Mechanochemical reaction method and reaction apparatus

Abstract

The present invention provides a mechanochemical reaction method and reaction apparatus that allows for operations such as adding reagents during the reaction, removing reaction products, and adding substrates for the next reaction without removing the lid of the reaction vessel, while preventing a decrease in reaction efficiency and ensuring safety. Furthermore, it allows for checking the state inside the reaction vessel, and improves operability and workability, while shortening (accelerating) the reaction process. [Solution] A mechanochemical reaction method using a reaction apparatus A comprising a reaction vessel 11 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 are provided in the reaction vessel other than the opening and / or in the lid, communicating the inside of the reaction vessel with the outside of the reaction vessel.

Description

Technical Field

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

Background Art

[0002] The mechanochemical reaction method is an organic synthesis method that does not use an organic solvent or uses only a very small amount of an organic solvent, and directly contacts reaction raw materials with each other. It is an interesting synthetic method both academically and industrially as a synthetic method with a low environmental load. The mechanochemical reaction method is a method of adding mechanical energy to a substrate to cause a reaction. The mechanical energy can be mechanically generated by means such as grinding, shearing, impact, compression, vibration, pressing, dispersion, kneading, crushing, etc. By applying such mechanical energy to the substrate, these can be activated to cause a reaction. The mechanochemical reaction method is an organic synthesis reaction method in which each component contained in the reaction system is directly contacted, mixed, and reacted, and does not require the use of an organic solvent / only uses a very small amount of an organic solvent. It is a reaction method with a high reactivity and a high reaction efficiency while having a low environmental load.

[0003] The mechanochemical reaction method has hitherto been used to develop various functional materials using various organic compounds as raw materials, such as pharmaceuticals, agricultural chemicals, liquid crystal compounds, organic electroluminescence 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), organic semiconductor materials, etc.

[0004] Patent Document 1 discloses a cross-coupling reaction method without using a solvent and a method for producing a cross-coupling reaction product using the mechanochemical reaction method. Patent Document 2 discloses a method for producing an organometallic nucleophile and a reaction method using the organometallic nucleophile using the mechanochemical reaction method. Patent Document 3 discloses a mechanoredox reaction using a piezoelectric material with a mechanochemical reaction method, and more specifically, a mechanoredox reaction and a method for producing a redox reaction product using the reaction method. Patent Document 4 discloses a method for producing a monocoscoupled aromatic compound having one fewer 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 generation of by-reactants, achieve high yield, and carry out the coupling reaction simply. [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 Publication No. 2023-139499 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] Mechanochemical reaction methods are useful synthesis methods that allow for the simpler and faster synthesis of target compounds compared to conventional organic synthesis methods. However, mechanochemical reaction methods are not usually limited in terms of the atmosphere inside the reaction vessel (the atmosphere of the reaction system). For this reason, all reagents are added to the mouth of the reaction vessel body under an atmospheric atmosphere, and after closing the mouth with a lid that can be opened and closed under an atmospheric atmosphere, mechanical energy is added to the substrate by means of shaking, stirring, etc., using a ball mill or the like for a predetermined time, to synthesize the target compound. As a result, in some cases, the following situations may occur: (i) the reaction product may be deactivated / degraded under an oxygen-containing atmosphere such as an air atmosphere, (ii) the reaction product may ignite or explode under an oxygen-containing atmosphere, (iii) gas may be generated during the reaction and the internal pressure may increase, and (iv) the reaction state may need to be checked. Therefore, operations such as removing the lid of the reaction vessel to add reagents during the reaction, remove the reaction product, add the substrate to be used in the next reaction, and check the reaction state have been required 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 that allows operations such as adding reagents during the reaction, removing reaction products, and adding substrates 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 also allows for checking the state inside the reaction vessel, and furthermore, improves 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 mechanochemical reaction method using a reaction apparatus 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, wherein one or more through holes are provided in the reaction vessel other than the opening and / or in the lid, which connect the inside of the reaction vessel to the outside of the reaction vessel. One of the problems that the present invention aims to solve is to provide a mechanochemical reaction apparatus that allows operations such as adding reagents during the reaction, removing reaction products, and adding substrates 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 also allows the state inside the reaction vessel to be checked, and furthermore, improves 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 apparatus used in a mechanochemical reaction method, comprising a reaction vessel having an opening, a lid that can be opened and closed to seal the opening of the reaction vessel, and one or more through holes that connect the inside of the reaction vessel to the outside of the reaction vessel, provided in addition to the opening of the reaction vessel and / or in the lid. [Means for solving the problem]

[0008] As a result of diligent research, the present inventors have discovered that the above problems can be solved by a mechanochemical reaction method using a reaction apparatus having a specific structure, or by a reaction apparatus having a specific structure used in a mechanochemical reaction method, and have completed the present invention. In other words, the present invention relates to a mechanochemical reaction method and reaction equipment according to the following items 1 to 5. [Item 1] A mechanochemical reaction method using a reaction apparatus comprising a reaction vessel having an opening and a lid that seals the opening of the reaction vessel in a manner that allows it to be opened and closed, wherein one or more through holes are provided in the reaction vessel other than the opening and / or in the lid, which connect the inside of the reaction vessel to the outside of the reaction vessel. [Item 2] The mechanochemical reaction method described in Item 1, wherein the reaction uses Li or a Li compound. [Item 3] A mechanochemical reaction 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 one equivalent of the organic halide. [Item 4] A reaction apparatus used in a 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 so as to be openable and closable, wherein one or more through holes are provided in the lid and / or other than the opening of the reaction vessel, for communication between the inside of the reaction vessel and the outside of the reaction vessel. [Clause 5] The reaction apparatus according to Claim 4, wherein the reaction vessel and / or lid are made of a material comprising 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. [Effects of the Invention]

[0009] The present invention provides a mechanochemical reaction method that allows for operations such as adding reagents during the reaction, removing reaction products, and adding substrates 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. Furthermore, it allows for checking the state inside the reaction vessel, and provides an improved operability and workability, as well as a shortened (faster) reaction process. The present invention provides a mechanochemical reaction method using a reaction apparatus 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 are provided in the reaction vessel other than the opening and / or in the lid, communicating the inside of the reaction vessel with the outside of the reaction vessel. The present invention provides a mechanochemical reaction apparatus that allows for operations such as adding reagents during the reaction, removing reaction products, and adding substrates for the next reaction without removing the lid of the reaction vessel, while preventing a decrease in reaction efficiency and ensuring safety. Furthermore, it allows for checking the state inside the reaction vessel, and provides improved operability and workability, as well as shortening (accelerating) the reaction process. The present invention provides a reaction apparatus used in a mechanochemical reaction method, comprising a reaction vessel having an opening and a lid for sealing the opening of the reaction vessel in an openable and closable manner, wherein one or more through-holes for communicating the inside and outside of the reaction vessel are provided in the reaction vessel other than the opening and / or in the lid.

[0010] The mechanochemical reaction method and reaction apparatus of the present invention are applicable to all conventional mechanochemical reactions. Without removing the lid of the reaction vessel, it is possible to add reagents during the reaction, add reagents for the next reaction, check the state inside the reaction vessel at any point during the reaction, take out gases, reaction products, etc. from inside the reaction vessel at any point during the reaction, and so on. Therefore, it is possible to prevent the inactivation of reaction products and intermediates, prevent a decrease in reaction efficiency, check the state inside the reaction vessel in real time, and it is excellent in safety, operability, and workability, and highly useful. Here, examples of the state inside the reaction vessel include one or more selected from the group consisting of internal temperature, internal pressure, the amount of specific components such as moisture, atmosphere (concentration of various gases), state of the substrate, movement of the stirring member, state of the reaction product, state of the inner wall of the reaction vessel, and the like.

Brief Description of the Drawings

[0011] [Figure 1] A diagram showing a reaction apparatus according to an embodiment of the present invention.

Embodiments for Carrying Out the Invention

[0012] Hereinafter, the mechanochemical reaction method and reaction apparatus 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 implemented without changing the gist of the present invention.

[0013] [Reaction Apparatus Used in Mechanochemical Reaction Method] The reaction equipment used in the mechanochemical reaction method includes a reaction vessel having an opening and a lid that hermetically seals the opening of the reaction vessel in an openable and closable manner, and one or more through-holes that communicate the inside and outside of the reaction vessel are provided in the reaction vessel other than the opening and / or the lid. It is not particularly limited as long as a mechanochemical reaction can be carried out by applying mechanical energy to the substrate in the reaction equipment.

[0014] As a device that can apply mechanical energy to the substrate in the reaction equipment, for example, Grinding machines such as ball mills, rod mills, jet mills, and SAG mills; Grinding machines such as rotary mortars and pounding machines; (Horizontally rotating) container rotation type mixing devices such as horizontal cylindrical type, V type, double cone type, cubic type, S type, and continuous V type; (Horizontally rotating with baffle blades) container rotation type mixing devices such as horizontal cylindrical type, V type, double cone type, and ball mill type; (Rotary vibration) container rotation type mixing devices such as rocking type and cross rotary type; (Horizontally rotating) fixed container type mixing devices such as ribbon type, paddle type, single shaft rotor type, and bug mill type; (Vertically rotating) fixed container type mixing devices such as ribbon type, screw type, planetary type, turbine type, high speed fluid type, rotating disk type, and muller type; (Vibrating) fixed container type mixing devices such as vibration mill type and sieve; (Fluidized) fluid motion type mixing devices such as uneven fluidized bed, swirling fluidized bed, riser pipe type, and jet pump type; (Gravity) fluid motion type mixing devices such as gravity type and static mixer; Low frequency resonance acoustic mixer (RAM); A reciprocating mixer mill in which the reaction vessel and the balls perform a reciprocating relative motion, a planetary ball mill in which the reaction vessel and the balls perform a rotational relative motion, a rotary ball mill, etc., which are provided with a reaction vessel and one or more stirring members (balls) introduced into the reaction vessel, and generate a relative motion by the reciprocating motion and / or rotational motion of the reaction vessel and other arbitrary motions; One or more selected from the group consisting of etc. can be used.

[0015] The amount of energy added when carrying out a mechanochemical process is not particularly limited and can be determined appropriately, taking into consideration the type and amount of reaction materials, reaction temperature, processing time, etc. For example, when using a ball mill, the shaking can be performed at 5 Hz or higher, preferably 10 Hz or higher, and more preferably 20 Hz or higher. The processing time is not particularly limited. For example, it can be one minute or more. Mechanochemical reaction methods are particularly advantageous because they allow the reaction to be completed in a short time. The reaction temperature during a mechanochemical reaction is not particularly limited. For example, it can be above -100°C, above 0°C, or above 15°C, and can also be below 300°C, below 250°C, or below 200°C. Heating devices such as heaters and heat guns can be used for heating.

[0016] The reaction apparatus shown in Figure 1 represents one embodiment of the reaction apparatus used in the mechanochemical reaction method of the present invention. The reaction apparatus A shown in Figure 1 comprises a reaction vessel 11 and a reaction vessel lid 12 that can open and close to seal the reaction vessel opening 13. The reaction vessel 11 and the reaction vessel lid 12 form the interior 40 of the reaction vessel. In Figure 1, the reaction vessel 11 is provided with one through hole 21 that connects the interior 40 of the reaction vessel to the exterior of the reaction vessel. The through hole 21 can be opened and closed by a through hole closing member 31.

[0017] The materials constituting the reaction vessel 11 are not particularly limited. For example, materials comprising 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.

[0018] The material constituting the reaction vessel lid 12 is not particularly limited. For example, a material comprising 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.

[0019] One or more through-holes 21 connecting the inside 40 of the reaction vessel to the outside of the reaction vessel can be provided in the reaction vessel 11 and / or the reaction vessel lid 12. The position, size, and shape of the through-holes 21 are not particularly limited. They can be arbitrarily set according to the purpose and manner of use of the through-holes 21.

[0020] The through-hole 21 can be closed / opened at any time using the through-hole closing member 31. This allows for the safe addition of reagents during the reaction, the addition of reagents for the next reaction after the reaction is complete, sampling of contents during the reaction, sampling of reaction products, and removal of gases, all without deactivating or altering the substances in the reaction vessel. Examples of through-hole sealing members 31 include plugs, screw plugs, etc., and if necessary, members such as packing can be used to improve airtightness. For example, flanged screw plugs are advantageous in terms of handling and other aspects.

[0021] It is also possible to install measuring instruments such as cameras, thermometers, and lighting in the through-hole 21 to observe the inside of the reaction vessel 40 during the mechanochemical reaction. Multiple through-holes 21 are provided, allowing for the circulation of an inert gas. In this case, by installing porous materials or the like on the side of the through-holes 21 that faces the inside 40 of the reaction vessel, leakage of substances from inside the reaction vessel can be prevented. A pipe is connected to the through-hole 21 and, if necessary, to a supply means and / or sampling means via a valve and / or valve. One or more control means are provided for the valve, valve, supply means and sampling means, allowing for the introduction of reagents, sampling of contents (reaction products), removal of gases, replacement of the atmosphere, etc. These controls can also be automated using a computer program or the like. If there are multiple through-holes 21, each through-hole 21 can be used for one or more of the following purposes: observation of the inside of the reaction vessel, gas flow, supply / sampling, or control. In this case, the uses of each through-hole 21 may be the same or different.

[0022] The volume of the reaction vessel interior 40 is not particularly limited. It can range from microliters to kiloliters. The reaction vessel interior 40 may be equipped with mechanisms and components for applying mechanical energy to the substrate. For example, hard material balls such as stainless steel balls, a stirring bar, an ultrasonic resonance mechanism, etc., can be used. When using balls, the number of balls to be placed in the reaction vessel interior 40 is not particularly limited. Any number can be placed depending on the mechanical energy applied to the reaction, the amount of heat generated during the reaction, etc.

[0023] The materials constituting the reaction vessel 11 and / or the reaction vessel lid 12 are not particularly limited. Appropriate materials can be used from the viewpoint of durability, chemical resistance, etc. For example, materials 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 apparatus may further include, as necessary, means for fixing the reaction vessel to a device capable of supplying mechanical energy, heating means for heating the inside of the reaction vessel, cooling means for cooling the inside of the reaction vessel, and other mechanisms necessary for carrying out the mechanochemical reaction. Furthermore, the reaction apparatus can be used in combination with one or more devices other than a device capable of supplying mechanical energy, such as 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, a device for irradiating with visible light or ultraviolet light, a device for filling reaction products, various control devices, and other devices necessary for the mechanochemical reaction.

[0025] [Mechanochemical reaction methods] The present invention relates to a mechanochemical reaction method that uses a reaction apparatus comprising a reaction vessel having an opening and a lid that can open and close to seal the opening of the reaction vessel, wherein one or more through holes are provided in the reaction vessel other than the opening and / or in the lid, allowing communication between the inside of the reaction vessel and the outside of the reaction vessel.

[0026] The mechanochemical reaction method of the present invention can be applied to various chemical reactions such as reduction reactions, coupling reactions, oxidation reactions, addition reactions, and 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 the formation reactions of 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 and a metal or metal compound are reacted by a mechanochemical reaction method in the presence of 0.5 to 10.0 equivalents of an ether compound per equivalent of 1 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 the form of wire (thread), powder, lump, foil, etc., lithium salts such as chloride, bromide, iodide, nitrate, sulfate, carbonate, and lithium oxides. The mechanochemical reactions using Li or Li compounds are not particularly limited. For example, they include reactions in which Li reacts with organic halides to form organometallic nucleophiles.

[0028] Reactions using Li or Li compounds are prone to reduced reaction efficiency due to the denaturation and deactivation of reaction products / intermediates in the presence of moisture and oxygen. In the mechanochemical reaction method of the present invention, it is possible to inject the substrate to be used in the next reaction, inert gas, etc. into the reaction vessel without opening the lid of the reaction vessel, and furthermore, the reaction products can be easily removed, preventing denaturation and deactivation of reaction products / intermediates when the reaction vessel is opened. In addition, conventional mechanochemical reaction methods using Li or Li compounds require an inert gas atmosphere when opening the lid of the reaction vessel, which has problems such as requiring large-scale equipment and reducing work efficiency, but these problems can be solved with the mechanochemical reaction method of the present invention.

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

[0030] As for organic halides, see formula (I): A 1 -Xm (I) One or more compounds represented by can be used. The compound represented by formula (I) can be used as is or after purification as a commercially available product.

[0031] In formula (I), A 1This represents any of the following: an aromatic hydrocarbon group having 6 to 30 carbon atoms with an optional m-valence, an optional m-valence heterocyclic group, an optional m-valence aromatic aliphatic hydrocarbon group having 7 to 30 carbon atoms, an optional m-valence aliphatic hydrocarbon group having 1 to 20 carbon atoms, or an optional m-valence unsaturated aliphatic hydrocarbon group having 2 to 20 carbon atoms. In formula (I), X independently represents F (fluorine), Cl (chlorine), Br (bromine), or I (iodine). In equation (I), m represents a number X that is an integer greater than or equal to 1.

[0032] A in equation (I) 1 Examples of aromatic hydrocarbon groups include monocyclic aromatic hydrocarbon groups, polycyclic aromatic hydrocarbon groups, and fused ring aromatic hydrocarbon groups. The aromatic hydrocarbon group may also be an aroliphatic hydrocarbon group formed by the bonding of an aromatic ring and an aliphatic group. A in equation (I) 1 In this context, the heterocyclic group is, for example, a group having an aliphatic heterocyclic structure and / or an aromatic heterocyclic structure with 5 to 8 members, and containing at least one, preferably 1 to 3, heteroatoms such as nitrogen, oxygen, and sulfur atoms as heteroatoms. Examples include monocyclic heterocyclic groups, polycyclic heterocyclic groups, and fused heterocyclic groups. A in equation (I) 1 The aliphatic hydrocarbon group in this may be, for example, a linear saturated aliphatic hydrocarbon group, a branched saturated aliphatic hydrocarbon group, or a cyclic saturated aliphatic hydrocarbon group. A in equation (I) 1 In this context, the unsaturated aliphatic hydrocarbon group 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 one or more such bonds are sufficient. Examples of substituents include one or more selected from the group consisting of C1-C20 alkyl groups, C1-C20 alkoxy groups, C3-C20 cycloalkyl groups, C1-C24 alkenyl groups, C1-C24 alkynyl groups, C5-C24 aryl groups, C7-C24 arylalkyl groups, C5-C24 aryloxy groups, C4-C24 heteroaryl groups, C1-C24 acyl groups, C0-C24 amino groups, fluorine, fluorine-containing groups such as C1-C30 fluorine-containing hydrocarbon groups, cyano groups, nitro groups, and the like. The substituents may be cross-linked with each other, or the substituents as a whole may form a cyclic structure. The substituents may have further substituents.

[0033] The metal or metal compound is not particularly limited as long as it can react with an organohalide 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 elemental 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. Of 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. is preferred.

[0034] The amount of metal or metal compound used is not particularly limited. For example, it is 0.1 equivalents or more, preferably 0.5 equivalents or more, more preferably 0.7 equivalents or more, per equivalent of one equivalent of organic halide, and 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 equivalents, the reaction may not proceed sufficiently, and the yield may decrease. If the amount exceeds 10.0 equivalents, it will be necessary to remove unreacted metal or metal compound, and unreacted metal or metal compound may cause side reactions.

[0035] As for the ether compound, any compound having one or more ether bonds (-O-) in its molecule can be used, and is not particularly limited as long as it is an inert compound in the reaction between the organic halide and the 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, etc.

[0036] The amount of ether compound used is 0.5 to 10.0 equivalents per equivalent of the organic halide. Preferably, it is 0.7 equivalents or more, more preferably 1.0 equivalent or more, even more preferably 1.2 equivalents or more, and even more preferably 1.5 equivalents or more. Also, preferably 7.0 equivalents or less, and more preferably 5.0 equivalents or less. If the amount is less than 0.5 equivalents, organometallic nucleophiles, especially Grignard reagents, cannot be efficiently synthesized, and the reaction may not proceed sufficiently when subjected to subsequent reactions. If the amount exceeds 10.0 equivalents, the ether compound will substantially function as a solvent, making it difficult to impart mechanochemical action to the substrate (reactant component), and thus, organometallic nucleophiles, especially Grignard reagents, cannot be efficiently synthesized, and the reaction may not proceed sufficiently when subjected to subsequent reactions. [Examples]

[0037] The present invention will be described in detail below with reference to examples. These examples represent only one aspect of the present invention. The present invention is not limited in any way by these examples.

[0038] In the examples, when carrying out the reaction using a ball mill, a ball mill MM manufactured by Verder Scientific Co., Ltd. (formerly Retsch) was used. I used the 400 model. Unless otherwise specified, the compounds used in the examples were commercially available products that were used without being regenerated.

[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] Two 10mm diameter stainless steel balls were placed in a 5.0 mL stainless steel ball mill jar (a reaction vessel with a through-hole), which had a through-hole connecting the inside and outside of the reaction vessel and was sealed with a plug. Under an argon atmosphere, 209 μL (2.0 mmol, 1.0 equivalent) of bromobenzene (1a) as the organic halide substrate, 30.5 mg (4.4 mmol, 2.2 equivalents) of lithium (wire form), and 450 μL (4.4 mmol, 2.2 equivalents) of diethyl ether were added. The lid of the ball mill jar was closed, 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 5 minutes. After the reaction was complete, 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) as an organic carbonyl compound was added 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) at a frequency of 30 Hz for 15 minutes. After the reaction was complete, saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted three times with ethyl acetate. Magnesium sulfate was added to the collected organic layer and dried, then filtered through pleated filter paper. Ethyl acetate was removed from the resulting organic layer using an evaporator to obtain the target reaction product (2-phenyl-2-hydroxy-4-methylpentane(3a)). 1 The NMR yield of the target reaction product (3a) by 1H NMR was 74%.

[0043] [Examples 2-5] Except for using the organic halide and organic carbonyl compounds shown in Table 1, the corresponding reaction products (3b) to (3e) were obtained in the same manner as in Example 1. 1 The NMR yields of the target reaction products (3b) to (3e) obtained by 1H NMR are shown in Table 1.

[0044] [Table 1]

[0045] [Examples] For example, when using Li or Li compounds in a mechanochemical reaction, potentially flammable organolithium species are generated during the reaction, making it necessary to operate under a strictly inert atmosphere. Therefore, conventional mechanochemical reaction methods have been difficult to operate safely. In the present invention, a mechanochemical reaction method can be carried out using a reaction apparatus that includes a reaction vessel having an opening, a lid that can be opened and closed to seal the opening of the reaction vessel, and 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 the lid. This allows the mechanochemical reaction method to be carried out safely, even when using Li or Li compounds, and reaction products can be obtained in high yield in a short time. From this, it can be seen that this invention is extremely useful in industry. [Explanation of Symbols]

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

Claims

1. A mechanochemical reaction method using a reaction apparatus comprising a reaction vessel having an opening and a lid that seals the opening of the reaction vessel in a manner that allows it to be opened and closed, wherein one or more through holes are provided in 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.

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

3. A mechanochemical reaction 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 one equivalent of the organic halide.

4. A reaction apparatus used in a mechanochemical reaction method according to claim 1 or 2, comprising a reaction vessel having an opening, and a lid that seals the opening of the reaction vessel so as to be openable and closable, wherein one or more through holes are provided in the area other than the opening of the reaction vessel and / or in the lid, communicating the inside of the reaction vessel with the outside of the reaction vessel.

5. The reaction apparatus according to claim 4, wherein the reaction vessel and / or lid is made of a material comprising 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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