Method for producing composite body, and composite body

Abstract

Provided is a method for producing a composite body including a first compound, a second compound, and a polarization source compound, the method comprising: (1) obtaining a composite body from the first compound, the second compound, and the polarization source compound by a mechanochemical method.

Description

Method for producing the composite and the composite

[0001] This disclosure relates to a method for producing a composite and to the composite itself.

[0002] Nuclear magnetic resonance (NMR) spectroscopy is a spectroscopic technique used in the fields of medicine, pharmacy, chemistry, and materials science. A major drawback of NMR is its low sensitivity.

[0003] To address this problem, methods such as Dynamic Nuclear Polarization (DNP) are being studied. DNP allows for increased polarization of the target molecule, resulting in improved NMR sensitivity. However, while conventional DNP methods can improve sensitivity in NMR and other applications, they require the sample to be cooled to extremely low temperatures, making the equipment expensive and large.

[0004] Patent Document 1 discloses the execution of triplet DNP (hereinafter also referred to as "TDNP"). This makes it possible to achieve high polarization at room temperature without cooling the sample to extremely low temperatures. The polarized sample used in the triplet DNP is formed using the melt quench method. The melt quench method is a method of forming a molten sample by raising the temperature of multiple compounds containing the compound to be measured, and then rapidly cooling the sample to form the crystal to be measured.

[0005] International Publication No. 2024 / 185393

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

[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, comprising: (1) obtaining a composite from the first compound, the second compound, and the polarization source compound by a mechanochemical method; [2] The method for producing a composite according to [1], wherein the mechanochemical method is carried out using a mixer mill; [3] The method for producing a composite according to [1] or [2], wherein the mechanochemical method is carried out at a temperature of 0 to 70°C; [4] The method for producing a composite according to any one of [1] to [3], wherein the mechanochemical method is carried out by mixing for 15 to 240 minutes; [5] The method for producing a composite according to any one of [1] to [4], wherein the mechanochemical method is carried out by applying an vibration frequency of 10 to 50 Hz. [6] The method for producing the composite according to any one of [1] to [5], wherein the mechanochemical method is performed by applying an vibration frequency of 10 to 50 Hz using a mixer mill at a temperature of 0 to 70°C for 15 to 240 minutes. [7] The method for producing the composite according to any one of [1] to [6], wherein the first compound has an aromatic ring and an amide group. [8] The method for producing the composite 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 composite 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] The method for producing the composite according to any one of [1] to

[10] , wherein the polarization source compound contains 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] The method for producing the complex 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 a composite according to any one of [1] to

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

[17] A composite comprising the first compound, the second compound and the polarization source compound.

[18] The composite according to

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

[19] The composite according to

[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 any one of

[17] to

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

[21] The complex according to any one of

[17] to

[20] , which is solid at any temperature between 0 and 70°C.

[0008] This disclosure can provide a method different from the melt quenching method in order to broaden the range of composites that can be used for TDNPs.

[0009] Figure 1 shows the composite obtained in Example 1. １ Figure 2 shows the 1H NMR spectrum. Figure 2 shows the composite obtained in Example 2. １ This figure shows the 1H NMR spectrum. Figure 3 shows the composite obtained in Example 3. １ This figure shows the 1H NMR spectrum. Figure 4 shows the composite obtained in Example 4. １ This figure shows the 1H NMR spectrum.

[0010] The following describes this disclosure, but it is not limited to the following statements.

[0011] [Method for producing a polarized composite] This disclosure relates to a method for producing a composite comprising a first compound, a second compound, and a polarization source compound, the method comprising (1) obtaining the composite from the first compound, the second compound, and the polarization source compound by a mechanochemical method.

[0012] In the melt-quench method, it was necessary to raise the temperature of the compound to be measured to form a liquid sample, and then rapidly cool the sample to form crystals. In contrast, this disclosure uses a mechanochemical method. The mechanochemical method is a method of applying mechanical energy to a first compound, a second compound, and a polarization source compound, thereby causing the first compound, the second compound, and the polarization source compound to cocrystallize. Unlike the melt-quench method, the mechanochemical method does not involve crystal formation by raising 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, and 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 method is performed.

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

[0032] The first compound is preferably solid during mixing in the mechanochemical process.

[0033] The second compound only needs to have a group capable of interacting with the first compound, and is not particularly limited. For example, it may have a carboxy group and a hydroxyl group.

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

[0035] The second compound can 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 aspect, the second compound is liquid at any temperature from 0 to70 °C, specifically at any temperature from 0 to 50 °C, more specifically at any temperature from 15 to 50 °C, and still more specifically at any temperature from 15 to 35 °C.

[0038] In one aspect, the second compound is solid at any temperature from 0 to 70 °C, specifically at any temperature from 0 to 50 °C, more specifically at any temperature from 15 to 50 °C, and still more specifically at any temperature from 15 to 35 °C.

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

[0040] The polarization source compound is a compound in which polarization occurs upon irradiation with light.

[0041] The polarization source compound preferably contains an aromatic ring. By having this aspect, the impact resistance of the polarization source compound is improved, and even when the polarization compound is mixed with the first compound and the second compound, the structure can be maintained.

[0042] More preferably, the polarization source compound is a compound in which a plurality of aromatic rings are directly bonded. By having this aspect, the durability of the polarization source compound against external stresses, such as physical stimuli such as heat or mixing, or chemical stimuli, is improved, and the modification rate of the polarization source compound due to external stresses is suppressed.

[0043] The aromatic ring in the polarization source compound preferably contains a heteroatom. The heteroatom is not particularly limited, but is, for example, at least one of a nitrogen atom, an oxygen atom, and a sulfur atom, and specifically, a nitrogen atom. By containing a heteroatom, it becomes easier to form a hydrogen bond with the first compound and / or the second compound. When the number of hydrogen bonds increases, the bond in the co-crystal can become stronger, and as a result, the detection sensitivity of NMR can be made higher.

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

[0045] In addition, at least one of the first compound, the second compound, and the polarization source compound may be present alone together with the complex. A derivative of the first compound, the second compound, or the polarization source compound may be present together with the complex.

[0046] Preferably, (2) the complex obtained in step (1) is caused to generate polarization.

[0047] In step (2), polarization is preferably generated by the triplet DNP method, and more preferably by light irradiation. Examples of light irradiation include irradiation with laser light. This polarizes the polarization source compound. Specifically, the following explanation will be given using 5,12-diazatetracene. First, by light irradiation, the electrons of the irradiated 5,12-diazatetracene enter a photoexcited state. Subsequently, these electrons transition from the excited state to the triplet state, and the electron spins of the 5,12-diazatetracene enter a polarized state. Then, by irradiation with microwaves, the polarization of the electron spins is transferred to the hydrogen spins of the 5,12-diazatetracene, and the hydrogen spins of the 5,12-diazatetracene enter a polarized state.

[0048] The amount of light irradiation in step (2) is, for example, 0.1 to 0.2 J / cm². ２ It may 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] [Composite] This disclosure discloses a composite comprising a first compound, a second compound, and a polarization source compound. The composite 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.

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

[0059] [Measurement device] [Mixer mill] MM400 (manufactured by RETSCH) Vibration frequency: 30 Hz Mixing time: 30 to 180 minutes Grinding balls (material): 2 x 10 mm balls (zirconia) Grinding jar (material): 10 ml (zirconia)

[0060] [Triple-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 Technologies 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] 2.0 mol of nicotinamide and 1.0 mol of fumaric acid were added to a grinding jar, and then 0.001 mol of 5,12-diazatetracene was further added. Using a mixer mill, nicotinamide, fumaric acid, and 5,12-diazatetracene were mixed and pulverized at a vibration frequency of 30 Hz for 180 minutes to obtain a complex. The obtained complex was added to a container for TDNP measurement, and TDNP measurement was performed. Then, １ 1H NMR measurement was performed to obtain a spectrum.

[0062] [Comparative Example 1] It was carried out in the same manner as in Example 1 except that TDNP was not performed.

[0063] [Second Experimental Example] [Example 2] 1.0 mol of isonicotinamide and 1.0 mol of formic acid were added to a grinding jar, and then 0.001 mol of 5,12-diazatetracene was further added. Using a mixer mill, isonicotinamide, formic acid, and 5,12-diazatetracene were mixed and pulverized at a vibration frequency of 30 Hz for 30 minutes to obtain a complex. The obtained complex was added to a container for TDNP measurement, and TDNP measurement was performed. Then, １ 1H NMR measurement was performed to obtain a spectrum.

[0064] [Comparative Example 2] It was carried out in the same manner as in Example 2 except that TDNP was not performed.

[0065] [Third Experimental Example] [Example 3] It was carried out in the same manner as in Example 2 except that acetic acid was used instead of formic acid.

[0066] [Comparative Example 3] It was carried out in the same manner as in Example 3 except that TDNP was not performed.

[0067] [Fourth Experimental Example] [Example 4] It was carried out in the same manner as in Example 2 except that water was used instead of formic acid.

[0068] [Comparative Example 4] It was carried out in the same manner as in Example 4 except that TDNP was not performed.

[0069] The NMR spectra of the obtained complexes are shown in FIGS. 1 to 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 measurement of fumaric acid, formic acid, acetic acid, and water is possible.

[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, comprising: (1) obtaining a composite from the first compound, the second compound, and the polarization source compound by a mechanochemical method.

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. A method for producing a composite according to any one of claims 1 to 3, wherein the mechanochemical method is carried out by mixing for 15 to 240 minutes.

5. A method for producing a composite according to any one of claims 1 to 4, wherein the mechanochemical method is performed by applying an vibration frequency of 10 to 50 Hz.

6. The method for producing a composite according to any one of claims 1 to 5, wherein the mechanochemical method is performed by applying an vibration frequency of 10 to 50 Hz using a mixer mill at a temperature of 0 to 70°C for 15 to 240 minutes.

7. A method for producing the composite according to any one of claims 1 to 6, wherein the first compound has an aromatic ring and an amide group.

8. A method for producing a complex according to any one of claims 1 to 7, wherein the first compound is at least one selected from nicotinamide and isonicotinamide.

9. A method for producing a composite according to any one of claims 1 to 8, wherein the second compound is water or a carboxylic acid.

10. The method for producing a composite according to any one of claims 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 a complex according to any one of claims 1 to 10, wherein the polarization source compound includes an aromatic ring.

12. The method for producing a composite according to any one of claims 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 claims 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 claims 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 claims 1 to 14, wherein the composite is solid at the temperature at which the mechanochemical method is performed.

16. A method for producing a composite according to any one of claims 1 to 15, wherein the composite is solid at any temperature between 0 and 70°C.

17. A complex comprising the first compound, the second compound, and the 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 complex 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 any one of claims 17 to 19, wherein the polarization source compound is at least one selected from diazatetracene and diazapentacene.

21. The composite according to any one of claims 17 to 20, which is solid at any temperature between 0 and 70°C.

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