2-nuclear magnetic resonance imaging contrast agent taking 2, 3-biquinoxaline as connecting body and preparation method thereof

Abstract

The invention discloses a 2-nuclear magnetic resonance imaging contrast agent taking 2, 3-biquinoxaline as a connecting body and a preparation method of the 2-nuclear magnetic resonance imaging contrast agent, relating to the technical field of magnetic resonance imaging contrast agents. The 2-nuclear magnetic resonance imaging contrast agent taking the 2, 3-biquinoxaline as the connecting body solves the problems that the relaxation efficiency is low and the thermodynamic stability is poor as the contrast agent adopts a flexible chain to connect a group in the prior art. According to the contrast agent, two DO3A groups are in covalent connection on the rigid-connection group 2, 3-biquinoxaline, and then the rigid-connection group 2, 3-biquinoxaline is chelated with paramagnetism metal ion Gd3<+> to obtain the 2-nuclear magnetic resonance imaging contrast agent. The invention also provides the preparation method of the 2-nuclear magnetic resonance imaging contrast agent taking the 2, 3-biquinoxaline as the connecting body. The relaxation efficiency of the contrast agent (Gd-Do3A)-BMQX can achieve 6.2mM<-1>s<-1>, and the 2-nuclear magnetic resonance imaging contrast agent has good stability and is low in toxicity.

Description

technical field

[0001] The invention relates to a magnetic resonance imaging contrast agent, in particular to a dinuclear magnetic resonance imaging contrast agent with 2,3-diquinoxaline as a linker and a preparation method thereof. Background technique

[0002] In recent years, Magnetic Resonance Imaging (MRI) has become a routine diagnostic method in medical diagnosis. With new magnetic imaging techniques, such as Functional MRI, Perfusion MRI, etc. The development and clinical application of high magnetic field strength instruments, and the use of high magnetic field strength instruments, the demand for excellent contrast agents with high magnetic relaxation efficiency, high water solubility, low osmotic pressure, and low toxicity has become increasingly important. The role of contrast agents in magnetic resonance imaging is to change the relaxation time of hydrogen atoms in water molecules around paramagnetic ions, increase the magnetic signal difference between the dete...

Examples

Embodiment 1

[0047] Example 1 (Gd-DO3A) 2 - Synthesis of BMQX

[0048] Step 1: Synthesis of 2,3-bis(bromomethyl)quinoxaline

[0049] Under nitrogen protection, add 0.681 g of o-phenylenediamine to a 50 ml round bottom flask, add 4 ml of anhydrous tetrahydrofuran to dissolve, stir at 5°C, add 1.46 g of 1,4-dibromo-2,3- 8 milliliters of tetrahydrofuran solution of diacetyl, obtain mixed solution, allow mixed solution rise to room temperature gradually, stop reaction after continuing to react for 3 hours, remove solvent tetrahydrofuran under reduced pressure distillation, obtain reaction product, product carries out chromatographic separation with silica gel column, The eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:12, and the eluent was evaporated to obtain 1.67 g of 2,3-bis(bromomethyl)quinoxaline as a white solid;

[0050] Step two: ( t Bu-DO3A) 2 - Synthesis of BMQX

[0051] Under nitrogen protection, 1.22 g t Bu-DO3A HBr, 0.682 g NaHCO 3 Add it t...

Embodiment 2

[0058] Embodiment 2, (Gd-DO3A) 2 - Synthesis of BMQX

[0059] Step 1: Synthesis of 2,3-bis(bromomethyl)quinoxaline

[0060] Under nitrogen protection, add 0.681 g of o-phenylenediamine to a 50 ml round bottom flask, add 4 ml of anhydrous tetrahydrofuran to dissolve, stir at 10°C, add 1.46 g of 1,4-dibromo-2,3- 8 milliliters of tetrahydrofuran solution of diacetyl, to obtain mixed solution, allow mixed solution to rise to room temperature gradually, stop reaction after continuing to react for 2 hours, remove solvent tetrahydrofuran under reduced pressure distillation, obtain reaction product, product carries out chromatographic separation with silica gel column, The eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:12, and the eluent was evaporated to obtain 1.67 g of 2,3-bis(bromomethyl)quinoxaline as a white solid;

[0061] Step two: ( t Bu-DO3A) 2 - Synthesis of BMQX

[0062] Under nitrogen protection, 1.22 g t Bu-DO3A HBr, 0.682 g NaHCO ...

Embodiment 3

[0075] Example 3 (Gd-DO3A) 2 - Synthesis of BMQX

[0076] Step 1: Synthesis of 2,3-bis(bromomethyl)quinoxaline

[0077] Under nitrogen protection, add 2.724 grams of o-phenylenediamine to a 100 ml round bottom flask, add 16 ml of anhydrous tetrahydrofuran to dissolve, stir at 0°C, add 5.84 g of 1,4-dibromo-2,3- 32 milliliters of tetrahydrofuran solution of diacetyl, to obtain mixed solution, remove the ice-water bath, allow mixed solution to rise to room temperature gradually, stop reaction after continuing to react for 4 hours, remove solvent tetrahydrofuran under reduced pressure distillation, obtain reaction product, product is carried out with silica gel column It was separated by chromatography, and the eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:12. The eluent was evaporated to obtain 6.8 g of white solid 2,3-bis(bromomethyl)quinoxaline;

[0078] Step two: ( t Bu-DO3A) 2 - Synthesis of BMQX

[0079] Under nitrogen protection, 2....

technical field

[0001] The invention relates to a magnetic resonance imaging contrast agent, in particular to a dinuclear magnetic resonance imaging contrast agent with 2,3-diquinoxaline as a linker and a preparation method thereof. Background technique

[0002] In recent years, Magnetic Resonance Imaging (MRI) has become a routine diagnostic method in medical diagnosis. With new magnetic imaging techniques, such as Functional MRI, Perfusion MRI, etc. The development and clinical application of high magnetic field strength instruments, and the use of high magnetic field strength instruments, the demand for excellent contrast agents with high magnetic relaxation efficiency, high water solubility, low osmotic pressure, and low toxicity has become increasingly important. The role of contrast agents in magnetic resonance imaging is to change the relaxation time of hydrogen atoms in water molecules around paramagnetic ions, increase the magnetic signal difference between the dete...

Examples

Embodiment 1

[0047] Example 1 (Gd-DO3A) 2 - Synthesis of BMQX

[0048] Step 1: Synthesis of 2,3-bis(bromomethyl)quinoxaline

[0049] Under nitrogen protection, add 0.681 g of o-phenylenediamine to a 50 ml round bottom flask, add 4 ml of anhydrous tetrahydrofuran to dissolve, stir at 5°C, add 1.46 g of 1,4-dibromo-2,3- 8 milliliters of tetrahydrofuran solution of diacetyl, obtain mixed solution, allow mixed solution rise to room temperature gradually, stop reaction after continuing to react for 3 hours, remove solvent tetrahydrofuran under reduced pressure distillation, obtain reaction product, product carries out chromatographic separation with silica gel column, The eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:12, and the eluent was evaporated to obtain 1.67 g of 2,3-bis(bromomethyl)quinoxaline as a white solid;

[0050] Step two: ( t Bu-DO3A) 2 - Synthesis of BMQX

[0051] Under nitrogen protection, 1.22 g t Bu-DO3A HBr, 0.682 g NaHCO 3 Add it t...

Embodiment 2

[0058] Embodiment 2, (Gd-DO3A) 2 - Synthesis of BMQX

[0059] Step 1: Synthesis of 2,3-bis(bromomethyl)quinoxaline

[0060] Under nitrogen protection, add 0.681 g of o-phenylenediamine to a 50 ml round bottom flask, add 4 ml of anhydrous tetrahydrofuran to dissolve, stir at 10°C, add 1.46 g of 1,4-dibromo-2,3- 8 milliliters of tetrahydrofuran solution of diacetyl, to obtain mixed solution, allow mixed solution to rise to room temperature gradually, stop reaction after continuing to react for 2 hours, remove solvent tetrahydrofuran under reduced pressure distillation, obtain reaction product, product carries out chromatographic separation with silica gel column, The eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:12, and the eluent was evaporated to obtain 1.67 g of 2,3-bis(bromomethyl)quinoxaline as a white solid;

[0061] Step two: ( t Bu-DO3A) 2 - Synthesis of BMQX

[0062] Under nitrogen protection, 1.22 g t Bu-DO3A HBr, 0.682 g NaHCO ...

Embodiment 3

[0075] Example 3 (Gd-DO3A) 2 - Synthesis of BMQX

[0076] Step 1: Synthesis of 2,3-bis(bromomethyl)quinoxaline

[0077] Under nitrogen protection, add 2.724 grams of o-phenylenediamine to a 100 ml round bottom flask, add 16 ml of anhydrous tetrahydrofuran to dissolve, stir at 0°C, add 5.84 g of 1,4-dibromo-2,3- 32 milliliters of tetrahydrofuran solution of diacetyl, to obtain mixed solution, remove the ice-water bath, allow mixed solution to rise to room temperature gradually, stop reaction after continuing to react for 4 hours, remove solvent tetrahydrofuran under reduced pressure distillation, obtain reaction product, product is carried out with silica gel column It was separated by chromatography, and the eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:12. The eluent was evaporated to obtain 6.8 g of white solid 2,3-bis(bromomethyl)quinoxaline;

[0078] Step two: ( t Bu-DO3A) 2 - Synthesis of BMQX

[0079] Under nitrogen protection, 2....

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