Preparation method of fluorescence-magnetic resonance bimodal contrast agent

Abstract

The invention relates to the field of medical diagnosis imaging, in particular to a preparation method of a fluorescence-magnetic resonance bimodal contrast agent. The fluorescent-magnetic resonance bimodal contrast agent has a structure as shown in a formula I. The preparation method comprises the following steps: in an inert gas atmosphere, taking n-butyl cyclophosphoric anhydride as a condensing agent, and in a solvent system containing organic alkali, carrying out condensation reaction on a compound II and a compound III to prepare a target compound I. The invention further discloses a preparation method of the fluorescent-magnetic resonance bimodal contrast agent. The fluorescent-magnetic resonance bimodal contrast agent provided by the invention is simple in preparation method, has the characteristics of high yield and high purity, and can meet the requirements of industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of medical diagnostic imaging, and in particular to a method for preparing a fluorescence-magnetic resonance dual-modality contrast agent. Background Art

[0002] With the continuous development of molecular imaging methods, dual-modal or multi-modal molecular probes that combine multiple imaging methods are favored by people. Such probes can be used for detection of different imaging devices at the same time, realizing the complementary advantages of multiple imaging modes, and can provide more comprehensive diagnostic information for complex diseases. Among them, the MRI / NIR dual-modal probe based on nuclear magnetic resonance imaging and near-infrared imaging has the characteristics of high spatial resolution of MRI, high sensitivity of NIR and rapid imaging. It can provide more accurate imaging information in the early diagnosis of malignant tumors and intraoperative fluorescence navigation applications, which is of great significance in medical diagnosis. The preparation of MRI / NIR dual-modal probes with high MRI relaxation rate, NIR fluorescence efficiency and tumor targeting recognition ability is becoming one of the research hotspots.

[0003] Patent CN115364245A discloses a novel fluorescence-magnetic resonance dual-modal contrast agent compound I, which has the advantages of high relaxation rate, excellent thermal stability, low toxic side effects, good correspondence between fluorescence and magnetic resonance signals, etc., and can be effectively applied to magnetic resonance imaging and fluorescence imaging of living cells and living bodies. At the same time, the patent also provides a preparation method of compound I (the reaction formula is as follows, and the compound number is re-edited): compound II and compound IV are dissolved in DMSO at an equivalent ratio of 1:0.5-1:3, 1-5 equivalents of N,N-diisopropylethylamine are added, and the reaction is carried out at 0-50°C for 8h. After column purification, the target product I is obtained with a purity of 96.3% and a yield of 51%. The yield of the target product of this preparation method is low, the reaction takes a long time, and it is not suitable for industrial production.

[0004]

[0005] Therefore, it is urgent to develop a method suitable for the industrial preparation of compound I to further improve the yield and purity of the target product. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention aims to provide a method for preparing the above-mentioned contrast agent compound I, thereby improving the yield and purity of compound I. The specific technical scheme adopted by the present invention is as follows:

[0007] A method for preparing a fluorescence-magnetic resonance dual-modality contrast agent comprises the following steps: in an inert gas atmosphere, using n-butyl cyclophosphoric anhydride as a condensation agent, in a solvent system containing an organic base, a compound II and a compound III are subjected to a condensation reaction to obtain a target compound I.

[0008] The structural formula of the fluorescence-magnetic resonance dual-modality contrast agent is shown in Formula I, and the reaction formula of the preparation method is as follows:

[0009]

[0010] The organic base in the preparation method of the present invention is one or more of N-methylmorpholine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylmethylamine, and N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

[0011] The solvent in the preparation method of the present invention is one or more of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide.

[0012] Preferably, the molar ratio of the organic base to the compound III is (4-8):1; in the exemplary embodiment, the molar ratio of the organic base to the compound III can be 4:1, 5:1, 6:1, 7:1 or 8:1; the molar ratio of the organic base to the compound III is preferably (5-7):1, and further preferably 6:1.

[0013] Preferably, the volume mass ratio of the solvent to the compound III is 15-30 mL / g; in the exemplary embodiment, the volume mass ratio of the solvent to the compound III can be 15 mL / g, 16 mL / g, 18 mL / g, 20 mL / g, 22 mL / g, 25 mL / g, 28 mL / g, 30 mL / g; the volume mass ratio of the solvent to the compound III is preferably 15-25 mL / g, further preferably 20 mL / g.

[0014] Preferably, the solvent is a mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide, and the volume ratio of dimethyl sulfoxide to N,N-dimethylformamide is (6-10):1; in the exemplary embodiment, the volume ratio of dimethyl sulfoxide to N,N-dimethylformamide can be 6:1, 7:1, 8:1, 9:1 or 10:1.

[0015] Preferably, the molar ratio of the n-butyl cyclic phosphoric anhydride to the compound III is (1.2-2):1; in the exemplary embodiment, the molar ratio of the n-butyl cyclic phosphoric anhydride to the compound III can be 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or 2:1; the molar ratio of the n-butyl cyclic phosphoric anhydride to the compound III is preferably (1.5-1.8):1, and more preferably 1.6:1.

[0016] Preferably, the molar ratio of the compound II to the compound III is (1-2):1; in the exemplary embodiment, the molar ratio of the compound II to the compound III can be 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or 2:1; the molar ratio of the compound II to the compound III is preferably (1.5-1.8):1, and more preferably 1.6:1.

[0017] Preferably, the reaction temperature is 10-50°C, more preferably 15-25°C; the reaction time is 1-3h.

[0018] During the experiment, the inventor unexpectedly discovered that the above-mentioned preparation method can significantly improve the yield of the target product by adopting a specific order of addition. When the reaction is carried out in the order of "adding compound III and n-butyl cyclophosphoric acid to a solvent containing an organic base in sequence, stirring for one hour, and then adding compound II", it is found that the residual amount of compound III in the reaction product is large, and the yield of the target compound I is low. When the reaction is carried out in the order of "adding compound III and compound II to a solvent containing an organic base in sequence, stirring for one hour, and then adding n-butyl cyclophosphoric acid", there is still a large residual amount of compound III in the reaction product, and the yield of the target product is low. When the reaction is carried out in the order of "adding compound III, n-butyl cyclophosphoric anhydride, and compound II to a solvent containing an organic base in sequence", the residual amount of compound III in the reaction product is low, and the yield of the target product is significantly improved.

[0019] The preparation method of the present invention further includes a post-treatment process, which is specifically performed as follows: the reaction solution obtained by the above preparation method is added dropwise to an acetonitrile solvent at 10-20° C., wherein the volume ratio of the acetonitrile solvent to the solvent in the reaction solution is (2-5):1, stirred for 2-4 hours, filtered, the filter cake is washed with ethyl acetate, and vacuum dried.

[0020] Compared with the prior art, the present invention has the following beneficial effects: the preparation method of the fluorescence-magnetic resonance dual-modality contrast agent provided by the present invention is simple, has the characteristics of high yield and high purity, and can meet the needs of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the HPLC detection spectrum of the reaction product in Example 1.

[0022] Figure 2 This is the HPLC detection spectrum of the reaction product of Comparative Example 3. DETAILED DESCRIPTION

[0023] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0024] HPLC detection method for target compound I: flow rate 1.5 mL / min, injection volume 10 μL, detection wavelength 254 nm, chromatographic column Waters Cortecs C18, 4.6 mm×150 mm, 2.7 um, eluent A is 60 mM ammonium acetate, eluent B is acetonitrile: methanol = 1:1, diluent is methanol, and the mobile phase gradient is as follows:

[0025]

[0026] Example 1

[0027] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.17g, and the yield is 95.87%.

[0028] Example 2

[0029] Under nitrogen protection, add 67.5mL of dimethyl sulfoxide, 8.4mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 220mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.12g, and the yield is 94.72%.

[0030] Example 3

[0031] Under nitrogen protection, add 34.5mL of dimethyl sulfoxide, 4.3mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the obtained mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 120mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.06g, and the yield is 93.34%.

[0032] Example 4

[0033] Under nitrogen protection, add 56mL of dimethyl sulfoxide, 7mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 190mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.15g, and the yield is 95.41%.

[0034] Example 5

[0035] Under nitrogen protection, add 43mL of dimethyl sulfoxide, 7mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.16g, and the yield is 95.64%.

[0036] Example 6

[0037] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 4.5mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. HPLC detection and calculation show that the target compound I is 4.04g with a yield of 92.88%.

[0038] Example 7

[0039] Under nitrogen protection, add 50mL of dimethyl sulfoxide and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 3.76g, and the yield is 86.45%.

[0040] Example 8

[0041] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 1.94g of 4-dimethylaminopyridine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 3.96g, and the yield is 91.04%.

[0042] Example 9

[0043] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 1.61g of N-methylmorpholine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 3.98g, and the yield is 91.50%.

[0044] Example 10

[0045] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 2.30g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.01g, and the yield is 92.19%.

[0046] Embodiment 11

[0047] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.83g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution, and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20°C. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.08g, and the yield is 93.80%.

[0048] Example 12

[0049] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.71g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution, and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20°C. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.02g, and the yield is 92.42%.

[0050] Example 13

[0051] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 1.40g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 3.95g, and the yield is 90.81%.

[0052] Embodiment 14

[0053] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.60g of compound II to the mixed solution in sequence, and keep warm for 3h at 10°C. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 4.10g, and the yield is 94.26%.

[0054] Embodiment 15

[0055] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 2.15g of compound II to the mixed solution in sequence, and keep warm at 55°C for 1h. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 3.92g, and the yield is 90.13%.

[0056] Comparative Example 1

[0057] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.41g of DBU to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution, and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20°C. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 3.60g, and the yield is 82.77%.

[0058] Comparative Example 2

[0059] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 1.56g of 1-methylpiperidine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III, 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution and 3.00g of compound II to the mixed solution in sequence, and keep warm for 2h at 20℃. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20℃. After the addition is completed, continue to keep warm and stir for 2-4h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 3.53g, and the yield is 81.16%.

[0060] Comparative Example 3

[0061] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III and 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution to the mixed solution in sequence, stir for one hour, then add 3.00g of compound II, and keep warm at 20°C for 2h. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 2.30g, and the yield is 52.88%.

[0062] Comparative Example 4

[0063] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, and 2.04g of N,N-diisopropylethylamine to the reaction bottle to obtain a mixed solution. Add 2.52g of compound III and 3.00g of compound II to the mixed solution, stir for one hour, and then add 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution, and keep warm at 20°C for 2h. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 2.93g, and the yield is 67.36%.

[0064] Comparative Example 5

[0065] Under nitrogen protection, add 45mL of dimethyl sulfoxide, 5.6mL of N,N-dimethylformamide, 2.41g of DBU, 2.52g of compound III, and 3.00g of compound II to the reaction bottle, stir at 20°C until dissolved, add 3.04g of 50wt% n-butyl cyclophosphoric anhydride-ethyl acetate solution, and keep warm for 2h. After the reaction is completed, add the reaction solution dropwise to 150mL of acetonitrile at a temperature of 10-20°C. After the addition is completed, continue to keep warm and stir for 2-4h, filter, wash the filter cake with ethyl acetate, and dry in vacuum. According to HPLC detection and calculation, the target compound I is 2.36g, and the yield is 54.26%.

[0066] Comparative Example 6

[0067] Under nitrogen protection, 45 mL of dimethyl sulfoxide, 5.6 mL of N,N-dimethylformamide, and 2.04 g of N,N-diisopropylethylamine were added to the reaction bottle to obtain a mixed solution. 2.52 g of compound III and 3.00 g of compound II were added to the mixed solution in sequence, and the mixture was kept warm for 2 h at 20°C. HPLC detection showed that no target compound I was generated.

[0068] The HPLC test results of the reaction products of Examples 1-15 and Comparative Examples 1-5 are shown in Table 1:

[0069] Table 1

[0070]

Claims

1. A method for preparing a fluorescence-magnetic resonance dual-modality contrast agent, characterized in that: The method comprises the following steps: in an inert gas atmosphere, using n-butyl cyclophosphoric anhydride as a condensation agent, in a solvent system containing an organic base, subjecting compound II and compound III to a condensation reaction to obtain a target compound I; Wherein, the structure of the fluorescence-magnetic resonance dual-modality contrast agent is shown in Formula I, and the reaction formula of the preparation method is as follows:

2. The preparation method according to claim 1, characterized in that: The organic base is one or more of N-methylmorpholine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylmethylamine, and N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

3. The preparation method according to claim 1, characterized in that: The volume mass ratio of the solvent to the compound III is 15-30 mL / g; the solvent is one or more of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide.

4. The preparation method according to claim 3, characterized in that: The solvent is a mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide, wherein the volume ratio of the two solvents is (6-10):

1.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the organic base to the compound III is (4-8):

1.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the n-butyl cyclophosphoric anhydride to the compound III is (1.2-2):

1.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the compound II to the compound III is (1-2):

1.

8. The preparation method according to claim 1, characterized in that: The reaction adding sequence is as follows: Compound III, n-butyl cyclophosphoric anhydride and Compound II are added into a solvent containing an organic base to react.

9. The preparation method according to claim 1, characterized in that: The reaction temperature is 10-50°C; the reaction time is 1-3h.

10. The preparation method according to claim 1, characterized in that: The method further comprises post-treatment, which is specifically as follows: adding the reaction solution dropwise into acetonitrile solvent at 10-20° C., wherein the volume ratio of the acetonitrile solvent to the solvent in the reaction solution is (2-5):1, stirring for 2-4 hours, filtering with suction, washing the filter cake with ethyl acetate, and vacuum drying.

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