Method for producing the composite and the composite

Abstract

This provides a method for broadening the range of complexes that can be used for triplet dynamic nuclear polarization. [Solution] A method for producing a composite comprising a first compound, a second compound, and a polarization source compound, (1) Obtain a composite from the first compound, the second compound, and the polarization source compound by a mechanochemical method. A method for producing a composite containing the above.

Description

Technical Field

[0001] The present disclosure relates to a method for manufacturing a composite and a composite.

Background Art

[0002] Nuclear Magnetic Resonance (NMR) spectroscopy is a spectroscopic method used in the fields of medicine, pharmacy, chemistry, and materials science. A problem with the NMR method is its low sensitivity.

[0003] To solve this problem, for example, the Dynamic Nuclear Polarization (DNP) method has been studied. By using the DNP method, the polarization of the molecules to be measured can be increased, and as a result, the NMR sensitivity is improved. However, conventional DNP methods can improve the sensitivity in NMR and the like, but require cooling the sample to extremely low temperatures, making the apparatus expensive and large in size.

[0004] Patent Document 1 discloses performing triplet DNP (hereinafter also referred to as "TDNP"). This enables high polarization at room temperature without cooling the sample to extremely low temperatures. The polarization sample used in the triplet DNP is formed using the melt quench method. The melt quench method is a method of forming crystals to be measured by heating a plurality of compounds including the compound to be measured to form a molten sample and rapidly cooling the sample.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] However, the melt quenching method could not be applied to compounds with high melting points or compounds that were in a liquid state at the measurement temperature. This disclosure aims to provide a method different from the melt quenching method in order to broaden the range of composites that can be used for TDNP. [Means for solving the problem]

[0007] This disclosure provides the following [1] to

[21] . [1] A method for producing a composite comprising a first compound, a second compound, and a polarization source compound, (1) Obtain a composite from the first compound, the second compound, and the polarization source compound by a mechanochemical method. A method for producing a composite containing the above. [2] The mechanochemical method is a method for producing the composite described in [1], which is carried out using a mixer mill. [3] The mechanochemical method is a method for producing the composite according to [1] or [2], carried out at a temperature of any of 0 to 70°C. [4] A method for producing a composite according to any one of [1] to [3], wherein the mechanochemical method is performed by mixing for 15 to 240 minutes. [5] The mechanochemical method is carried out by applying a vibration frequency of 10 to 50 Hz, as described in any one of [1] to [4]. [6] The mechanochemical method is a method for producing a composite according to any one of [1] to [5], which involves applying an vibration frequency of 10 to 50 Hz for 15 to 240 minutes using a mixer mill at a temperature of 0 to 70°C. [7] The first compound is a compound having an aromatic ring and an amide group. A method for producing a composite according to any one of [1] to [6]. [8] A method for producing a complex according to any one of [1] to [7], wherein the first compound is at least one selected from nicotinamide and isonicotinamide. [9] The method for producing the complex according to any one of [1] to [8], wherein the second compound is water or a carboxylic acid.

[10] The method for producing the composite according to any one of [1] to [9], wherein the second compound is at least one selected from fumaric acid, formic acid, acetic acid, and water.

[11] A method for producing the complex according to any one of [1] to

[10] , wherein the polarization source compound comprises an aromatic ring.

[12] The method for producing the complex according to any one of [1] to

[11] , wherein the polarization source compound is at least one selected from diazatetracene and diazapentacene.

[13] A method for producing a composite according to any one of [1] to

[12] , wherein the first compound and the second compound are contained in a molar ratio in the range of 1:0.5 to 1:2.5.

[14] A method for producing a composite according to any one of [1] to

[13] , wherein the first compound and the polarization source compound are contained in a molar ratio in the range of 1:0.0001 to 1:0.01.

[15] A method for producing a composite according to any one of [1] to

[14] , wherein the composite is solid at the temperature at which the mechanochemical method is performed.

[16] A method for producing the composite according to any one of [1] to

[15] , wherein the composite is solid at any temperature between 0 and 70°C.

[17] A complex comprising a first compound, a second compound, and a polarization source compound.

[18] The complex according to

[17] , wherein the first compound is at least one selected from nicotinamide and isonicotinamide.

[19] The second compound is at least one selected from fumaric acid, formic acid, acetic acid, and water, and is the complex described in

[17] or

[18] .

[20] The polarization source compound is at least one selected from diazatetracene and diazapentacene, and is the complex described in any one of

[17] to

[19] .

[21] The complex described in any one of

[17] to

[20] , which is solid at any temperature from 0 to 70 °C. [Advantages of the Invention]

[0008] The present disclosure can provide a method different from the melt quenching method in order to broaden the range of complexes that can be used for TDNP. [Brief Description of the Drawings]

[0009] [Figure 1] FIG. 1 is a diagram showing the 1H NMR spectrum of the complex obtained in Example 1. [Figure 2] FIG. 2 is a diagram showing the 1H NMR spectrum of the complex obtained in Example 2. [Figure 3] FIG. 3 is a diagram showing the 1H NMR spectrum of the complex obtained in Example 3. [Figure 4] FIG. 4 is a diagram showing the 1H NMR spectrum of the complex obtained in Example 4. [Modes for Carrying Out the Invention]

[0010] Hereinafter, the present disclosure will be described, but the present disclosure is not limited to the following description.

[0011] [Method for Producing Polarization Complex] The present disclosure is a method for producing a complex containing a first compound, a second compound, and a polarization source compound, (1) obtaining the above complex from the first compound, the second compound, and the polarization source compound by a mechanochemical method This relates to a method for producing a composite containing the above.

[0012] In the melt-quench method, it was necessary to heat the compound to be measured to form a liquid sample, and then rapidly cool the sample to form crystals. In contrast, this disclosure employs a mechanochemical method. A mechanochemical method is a method of applying mechanical energy to a first compound, a second compound, and a polarization source compound, thereby cocrystallizing the first compound, the second compound, and the polarization source compound. Unlike the melt-quench method, the mechanochemical method does not involve crystal formation by heating or rapidly cooling the compounds. The mechanochemical method can form a composite containing compounds with high melting points, compounds that do not melt, compounds with low heat resistance, compounds with high volatility, or compounds that are liquid at the measurement temperature. This composite can be the target of TDNP measurement.

[0013] The mechanochemical method is not particularly limited as long as it applies mechanical energy, such as stirring, to the target composition, but can be carried out using, for example, a mixer mill. The target composition refers to, for example, a composition containing a first compound, a second compound, and a polarization source compound, and / or a composition containing a cocrystal obtained from the first compound, the second compound, and the polarization source compound.

[0014] A mixer mill is a device used to grind and mix a target composition. For example, the MM400 (manufactured by RETSCH) can be used as a mixer mill.

[0015] By using a mixer mill, composites (e.g., cocrystals) with a minimum particle size of 5 to 200 μm, specifically 10 to 150 μm, can be obtained. The particle size can be measured, for example, using a scanning electron microscope.

[0016] The vibration frequency of the mixer mill may be, for example, 10 to 50 Hz, more specifically 10 to 40 Hz, more specifically 20 to 40 Hz, even more specifically 20 to 35 Hz, and especially specifically 30 Hz. In another embodiment, the vibration frequency of the mixer mill may be 10 to 30 Hz.

[0017] Mixing in the mechanochemical process can be carried out at any temperature between 0 and 70°C, more specifically at any temperature between 0 and 50°C, more specifically at any temperature between 15 and 50°C, even more specifically at any temperature between 15 and 40°C, and particularly specifically at any temperature between 15 and 35°C. Mixing in the mechanochemical process can also be carried out at room temperature, for example.

[0018] Mixing in the mechanochemical method may be carried out for, for example, 15 to 240 minutes, more specifically 20 to 200 minutes, or more specifically 30 to 180 minutes. For example, (i) mixing may be performed for 20 to 40 minutes, more specifically 30 minutes, and (ii) mixing may then be stopped for 5 to 20 minutes, more specifically 10 minutes, and (i) and (ii) may be repeated.

[0019] Mixing in the mechanochemical method can be performed, for example, by applying an vibration frequency of 10 to 50 Hz to the first compound, the second compound, and the polarized compound, more specifically 10 to 40 Hz, more specifically 20 to 40 Hz, even more specifically 20 to 35 Hz, and particularly specifically 30 Hz. In another embodiment, the vibration frequency of the mixer mill may be 10 to 30 Hz.

[0020] Mixing in the mechanochemical method can preferably be carried out by applying an vibration frequency of 10 to 50 Hz to the first compound, the second compound, and the polarization source compound using a mixer mill at a temperature of 0 to 70°C for 15 to 240 minutes, more preferably at a vibration frequency of 20 to 40 Hz to the temperature of 0 to 50°C using a mixer mill for 20 to 200 minutes, and particularly preferably at a vibration frequency of 20 to 35 Hz to the temperature of 15 to 50°C using a mixer mill for 30 to 180 minutes.

[0021] Step (1) yields a composite that is a cocrystal.

[0022] The composite obtained by mixing in step (1) is preferably a solid at the temperature at which the mechanochemical process is carried out.

[0023] The composite obtained by mixing in step (1) is a solid at a temperature preferably of any temperature from 0 to 70°C, more preferably of any temperature from 0 to 50°C, even more preferably of any temperature from 15 to 50°C, particularly preferably of any temperature from 15 to 40°C, specifically at any temperature from 15 to 35°C.

[0024] The complex obtained in step (1) contains the first compound and the second compound in a molar ratio preferably in the range of 1:0.5 to 1:2.5, and more preferably in the range of 1:1 to 1:2.

[0025] The complex obtained in step (1) contains the first compound and the polarization source compound in a molar ratio preferably in the range of 1:0.0001 to 1:0.01, more preferably 1:0.0005 to 1:0.005, and even more preferably 1:0.001 to 1:0.001.

[0026] The complex obtained in step (1) contains the second compound and the polarization source compound in a molar ratio preferably in the range of 1:0.0001 to 1:0.05, more preferably 1:0.0005 to 1:0.025, and even more preferably 1:0.0005 to 1:0.001.

[0027] The first compound is not particularly limited, as long as it has a group that can interact with the second compound, but for example, it may have an amide group.

[0028] The first compound may preferably have an amide group and an aromatic ring. More preferably, the first compound has a structure in which the amide group and the aromatic ring are directly bonded. This configuration improves the reactivity of the amide group.

[0029] The aromatic ring of the first compound preferably contains a complex atom. The complex atom is not particularly limited, but for example, it may be at least one of a nitrogen atom, an oxygen atom, and a sulfur atom, and specifically, a nitrogen atom.

[0030] The first compound is preferably at least one selected from nicotinamide and isonicotinamide.

[0031] The first compound is preferably a solid at any temperature between 0 and 70°C, more preferably at any temperature between 0 and 50°C, even more preferably at any temperature between 15 and 50°C, and particularly preferably at any temperature between 15 and 35°C.

[0032] The first compound is preferably a solid when mixed in the mechanochemical process.

[0033] The second compound is not particularly limited, as long as it has a group that can interact with the first compound, but for example, it may have a carboxyl group and a hydroxyl group.

[0034] The second compound may have a carbon-carbon double bond in its structure.

[0035] The second compound may be, for example, water or a carboxylic acid.

[0036] The second compound is preferably at least one selected from fumaric acid, formic acid, acetic acid, and water.

[0037] In one embodiment, the second compound is a liquid at any temperature between 0 and 70°C, more specifically at any temperature between 0 and 50°C, more specifically at any temperature between 15 and 50°C, and even more specifically at any temperature between 15 and 35°C.

[0038] In one embodiment, the second compound is a solid at any temperature between 0 and 70°C, more specifically at any temperature between 0 and 50°C, more specifically at any temperature between 15 and 50°C, and even more specifically at any temperature between 15 and 35°C.

[0039] In one embodiment, the second compound is preferably a solid or liquid at the temperature at which the mechanochemical process is carried out.

[0040] Polarization-source compounds are compounds that become polarized when exposed to light.

[0041] The polarization source compound preferably contains an aromatic ring. This embodiment improves the impact resistance of the polarization source compound, and allows it to maintain its structure even when the polarization compound is mixed with the first and second compounds.

[0042] The polarization source compound is more preferably a compound in which multiple aromatic rings are directly bonded. With this embodiment, the resistance of the polarization source compound to external stress, such as physical stimuli like heat or mixing, or chemical stimuli is improved, and the rate of denaturation of the polarization source compound due to external stress is suppressed.

[0043] The aromatic ring in the polarization source compound preferably contains a complex atom. The complex atom is not particularly limited, but for example, it may be at least one of nitrogen, oxygen, and sulfur atoms, and specifically, nitrogen. The presence of a complex atom facilitates the formation of hydrogen bonds with the first and / or second compound. A greater number of hydrogen bonds can lead to stronger bonding in the cocrystal, and as a result, higher detection sensitivity in NMR can be achieved.

[0044] The polarization source compound is preferably at least one selected from diazatetracene and diazapentacene. Diazatetracene is preferably 5,12-diazatetracene. Diazapentacene is preferably 6,13-diazapentacene.

[0045] Furthermore, at least one of the first compound, the second compound, and the polarization source compound may exist individually along with the complex. Derivatives of the first compound, the second compound, or the polarization source compound may also exist along with the complex.

[0046] Preferably, (2) Polarization is introduced into the composite obtained in step (1).

[0047] In step (2), polarization is preferably induced by the triplet DNP method, and more preferably by light irradiation. Examples of light irradiation include laser irradiation. This polarizes the polarization source compound. A specific example will be given below using 5,12-diazatetracene. First, light irradiation causes the electrons of the irradiated 5,12-diazatetracene to enter a photoexcited state. Subsequently, these electrons transition from the excited state to a triplet state, causing the electron spins of the 5,12-diazatetracene to become polarized. Then, microwave irradiation transfers the polarization of the electron spins to the hydrogen spins of the 5,12-diazatetracene, causing the hydrogen spins of the 5,12-diazatetracene to become polarized. [ka]

[0048] The amount of light irradiation in step (2) is, for example, 0.1 to 0.2 J / cm². 2 It may also be within the range of 0.1 J / cm². 2 That's fine.

[0049] The light irradiation time in step (2) may be in the range of 10 to 2,000 seconds, or in the range of 100 to 1,000 seconds. For example, the light irradiation time may be 600 seconds.

[0050] [complex] This disclosure discloses a complex comprising a first compound, a second compound, and a polarization source compound. The complex is a polarized cocrystal.

[0051] The first compound, the second compound, and the polarization source compound have the same meanings as described above.

[0052] Preferably, the first compound is at least one selected from nicotinamide and isonicotinamide.

[0053] Preferably, the second compound is at least one selected from fumaric acid, formic acid, acetic acid, and water.

[0054] Preferably, the polarization source compound is at least one selected from diazatetracene and diazapentacene. Diazatetracene is preferably 5,12-diazatetracene. Diazapentacene is preferably 6,13-diazapentacene.

[0055] The composite is a solid, preferably at any temperature between 0 and 70°C, more preferably at any temperature between 0 and 50°C, even more preferably at any temperature between 15 and 50°C, and particularly preferably at any temperature between 15 and 40°C.

[0056] The composite is obtained by the method of the present disclosure described above.

[0057] The method for producing the composite and the composite described herein have been described in detail above. However, this disclosure is not limited to those exemplified above. [Examples]

[0058] The present disclosure will be described below with reference to examples, but the present disclosure is not limited to the following examples.

[0059] [Measuring device] [Mixer mill] MM400 (manufactured by Retsch) Vibration frequency: 30Hz Mixing time: 30~180 minutes Crushed balls (material): Two 10mm balls (zirconia) Grinding jar (material): 10ml (zirconia)

[0060] [Triplet-DNP measurement] 0.4T electromagnet: Echo Electronics EM40050 0.4T electromagnet power supply: Echo Electronics EMS-08064S Laser: Photonics Industries DM60-527LP Dye conversion: radiant dye laser RDP-1 Microwave source: Keysight Technologies 8720ES Microwave Amplifier: Quinstar Technology 06184350SE1 Magnetic field sweep power supply: Kikusui Electronics PAN60-10A Magnetic field sweep function generator: Agilent 33522A NMR amplifier (0.4T, 13 C): THAMWAY N146-5599A

[0061] [First Experimental Example] [Example 1] Two moles of nicotinamide and one mole of fumaric acid were added to a grinding jar, and then an additional 0.001 moles of 5,12-diazatetracene was added. Using a mixer mill, the nicotinamide, fumaric acid, and 5,12-diazatetracene were mixed and ground for 180 minutes at an oscillation frequency of 30 Hz to obtain a composite. The resulting composite was added to a container for TDNP measurement, and TDNP measurement was performed. Afterward, 1 A spectrum was obtained by performing a 1H NMR measurement.

[0062] [Comparative Example 1] The procedure was the same as in Example 1, except that TDNP was not performed.

[0063] [Second Experimental Example] [Example 2] 1.0 mole of isonicotinamide and 1.0 mole of formic acid were added to a grinding jar, and then 0.001 mole of 5,12-diazatetracene was added. Using a mixer mill, the isonicotinamide, formic acid, and 5,12-diazatetracene were mixed and ground for 30 minutes at an oscillation frequency of 30 Hz to obtain a composite. The resulting composite was added to a container for TDNP measurement, and TDNP measurement was performed. Afterward, 1A spectrum was obtained by performing a 1H NMR measurement.

[0064] [Comparative Example 2] The procedure was the same as in Example 2, except that TDNP was not performed.

[0065] [Third experimental example] [Example 3] The procedure was the same as in Example 2, except that acetic acid was used instead of formic acid.

[0066] [Comparative Example 3] The procedure was the same as in Example 3, except that TDNP was not performed.

[0067] [Fourth Experimental Example] [Example 4] The procedure was the same as in Example 2, except that water was used instead of formic acid.

[0068] [Comparative Example 4] The procedure was the same as in Example 4, except that TDNP was not performed.

[0069] The NMR spectra of the obtained complex are shown in Figures 1-4.

[0070] Figure 1 shows the spectra obtained in the first experimental example. The upper spectrum in Figure 1 was obtained using the composite obtained in Example 1, and the lower spectrum was obtained using the composite obtained in Comparative Example 1.

[0071] Figure 2 shows the spectra obtained in the second experimental example. The upper spectrum in Figure 2 was obtained using the composite obtained in Example 2, and the lower spectrum was obtained using the composite obtained in Comparative Example 2.

[0072] Figure 3 shows the spectra obtained in the third experimental example. The upper spectrum in Figure 3 was obtained using the composite obtained in Example 3, and the lower spectrum was obtained using the composite obtained in Comparative Example 3.

[0073] Figure 4 shows the spectra obtained in the fourth experimental example. The upper spectrum in Figure 4 was obtained using the composite obtained in Example 4, and the lower spectrum was obtained using the composite obtained in Comparative Example 4.

[0074] Figures 1-4 show that absorption occurs when the composites obtained in Examples 1-4 are used. This indicates that TDNP measurements of fumaric acid, formic acid, acetic acid, and water are possible. [Industrial applicability]

[0075] By using a mechanochemical method, a composite can be obtained containing compounds with high melting points, compounds that do not melt, compounds with low heat resistance, compounds with high volatility, or compounds that are liquid at the measurement temperature. This composite can be used as a target for TDNP measurement.

Claims

1. A method for producing a composite comprising a first compound, a second compound, and a polarization source compound, (1) Obtain a composite from the first compound, the second compound, and the polarization source compound by a mechanochemical method. A method for producing a composite containing the above.

2. The method for producing the composite according to claim 1, wherein the mechanochemical method is carried out using a mixer mill.

3. The method for producing the composite according to claim 1 or 2, wherein the mechanochemical method is carried out at a temperature of any of 0 to 70°C.

4. The method for producing the composite according to claim 1 or 2, wherein the mechanochemical method is carried out by mixing for 15 to 240 minutes.

5. The method for producing the composite according to claim 1 or 2, wherein the mechanochemical method is performed by applying a vibration frequency of 10 to 50 Hz.

6. The method for producing the composite according to claim 1 or 2, wherein the mechanochemical method is performed by applying an vibration frequency of 10 to 50 Hz for 15 to 240 minutes using a mixer mill at a temperature of 0 to 70°C.

7. The first compound has an aromatic ring and an amide group, and the method for producing the composite according to claim 1 or 2.

8. The method for producing the complex according to claim 1 or 2, wherein the first compound is at least one selected from nicotinamide and isonicotinamide.

9. The method for producing the composite according to claim 1 or 2, wherein the second compound is water or a carboxylic acid.

10. The method for producing the composite according to claim 1 or 2, wherein the second compound is at least one selected from fumaric acid, formic acid, acetic acid, and water.

11. A method for producing the complex according to claim 1 or 2, wherein the polarization source compound includes an aromatic ring.

12. The method for producing the composite according to claim 1 or 2, wherein the polarization source compound is at least one selected from diazatetracene and diazapentacene.

13. A method for producing a composite according to claim 1 or 2, wherein the first compound and the second compound are contained in a molar ratio in the range of 1:0.5 to 1:2.

5.

14. A method for producing a composite according to claim 1 or 2, wherein the first compound and the polarization source compound are contained in a molar ratio in the range of 1:0.0001 to 1:0.

01.

15. A method for producing a composite according to claim 1 or 2, wherein the composite is solid at the temperature at which the mechanochemical method is performed.

16. A method for producing a composite according to claim 1 or 2, wherein the composite is solid at any temperature between 0 and 70°C.

17. A complex comprising a first compound, a second compound, and a polarization source compound.

18. The complex according to claim 17, wherein the first compound is at least one selected from nicotinamide and isonicotinamide.

19. The composite according to claim 17 or 18, wherein the second compound is at least one selected from fumaric acid, formic acid, acetic acid, and water.

20. The complex according to claim 17 or 18, wherein the polarization source compound is at least one selected from diazatetracene and diazapentacene.

21. The composite according to claim 17 or 18, which is solid at any temperature between 0 and 70°C.

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