WO2025009373A1 - Method for producing organic compound and mechanochemical reactor - Google Patents

Abstract

Provided are: a method for producing an organic compound, the method simply and economically rationally enabling a reaction by a mechanochemical method; and a mechanochemical reactor. Provided is a method for producing an organic compound, the method comprising a step for carrying out a reaction in a reactor, wherein the reactor comprises a non-metal reaction container and a plurality of stirring media having been charged into the reaction container, at least the surfaces of the stirring media being non-metal, and the reaction is carried out by a mechanochemical method by means of relative movement between the reaction container and the stirring media. In this method, the acceleration of the movement of the stirring media caused by the movement of the reaction container is 9.83 m/s² or less.

Description

Method for producing organic compounds and mechanochemical reaction device

The present invention relates to a method for producing organic compounds and a mechanochemical reaction device.

In recent years, mechanochemical reactions, which directly react raw materials with each other using mechanical energy without using organic solvents, have been attracting attention as a synthesis method with low environmental impact. For example, technologies have been proposed for mechanochemical reactions to proceed with Scholl reactions and coupling reactions without using organic solvents (Chem. Commun., 2018, 54, 5307; J. Am. Chem. Soc. 2021, 143, 6165-6175).

Chem.Commun., 2018, 54, 5307 J. Am. Chem. Soc., 2021, 143, 6165-6175

However, in order to drive a reaction, it is generally necessary to apply very high mechanical energy (e.g., collision energy, shear energy, etc.), which places significant constraints on reaction conditions and equipment. In particular, in terms of equipment, if the reaction vessel or accessories are made of metal to withstand high mechanical energy, corrosion and wear of the metal will occur as the reaction progresses, leading to contamination of the reaction system and increased running costs. On the other hand, if the focus is on preventing metal corrosion, harsh conditions that cause corrosion (e.g., strong acids and strong bases) cannot be used, which places constraints on reaction conditions. In addition, metal vessels and the like are very difficult to scale up, and even if it were possible to scale up, the equipment would be very complex and heavy, making it uneconomical.

The objective of the present invention is to provide a method for producing organic compounds and a mechanochemical reaction device that can easily and economically realize reactions using mechanochemical methods.

The inventors of the present invention were conducting intensive research into the application of the mechanochemical method to organic synthesis reactions, not from the perspective of raw material compounds, but from the perspective of improving reaction equipment, when they unexpectedly discovered that a mechanochemical reaction can be carried out simply by placing a non-metallic ball in a typical resin or glass container used for storing reagents and rolling it around. The present invention is the result of a shift in thinking that is not bound by the conventional concept that the mechanochemical method is carried out by applying high mechanical energy inside a metal container.

In one embodiment, the present invention comprises:
A method for producing an organic compound, comprising the steps of:
The method includes a step of carrying out a reaction by a mechanochemical method using relative motion between a non-metallic reaction vessel and a plurality of stirring media, the stirring media having at least a non-metallic surface, placed in the reaction vessel, in a reaction apparatus comprising the reaction vessel and the stirring media,
The present invention relates to a method for producing an organic compound, wherein the acceleration of the movement of the stirring medium caused by the movement of the reaction vessel is 9.83 m/ ^s2 or less.

In a further embodiment, the present invention comprises
A non-metallic reaction vessel;
A plurality of stirring media, at least the surfaces of which are made of non-metal, are placed in the reaction vessel,
A reaction is carried out by a mechanochemical method using relative motion between the reaction vessel and the stirring medium,
The present invention relates to a mechanochemical reactor, wherein the acceleration of the stirring medium caused by the movement of the reaction vessel is 9.83 m/s2 ^or less.

According to the method for producing an organic compound and the mechanochemical reaction apparatus, a reaction can be carried out by the mechanochemical method by simply moving a stirring medium whose surface is nonmetallic at an acceleration of 9.83 m/s ² (substantially 1 G) or less in a nonmetallic reaction vessel without applying high mechanical energy, and an organic compound can be produced simply and economically. In addition, since both the reaction vessel and the stirring medium have nonmetallic surfaces, corrosion and wear can be reduced, and contamination in the reaction system and an increase in running costs can be suppressed. Even if the reaction vessel and the stirring medium (hereinafter, collectively referred to as "reaction vessel, etc.") reach their endurance limits, they can be easily replaced as disposable products. Furthermore, corrosion of the reaction vessel, etc. due to harsh conditions can be suppressed, and the range of reaction conditions can be expanded. In addition, since complex and heavy equipment is not required, scale-up is also easy.

In the organic compound production method and the mechanochemical reaction apparatus, the acceleration of the stirring medium caused by the movement of the reaction vessel may be 9.83 m/ ^s2 or less, and the acceleration caused by the accompanying contact or collision between the stirring media may exceed 9.83 m/ ^s2 .

FIG. 2 is a partial perspective view showing a schematic diagram of a reaction apparatus using a mechanochemical method. FIG. 2 is an explanatory diagram illustrating the movement of a reaction vessel. FIG. 2 is an explanatory diagram illustrating the movement of a reaction vessel. FIG. 2 is an explanatory diagram illustrating the movement of a reaction vessel.

Below, the embodiments of the present invention will be described in detail with reference to the drawings, but the present invention is not limited to these embodiments. Combinations of preferred aspects are also preferred.

<<Method for producing organic compounds>>
The method for producing an organic compound according to this embodiment includes a step of carrying out a reaction by a mechanochemical method using relative motion between a non-metallic reaction vessel and a plurality of stirring media, at least the surfaces of which are non-metallic, placed in the reaction vessel (hereinafter also referred to as a "reaction step"), in a reaction apparatus including the reaction vessel and a plurality of stirring media, at least the surfaces of which are non-metallic, and the acceleration of the motion of the stirring media caused by the motion of the reaction vessel is 9.83 m/s2 or ^less . The reaction apparatus and the reaction step will be described in order below.

<Reaction Apparatus>
The reaction by the mechanochemical method is a reaction that is carried out by increasing the activity of the raw material compounds by mechanical energy such as impact, shear, and friction. FIG. 1 is a partial perspective view showing a reaction apparatus by the mechanochemical method. The reaction apparatus 10 comprises a nonmetallic reaction vessel 1 and a plurality of stirring media 2, at least the surfaces of which are nonmetallic, that are placed in the reaction vessel 1. In the reaction apparatus 10, the components in the reaction apparatus 10 are given mechanical energy by the relative motion between the reaction vessel 1 and the stirring media 2, and the raw material compounds can react with each other. The reaction apparatus 10 is based on the novel finding that the mechanochemical reaction can be promoted even with mechanical energy that is extremely low compared to the conventional art, that is, the acceleration of the motion of the stirring media 2 caused by the motion of the reaction vessel 1 is 9.83 m/s ² or less.

(Reaction vessel)
The shape of the reaction vessel 1 shown in Fig. 1 is cylindrical. The shape of the reaction vessel 1 is not limited to cylindrical, and any shape such as an elliptical cylinder, a prism, a sphere, an oblate spheroid, a barrel, a cone, a pyramid, or a polyhedron other than those mentioned above can be adopted. Considering the ease and efficiency of moving the reaction vessel 1, the stirring efficiency of the contents, etc., the cylindrical shape is preferable as the shape of the reaction vessel 1.

The reaction vessel 1 has one or more openings (not shown) to allow for the introduction and removal of raw materials, etc. The openings can be sealed with lids or caps.

There are no limitations on the material of the reaction vessel 1 as long as it is made of a non-metallic material. The material of the reaction vessel 1 is preferably synthetic resin, glass, or a combination of these.

Any known synthetic resin can be used as long as it has chemical resistance. The synthetic resin is preferably a thermoplastic resin, a thermosetting resin, or a combination of these.

The thermoplastic resin is not particularly limited, and examples thereof include polyolefin resins such as polypropylene and polyethylene, acrylic resins, amorphous polyarylate resins, polycarbonate resins, polyamide resins, other polyester resins, polyacetal resins, polyphenylene ether resins, polysulfone resins, polyethersulfone resins, polyetherimide resins, polyamideimide resins, fluororesins, thermoplastic elastomers, etc. These resins can be used alone or in combination of two or more.

Thermosetting resins are not particularly limited, and examples include phenolic resins, amino resins, unsaturated polyester resins, epoxy resins, polyurethane resins, melamine resins, thermosetting silicone resins, thermosetting polyimide resins, urea resins, alkyd resins, etc. These resins can be used alone or in combination of two or more.

The capacity of the reaction vessel 1 is not particularly limited, and a desired scale can be adopted from small to large capacity. The lower limit of the capacity of the reaction vessel 1 may be 1 mL, 5 mL, 10 mL, 20 mL, 30 mL, 50 mL, or 100 mL. The upper limit of the capacity of the reaction vessel 1 may be 50,000 mL, 40,000 mL, 30,000 mL, 20,000 mL, 10,000 mL, 5,000 mL, 3,000 mL, or 1,000 mL.

The reaction vessel 1 may have at least one communication pipe 3 that communicates with the outside of the reaction vessel 1. By providing the reaction vessel 1 with the communication pipe 3, it is possible to fill the reaction vessel 1 with an inert gas, to add additional components during the reaction, to discharge by-products (by-product gases) generated by the reaction to the outside, and to prevent the pressure inside the reaction vessel 1 from increasing due to reaction heat or heating.

The number of communicating tubes 3 is not particularly limited, and may be one, two, three, four or more, and may be set appropriately depending on the intended operation. The diameter of the communicating tube 3 is also not particularly limited, and the lower limit of the diameter may be 1 mm, 2 mm, 3 mm, or 5 mm. The upper limit of the diameter may be 50 mm, 40 mm, 30 mm, or 10 mm.

　Materials for the communicating tube 3 include the above-mentioned thermoplastic resins, synthetic rubber, natural rubber, etc. Examples of synthetic rubber include styrene-butadiene rubber, butadiene rubber, acrylonitrile-butadiene rubber, isoprene rubber, ethylene-propylene rubber, acrylic rubber, silicone rubber, fluororubber, urethane rubber, etc.

A three-way cock, rotary connector, check valve, etc. may be used to connect the communicating tube 3 to the reaction vessel 1.

(Stirring medium)
The reaction apparatus 10 includes a plurality of stirring media 2, at least the surfaces of which are made of a nonmetal, placed in the reaction vessel 1. The shape of the stirring media 2 shown in Fig. 1 is spherical, but is not limited thereto, and any shape such as an oval sphere, a polyhedron, a rod, a plate, a doughnut, or an irregular shape may be adopted. From the viewpoint of stirring efficiency, the shape of the stirring media 2 is preferably spherical.

At least the surface of the stirring medium 2 is non-metallic. The entire stirring medium 2, including not only the surface but also the interior side of the surface, may be non-metallic. The surface of the stirring medium 2 may be non-metallic and the interior may be metallic. Alternatively, the surface of the stirring medium 2 may be non-metallic and the interior may be hollow and spherical.

The material of the stirring medium (the entire stirring medium including the inside) or its surface is preferably synthetic resin, ceramic, glass, or a combination of these.

The synthetic resins listed above as materials for the reaction vessel 1 can be suitably used as the synthetic resins that make up the stirring medium 2.

Examples of ceramics include oxide-based ceramics (alumina (Al ₂ O ₃ ), zirconia (ZrO ₂ ), barium titanate (BaTiO ₃ ), etc.), hydroxide-based ceramics (hydroxyapatite, etc.), carbide-based ceramics (silicon carbide (SiC), tungsten carbide (WC)), nitride-based ceramics (silicon nitride (Si ₃ N ₄ ), etc.), carbonate-based ceramics, halide-based ceramics (fluorite, etc.), phosphate-based ceramics, etc.

If the inside of the stirring medium 2 is made of metal, examples of the metal include stainless steel, chrome steel, titanium, aluminum, chromium, niobium, tantalum, zirconium, nickel alloys, aluminum alloys, etc., from the standpoint of corrosion resistance and durability.

The number of stirring media 2 is not particularly limited as long as there are multiple pieces and the reaction by the mechanochemical method proceeds. It may be in the range of 2 to 10 pieces, 11 to 100 pieces, 101 to 1000 pieces, or 1001 to 10,000 pieces. It can be set appropriately depending on the reaction efficiency, the capacity of the reaction vessel 1, the amount of contents, etc.

The size of the stirring medium 2 is not particularly limited and can be set appropriately depending on the reaction efficiency, the capacity of the reaction vessel, etc. The lower limit of the maximum diameter of the stirring medium 2 (the diameter of the smallest encompassing circle) may be 1 mm, 2 mm, 3 mm, 5 mm, or 10 mm. The upper limit of the above maximum diameter may be 100 mm, 80 mm, 50 mm, or 30 mm.

(Relative movement between reaction vessel and stirring medium)
In the reaction apparatus 10, the stirring medium 2 also moves due to the movement of the reaction vessel 1, and the mechanochemical reaction proceeds due to the relative movement of the two. The movement of the reaction vessel 1 is not particularly limited as long as the acceleration of the movement of the stirring medium 2 caused by this movement is 9.83 m/ ^s2 or less. When a motion axis passing through the reaction vessel is determined, the movement of the reaction vessel is preferably a rotational movement about the motion axis as a rotation axis, a vibrational movement in which the motion axis is displaced periodically or non-periodically, or a combination of the rotational movement and the vibrational movement. These movements will be described with reference to the drawings.

FIGS. 2 to 4 are explanatory diagrams that show a schematic representation of the movement of the reaction vessel 1. The stirring medium 2 has been omitted from FIGS. 2 to 4. When defining the movement, a movement axis a (the length of the movement axis a is assumed to be finite) that passes through the reaction vessel 1 is determined. There are no particular limitations on how the movement axis a is determined, and it can be set appropriately depending on the desired movement and the shape of the reaction vessel 1, etc. In the cylindrical reaction vessel 1 shown in FIGS. 2 to 4, the movement axis a is the line segment that passes through (passes through) the center of the circle on both end faces (both bottom faces). In FIGS. 2 and 3, the movement axis a and the y axis are parallel.

As shown in FIG. 2, the rotational motion is a motion in which the reaction vessel 1 rotates in the direction of the arrow r around the axis of motion a. The rotational direction may be the opposite direction to the arrow r. The rotational motion in the direction of the arrow r and the rotational motion in the opposite direction to the arrow r may be alternated periodically or non-periodically.

The rotation speed of the reaction vessel 1 is set so that the acceleration of the movement of the stirring medium 2 caused by the movement is 9.83 m/ ^s2 or less, taking into consideration the scale of the reaction (the capacity of the reaction vessel 1, the amount of raw materials input, etc.). The lower limit of the rotation speed is preferably 30 rpm, more preferably 50 rpm, and even more preferably 80 rpm. The upper limit of the rotation speed is preferably 600 rpm, more preferably 400 rpm, and even more preferably 200 rpm.

As shown in Figure 3, vibration motion is motion that displaces the motion axis a periodically or non-periodically. In Figure 3 (A), the directions of displacement of the motion axis a are indicated by solid and dashed white arrows. The direction of displacement over a certain predetermined time interval (for convenience, referred to as the "first time interval") is indicated by a solid white arrow, and the direction of displacement over the next predetermined time interval (for convenience, referred to as the "second time interval") is indicated by a dashed white arrow. In Figure 3 (A), the motion axis a translates in the positive direction of the z axis during the first time interval, and translates in the negative direction of the z axis during the second time interval.

In Figure 3(B), only the axis of motion a is shown. By alternating between the motion in the first time interval and the motion in the second time interval, as shown in Figure 3(B), the axis of motion a repeats parallel translation in both the positive and negative directions of the z axis, so that the axis of motion a moves back and forth up and down, so to speak.

In FIG. 3, the axis of motion a is shown to repeat parallel translation in the z-axis direction, but is not limited to this, and the axis of motion a may repeat parallel translation in the x-axis direction or the y-axis direction. In addition, at least two types of motion selected from the group consisting of motion in the x-axis direction, motion in the y-axis direction, and motion in the z-axis direction may be combined. Furthermore, the axis of motion a may be moved such that the trajectory of the motion is a circle or an ellipse when viewed from the y-axis direction.

FIG. 4 is a schematic diagram showing another aspect of the vibration motion. As with the motion described with reference to FIG. 3, in FIG. 4(A), the direction of displacement over a first time interval is indicated by a solid white arrow, and the direction of displacement over a second time interval is indicated by a dashed white arrow. During the first time interval, the positive end side of the motion axis a (right side in the figure) displaces in the negative direction of the z axis, while the other negative end side of the motion axis a (left side in the figure) displaces in the positive direction of the z axis. During the following second time interval, the positive end side of the motion axis a (right side in the figure) displaces in the positive direction of the z axis, while the other negative end side of the motion axis a (left side in the figure) displaces in the negative direction of the z axis.

In Figure 4(B), only the axis of motion a is shown. By alternately repeating the motion in the first time interval and the motion in the second time interval, as shown in Figure 4(B), the axis of motion a repeats displacement motion (reciprocating motion) in both positive and negative directions of the z axis at one end, and repeats displacement motion (reciprocating motion) at the other end in a direction opposite in phase to the one end (so that if one end is displaced in the positive direction of the z axis, the other end is displaced in the negative direction of the z axis), and the entire axis of motion a performs a vibrating motion, so to speak, like a seesaw.

In Figure 4, both ends of the motion axis a are shown repeating opposite-phase displacements in the z-axis direction, but this is not limited to this, and both ends of the motion axis a may repeat opposite-phase displacements in the x-axis direction or any other direction. Furthermore, when one end of the motion axis a is viewed from the y-axis direction, the motion may be such that the trajectory of the motion forms a circle or an ellipse. In this case, the other end of the motion axis a will also perform a circular motion or the like in opposite phase to the one end.

In addition to the above, although not shown, one end of the motion axis a may be fixed, and only the other end may perform reciprocating motion or circular motion in a fixed direction. Any motion may be adopted as the motion of the motion axis a.

Regardless of the type of vibration motion, the first time interval and the second time interval may be the same or different. Furthermore, when the first time interval and the second time interval form one cycle and this cycle is repeated, the first time interval of each cycle may be constant or may vary. The second time interval of each cycle may also be constant or may vary. Furthermore, in addition to the first time interval and the second time interval, a third time interval may be provided.

Each time interval is not particularly limited, and can be set independently and appropriately while taking into consideration the reaction efficiency, reaction scale, acceleration of the stirring medium, etc. The lower limit of each time interval may be 0.5 seconds, 1 second, 2 seconds, 3 seconds, 5 seconds, or 10 seconds. The upper limit of each time interval may be 50 seconds, 40 seconds, 30 seconds, or 20 seconds.

The amount of displacement of the motion axis a (or its end) can also be set independently and appropriately, taking into consideration the reaction efficiency, reaction scale, acceleration of the stirring medium, etc. For example, in the case of a reciprocating up and down motion as shown in Figure 3, the displacement distance can be set appropriately in millimeters, centimeters, or meters. In the case of a seesaw-like oscillating motion as shown in Figure 4, the lower limit of the displacement angle (the maximum displacement angle of the motion axis as viewed from the center of vibration of the motion axis) can be 1 degree, 2 degrees, 3 degrees, 5 degrees, or 10 degrees. The upper limit of the displacement amount can be 60 degrees, 50 degrees, 40 degrees, 30 degrees, or 20 degrees.

By performing the above-mentioned rotational motion, the above-mentioned vibrational motion, or a combination of these as the motion of the reaction vessel 1, the mechanochemical reaction can proceed efficiently.

A known or commercially available device can be used as a device for imparting the above-mentioned motion to the reaction vessel 1. Examples include a roller mixer in which multiple rotatable rollers are arranged in parallel, with one or both ends of each roller being capable of moving up and down, and a rotary/vibration mixer that clamps the reaction vessel from both ends in the direction of the reaction vessel's axis of motion and performs rotary or vibratory motion.

Furthermore, the reaction device 10 may further include at least one selected from a heater and a cooler for the purpose of controlling the reaction state. Examples of the heater and cooler methods include a method of immersing all or part of the reaction vessel 1 in a temperature-controlled water bath or oil bath, a method of attaching a member capable of cooling or heating (e.g., a rubber heater, etc.) around the reaction vessel 1, a method of housing the reaction vessel 1 or the entire reaction device 10 in a housing capable of cooling or heating, a method of blowing hot or cold air onto the reaction vessel 1, etc.

<Reaction Step>
The reaction by the mechanochemical method in this production method is not particularly limited, and various conventionally known chemical reactions can be adopted. By adopting the mechanochemical method that does not substantially use a solvent and proceeds under mild reaction conditions, it is possible to efficiently produce the target organic compound while extremely reducing the burden on the environment. Examples of the chemical reaction include a carbon-carbon bond forming reaction, a carbon-nitrogen bond forming reaction, a carbon-oxygen bond forming reaction, a carbon-hydrogen bond forming reaction, a carbon-sulfur bond forming reaction, and a carbon-metal bond forming reaction.

Examples of carbon-carbon bond-forming reactions include the Suzuki coupling reaction, Scholl reaction, Grignard reaction, Friedel-Crafts reaction, aldol reaction, Diels-Alder reaction, Heck reaction, Michael addition reaction, Wittig reaction, and double bond-forming reactions by dehydration.

Examples of carbon-nitrogen bond forming reactions include amidation reactions, reductive amination reactions, Mitsunobu reactions, Buchwald-Hartwig amination reactions, nucleophilic substitution reactions with amines, Gabriel synthesis reactions, Hofmann rearrangement reactions, Mannich reactions, and azo coupling reactions.

Examples of carbon-oxygen bond forming reactions include hydration reactions, acetalization reactions, oxidation reactions, esterification reactions, and Williamson synthesis reactions.

Examples of carbon-hydrogen bond forming reactions include reduction reactions and hydrogenation reactions.

Examples of carbon-sulfur bond forming reactions include sulfonation reactions and Reid reactions.

Examples of carbon-metal bond forming reactions include the Grignard reaction and the lithiation reaction.

The reaction time may be appropriately set so as to obtain a desired yield. Since the reaction can proceed in a gentle environment using a non-metallic reaction vessel 1 and a stirring medium 2 having at least a non-metallic surface, and the acceleration of the movement of the stirring medium 2 is 9.83 m/ ^s2 or less, a time span (e.g., several tens of hours to several days, several weeks, etc.) that was not envisioned in conventional high-energy reaction devices can also be adopted. The lower limit of the reaction time may be 0.1 hours, 0.2 hours, 0.5 hours, 1 hour, 2 hours, or 3 hours. The upper limit of the reaction time may be 500 hours, 100 hours, 50 hours, 10 hours, or 5 hours.

The reaction temperature can be set appropriately depending on the reaction efficiency, the material of the reaction vessel 1, the material of the stirring medium 2, etc. According to this manufacturing method, the reaction can proceed sufficiently even at room temperature (normal temperature). The lower limit of the reaction temperature may be -20°C, -10°C, or 0°C. The upper limit of the reaction temperature may be 100°C, 80°C, or 50°C. The reaction temperature is the temperature around the reaction vessel 1. For example, if no heater or cooler is used, the reaction temperature is room temperature, and if a heater or cooler is used, the reaction temperature is a temperature generally determined depending on the heating method or cooling method. If a part of the reaction vessel 1 is immersed in a water bath or oil bath, the temperature is the temperature of the water bath or oil bath. If the reaction vessel 1 is placed in a heating or cooling chamber, the temperature is the temperature inside the heating or cooling chamber.

In this reaction step, pressurization or depressurization from outside the reaction system may be performed as appropriate, but it is preferable to perform the reaction step without pressurization or depressurization from outside the reaction vessel. This production method is based on the novel finding that the reaction can proceed without pressurization or depressurization from outside the reaction system. Note that pressurization and depressurization here are operations (treatments) that are intentionally applied from outside the reaction system, and do not include pressure increases due to heat or reaction heat generated by impact or friction within the reaction system (inside the reaction vessel), pressure increases due to the generation of gases, and pressure decreases due to the consumption of raw material gases.

In this reaction process, the mechanochemical reaction can proceed without using a solvent. However, as the reaction progresses and the amount of product increases, the viscosity of the reaction system increases, and in some cases the yield may decrease. In such cases, it is preferable to carry out the reaction in the presence of a diluent to suppress the increase in viscosity.

Examples of the diluent include alkanes such as n-pentane, n-hexane, n-heptane, n-octane, n-nonane, and n-decane;
Cycloalkanes such as cyclohexane, cycloheptane, cyclooctane, decalin, and norbornane;
Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and cumene;
Halogenated hydrocarbons such as chlorobutanes, bromohexanes, dichloromethane, dichloroethanes, hexamethylene dibromide, and chlorobenzene;
Saturated carboxylates such as ethyl acetate, n-butyl acetate, i-butyl acetate, and methyl propionate;
Ketones such as acetone, methyl ethyl ketone, 2-butanone, 4-methyl-2-pentanone, and 2-heptanone;
Ethers such as tetrahydrofuran, dimethoxyethanes, and diethoxyethanes;
Alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 4-methyl-2-pentanol;
These diluents may be used alone or in combination of two or more.

The amount of diluent to be used is not particularly limited as long as it can suppress the increase in viscosity that accompanies the progress of the reaction. When the diluent is used, the lower limit of the amount is preferably 1 equivalent, more preferably 2 equivalents, and even more preferably 3 equivalents per equivalent of the reaction raw materials that constitute the target organic compound (total if there are multiple types of reaction raw materials). The upper limit of the amount is preferably 50 equivalents, more preferably 30 equivalents, and even more preferably 30 equivalents.

Mechanochemical Reactor
The mechanochemical reaction apparatus includes a non-metallic reaction vessel and a plurality of stirring media, at least the surfaces of which are made of a non-metallic material, which are placed in the reaction vessel. The reaction is carried out by a mechanochemical method using relative motion between the reaction vessel and the stirring media, and the acceleration of the stirring media caused by the motion of the reaction vessel is 9.83 m/ ^s2 or less.

The mechanochemical reaction apparatus is based on the novel finding that a mechanochemical reaction can proceed even with extremely low mechanical energy, as compared with the conventional case, of 9.83 m/ ^s2 or less, in which the acceleration of the motion of the stirring medium caused by the motion of the reaction vessel is extremely low. As such a mechanochemical reaction apparatus, the reaction apparatus in the reaction step of the above-mentioned method for producing an organic compound can be suitably adopted.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. In the following examples, unless otherwise specified, the structure of the product was confirmed by MALDI-TOFMS and ¹ H NMR. Regarding the acceleration, the gravitational acceleration when the stirring medium falls freely was used for the mix rotor, and the acceleration of the mixer mill was calculated from the vibration frequency and amplitude assuming simple harmonic motion, and the centrifugal acceleration of the planetary ball mill was calculated from the rotation radius and rotation frequency.

Suzuki Coupling Reaction
The Suzuki coupling reaction was carried out using the following reaction apparatus and procedure. The reaction formula is shown below (only the main raw materials and the target compound are shown).

<Reaction Apparatus>
(Example)
The reaction vessel was rotated by a Mix Rotor VMR-5 (manufactured by AS ONE), with a rotation speed of 100 rpm.
Reaction vessel: PE (polyethylene) cylindrical vessel (capacity 250 mL, 1000 mL)
Stirring media: _SiO2 (glass) balls (diameter 3 mm), _ZrO2 balls (diameter 3 mm)

Comparative Example
The reciprocating mixer mill was a mixer mill MM400 (manufactured by Retsch, Germany), and the reactor vibration frequency was 30 Hz.
Reaction vessel: SUS cylindrical vessel (capacity 5 mL)
Stirring medium: SUS balls (diameter 5 mm, 7 mm)

[Example 1-1]
4,4''-dibromo-p-terphenyl (1 equivalent), 1-naphthaleneboronic acid (3 equivalents), palladium(II) acetate (0.1 equivalent), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) (0.15 equivalents), cesium fluoride (CsF) (6 equivalents), H ₂ O (7.2 equivalents), 1,5-cyclooctadiene (1,5-cod) (3 equivalents) and dichloromethane (CH ₂ Cl ₂ ) (10 equivalents) were charged into a PE reaction vessel (volume 250 mL), and 150 g of SiO ₂ (glass) balls (3 mm) were also charged, followed by sealing. The reaction vessel was placed in the rotating part of a mix rotor VMR-5, and the reaction vessel was rotated at 100 rpm for 180 minutes to carry out a coupling reaction. The reaction yield was 35%.

[Examples 1-2 to 1-5]
The reactions were carried out in the same manner as in Example 1-1, except that the reaction vessel, stirring medium, kinetic conditions, raw material/reagent ratio, and reaction time were changed as shown in Table 1 below. The yields of each reaction are also shown in Table 1 below. In the table, THF stands for tetrahydrofuran.

[Comparative Examples 1-1 to 1-2]
The reactions were carried out in the same manner as in Example 1-1, except that the reaction apparatus, reaction vessel, stirring medium, motion conditions, and raw material/reagent ratios were changed as shown in Table 1. The yields of each reaction are also shown in Table 1.

In the examples, the Suzuki coupling reaction was carried out using non-metallic equipment without applying excessive mechanical energy. It was also found that the reaction could be easily scaled up. In the comparative examples, the reaction vessel was limited to a low capacity.

The Scholastic Reaction
The Scholl reaction was carried out using the following reaction apparatus and procedure. The reaction formula is shown below.

<Reaction Apparatus>
(Example)
The reaction vessel was rotated by a Mix Rotor VMR-5 (manufactured by AS ONE), with a rotation speed of 100 rpm.
Reaction vessel: PE cylindrical vessel (capacity: 30 mL, 100 mL, 250 mL)
Reactor exhaust line (connecting pipe): check valve, three-way cock, rotating connector, rubber tube Stirring medium: _ZrO2 ball (diameter 3 mm)

Comparative Example
The planetary ball mill was Premium Line-7 (manufactured by Fritsch, Germany), with a rotation speed of 100 rpm.
Reaction vessel: _ZrO2 vessel (capacity 20 mL)
Stirring medium: _ZrO2 ball (diameter 3 mm)

[Example 2-1]
The compound (B-1) represented by the above formula (B-1) (1 equivalent), FeCl ₃ (12 equivalents), and NaCl (332 equivalents) were each charged into a PE reaction vessel (volume 30 mL), and 30 g of ZrO ₂ balls (diameter 3 mm) were also charged, followed by sealing. The reaction vessel was placed in the rotating part of a mix rotor VMR-5, and the reaction vessel was rotated at 100 rpm for 120 minutes to carry out the Scholl reaction, thereby obtaining the compound represented by the above formula (B-2). The reaction yield was 57%.

[Examples 2-2, 2-3, 2-5, and 2-6]
The reactions were carried out in the same manner as in Example 2-1, except that the reaction vessel, stirring medium, kinetic conditions, and raw material/reagent ratios were changed as shown in Table 2. The yields of each reaction are also shown in Table 2.

[Example 2-4]
In Example 2-4, the total amount of hydrogen chloride gas generated increased due to an increase in the reaction scale, so the reaction was carried out with a gas exhaust line (communication pipe) provided in the reaction vessel in order to safely carry out the reaction and post-treatment. As shown in Table 2 below, the reaction vessel, stirring medium, motion conditions, and raw material/reagent ratio were changed, but the raw materials/reagents were charged into the reaction vessel in the same manner as in Example 2-1. The check valve, three-way cock, rubber tube, rotating connector, and rubber tube were connected to the lid of the vessel in this order, and the tip of the rubber tube was placed in a polycup containing water. The reaction vessel was placed in a mix rotor VMR-5, and the reaction was carried out by rotating the three-way cock with the opening so that the generated gas would flow toward the polycup. The generated hydrogen chloride gas was treated by trapping it in the water in the polycup. The reaction yield is also shown in Table 2 below.

[Comparative Examples 2-1 and 2-2]
The reactions were carried out in the same manner as in Example 2-1, except that the reaction apparatus, reaction vessel, stirring medium, motion conditions, and raw material/reagent ratios were changed as shown in Table 2. The yields of each reaction are also shown in Table 2.

In the examples, non-metallic equipment was used, and the Scholl reaction was able to proceed without applying excessive mechanical energy. It was also found that the reaction could be easily scaled up. In examples 2-3 to 2-6, in which a diluent was added, the increase in viscosity that accompanied the reaction was suppressed, resulting in a good yield. In the comparative examples, the capacity of the reaction vessel was limited, and the metal parts of the device, such as the exterior of the reaction vessel and the screws for fixing the lid, were significantly corroded by the hydrogen chloride gas that was generated.

<Amidation Reaction>
The amidation reaction was carried out using the following reaction apparatus and procedure. The reaction formula is shown below.

<Reaction Apparatus>
(Example)
The reaction vessel was rotated by a Mix Rotor VMR-5 (manufactured by AS ONE), with a rotation speed of 100 rpm.
Reaction vessel: PE cylindrical vessel (volume 20 mL), glass cylindrical vessel (volume 20 mL)
Stirring medium: _ZrO2 ball (diameter 3 mm)

Comparative Example
The reciprocating mixer mill was a mixer mill MM400 (manufactured by Retsch, Germany), and the reactor vibration frequency was 30 Hz.
Reaction vessel: SUS cylindrical vessel (capacity 5 mL)
Stirring medium: SUS ball (diameter 5 mm)

[Example 3-1]
1-Naphthyl acetate (1 equivalent) and p-bromoaniline (1 equivalent) were added to a PE reaction vessel (volume 20 mL), and 30 g of _ZrO2 balls (diameter 3 mm) were added, followed by sealing. The reaction vessel was placed in the rotating part of a mix rotor VMR-5, and the reaction was carried out by rotating the reaction vessel at 100 rpm for 60 minutes. The reaction yield was 95%.

[Example 3-2, Comparative Example 3-1]
The reactions were carried out in the same manner as in Example 3-1, except that the reaction apparatus, reaction vessel, stirring medium, motion conditions, and raw material/reagent ratios were changed as shown in Table 3. The yields of each reaction are also shown in Table 3.

In the examples, non-metallic equipment was used, and the amidation reaction was able to proceed without applying excessive mechanical energy. It was also found that the reaction could be easily scaled up. In the comparative examples, the reaction vessel was limited to a low capacity.

Grignard reaction
The Grignard reaction was carried out using the following reaction apparatus and procedure. The reaction formula is shown below.

<Reaction Apparatus>
(Example)
The reaction vessel rotation device was a Mix Rotor VMR-5 (manufactured by AS ONE), with a rotation speed of 1000 rpm.
Roller mixer ANZ-72D (manufactured by Nitto Scientific), device rotation speed 300 rpm
Reaction vessel: PE cylindrical vessel (capacity 30 mL, 100 mL)
Stirring media: _SiO2 balls (diameter 3 mm), _ZrO2 balls (diameter 3 mm)
Cooling container: PE container (2L)

Comparative Example
The reciprocating mixer mill was a mixer mill MM400 (manufactured by Retsch, Germany), and the reactor vibration frequency was 30 Hz.
Reaction vessel: SUS cylindrical vessel (capacity 5 mL)
Stirring medium: SUS ball (diameter 5 mm)

[Example 4-1]
Mg powder (1.5 equivalents) (1 equivalent, 0.003 mol), bromobenzene (1.5 equivalents), tetrahydrofuran (THF) (3 equivalents) were added to a PE reaction vessel (volume 30 mL), and 40 g of _ZrO2 balls (diameter 3 mm) were added, followed by sealing. The reaction vessel was placed in the rotating part of a mix rotor VMR-5, and the reaction was carried out by rotating the reaction vessel at 100 rpm for 60 minutes. The Grignard conversion rate was 85%.

[Example 4-2]
The reaction was carried out in the same manner as in Example 4-1, except that the ratio of the raw materials/reagents was changed as shown in Table 4 below. The reaction yields are also shown in Table 4 below.

[Example 4-3]
After carrying out Grignard conversion in the same manner as in Example 4-2, the vessel was opened, and benzaldehyde (1 equivalent, 0.003 mol) was added, and then the vessel was sealed again. The reaction vessel was placed in the rotating part of a mix rotor VMR-5, and the reaction vessel was rotated at 100 rpm for 45 minutes to carry out the reaction. The addition rate of the Grignard reagent was 96%.

[Example 4-4]
As shown in Table 4 below, the reaction vessel, stirring medium, motion conditions, and raw material/reagent ratio were changed, and the reagents were placed in a reaction vessel (volume 100 mL) and sealed in the same manner as in Example 4-1. Since the reaction scale was increased, the reaction vessel was placed in a 2 L PE vessel filled with water in order to remove the heat of reaction, and the vessel was sealed after being fixed to the side with adhesive tape. The 2 L vessel was placed in a roller mixer ANZ-72D and then rotated at 300 rpm for 1 hour to carry out the reaction. The reaction yield is also shown in Table 4 below.

[Comparative Examples 4-1 to 4-3]
The reactions were carried out in the same manner as in Example 4-1 or 4-3, except that the reaction apparatus, reaction vessel, stirring medium, kinetic conditions, and raw material/reagent ratios were changed as shown in Table 4. The yields of each reaction are also shown in Table 4.

In the examples, the Grignard reaction was carried out in an air atmosphere using non-metallic equipment without applying excessive mechanical energy. It was also found that the reaction could be easily scaled up. In the comparative examples, the reaction vessel was limited to a low capacity and the yield was low.

Friedel-Crafts reaction
The Friedel-Crafts reaction was carried out using the following reaction apparatus and procedure. The reaction formula is shown below.

<Reaction Apparatus>
(Example)
The reaction vessel was rotated by a Mix Rotor VMR-5 (manufactured by AS ONE), with a rotation speed of 100 rpm.
Reaction vessel: PE cylindrical vessel (capacity 500 mL)
Reactor exhaust line (connecting pipe): check valve, three-way cock, rotating connector, rubber tube Stirring medium: _SiO2 ball (diameter 10 mm)

Comparative Example
The reciprocating mixer mill was a mixer mill MM400 (manufactured by Retsch, Germany), and the reactor vibration frequency was 30 Hz.
Reaction vessel: SUS cylindrical vessel (capacity 5 mL)
Stirring medium: SUS ball (diameter 5 mm)

[Example 5-1]
Diphenylmethane (1 equivalent), acetyl chloride (8.55 equivalents), and AlCl ₃ (10 equivalents) were each charged into a PE reaction vessel (volume 500 mL), and 300 g of SiO ₂ (glass) balls (diameter 10 mm) were also charged, followed by sealing. Thereafter, a gas exhaust line was connected to the lid of the reaction vessel in the same manner as in Example 4 of the Scholl reaction described above. The reaction vessel was placed in the rotating part of a mix rotor VMR-5, and the reaction was carried out by rotating the reaction vessel at 100 rpm for 60 minutes. The reaction yield was 59%.

[Comparative Example 5-1]
The reactions were carried out by changing the reaction apparatus, reaction vessel, stirring medium, kinetic conditions and raw material/reagent ratios as shown in Table 5. The yields of each reaction are also shown in Table 5.

In the examples, non-metallic equipment was used, and the Friedel-Crafts reaction was able to proceed without applying excessive mechanical energy. It was also found that the reaction could be easily scaled up. In the comparative examples, the capacity of the reaction vessel was limited, and the metal parts of the equipment were severely corroded by the hydrogen chloride gas produced.

<Reduction reaction>
The reduction reaction was carried out using the following reaction apparatus and procedure. The reaction formula is shown below.

<Reaction Apparatus>
(Example)
The reaction vessel was rotated by a Mix Rotor VMR-5 (manufactured by AS ONE), with a rotation speed of 100 rpm.
Reaction vessel: PE cylindrical vessel (capacity 1000 mL)
Reactor exhaust line (connecting pipe): check valve Stirring medium: _SiO2 ball (diameter 10 mm)

Comparative Example
The reciprocating mixer mill was a mixer mill MM400 (manufactured by Retsch, Germany), and the reactor vibration frequency was 30 Hz.
Reaction vessel: SUS cylindrical vessel (capacity 5 mL)
Stirring medium: SUS ball (diameter 5 mm)

[Example 6-1]
Bis(4-acetylphenyl)methane (1 equivalent), NaBH ₄ (8 equivalents), and methanol (4 equivalents) were each placed in a PE reaction vessel (volume 1000 mL), and 600 g of SiO ₂ (glass) balls (diameter 10 mm) were also placed in the vessel, which was then sealed. A check valve was attached to the lid of the reaction vessel in order to vent the hydrogen gas produced. The reaction vessel was placed in the rotating part of a mix rotor VMR-5, and the reaction was carried out by rotating the reaction vessel at 100 rpm for 60 minutes. The reaction yield was 95%.

[Comparative Example 6-1]
The reactions were carried out by changing the reaction apparatus, reaction vessel, stirring medium, kinetic conditions and raw material/reagent ratios as shown in Table 6 below. The yields of each reaction are also shown in Table 6 below.

In the examples, non-metallic equipment was used, and the reduction reaction was able to proceed without applying excessive mechanical energy. It was also found that the reaction could be easily scaled up. In the comparative examples, the reaction vessel was limited to a low capacity, and the yield was also low.

According to the method for producing an organic compound of the present invention, a target reaction can be carried out using non-metallic equipment without applying excessive mechanical energy. According to the mechanochemical reaction apparatus of the present invention, a reaction by a mechanochemical method can be carried out without applying excessive mechanical energy.

Claims (17)

A method for producing an organic compound, comprising the steps of:
The method includes a step of carrying out a reaction by a mechanochemical method using relative motion between a non-metallic reaction vessel and a plurality of stirring media, the stirring media having at least a non-metallic surface, in a reaction apparatus including the reaction vessel and the stirring media,
The method for producing an organic compound, wherein the acceleration of the movement of the stirring medium caused by the movement of the reaction vessel is 9.83 m/s2 or ^less . The method for producing an organic compound according to claim 1, in which the reaction step is carried out without applying pressure or reducing pressure from outside the reaction vessel. The method for producing an organic compound according to claim 1, wherein the motion of the reaction vessel is a rotational motion about the axis of motion, when the axis of motion is defined to pass through the reaction vessel, a vibrational motion that displaces the axis of motion periodically or non-periodically, or a combination of the rotational motion and the vibrational motion. The method for producing an organic compound according to claim 1, wherein the material of the reaction vessel is a synthetic resin, glass, or a combination thereof. The method for producing an organic compound according to claim 4, wherein the synthetic resin is a thermoplastic resin, a thermosetting resin, or a combination thereof. The method for producing an organic compound according to any one of claims 1 to 5, wherein the material of the stirring medium or its surface is a synthetic resin, ceramic, glass, or a combination thereof. The method for producing an organic compound according to any one of claims 1 to 5, wherein the reaction is carried out in the presence of a diluent. The method for producing an organic compound according to any one of claims 1 to 5, wherein the reaction vessel has at least one communication tube that communicates with the outside of the reaction vessel. The method for producing an organic compound according to any one of claims 1 to 5, wherein the reaction apparatus is equipped with at least one selected from a heater and a cooler. A non-metallic reaction vessel;
A plurality of stirring media, at least the surfaces of which are made of non-metal, are placed in the reaction vessel,
A reaction is carried out by a mechanochemical method using relative motion between the reaction vessel and the stirring medium,
A mechanochemical reaction apparatus, wherein the acceleration of the stirring medium caused by the movement of the reaction vessel is 9.83 m/s2 ^or less. The mechanochemical reaction device according to claim 10, in which the reaction is carried out without applying pressure or pressure outside the reaction vessel. The mechanochemical reaction device according to claim 10, wherein the motion of the reaction vessel is a rotational motion about the axis of motion, which passes through the reaction vessel, a vibrational motion that displaces the axis of motion periodically or non-periodically, or a combination of the rotational motion and the vibrational motion. The mechanochemical reaction device according to claim 10, wherein the material of the reaction vessel is a synthetic resin, glass, or a combination thereof. The mechanochemical reaction device according to claim 13, wherein the synthetic resin is a thermoplastic resin, a thermosetting resin, or a combination thereof. The mechanochemical reaction device according to any one of claims 10 to 14, wherein the material of the stirring medium or its surface is a synthetic resin, ceramic, glass, or a combination thereof. The mechanochemical reaction device according to any one of claims 10 to 14, wherein the reaction vessel has at least one communication pipe that communicates with the outside of the reaction vessel. The mechanochemical reaction device according to any one of claims 10 to 14, further comprising at least one selected from a heater and a cooler.

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