Bi-radical compound composed of triaryl methyl radical and nitroxide radical and salt thereof and preparation method and application of bi-radical compound composed of triaryl methyl radical and nitroxide radical and salt thereof

Abstract

The invention provides a bi-radical compound composed of a triaryl methyl radical and a nitroxide radical and salt thereof and a preparation method and application of the bi-radical compound composedof the triaryl methyl radical and the nitroxide radical and the salt thereof. A structural formula of the bi-radical compound is as shown in the formula 1; the formula is shown in the description; thepreparation method comprises the steps that a compound A1 and a compound A2 are subjected to acid amide condensation reaction to obtain a compound A3; the compound A3 and a compound A4 are subjectedto acid amide condensation reaction to obtain the bi-radical compound and the salt thereof. The portion, provided with both the nitroxide radical and the triaryl methyl radical, of a bi-radical polarization agent has the following advantages that the frequency matching ability is better, and the CE efficiency is higher; under a magic angle spinning condition, a depolarization effect does not exist, and a high field DNP enhancing effect is better; exchange interaction is stronger; the water solubility is good, so that the DNP enhancing multiple is high; by modifying R1, R2, R3, R4, R5 and R6 groups, exchange interaction can be improved moderately, bi-radical relaxation time can be prolonged moderately, and the bi-radical water solubility can be improved moderately, so that the DNP propertyof the polarization agent is improved.

Description

technical field

[0001] The invention relates to the technical field of nuclear magnetic resonance, in particular to a diradical compound composed of a triarylmethyl radical and a nitroxide radical and a salt thereof, a preparation method and an application thereof. Background technique

[0002] NMR technology is an important means for characterizing the chemical structure of substances, widely used in chemistry, materials science, biochemistry and other fields, especially solid-state NMR technology makes it possible to analyze the structure of biological macromolecules such as protein molecules, but its application is limited Limited to inherently low sensitivity. In response to this defect, there are currently two efforts. One is to increase the magnetic field strength of the instrument, thereby increasing the polarizability of the nucleus under thermal equilibrium. However, this method is expensive and requires high technology; DNP technology improves the polarization eff...

Examples

Embodiment 1

[0051] A diradical compound composed of triarylmethyl radicals and nitroxide radicals and salts thereof described in this embodiment has a structural formula as follows:

[0052]

[0053] The preparation steps of compound 1 are as follows formula 11:

[0054]

[0055]

[0056] One, the preparation of compound A4:

[0057]

[0058] Two, the preparation of compound 1:

[0059] 1. Dissolve compound A1 (1-1.5eq) and HOBt (2-5eq) in redistilled DCM, stir, add DIPEA (3-10eq), BOP (0.9-1.5eq) first dissolve in redistilled DCM, then Add the reaction solution, activate for 0.5-2h, then dissolve compound A2 (0.9-2eq) in redistilled DCM, add the reaction solution, and react at room temperature for 0.5-18h. Treatment: extract with DCM and water, successively wash with citric acid, saturated sodium carbonate solution, saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate with normal phase silica gel column, mobile phase: ethy...

Embodiment 2

[0068] A diradical compound composed of triarylmethyl radicals and nitroxide radicals and salts thereof described in this embodiment has a structural formula as follows:

[0069]

[0070] 1. The preparation steps of compound 2 are the same as the method in Example 1.

[0071] In this example, compound A1 is Commercially available.

[0072] Such as figure 2 It is the high-resolution mass spectrometry data of compound 2 in this example

[0073] 2. DNP enhancement effect experiment of compound 2

[0074] The experimental method of DNP enhanced performance test is the same as that of compound 1 test.

[0075] The DNP enhancement factor of compound 2 was 76. Compared with compound 1, the enhancement factor of DNP has increased by 33%, and the improvement effect is remarkable.

Embodiment 3

[0077] A diradical compound composed of triarylmethyl radicals and nitroxide radicals and salts thereof described in this embodiment has a structural formula as follows:

[0078]

[0079] The preparation steps of compound 3 are as follows formula 13:

[0080]

[0081] One, the preparation of compound 3:

[0082] Diethylene glycol amine (0.5-2eq), imidazole (2-5eq), DMAP (0.05-0.5eq), tert-butyldimethylsilyl chloride (0.5-2eq) were placed in the reaction flask, argon protection, ice Bath, add anhydrous DCM, stir at zero degree for half an hour, then transfer to room temperature and stir for 2-18 hours to complete the reaction. Post-reaction treatment: wash with saturated brine and evaporate to dryness to obtain the pure product 6 as a colorless transparent oil with a yield of 75-95%.

[0083] The product obtained in the previous step (0.9-2eq) and nitroxide radical (1eq) were dissolved in anhydrous THF, protected by argon, stirred at room temperature for 2 hours, and th...

technical field

[0001] The invention relates to the technical field of nuclear magnetic resonance, in particular to a diradical compound composed of a triarylmethyl radical and a nitroxide radical and a salt thereof, a preparation method and an application thereof. Background technique

[0002] NMR technology is an important means for characterizing the chemical structure of substances, widely used in chemistry, materials science, biochemistry and other fields, especially solid-state NMR technology makes it possible to analyze the structure of biological macromolecules such as protein molecules, but its application is limited Limited to inherently low sensitivity. In response to this defect, there are currently two efforts. One is to increase the magnetic field strength of the instrument, thereby increasing the polarizability of the nucleus under thermal equilibrium. However, this method is expensive and requires high technology; DNP technology improves the polarization eff...

Examples

Embodiment 1

[0051] A diradical compound composed of triarylmethyl radicals and nitroxide radicals and salts thereof described in this embodiment has a structural formula as follows:

[0052]

[0053] The preparation steps of compound 1 are as follows formula 11:

[0054]

[0055]

[0056] One, the preparation of compound A4:

[0057]

[0058] Two, the preparation of compound 1:

[0059] 1. Dissolve compound A1 (1-1.5eq) and HOBt (2-5eq) in redistilled DCM, stir, add DIPEA (3-10eq), BOP (0.9-1.5eq) first dissolve in redistilled DCM, then Add the reaction solution, activate for 0.5-2h, then dissolve compound A2 (0.9-2eq) in redistilled DCM, add the reaction solution, and react at room temperature for 0.5-18h. Treatment: extract with DCM and water, successively wash with citric acid, saturated sodium carbonate solution, saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate with normal phase silica gel column, mobile phase: ethy...

Embodiment 2

[0068] A diradical compound composed of triarylmethyl radicals and nitroxide radicals and salts thereof described in this embodiment has a structural formula as follows:

[0069]

[0070] 1. The preparation steps of compound 2 are the same as the method in Example 1.

[0071] In this example, compound A1 is Commercially available.

[0072] Such as figure 2 It is the high-resolution mass spectrometry data of compound 2 in this example

[0073] 2. DNP enhancement effect experiment of compound 2

[0074] The experimental method of DNP enhanced performance test is the same as that of compound 1 test.

[0075] The DNP enhancement factor of compound 2 was 76. Compared with compound 1, the enhancement factor of DNP has increased by 33%, and the improvement effect is remarkable.

Embodiment 3

[0077] A diradical compound composed of triarylmethyl radicals and nitroxide radicals and salts thereof described in this embodiment has a structural formula as follows:

[0078]

[0079] The preparation steps of compound 3 are as follows formula 13:

[0080]

[0081] One, the preparation of compound 3:

[0082] Diethylene glycol amine (0.5-2eq), imidazole (2-5eq), DMAP (0.05-0.5eq), tert-butyldimethylsilyl chloride (0.5-2eq) were placed in the reaction flask, argon protection, ice Bath, add anhydrous DCM, stir at zero degree for half an hour, then transfer to room temperature and stir for 2-18 hours to complete the reaction. Post-reaction treatment: wash with saturated brine and evaporate to dryness to obtain the pure product 6 as a colorless transparent oil with a yield of 75-95%.

[0083] The product obtained in the previous step (0.9-2eq) and nitroxide radical (1eq) were dissolved in anhydrous THF, protected by argon, stirred at room temperature for 2 hours, and th...

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