaction vessel and / or in the lid. [Item 2] The mechanochemical reaction method according to item 1, in which 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, comprising reacting an organic halide with a metal or a metal compound by a mechanochemical reaction 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 for use 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, the reaction device having one or more through-holes communicating the inside of the reaction vessel with the outside of the reaction vessel, and / or the lid, other than the opening of the reaction vessel. [Item 5] The reaction device 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.

[0009] The present invention provides a mechanochemical reaction method 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, thereby improving operability and workability and shortening (speeding up) the reaction process.The present invention also provides a mechanochemical reaction method that uses a reaction device equipped with a reaction vessel having an opening and a lid that can open and close and seal the opening of the reaction vessel, wherein one or more through-holes that communicate between the inside of the reaction vessel and the outside of the reaction vessel are provided in the lid and / or other than the opening of the reaction vessel. According to the present invention, there is provided 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 to be performed 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 improves operability and workability and shortens (speeds up) the reaction process. According to the present invention, there is provided 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 are provided in the part of the reaction vessel other than the opening and / or in the lid, which connect the inside of the reaction vessel with the outside of the reaction vessel.

[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 provides excellent safety, operability, and workability, making it highly useful. Here, 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 (various gas concentrations), 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.

[0011] 1 is a diagram showing a reaction device according to one embodiment of the present invention.

[0012] The mechanochemical reaction method and reaction device according to the present invention will be described in detail below 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 of the present invention.

[0013] [Reaction equipment used in mechanochemical reaction method] The reaction equipment used in the mechanochemical reaction method is not particularly limited as long as it 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 has one or more through-holes that connect the inside of the reaction vessel to the outside of the reaction vessel other than the opening of the reaction vessel and / or in the lid, and is capable of carrying out a mechanochemical reaction by applying mechanical energy to a substrate in the reaction equipment.

[0014] Examples of devices capable of imparting mechanical energy to the substrate in the reaction equipment include: crushers such as ball mills, rod mills, jet mills, and SAG mills; attritors such as rotary mills and crushers; (horizontal axis rotation) container rotation type mixers such as horizontal cylindrical, V-type, double cone, square cube, S-type, and continuous V-type; (baffle blade equipped) container rotation type mixers such as horizontal cylindrical, V-type, double cone, and ball mill types; (rotation vibration) container rotation type mixers such as rocking type and cross rotary type; (horizontal axis rotation) fixed container type mixers such as ribbon type, paddle type, single shaft rotor type, and bug mill type; (vertical axis rotation) fixed container type mixers such as ribbon type, screw type, planetary type, turbine type, high speed fluid type, rotating disk type, and Mahler type; (vibration) fixed container type mixers such as vibration mill type and sieve; One or more selected from the group consisting of (fluidization) fluid motion type mixers such as heterogeneous fluidized beds, swirling fluidized beds, riser-equipped types, and jot pump types; (gravity) fluid motion type mixers such as gravity type and static mixers; low-frequency acoustic resonance mixers (RAM); and devices which are provided with a reaction vessel and one or more stirring members (balls) placed in the reaction vessel, and which generate relative motion by the reciprocating and / or rotational motion of the reaction vessel or any other arbitrary motion, such as a reciprocating mixer mill in which a reaction vessel and a ball reciprocate relative to each other, a planetary ball mill in which a reaction vessel and a ball rotate relative to each other, and the like, can be used.

[0015] The amount of energy added when carrying out the mechanochemical reaction is not particularly limited and can be determined appropriately taking into consideration the type and amount of reaction raw materials, the reaction temperature, the treatment time, etc. For example, when using a ball mill, 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 is possible to complete the reaction in a short period of time. The reaction temperature during the mechanochemical reaction is not particularly limited. For example, it can be -100°C or more, 0°C or more, or 15°C or more, and can be, for example, 300°C or less, 250°C or less, or 200°C or less. For heating, a heating tool such as a heater or a heat gun can be used.

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

[0017] There are no particular limitations on the material forming the reaction vessel 11. For example, it is possible to use 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.

[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 a through-hole closing member 31. This allows for the safe addition of reagents during a reaction, the addition of reagents for the next reaction after the reaction is completed, the collection of contents during a reaction, the collection of reaction products, the removal of gas, and the like, without deactivating or altering the substances in the reaction vessel. Examples of the through-hole closing member 31 include stoppers and screw plugs, and, if necessary, members such as packing can be used to improve the sealing performance. For example, a flanged screw plug is advantageous in terms of ease of handling.

[0021] Measuring instruments such as cameras, thermometers, and lights can be installed in the through-holes 21 to observe the interior 40 of the reaction vessel during the mechanochemical reaction. Multiple through-holes 21 can be provided to allow an inert gas to flow through. In this case, installing a porous member or the like on the through-hole 21 facing the interior 40 of the reaction vessel can prevent leakage of substances from the reaction vessel. Pipes can be connected to the through-holes 21 and, if necessary, connected to a supply means and / or a sampling means via valves and / or valves. One or more control means for the valves, valves, supply means, and sampling means can be provided to perform tasks such as adding reagents, sampling the contents (reaction products), removing gas, and replacing the atmosphere. These controls can also be automatically controlled by a computer program or the like. When multiple through-holes 21 are provided, each through-hole 21 can be used for one or more of observing the interior of the reaction vessel, circulating gas, supplying / sampling, and controlling. In this case, the uses of the through-holes 21 may be the same or different.

[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, member, etc. 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 introduced into the reaction vessel interior 40 is not particularly limited. Any number of balls can be introduced depending on the mechanical energy to be introduced into 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, polyether ether ketone, 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 a portion other than the opening of the reaction vessel and / or in the lid.

[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 one or more selected from the group consisting of metallic lithium in wire (fiber), powder, lump, foil, or other forms; lithium salts such as chlorides, bromides, iodides, nitrates, sulfates, and carbonates; and lithium oxides. The mechanochemical reaction using Li or Li compounds is not particularly limited. Examples include reactions in which Li reacts with organic halides to form organometallic nucleophiles.

[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, it is possible to easily remove the reaction product, thereby 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 opening the lid of the reaction vessel, which resulted in problems such as the apparatus becoming large-scale and reduced 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 represented by the following formula (I): １ One or more compounds represented by the formula (I) can be used. The compound represented by the formula (I) can be a commercially available product, which can 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 is an integer of 1 or greater.

[0032] A in formula (I) １ Examples of the aromatic hydrocarbon group in formula (I) include a monocyclic aromatic hydrocarbon group, a polycyclic aromatic hydrocarbon group, and a fused ring aromatic hydrocarbon group. The aromatic hydrocarbon group may be an aromatic aliphatic hydrocarbon group formed by bonding an aromatic ring and an aliphatic group. １ The heterocyclic group in 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, a sulfur atom, etc., 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. １ The aliphatic hydrocarbon group in formula (I) 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. １The unsaturated aliphatic hydrocarbon group in (I) 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 at least one such bond. Examples of the substituent include an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a cycloalkyl group having 3 to 20 carbon atoms, an alkenyl group having 1 to 24 carbon atoms, an alkynyl group having 1 to 24 carbon atoms, an aryl group having 5 to 24 carbon atoms, an arylalkyl group having 7 to 24 carbon atoms, an aryloxy group having 5 to 24 carbon atoms, a heteroaryl group having 4 to 24 carbon atoms, an acyl group having 1 to 24 carbon atoms, an amino group having 0 to 24 carbon atoms, fluorine, a fluorine-containing group such as a fluorine-containing hydrocarbon group having 1 to 30 carbon atoms, a cyano group, a nitro group, and the like. The substituents may be crosslinked to each other, or the substituents may together form a cyclic structure. 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 at least one 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 at least one selected from the group consisting of salts of these metals (chlorides, bromides, iodides, nitrates, sulfates, carbonates, etc.), oxides of these metals, etc. Among these, at least one 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. is preferred.

[0034] The amount of metal or metal compound used is not particularly limited. For example, it is 0.1 equivalent or more, preferably 0.5 equivalent or more, more preferably 0.7 equivalent or more, and for example, 10.0 equivalent or less, preferably 5.0 equivalent or less, more preferably 3.0 equivalent or less, relative to 1 equivalent of organic halide. If it is less than 0.1 equivalent, the reaction may not proceed sufficiently, resulting in a reduced yield. If it 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 inert in the reaction between an organic halide and a metal or metal compound. Examples of the ether compound include 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, and 1-ethoxy-1,1,2,2-tetrafluoroethane.

[0036] The amount of the ether compound used is 0.5 to 10.0 equivalents per equivalent of the 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, the organometallic nucleophile, particularly the Grignard reagent, cannot be efficiently synthesized, and the reaction may not proceed sufficiently when used in a subsequent reaction. 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 the organometallic nucleophile, particularly the Grignard reagent, and the reaction may not proceed sufficiently when used in a subsequent reaction.

[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. Unless otherwise specified, the compounds used in the examples were commercially available products and were used as they were without further purification.

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

[0040]

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

[0042] Example 1 Two 10 mm diameter stainless steel balls were placed in a 5.0 mL stainless steel ball mill jar (a reaction vessel with a through-hole) with a through-hole connecting the inside and outside of the reaction vessel and plugged with a plug. Under an argon atmosphere, 209 μL (2.0 mmol, 1.0 equivalent) of bromobenzene (1a) as the substrate organic halide, 30.5 mg (4.4 mmol, 2.2 equivalents) of lithium (wire-like), and 450 μL (4.4 mmol, 2.2 equivalents) 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 to allow the reaction to proceed. 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 reaction vessel through the through-hole. The plug was then closed under an argon gas atmosphere. The ball mill jar was attached to the ball mill, and the reaction was carried out by shaking and stirring at room temperature (25°C) and a frequency of 30 Hz for 15 minutes. After the reaction was completed, a 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 H NMR.

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

[0044]

[0045] [Examples] For example, when a mechanochemical reaction method is performed using Li or a Li compound, a strict inert atmosphere is required because potentially flammable organolithium species are generated during the reaction. Therefore, safe operation of previous mechanochemical reaction methods has been difficult. In the present invention, a mechanochemical reaction method is performed using a reaction device comprising 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 communicating the inside of the reaction vessel with the outside of the reaction vessel are provided in the area other than the opening of the reaction vessel and / or the lid. This makes it possible to safely perform the mechanochemical reaction method, even when using Li or a Li compound, and to obtain a reaction product in high yield in a short time. This demonstrates that the present invention is an extremely useful invention for industry.

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

Claims

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.

2. The mechanochemical reaction method according to claim 1, wherein the reaction uses Li or a Li compound.

3. The mechanochemical reaction method according to claim 1 or 2, which is a method for producing an organometallic nucleophile, comprising reacting an organic halide 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.

4. A reaction device used in the mechanochemical reaction method described in claim 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, and wherein 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.

5. The reaction device according to claim 4, wherein the reaction vessel and / or the lid are made of a material including 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.

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