Method for obtaining polarized cocrystal and cocrystal obtained therfrom

Abstract

Provided is a production method for obtaining a polarized cocrystal of a first compound and a second compound, said method comprising (1) polarizing the first compound, and (2) mixing the polarized first compound and the unpolarized second compound to obtain the polarized cocrystal.

Description

A method for obtaining polarized cocrystals, and cocrystals obtained by the said method.

[0001] This disclosure relates to a method for obtaining polarized cocrystals and to cocrystals obtained by said method.

[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] Further investigations are being conducted in response to this. Patent Document 1 describes a method in which benzoic acid and a target molecule are mixed to form a eutectic, and pentacene is added to the resulting eutectic as a polarization source to obtain a highly polarized object. Triplet DNP is disclosed for this method. This makes it possible to achieve high polarization at room temperature without cooling the sample to extremely low temperatures.

[0005] International Publication No. 2019 / 039477

[0006] This disclosure aims to provide a method for more easily forming cocrystals.

[0007] This disclosure provides the following: [1] A method for obtaining a polarized cocrystal of a first compound and a second compound, comprising: (1) polarizing the first compound; and (2) mixing the polarized first compound with the unpolarized second compound to obtain a polarized cocrystal. [2] The manufacturing method according to [1], wherein in step (2), the first compound and the second compound form a cocrystal 0.1 to 30 seconds after mixing. [3] The manufacturing method according to [1] or [2], wherein the mixing in step (2) is carried out at a temperature of 0 to 50°C. [4] The manufacturing method according to any one of [1] to [3], wherein the mixing in step (2) is carried out by stirring the first compound and the second compound. [5] The manufacturing method according to any one of [1] to [4], wherein the mixing in step (2) is obtained by stirring the first compound and the second compound at a temperature of 0 to 50°C. [6] The first compound is polarized by a triplet dynamic nuclear polarization method, according to any one of [1] to [5]. [7] The first compound is polarized by light irradiation, according to any one of [1] to [6]. [8] In the mixing of step (2), the first compound is solid and the second compound is liquid, according to any one of [1] to [7]. [9] The first compound is solid at any temperature from 0 to 50°C, according to any one of [1] to [8].

[10] The second compound is liquid at any temperature from 0 to 50°C, according to any one of [1] to [9].

[11] The first compound is at least one selected from picolinamide, benzoic acid, 1,4-di(4-pyridyl)benzene, biphenyl-4-carboxylic acid, nicotinamide, benzamide, 2,2'-bipyridyl, and 4-phenylpyridine, according to any one of [1] to

[10] .

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

[11] , wherein the second compound is at least one selected from pyruvate, formic acid, acetic acid, and pyridine.

[13] A method for producing the product according to any one of [1] to

[12] , further comprising (3) cross-polarization to move the polarization from a hydrogen atom to a carbon atom.

[14] A cocrystal of a first compound and a second compound, wherein the second compound is polarized.

[15] The cocrystal according to

[14] , wherein the first compound is at least one selected from picolinamide, benzoic acid, 1,4-di(4-pyridyl)benzene, biphenyl-4-carboxylic acid, nicotinamide, benzamide, 2,2'-bipyridyl, and 4-phenylpyridine.

[16] The cocrystal according to

[14] or

[15] , wherein the second compound is at least one selected from pyruvate, formic acid, acetic acid, and pyridine.

[0008] This disclosure provides a method for more easily forming cocrystals.

[0009] Figure 1A is a schematic diagram showing the sequential addition of the second compound 104 and the first compound 102 to the container 110. Figure 1B is a schematic diagram showing the mixing of the first compound 102 and the second compound 104 in the container 110 using a mixing member 112. Figure 1C is a schematic diagram showing the polarized cocrystal 106 formed from the first compound 102 and the second compound 104. Figure 2 is... １３ This figure shows the 13C NMR spectrum. Figure 3 shows the dissolution. １３ This figure shows the 13C NMR spectrum.

[0010] The following describes this disclosure, but it is not limited to what is stated below. Furthermore, some drawings are schematic and may not reflect actual dimensions or proportions.

[0011] [Method for producing a polarized composite] This disclosure relates to a method for obtaining a polarized cocrystal of a first compound and a second compound, comprising: step (1): polarizing the first compound; step (2): mixing the polarized first compound and the unpolarized second compound to obtain a polarized cocrystal.

[0012] The polarized cocrystal of this disclosure is a cocrystal comprising a first compound and a second compound, and the cocrystal has a polarized portion. By the method of this disclosure, a polarized cocrystal can be easily obtained.

[0013] The above method preferably further includes step (3): Cross Polarization, which shifts the polarization from hydrogen atoms to carbon atoms.

[0014] The following explanation will be given using Figures 1A, 1B, and 1C.

[0015] Step (1) The first compound 102 is used as a polarization source.

[0016] Polarization of the first compound 102 is preferably achieved by a triplet DNP method, and more preferably by light irradiation. Examples of light irradiation include irradiation with laser light. This polarizes the electron spin or nuclear spin of the hydrogen atoms of the first compound 102. Subsequently, the polarization of the electron spin can be transferred to the nuclear spin by irradiation with microwaves. By pre-polarizing the first compound 102, the polarization can be transferred to the second compound 104 in step (2).

[0017] The light irradiation dose 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.

[0018] The light irradiation time may be in the range of, for example, 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.

[0019] The polarization of the first compound 102 can be confirmed by NMR measurement.

[0020] The polarization of the first compound 102 may be performed after it has been added to the container 110. The container 110 is not particularly limited, but could be, for example, a container used for measurements such as NMR.

[0021] For example, as shown in Figure 1A, the second compound 104 is added to the container 110, then the first compound 102 is added from above the container, and then the first compound 102 is polarized, for example, by triplet DNP. The second compound 104 is added to the container 110 together with the first compound 102, but is not polarized by, for example, the triplet DNP method.

[0022] The second compound 104 described above is the compound that we ultimately want to polarize (hereinafter also referred to as the "target compound").

[0023] In step (1), the first compound 102 and the second compound 104 may be kept separate and not in contact.

[0024] While not particularly limited, for example, 0.01 to 0.2 millimoles of the first compound 102 and 0.01 to 0.2 millimoles of the second compound 104 may be added to the container 110.

[0025] The first compound 102 is a solid, for example, at any temperature between 0 and 50°C, more specifically at any temperature between 15 and 50°C, and more specifically at any temperature between 15 and 35°C.

[0026] The first compound 102 is more preferably at least one selected from picolineamide, benzoic acid, 1,4-di(4-pyridyl)benzene, biphenyl-4-carboxylic acid, nicotinamide, benzamide, 2,2'-bipyridyl, and 4-phenylpyridine, for example, picolineamide.

[0027] In one embodiment, a polarized cocrystal may be used as the first compound 102. The polarized cocrystal may be a polarized cocrystal obtained by the present disclosure, or it may be a polarized cocrystal other than that disclosed. Another polarized cocrystal may be, for example, at least one cocrystal selected from benzoic acid-isonicotinamide, salicylic acid-4-methylbenzamide, benzoic acid-benzamide, salicylic acid-salicylamide, and 1,4-di(4-pyridyl)benzene-paraterphenyl.

[0028] The second compound 104 is a liquid at any temperature between 0 and 50°C, more specifically at any temperature between 15 and 50°C, and more specifically at any temperature between 15 and 35°C.

[0029] The second compound 104 is more preferably at least one selected from pyruvate, formic acid, acetic acid, and pyridine, for example, at least one selected from pyruvate, formic acid, and acetic acid, specifically pyruvate.

[0030] Step (2) As shown in Figure 1B, the first compound 102 and the second compound 104 are mixed to obtain a polarized cocrystal 106 as shown in Figure 1C. Note that this can be done without moving the container 110 from the position where step (1) was performed.

[0031] In step (2), the first compound 102 and the second compound 104 can form a cocrystal, for example, 0.1 to 30 seconds after mixing, more specifically 1 to 15 seconds, and more specifically 1 to 5 seconds.

[0032] The mixing in step (2) may be carried out at a temperature of any of the following degrees: 0 to 50°C, specifically any of the following degrees: 10 to 50°C, more specifically any of the following degrees: 15 to 50°C, even more specifically any of the following degrees: 15 to 35°C, particularly specifically any of the following degrees: 20 to 30°C, specifically 25°C.

[0033] The mixing in step (2) can be carried out by applying pressure to the first compound 102 and the second compound 104. The pressure can be applied to the first compound and the second compound, for example, by directly applying physical pressure to the first compound 102 and the second compound 104 (e.g., by stirring). For example, a pressure of 0.1 to 6 MPa, specifically 0.25 to 1.5 MPa, can be applied. This allows the polarized cocrystal 106 to be formed in a short time.

[0034] The mixing in step (2) can be carried out by stirring the first compound 102 and the second compound 104. For example, this can be done by rotating the mixing member 112 at 10 to 60 rpm, specifically 48 rpm, along the axial direction perpendicular to the opening of the container 110.

[0035] The mixing in step (2) can be obtained, for example, by stirring the first compound 102 and the second compound 104 at any temperature from 0 to 50 °C. Further, for example, a pressure of 0.1 to 6 MPa, specifically a pressure of 0.25 to 1.5 MPa, may be applied.

[0036] In the mixing of step (2), it is preferable that the first compound 102 is solid and the second compound 104 is liquid. Thereby, the polarized cocrystal 106 can be formed in a short time.

[0037] In step (2), at any temperature from 0 to 50 °C, the first compound 102 can be solid and the second compound 104 can be liquid. Thereby, the formation of the polarized cocrystal 106 can be facilitated.

[0038] The mixing in step (2) can be performed, for example, using the mixing member 112. The shape of the mixing member 112 is not particularly limited, but for example, it is rod-shaped. The mixing member 112 can be, for example, a quartz glass tube or a glass rod.

[0039] In the polarized cocrystal 106, polarization can move from the first compound 102 to the second compound 104, specifically, from the hydrogen atom of the first compound 102 to the hydrogen atom of the second compound 104. Thereby, polarization moves to the second compound 104 which is the target molecule, and the measurement of the second compound 104 becomes possible. Note that the polarization of all of the first compound 102 may move, or the polarization of some of the first compound 102 may move. Also, all of the second compound 104 may be polarized, or some of the second compound 104 may be polarized.

[0040] In the polarized cocrystal 106, the first compound 102 and the second compound 104 can be included in a molar ratio in the range of, for example, 5:1 to 1:2, specifically in the range of 2:1 to 4:1.

[0041] Step (3) Cross polarization refers to a method of transferring the polarization possessed by a certain nuclide to another nuclide, and here, it refers to a method of transferring polarization from a hydrogen atom to a carbon atom. By performing cross polarization, the polarization period can be made larger.

[0042] Cross-polarization can be performed, for example, using RAMP-CP (Ramped-Amplitude Cross-Polarization), which is included in the TDNP method.

[0043] Cross-polarization may be performed on the second compound 104. All or only some of the polarization of the hydrogen atoms of the second compound 104 may be transferred.

[0044] Cross-polarization may be performed on the first compound 102.

[0045] [Cocrystal] The cocrystal of this disclosure will be described below.

[0046] Polarized cocrystal 106 contains a first compound 102 and a second compound 104, and the second compound 104 is polarized. The first compound 102, the second compound 104, and the polarized cocrystal 106 are each equivalent to those described above.

[0047] The polarized cocrystal 106 preferably does not have a polarization source.

[0048] Polarized cocrystal 106 is obtained by the method of the present disclosure described above.

[0049] The method for obtaining polarized cocrystals and the polarized cocrystals themselves have been described in detail above. However, this disclosure is not limited to those exemplified above.

[0050] The present disclosure will be described below with reference to examples, but the present disclosure is not limited to the following examples.

[0051] (Equipment) The following equipment was used for the measurements.

[0052] [Dissolution １３ [C NMR Measurement] SCM (Super Conducting Magnet): Varian AS500 NMR Amplifier (11.7T, １ H and １３ C): AMT 3900-15

[0053] [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 Industry PAN60-10A Magnetic Field Sweep Function Generator: Agilent 33522A NMR Amplifier (0.4T, １３ for C): THAMWAY N146-5599A

[0054] [Experimental Example 1: Polarization of Pyruvic Acid] (Example 1) 0.020 mmol of pyruvic acid was added to a container, and then 0.068 mmol of picolinamide was added. Note that 99% of the carbon atoms of the added pyruvic acid marked with * are １３ C. The above container was irradiated with laser light to perform triplet DNP (TDNP) to polarize picolinamide. Then, pyruvic acid and picolinamide were mixed in a container installed in the DNP apparatus to obtain a co-crystal. Note that the above mixing was performed by stirring with a stirring rod so as to press the raw materials (pyruvic acid and picolinamide) against the bottom surface of the container. The obtained co-crystal １３ 13C NMR (solid NMR) was measured.

[0055] (Comparative Example 1) It was carried out in the same manner as in Example 1 except that TDNP was performed. The obtained co-crystal １３ 13C NMR (solid NMR) was measured.

[0056] The １３ 13C NMR spectra of Example 1 and Comparative Example 1 are shown in FIG. 2. The results of Example 1 are shown on the upper side and those of Comparative Example 1 are shown on the lower side. In Example 1, １３ it was confirmed that the absorption intensity of 13C NMR increased. It was found that pyruvic acid could be hyperpolarized at room temperature by mixing the polarized picolinamide (the first compound) and pyruvic acid (the second compound: the target compound) to form a co-crystal.

[0057] dissolution １３ The 13C NMR spectrum is shown in Figure 3. The results for Example 1 are shown on the upper side, and the results for Comparative Example 1 are shown on the lower side. In Example 1, it was confirmed that the pyruvate peak was larger. This confirmed that pyruvate was polarized. １３ The 13C NMR spectrum was obtained by exposing a solid-state sample to a high magnetic field, causing the solid to dissolve, and then measuring the resulting state.

[0058] According to this disclosure, polarized cocrystals can be obtained more easily.

[0059] 102 First compound 104 Second compound 106 Polarized cocrystal 110 Container 112 Mixing component

Claims

1. A method for obtaining a polarized cocrystal of a first compound and a second compound, comprising: (1) polarizing the first compound; and (2) mixing the polarized first compound with the unpolarized second compound to obtain a polarized cocrystal.

2. The manufacturing method according to claim 1, wherein in step (2), the first compound and the second compound form a cocrystal 0.1 to 30 seconds after mixing.

3. The manufacturing method according to claim 1 or 2, wherein the mixing in step (2) is carried out at a temperature of 0 to 50°C.

4. The manufacturing method according to any one of claims 1 to 3, wherein the mixing in step (2) is carried out by stirring the first compound and the second compound.

5. The manufacturing method according to any one of claims 1 to 4, wherein the mixing in step (2) is obtained by stirring the first compound and the second compound at a temperature of 0 to 50°C.

6. The manufacturing method according to any one of claims 1 to 5, wherein the polarization of the first compound is produced by a triplet dynamic nuclear polarization method.

7. The manufacturing method according to any one of claims 1 to 6, wherein the polarization of the first compound is produced by light irradiation.

8. The manufacturing method according to any one of claims 1 to 7, wherein in the mixing of step (2), the first compound is a solid and the second compound is a liquid.

9. The manufacturing method according to any one of claims 1 to 8, wherein the first compound is solid at any temperature between 0 and 50°C.

10. The method for producing the second compound according to any one of claims 1 to 9, wherein the second compound is a liquid at a temperature of 0 to 50°C.

11. The method for producing the first compound according to any one of claims 1 to 10, wherein the first compound is at least one selected from picolinamide, benzoic acid, 1,4-di(4-pyridyl)benzene, biphenyl-4-carboxylic acid, nicotinamide, benzamide, 2,2'-bipyridyl, and 4-phenylpyridine.

12. The method for producing the second compound according to any one of claims 1 to 11, wherein the second compound is at least one selected from pyruvate, formic acid, acetic acid, and pyridine.

13. The manufacturing method according to any one of claims 1 to 12, further comprising (3) cross-polarization to shift the polarization from hydrogen atoms to carbon atoms.

14. A cocrystal of a first compound and a second compound, wherein the second compound is polarized.

15. The cocrystal according to claim 14, wherein the first compound is at least one selected from picolineamide, benzoic acid, 1,4-di(4-pyridyl)benzene, biphenyl-4-carboxylic acid, nicotinamide, benzamide, 2,2'-bipyridyl, and 4-phenylpyridine.

16. The cocrystal according to claim 14 or 15, wherein the second compound is at least one selected from pyruvate, formic acid, acetic acid, and pyridine.

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