Fluorinated monosaccharide derivatives, methods for their synthesis and use thereof

Abstract

The application discloses a fluorinated monosaccharide derivative and a synthesis method and application thereof. The fluorinated monosaccharide derivative is composed of three parts, the first part is a 1-substituted monosaccharide group, the second part is a fluorine signal source perfluoro-t-butyl ether group, and the third part is a triazole ring connecting the two. The fluorinated monosaccharide derivative of the application retains the 2-hydroxyl and 6-hydroxyl of the monosaccharide, thereby not affecting the recognition of the monosaccharide in the body, and having good water solubility and biocompatibility. The derivative contains nine magnetically equivalent fluorine-19, can produce a single and strong fluorine signal, and avoids problems such as fluorine signal splitting or low fluorine atom utilization. The fluorine signal strength has a good linear relationship with the concentration of the compound, which provides a basis for in vivo quantification 19 F MRI. 19 F MRI imaging of HepG2 cells has the potential to be used as a tumor selective 19 F MRI contrast agent.

Description

Technical Field

[0001] This invention belongs to the field of magnetic resonance contrast agent technology, specifically relating to a method for synthesizing a fluorinated monosaccharide derivative and its application in tumor-selective magnetic resonance imaging. Background Technology

[0002] Cancer is one of the leading causes of death worldwide, and early, accurate diagnosis is crucial for improving patient survival rates. As an important diagnostic technology, magnetic resonance imaging (MRI) offers advantages such as no ionizing radiation and high soft tissue contrast. Among these, fluorine-19 (… 19 F) is the signal source 19 fMRI has no background signal interference because 19 F is mainly found in bones and teeth in the human body. Its transverse relaxation time is very short, and its signal cannot be detected. It has the potential to become a traditional [signature / product / method]. 1 Complementary new techniques for hMRI enable precise imaging of tumors. However, 19 The applicability of fMRI is currently limited by the detection sensitivity of MRI technology and the need for high local concentrations of fluoride. Therefore, the design of highly fluorinated probes is a hot topic in current fluoride chemistry research. It is worth noting that... 19 F is a stable, naturally occurring isotope. 19 fMRI is a "longer-lived" tracing technique used for 19 F-labeled targets, such as drugs, nanoparticles, cells, and biomolecules, often have long half-lives. Meanwhile, to avoid... 19 fMRI chemical shift artifacts, improve 19 fMRI sensitivity and interatomic hydrophobic interactions lead to high sensitivity. 19 fMRI, during fluoride modification, it is necessary to maintain as much as possible... 19 F is in an isostatic chemical environment to provide a more uniform environment. 19 F signal. Compared to PET technology, 19 fMRI has significant advantages as being non-invasive and radiation-free, and 19 F derivatives generally have good in vitro stability and do not require special storage, thus avoiding the drawbacks of PET radiopharmaceuticals.

[0003] Research has found that tumor cells exhibit metabolic changes different from normal cells, a phenomenon known as metabolic reprogramming. Tumor cell metabolic reprogramming is an important cancer marker, playing a crucial role in the growth of malignant tumors and treatment resistance, with the Warburg effect being the most classic example. The Warburg effect refers to the enhanced glucose uptake by tumor cells regardless of oxygen availability and mitochondrial efficiency. Glucose is subsequently converted to lactate via glycolysis, while oxidative phosphorylation is accelerated, hence also known as "aerobic phosphorylation" in tumor cells. Tumor cells can adapt to altered metabolic environments by switching between glycolysis and oxidative phosphorylation (OXPHOS). Cancer cells preferentially utilize glycolysis as the primary energy source for ATP production, promoting cancer cell growth, survival, proliferation, and long-term maintenance. Glycolysis, as the main pathway of anaerobic respiration, is less efficient than aerobic respiration in normal cells, while rapid cell growth demands higher energy levels than normal cells. Therefore, some key proteins involved in this disruptive metabolism, such as glucose transporter (GLUT), hexokinase-2 (HK2), and phosphoglycerate dehydrogenase (PHGDH), are overexpressed in cancer cells and have been identified as potential targets. Numerous studies have reported on the design of conjugations between carbohydrate molecules and chromogenic groups or anticancer drugs to achieve targeted imaging or targeted therapy. Currently, monosaccharides such as glucose and galactose are commonly used active target glycosyl ligands, which have advantages such as good biocompatibility, stability, and low toxicity. Taking glucose as an example: as a hydrophilic molecule, glucose must be transported and modified by specific proteins in the cell. The glucose transporter (GLUT) protein family is overexpressed in tumor cells; therefore, using glucose as a target molecule to specifically target the overexpressed GLUT in cancer cells can better target and localize cancer cells (Gatenby, RA; Gillies, RJ Nature Reviews Cancer, 2004, 4, 891).

[0004] Numerous diagnostic drugs based on the Wagburg effect have been developed, including fluorodeoxyglucose (FDEG). 18 F-FDG is the most representative example, and its mechanism of action is based on the overexpression of GLUT in tumor cells. Through this process, tumor cells can access excessive glucose saline, while also... 18 Excessive uptake of F-FDG into tumor cells leads to its accumulation in tumor tissue. In positron emission tomography (PET) imaging, this process is used to detect fluorocarbons. 18F-FDG is already a widely used commercial PET radiopharmaceutical in clinical practice. However, its drawbacks are also quite obvious. The radioactive element damage from PET testing is unavoidable, and due to the radioactivity of the drug itself, 18 F-FDG requires special handling for storage and transportation.

[0005] Based on the targeting properties of monosaccharides in tumors and 19 fMRI offers two major advantages, and the coupling of fluorinated monomers and monosaccharides holds promise for overcoming [the challenges of] [the limitations ... 19 MRI contrast agents have many drawbacks. Fluorinated sugar derivatives are favored due to the advantages of strong hydrophilicity, high biocompatibility, and low cost and availability of carbohydrate compounds. 19 It has great application potential in 1F magnetic resonance imaging. Previous literature reports a fluorinated polymer with monosaccharides as tumor-targeting groups, which can be used as a reduction-responsive... 19 fluorinated sugar contrast agents are used in MRI to achieve targeted imaging of tumors (Fu, C.; Tang, J.; Pye, A. et al., Biomacromolecules, 2019, 20, 2043). However, these fluorinated sugar contrast agents are polymers, which are cumbersome to synthesize and purify, have poor reproducibility, and have low fluorine content. 19 F-magnetic resonance imaging has drawbacks such as low sensitivity. Summary of the Invention

[0006] Based on the aforementioned prior art, this invention provides a fluorinated monosaccharide derivative, its synthesis method, and its applications. This invention uses a carbohydrate compound as a targeting functional molecule, which is also a hydrophilic group; and a fluorinated compound as a labeling molecule, which is also a lipophilic group. The two parts are rationally coupled, thereby enabling the target compound to possess both water solubility and lipophilicity. This allows for highly selective and sensitive targeting of tumor cells in vivo. 19 fMRI imaging.

[0007] The technical solution adopted to achieve the above-mentioned objectives of this invention is as follows:

[0008] A fluorinated monosaccharide derivative, comprising three parts: a first part being a monosaccharide group substituted at the 1-position, a second part being a perfluorotert-butanol group (a fluorine signal source), and a third part being a triazole ring group connecting the two. Its general structural formula is as follows:

[0009]

[0010] Among them, monosaccharides are all aldoses that are normally exposed and functioning at position 1, n is an integer between 1 and 20, and F is fluorine-19.

[0011] Furthermore, the monosaccharide is glucose, galactose, mannose, fucose, rhamnose, arabinose, or ribose.

[0012] A method for synthesizing a fluorinated monosaccharide derivative includes the following steps:

[0013] S1. Under the condition of the presence of an acid-binding agent, n-butyninol undergoes a sulfonation reaction with p-toluenesulfonyl chloride to generate butynyl p-toluenesulfonate, and the reaction formula is as follows:

[0014]

[0015] S2, butynyl p-toluenesulfonate, undergoes a nucleophilic substitution reaction with potassium perfluorotert-butoxide to generate butynyl perfluorotert-butyl ether, as shown in the following reaction formula:

[0016]

[0017] S3. Under the presence of a catalyst and a reducing agent, compound (I) undergoes a click reaction with butynyl perfluorotert-butyl ether to generate compound (II), the reaction formula of which is as follows: (The synthesis of compound (I) has been reported in the literature, Kumar R, Maulik PR, Misra AK. [J]. Glycoconjugate journal, 2008, 25, 595)

[0018]

[0019] S4. Under alkaline conditions, the compound of formula (II) loses its acetyl group to generate the fluorinated monosaccharide derivative, as shown in the following reaction formula:

[0020]

[0021] Furthermore, the fucoidant is triethylamine or N,N-diisopropylethylamine.

[0022] Furthermore, the sulfonation reaction is carried out at room temperature, and the molar ratio of n-butyninol, p-toluenesulfonyl chloride and fusible acid agent is 1.0:1.0-1.5:2.0-3.0.

[0023] Furthermore, the affinity substitution reaction is carried out at a temperature of 70°C, and the molar ratio of butynyl p-toluenesulfonate to perfluorotert-butoxide potassium is 1.0:1.0-1.5.

[0024] Furthermore, the catalyst is copper sulfate pentahydrate, the reducing agent is sodium ascorbate, and the reaction solvent is a mixed solvent of tetrahydrofuran / water = 6.0-1.0 / 1.0 (volume ratio).

[0025] Furthermore, the click reaction is carried out under nitrogen protection and at room temperature, and the molar ratio of butynyl perfluorotert-butyl ether, compound (I), catalyst B and reducing agent is 1.0:1.0-1.5:0.25:0.5.

[0026] Furthermore, the alkali used in the alkaline conditions is sodium methoxide, and the deacetylation reaction is carried out at room temperature.

[0027] Application of a fluorinated monosaccharide derivative in the preparation of fluorine-19 contrast agents.

[0028] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0029] 1. The fluorinated monosaccharide derivatives of this invention retain the chemical structure of key sites in monosaccharide metabolism and are stably linked to the fluorine-19 signal source. Specifically, the active sites of pyranose monosaccharides are mainly the hydroxyl groups at positions 2 and 6, which play a crucial role in the recognition of monosaccharides by specific proteases during in vivo metabolism. The monosaccharide derivatives of this invention retain the hydroxyl groups at positions 2 and 6, while the hydroxyl group at position 1 can be rationally modified to act as a hydrogen bond acceptor, thus not affecting the recognition and metabolism of monosaccharides in vivo. Furthermore, the fluorinated monosaccharide derivatives synthesized in this invention use a triazole ring to connect the two functional parts. The triazole ring can act as both a hydrogen bond donor and acceptor, without affecting the normal biological recognition of monosaccharides in vivo. At the same time, the triazole ring has good biocompatibility, which is beneficial for the downstream applications of this type of derivative.

[0030] 2. The fluorinated monosaccharide derivative of the present invention contains nine magnetically equivalent fluorine-19 atoms, which can generate a single and strong fluorine signal, avoiding problems such as fluorine signal splitting or low fluorine atom utilization.

[0031] 3. The fluorinated monosaccharide derivative of the present invention has good biocompatibility, which provides a guarantee for the safety of high-dose fluorine-19 magnetic resonance imaging in vivo.

[0032] 4. The fluorinated monosaccharide derivatives of this invention have good water solubility, overcoming the problem of poor water solubility and the need for formulation administration of most fluorinated compounds. This series of monosaccharide derivatives can be directly dissolved in PBS or physiological saline and injected intravenously into the diagnostic subject to achieve fluorine-19 magnetic resonance imaging of tumor sites, which is convenient to use.

[0033] 5. Within the molecular concentration range of 8 mM to 0.25 mM, the fluorine signal of the fluorinated monosaccharide derivative of the present invention exhibits a good linear relationship with its concentration (R0). 2 =0.9999), this linear relationship is beneficial for quantitative monitoring of the distribution of this monosaccharide derivative in vivo.

[0034] 6. The fluorinated monosaccharide derivative of the present invention has a fluorine atom content of 35% by weight, which is difficult for large molecule drugs to achieve. Moreover, the small molecules are more easily metabolized, avoiding the contrast agent from staying in the body for too long and affecting the next imaging result, and reducing side effects.

[0035] 7. The synthetic route of this invention is reasonable, the reaction conditions are relatively mild, and most reactions are carried out at room temperature, which reduces the impact on the structure of the hexaglycol. Attached Figure Description

[0036] Figure 1 The image shows the fluorine-19 magnetic resonance spectrum of the fluorinated monosaccharide derivative of this invention.

[0037] The abbreviations for fluorinated glucose derivatives are F-Glc, fluorinated galactose derivatives are F-Gal, fluorinated mannose derivatives are F-Man, fluorinated fucose derivatives are F-Fuc, fluorinated rhamnose derivatives are F-Rha, fluorinated ribose derivatives are F-Rib, and fluorinated arabinose derivatives are F-Ara.

[0038] Figure 2 In vitro fluorine-19 density-weighted magnetic resonance imaging of the fluorinated glucose derivative (F-Glc) and fluorinated galactose derivative (F-Gal) at different fluorine concentrations, according to the present invention.

[0039] Figure 3 The graph shows the relationship between fluorine concentration and fluorine signal intensity for the fluorinated glucose derivative (F-Glc) and fluorinated galactose derivative (F-Gal) of this invention.

[0040] Figure 4 In vitro human liver tumor cells containing the fluorinated glucose derivative (F-Glc) and fluorinated galactose derivative (F-Gal) of the present invention 19 FMR imaging effect diagram. Detailed Implementation

[0041] The present invention will now be described in detail with reference to specific embodiments.

[0042] Example 1

[0043] 1. Synthesis of Butynyl p-Toluenesulfonate

[0044]

[0045] Butynol (5.10 g, 72.8 mmol) and 20 mL of dry dichloromethane (DCM) were added to a reaction flask. The flask was placed at 0 °C, and p-toluenesulfonyl chloride (TsCl) (14.15 g, 74.2 mmol) and triethylamine (Et3N) (14.75 g, 145.1 mmol) were added. The mixture was then kept at room temperature and stirred for 24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was quenched with saturated NH4Cl solution. The resulting mixture was extracted with dichloromethane (DCM), and the liquid was separated. The organic phase was washed three times successively with saturated NaHCO3 solution and saturated saline solution, dried, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give 15.32 g of a pale yellow transparent liquid (butynyl p-toluenesulfonate), with a yield of 93.9%.

[0046] 1 H NMR (400MHz, Chloroform-d) δ7.74(dd,J=8.4,2.0Hz,2H),7.31(d,J=8.1Hz,2H),4.07–4.02(m,2H),2.53–2.47(m,2H),2.39(s,3H),1.95(t,J=2.7Hz,1H).

[0047] 2. Synthesis of Butynyl Perfluorotert-Butyl Ether

[0048]

[0049] Potassium perfluorotert-butoxide (6.03 g, 24 mmol) and 8 mL of dimethyl sulfoxide (DMSO) were added to a sealing tube, followed by butynyl p-toluenesulfonate (4.48 g, 20 mmol). The reaction was carried out at 70 °C for 12 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the resulting mixture was poured into 100 mL of ice water, and a brownish-red lower layer precipitated. This lower layer was separated to obtain a brownish-red liquid. The brownish-red liquid was repeatedly washed with water and centrifuged to obtain 3.86 g of relatively pure crude product, with a yield of 67.1%. The crude product was then redistilled at 110 °C to obtain a transparent, colorless liquid (butynyl perfluorotert-butyl ether).

[0050] 1 H NMR (400MHz, Chloroform-d) δ4.15–4.07(m,2H),2.58(td,J=7.0,2.7Hz,2H),2.02(t,J=2.7Hz,1H). 19 F NMR(471MHz,Chloroform-d)δ-73.49(s).

[0051] 13C NMR (101MHz, Chloroform-d) δ120.4 (q, J = 292.8Hz), 80.4-79.5 (m), 78.6, 70.5, 67.6, 20.2.

[0052]

[0053] Synthesis of 3,5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-glucose-1,2,3-triazole

[0054] 1-Azide-pentaacetyl-D-α-glucose (synthesis method: Kumar R, Maulik PR, Misra A K. [J]. Glycoconjugate journal, 2008, 25, 595) (373 mg, 1.0 mmol) was weighed into a single-necked flask after purging with argon gas and completely dissolved in 12 mL of THF. Then, butynyl perfluorotert-butyl ether (375 mg, 1.3 mmol) was added. Anhydrous CuSO4 (40 mg, 0.25 mmol) and sodium ascorbate (99 mg, 0.5 mmol) were weighed into two EP tubes, dissolved in 1 mL of water respectively, and then injected into the single-necked flasks one after the other. The reaction was then carried out at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the THF in the resulting mixture was evaporated to dryness, and the residue was extracted with dichloromethane (DCM). The organic phase was first washed three times with saturated EDTA, then washed three times with saturated saline solution, and then dried with anhydrous Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 430 mg of white solid (5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl D-α-glucose-1,2,3-triazole), yield 65%.

[0055] 1 H NMR(500MHz,Chloroform-d)δ7.60(s,1H),5.85(dd,J=7.1,2.0Hz,1H),5.45–5.34(m,2H),5.28–5.16(m,1H),4.33–4.21(m, 3H), 4.13(dd,J=12.6,1.8Hz,1H),4.02–3.95(m,1H),3.10(t,J=6.3Hz,2H),2.04(d,J=1.8Hz,6H),2.01(s,3H),1.84(s,3H).

[0056] 19 F NMR(471MHz,Chloroform-d)δ-73.49(s).

[0057] 13 C NMR(101MHz,Chloroform-d)δ170.5,170.0,169.4,168.9,143.9,120.5,120.3(q,J=293.5H z),85.7,80.2-79.0(m),75.0,72.7,70.3,69.8,68.4,67.7,61.5,26.6,20.57,20.55,20.1.

[0058] HRMS-ESI m / z:[M+H] + calcd for C 22 H 24 F9N3O 10 684.1210, found 684.1201.

[0059]

[0060] 4. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-glucose-1,2,3-triazole

[0061] 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-glucose-1,2,3-triazole (132 mg, 0.2 mmol) was dissolved in 5 mL of anhydrous methanol, followed by the addition of anhydrous sodium methoxide (MeONa) (5.4 mg, 0.1 mmol). The mixture was stirred at room temperature for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, Amberlyst 15(H) cation exchange resin was immersed in the mixture. The reaction endpoint was determined by the change in pH of the solution. The endpoint was reached when the pH of the solution returned to neutral. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 72 mg of pale yellow solid (5-[(perfluorotert-butoxy)ethyl]-3-D-α-glucose-1,2,3-triazole), with a yield of 73%.

[0062] The structural formula of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-glucose-1,2,3-triazole (F-Glc) is as follows:

[0063]

[0064] 1H NMR (500MHz, Acetone-d6) δ7.98 (s, 1H), 5.62 (d, J = 9.0Hz, 1H), 4.66 (d, J = 4.2Hz, 1H), 4.62 (d, J = 5.1Hz, 1H), 4.48 (d, J = 4.5Hz, 1H), 4.39 (t, J = 7. 2Hz, 2H), 3.95 (d, J = 5.3Hz, 1H), 3.88–3.82 (m, 1H), 3.79 (t, J = 6.1Hz, 1H), 3.73–3.59 (m, 3H), 3.56 (dd, J = 9.2, 4.3Hz, 1H), 3.15 (t, J = 7.1Hz, 2H).

[0065] 19 F NMR(376MHz,Acetone-d6)δ-71.39(s).

[0066] 13 C NMR (126MHz, Acetone-d6) δ143.0, 122.4, 121.3 (q, J = 293.4Hz), 88.8, 81.3–80.1 (m), 80.9, 78.5, 73.7, 71.0, 70.1, 62.4, 27.1.

[0067] HRMS-ESI m / z:[M+Na] + calcd for C 14 H 16 F9N3O6 516.0787, found 516.0781.

[0068] Example 2

[0069] 1. The synthesis of butynyl p-toluenesulfonate and butynyl perfluorotert-butyl ether is exactly the same as in Example 1, and will not be repeated here.

[0070] 2. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-galactose-1,2,3-triazole

[0071] 1-Azide-pentaacetyl-D-α-galactose (synthesis method: Kumar R, Maulik PR, Misra A K. [J]. Glycoconjugate journal, 2008, 25, 595) (373 mg, 1.0 mmol) was weighed into a single-necked flask after purging with argon gas and completely dissolved in 12 mL of THF. Then, butynyl perfluorotert-butyl ether (375 mg, 1.3 mmol) was added. Anhydrous CuSO4 (40 mg, 0.25 mmol) and sodium ascorbate (99 mg, 0.5 mmol) were weighed into two EP tubes, dissolved in 1 mL of water respectively, and then injected into the single-necked flasks one after the other. The reaction was then carried out at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the THF in the mixture was evaporated to dryness, and the residue was extracted with dichloromethane (DCM). The organic phase was first washed three times with saturated EDTA, then washed three times with saturated saline solution, and then dried with anhydrous Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 265 mg of a clear, colorless, viscous liquid (5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-galactose-1,2,3-triazole) in 40% yield.

[0072] 1 H NMR(500MHz,Chloroform-d)δ7.64(s,1H),5.81(d,J=9.3Hz,1H),5.53–5.46(m,2H),5.22(dd,J=10.3,3.4Hz,1H) ,4.30–4.20(m,3H),4.16–4.02(m,2H),3.08(t,J=6.3Hz,2H),2.15(s,3H),1.98(s,3H),1.95(s,3H),1.83(s,3H).

[0073] 19 F NMR(471MHz,Chloroform-d)δ-73.34(s).

[0074] 13 C NMR(101MHz,Chloroform-d)δ170.4,170.04,169.95,169.0,143.9,120.7,120.3(q,J=293.3 Hz),91.7,86.2,80.8–78.8(m),73.9,70.9,68.5,67.9,67.0,61.3,26.6,20.64,20.57,20.2.

[0075] HRMS-ESI m / z:[M+H]+ calcd for C 22 H 24 F9N3O 10 684.1210, found 684.1200.

[0076]

[0077] 3. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-galactose-1,2,3-triazole (F-Gal)

[0078] 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-galactose-1,2,3-triazole (132 mg, 0.2 mmol) was dissolved in 5 mL of anhydrous methanol, and anhydrous sodium methoxide (MeONa) (5.4 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, Amberlyst 15(H) cation exchange resin was immersed in the mixture. The reaction endpoint was determined by the change in pH of the solution. The endpoint was reached when the pH of the solution returned to neutral. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 73 mg of a pale yellow oily liquid (5-[(perfluorotert-butoxy)ethyl]-3-D-α-glucose-1,2,3-triazole), with a yield of 74%.

[0079] The structural formula of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-galactose-1,2,3-triazole is as follows:

[0080]

[0081] 1 H NMR (500MHz, Acetone-d6) δ7.98(s,1H),5.58(d,J=9.2Hz,1H),4.39(t,J=7.1Hz,2H),4.25(t,J=9.2Hz,1H ), 4.08 (d, J = 3.3Hz, 1H), 3.88 (t, J = 6.0Hz, 1H), 3.77 (ddd, J = 17.6, 9.5, 4.8Hz, 3H), 3.14 (t, J = 7.1Hz, 2H).

[0082] 19 F NMR(376MHz,Acetone-d6)δ-71.43(s).

[0083] 13C NMR (126MHz, Acetone-d6) δ142.1, 121.4, 120.4 (q, J = 292.1Hz), 88.4, 80.4-79.3 (m), 78.2, 74.2, 70.2, 69.2, 69.0, 61.1, 26.2.

[0084] HRMS-ESI m / z:[M+Na] + calcd for C 14 H 16 F9N3O6 516.0787, found 516.0781.

[0085] Example 3

[0086] 1. The synthesis of butynyl p-toluenesulfonate and butynyl perfluorotert-butyl ether is exactly the same as in Example 1, and will not be repeated here.

[0087] 2. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-β-mannose-1,2,3-triazole

[0088] 1-Azide-pentaacetyl-D-β-mannose (synthesis method: Kumar R, Maulik PR, Misra A K. [J]. Glycoconjugate journal, 2008, 25, 595) (373 mg, 1.0 mmol) was weighed into a single-necked flask after purging with argon gas and completely dissolved in 12 mL of THF. Then, butynyl perfluorotert-butyl ether (375 mg, 1.3 mmol) was added. Anhydrous CuSO4 (40 mg, 0.25 mmol) and sodium ascorbate (99 mg, 0.5 mmol) were weighed into two EP tubes, dissolved in 1 mL of water respectively, and then injected into the single-necked flasks one after the other. The reaction was then carried out at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the THF in the mixture was evaporated to dryness, and the residue was extracted with dichloromethane (DCM). The organic phase was first washed three times with saturated EDTA, then washed three times with saturated saline solution, and then dried with anhydrous Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 271 mg of a clear, colorless, viscous liquid (5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-β-mannose-1,2,3-triazole) in 41% yield.

[0089] 1H NMR(500MHz,Chloroform-d)δ7.56(s,1H),5.98-5.93(m,2H),5.88(dd,J=9.0,3.6Hz,1H),5.34(t,J=9.0Hz,1H),4.35(dd,J=12.5,5.3Hz,1H),4.28(t,J =6.2Hz,2H),3.99(dd,J=12.5,2.6Hz,1H),3.80(ddd,J=9.1,5.3,2.6Hz,1H) ,3.14(t,J=6.3Hz,2H),2.15(s,3H),2.05(s,3H),2.03(s,3H),2.02(s,3H).

[0090] 19 F NMR(471MHz,Chloroform-d)δ-73.43(s).

[0091] 13 C NMR(101MHz,Chloroform-d)δ170.6,169.8,169.7,169.4,144.0,122.6,120.3(q,J=293.2 Hz),89.4,83.5,80.6-78.7(m),72.0,68.8,68.5,68.3,66.0,61.5,26.5,20.8,20.7,20.6.

[0092] HRMS-ESI m / z:[M+H] + calcd for C 22 H 24 F9N3O 10 ,684.1210; found,684.1202.

[0093]

[0094] 3. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-D-β-mannose-1,2,3-triazole (F-Man)

[0095] 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-β-mannose-1,2,3-triazole (132 mg, 0.2 mmol) was dissolved in 5 mL of anhydrous methanol, and anhydrous sodium methoxide (MeONa) (5.4 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, Amberlyst 15(H) cation exchange resin was immersed in the mixed product. The reaction endpoint was determined by the change in pH of the solution. The endpoint was reached when the pH of the solution returned to neutral. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 75 mg of a pale yellow oily liquid (5-[(perfluorotert-butoxy)ethyl]-3-D-β-mannose-1,2,3-triazole), with a yield of 75%.

[0096] The structural formula of 5-[(perfluorotert-butoxy)ethyl]-3-D-β-mannose-1,2,3-triazole is as follows:

[0097]

[0098] 1 H NMR (500MHz, Acetone-d6) δ7.98(s,1H),6.05(d,J=2.7Hz,1H),4.69(d,J=3.0Hz,1H),4.39(t,J=6.9Hz,2H),4.14(dd ,J=8.5,3.5Hz,1H),3.92(t,J=8.8Hz,1H),3.76(t,J=4.0Hz,2H),3.30(dt,J=8.4,3.8Hz,1H),3.16(t,J=6.6Hz,2H).

[0099] 19 F NMR(376MHz,Acetone-d6)δ-71.41(s).

[0100] 13 C NMR (126MHz, Acetone-d6) δ143.7, 123.7, 121.4 (q, J = 292.9Hz), 87.7, 81.4-80.2 (m), 77.8, 72.5, 70.3, 70.0, 68.4, 62.3, 27.2.

[0101] HRMS-ESI m / z:[M+Na] + calcd for C 14 H 16 F9N3O6,516.0787; found,516.0781.

[0102] Example 4

[0103] 1. The synthesis of butynyl p-toluenesulfonate and butynyl perfluorotert-butyl ether is exactly the same as in Example 1, and will not be repeated here.

[0104] 2. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-L-β-fucose-1,2,3-triazole

[0105] 1-Azide-pentaacetyl-L-β-fucose (synthesis method: Kumar R, Maulik PR, Misra A K. [J]. Glycoconjugate journal, 2008, 25, 595) (316 mg, 1.0 mmol) was weighed into a single-necked flask after purging with argon gas and completely dissolved in 12 mL of THF. Then, butynyl perfluorotert-butyl ether (375 mg, 1.3 mmol) was added. Anhydrous CuSO4 (40 mg, 0.25 mmol) and sodium ascorbate (99 mg, 0.5 mmol) were weighed into two EP tubes, dissolved in 1 mL of water respectively, and then injected into the single-necked flasks one after the other. The reaction was then carried out at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the THF in the mixture was evaporated to dryness, and the residue was extracted with dichloromethane DCM. The organic phase was first washed three times with saturated EDTA, then washed three times with saturated saline solution, and then dried with anhydrous Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 265 mg of a transparent, colorless, viscous liquid (5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-L-β-fucose-1,2,3-triazole) in 40% yield.

[0106] 1 H NMR(500MHz,Chloroform-d)δ7.61(s,1H),5.76(d,J=9.2Hz,1H),5.43(t,J=9.7Hz,1H),5.34-5.27(m,1H),5.19(dd,J=10.3,3.3H z,1H),4.31-4.14(m,2H),4.13-4.04(m,1H),3.04(t,J=6.4Hz,2H),2.12(s,3H),1.91(s,3H),1.78(s,3H),1.16(d,J=6.5Hz,3H).

[0107] 19 F NMR(471MHz,Chloroform-d)δ-73.25(s).

[0108] 13C NMR(101MHz,Chloroform-d)δ170.5,170.1,169.2,143.7,120.6,120.4(q,J=293.5Hz ),86.3,80.2-79.3(m),72.6,71.3,70.0,68.6,68.0,26.7,20.63,20.60,20.3,16.1.

[0109] HRMS-ESI m / z:[M+H] + calcd for C 20 H 22 F9N3O8,626.1155; found,626.1149.

[0110]

[0111] 3. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-L-β-fucose-1,2,3-triazole (F-Fuc)

[0112] 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-L-β-fucose-1,2,3-triazole (121 mg, 0.2 mmol) was dissolved in 5 mL of anhydrous methanol, and anhydrous sodium methoxide (MeONa) (5.4 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, Amberlyst 15(H) cation exchange resin was immersed in the mixture. The reaction endpoint was determined by the change in pH of the solution. The endpoint was reached when the pH of the solution returned to neutral. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 64 mg of a pale yellow oily liquid (5-[(perfluorotert-butoxy)ethyl]-3-L-β-fucose-1,2,3-triazole), with a yield of 67%.

[0113] The structural formula of 5-[(perfluorotert-butoxy)ethyl]-3-L-β-fucose-1,2,3-triazole is as follows:

[0114]

[0115] 1 H NMR (500MHz, Acetone-d6) δ7.95 (s, 1H), 5.54 (d, J = 9.1Hz, 1H), 4.38 (d, J = 7.4Hz, 2H), 4.20 (t, J = 9.3Hz, 1H), 3.99 (t, J = 6.7Hz, 1H), 3.78 (dd, J = 15.3, 6.6Hz, 22H), 3.13 (t, J = 7.2Hz, 2H), 1.27 (d, J = 6.6Hz, 3H).

[0116] 19 F NMR(376MHz,Acetone-d6)δ-71.41(s).

[0117] 13 C NMR (126MHz, Acetone-d6) δ143.0, 122.0, 121.3 (q, J = 293.0Hz), 89.2, 81.4-80.0 (m), 75.4, 74.4, 72.5, 70.9, 70.0, 27.2, 16.8.

[0118] HRMS-ESI m / z:[M+Na] + calcd for C 14 H 16 F9N3O5,500.0838; found,500.0831.

[0119] Example 5

[0120] 1. The synthesis of butynyl p-toluenesulfonate and butynyl perfluorotert-butyl ether is exactly the same as in Example 1, and will not be repeated here.

[0121] 2. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-L-α-rhamnose-1,2,3-triazole

[0122] 1-Azide-pentaacetyl-L-α-rhamnose (synthesis method: Kumar R, Maulik PR, Misra A K. [J]. Glycoconjugate journal, 2008, 25, 595) (316 mg, 1.0 mmol) was weighed into a single-necked flask after purging with argon gas and completely dissolved in 12 mL of THF. Then, butynyl perfluorotert-butyl ether (375 mg, 1.3 mmol) was added. Anhydrous CuSO4 (40 mg, 0.25 mmol) and sodium ascorbate (99 mg, 0.5 mmol) were weighed into two EP tubes, dissolved in 1 mL of water respectively, and then injected into the single-necked flasks one after the other. The reaction was then carried out at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the THF in the mixture was evaporated to dryness, and the residue was extracted with dichloromethane DCM. The organic phase was first washed three times with saturated EDTA, then washed three times with saturated saline solution, and then dried with anhydrous Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 199 mg of a transparent, colorless, viscous liquid (5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-L-α-rhamnose-1,2,3-triazole) in 33% yield.

[0123] 1 H NMR(500MHz,Chloroform-d)δ7.54(s,1H),5.94(dd,J=3.8,2.4Hz,1H),5.85(d,J=2.1Hz,1H),5.75(dd,J=9.3,3.8Hz,1H),5.09(t,J=9.2Hz,1H ),4.24(q,J=6.1Hz,2H),3.54(dq,J=9.1,6.3Hz,1H),3.09(td,J=6.3,2 .5Hz,2H),2.10(s,3H),1.97(s,3H),1.95(s,3H),1.14(d,J=6.3Hz,3H).

[0124] 19 F NMR(471MHz,Chloroform-d)δ-73.34(s).

[0125] 13 C NMR(101MHz,Chloroform-d)δ170.1,169.9,169.6,144.0,122.3,120.3(q,J=293.2H z),89.5,83.9,81.0-78.7(m),70.8,69.8,69.0,68.5,66.7,26.6,20.8,20.7,17.2.

[0126] HRMS-ESI m / z:[M+H] + calcd for C 20 H 22 F9N3O8,626.1155; found,626.1148.

[0127]

[0128] 3. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-L-α-rhamnose-1,2,3-triazole (F-Rha)

[0129] 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-L-α-rhamnose-1,2,3-triazole (121 mg, 0.2 mmol) was dissolved in 5 mL of anhydrous methanol, and anhydrous sodium methoxide (MeONa) (5.4 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, Amberlyst 15(H) cation exchange resin was immersed in the mixed product. The reaction endpoint was determined by the change in pH of the solution. The endpoint was reached when the pH of the solution returned to neutral. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 83 mg of a pale yellow oily liquid (5-[(perfluorotert-butoxy)ethyl]-3-L-α-rhamnose-1,2,3-triazole), with a yield of 88%.

[0130] The structural formula of 5-[(perfluorotert-butoxy)ethyl]-3-L-β-rhamnose-1,2,3-triazole is as follows:

[0131]

[0132] 1 H NMR (500MHz, Acetone-d6) δ7.95 (s, 1H), 5.98 (d, J = 2.2Hz, 1H), 4.68 (dd, J = 3.6, 2.1Hz, 1H), 4.40 (q, J = 7.4Hz, 3H),4.16-4.04(m,1H),3.58(t,J=8.8Hz,2H),3.34-3.25(m,1H),3.16(t,J=6.4Hz,3H),1.22(d,J=6.2Hz,3H).

[0133] 19 F NMR(376MHz,Acetone-d6)δ-71.43(s).

[0134] 13 C NMR (126MHz, Acetone-d6) δ143.7, 123.5, 121.3 (q, J = 291.9Hz), 87.6, 81.5-80.0 (m), 73.2, 72.5, 72.3, 70.2, 70.1, 27.0, 17.9.

[0135] HRMS-ESI m / z:[M+Na] + calcd for C 14 H 16 F9N3O5,500.0838; found,500.0830.

[0136] Example 6

[0137] 1. The synthesis of butynyl p-toluenesulfonate and butynyl perfluorotert-butyl ether is exactly the same as in Example 1, and will not be repeated here.

[0138] 2. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-ribose-1,2,3-triazole

[0139] 1-Azide-pentaacetyl D-α-ribose (synthesis method: Kumar R, Maulik PR, Misra AK. [J]. Glycoconjugate journal, 2008, 25, 595) (303 mg, 1.0 mmol) was weighed into a single-necked flask after purging with argon gas and completely dissolved in 12 mL of THF. Then, butynyl perfluorotert-butyl ether (375 mg, 1.3 mmol) was added. Anhydrous CuSO4 (40 mg, 0.25 mmol) and sodium ascorbate (99 mg, 0.5 mmol) were weighed into two EP tubes, dissolved in 1 mL of water respectively, and then injected into the single-necked flasks one after the other. The reaction was then carried out at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the THF in the mixture was evaporated to dryness, and the residue was extracted with dichloromethane (DCM). The organic phase was first washed three times with saturated EDTA, then washed three times with saturated saline solution, and then dried with anhydrous Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 247 mg of a clear, colorless, viscous liquid (5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-ribose-1,2,3-triazole) in 42% yield.

[0140] 1 H NMR(400MHz,Chloroform-d)δ7.54(s,0H),6.02(d,J=8.9Hz,0H),5.80(t,J=3.0Hz,0H),5.43-5.27(m,0H),5.19(ddd,J=10.5,5.6,2.9Hz ,0H),4.27(q,J=7.2Hz,1H),4.11-3.89(m,1H),3.11(t,J=6.3Hz,1H),2.21(d,J=1.1Hz,1H),2.05(d,J=1.2Hz,1H),1.86(d,J=1.1Hz,1H).

[0141] 19 F NMR(376MHz,Chloroform-d)δ-73.49(s).

[0142] 13C NMR(101MHz,Chloroform-d)δ169.8,169.5,168.9,143.8,121.1(q,J=292.7Hz), 118.9,89.9,83.6,80.2-79.3(m),68.5,68.0,65.8,63.8,26.7,20.8,20.7,20.2.

[0143] HRMS-ESI m / z:[M+H] + calcd for C 19 H 20 F9N3O8,612.0999; found,612.0992.

[0144]

[0145] 3. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-ribose-1,2,3-triazole (F-Rib)

[0146] 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-ribose-1,2,3-triazole (119 mg, 0.2 mmol) was dissolved in 5 mL of anhydrous methanol, and anhydrous sodium methoxide (MeONa) (5.4 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, Amberlyst 15(H) cation exchange resin was immersed in the mixture. The reaction endpoint was determined by the change in pH of the solution. The endpoint was reached when the pH of the solution returned to neutral. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 70 mg of a pale yellow oily liquid (5-[(perfluorotert-butoxy)ethyl]-3-D-α-ribose-1,2,3-triazole), with a yield of 76%.

[0147] The structural formula of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-ribose-1,2,3-triazole is as follows:

[0148]

[0149] 1H NMR (500MHz, Acetone-d6) δ7.95(s,1H),5.76(d,J=8.9Hz,1H),4.62(s,1H),4.39(t,J=7.0Hz,3H),4.28(d,J=3.0Hz,1 H),4.20-4.14(m,2H),3.95-3.84(m,1H),3.80(t,J=10.4Hz,1H),3.73(dd,J=10.8,5.3Hz,1H),3.13(d,J=6.9Hz,2H).

[0150] 19 F NMR(376MHz,Acetone-d6)δ-71.42(s).

[0151] 13 C NMR (126MHz, Acetone-d6) δ143.1, 122.5, 121.3 (q, J = 292.5Hz), 86.4, 81.4–80.0 (m), 72.0, 70.7, 70.1, 67.8, 66.4, 27.1.

[0152] HRMS-ESI m / z:[M+Na] + calcd for C 13 H 14 F9N3O5,486.0682; found,486.0676.

[0153] Example 7

[0154] 1. The synthesis of butynyl p-toluenesulfonate and butynyl perfluorotert-butyl ether is exactly the same as in Example 1, and will not be repeated here.

[0155] 2. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-arabinose-1,2,3-triazole

[0156] 1-Azide-pentaacetyl-D-α-arabinose (synthesis method: Kumar R, Maulik PR, Misra A K. [J]. Glycoconjugate journal, 2008, 25, 595) (303 mg, 1.0 mmol) was weighed into a single-necked flask after purging with argon gas and completely dissolved in 12 mL of THF. Then, butynyl perfluorotert-butyl ether (375 mg, 1.3 mmol) was added. Anhydrous CuSO4 (40 mg, 0.25 mmol) and sodium ascorbate (99 mg, 0.5 mmol) were weighed into two EP tubes, dissolved in 1 mL of water respectively, and then injected into the single-necked flasks one after the other. The reaction was then carried out at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the THF in the mixture was evaporated to dryness, and the residue was extracted with dichloromethane (DCM). The organic phase was first washed three times with saturated EDTA, then washed three times with saturated saline solution, and then dried with anhydrous Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 253 mg of a transparent, colorless, viscous liquid (5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-arabinose-1,2,3-triazole) in 43% yield.

[0157] 1 H NMR(400MHz,Chloroform-d)δ7.66(s,1H),5.73(d,J=9.1Hz,1H),5.57(dd,J=10.1,9.1Hz,1H),5.43–5.39(m,1H),5.23(dd,J=10.1,3.4Hz,1H ),4.32-4.22(m,2H),4.16(dd,J=13.4,2.1Hz,1H),3.93(dd,J=13.4,1.2Hz,1H),3.11(t,J=6.4Hz,2H),2.18(s,3H),2.01(s,3H),1.87(s,3H).

[0158] 19 F NMR(376MHz,Chloroform-d)δ-73.49(s).

[0159] 13 C NMR(101MHz,Chloroform-d)δ170.2,170.0,169.1,143.8,120.5,120.3(q,J=292 .9Hz),91.9,86.7,80.2-79.3(m),70.7,68.2,67.8,67.2,26.7,20.9,20.6,20.2.

[0160] HRMS-ESI m / z:[M+H] + calcd for C 19 H 20 F9N3O8,612.0999; found,612.0990.

[0161]

[0162] 3. Synthesis of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-arabinose-1,2,3-triazole (F-Ara)

[0163] 5-[(perfluorotert-butoxy)ethyl]-3-pentaacetyl-D-α-arabinose-1,2,3-triazole (119 mg, 0.2 mmol) was dissolved in 5 mL of anhydrous methanol, and anhydrous sodium methoxide (MeONa) (5.4 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, Amberlyst 15(H) cation exchange resin was immersed in the mixed product. The reaction endpoint was determined by the change in pH of the solution. The endpoint was reached when the pH of the solution returned to neutral. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 72 mg of a pale yellow oily liquid (5-[(perfluorotert-butoxy)ethyl]-3-D-α-arabinose-1,2,3-triazole), with a yield of 77%.

[0164] The structural formula of 5-[(perfluorotert-butoxy)ethyl]-3-Dα-arabinose-1,2,3-triazole is as follows:

[0165]

[0166] 1 H NMR (500MHz, Acetone-d6) δ7.98 (s, 1H), 5.51 (d, J = 9.0Hz, 1H), 4.32–4.22 (m, 2H ),4.02–3.98(m,2H),3.88(d,J=12.3Hz,1H),3.81(dd,J=9.0,3.5Hz,1H),3.18–

[0167] 3.08 (m, 2H).

[0168] 19 F NMR(376MHz,Acetone-d6)δ-71.42(s).

[0169] 13C NMR (126MHz, Acetone-d6) δ143.1, 130.4, 129.3, 122.1, 121.3 (q, J = 292.5Hz), 95.6, 89.6, 88.8, 81.5–79.6 (m), 74.8, 27.1.

[0170] HRMS-ESI m / z:[M+Na] + calcd for C 13 H 14 F9N3O5,486.0682; found,486.0676.

[0171] Experiment 1: The fluorinated monosaccharide derivative of the present invention 19 F NMR and relaxation time determination

[0172] Test method:

[0173] 1. Dissolve the fluorinated monosaccharide derivatives prepared in Examples 1-7 in 10% deuterated heavy aqueous solution (H2O / D2O = 9 / 1, volume ratio) to prepare samples with a concentration of 10 mM of fluorinated monosaccharide derivatives. Place each sample in a 5 mm NMR tube for analysis.

[0174] 2. First, proceed 19 F NMR signal acquisition (500MHz Bruker magnetic resonance spectrometer), followed by... 19 The longitudinal relaxation time T1 was determined using the inversion recovery method, and the transverse relaxation time T2 was determined using a CPMG pulse sequence. Three parallel tests were performed for T1 and T2, and the results shown are the average values.

[0175] Experimental results:

[0176] The T1 and T2 test results of the fluorinated monosaccharide derivatives prepared in Examples 1-7 are shown in Table 1 below:

[0177] Table 1. T1 and T2 test results of different fluorinated monosaccharide derivatives

[0178] F-Glc F-Gal F-Man F-Fuc F-Rha F-Rib F-Ara <![CDATA[T1(s)]]> 1.36 1.37 1.39 1.35 1.28 1.41 1.43 <![CDATA[T2(s)]]> 1.10 1.14 1.07 1.09 1.04 1.14 1.19

[0179] Experiment 2: In vitro testing of the fluorinated monosaccharide derivatives of the present invention 19 f MRI experiment

[0180] Test method:

[0181] 1. Using pure water as a solvent, prepare test solutions of 5-[(perfluorotert-butoxy)ethyl]-3-D-α-glucose-1,2,3-triazole (F-Glc) or 5-[(perfluorotert-butoxy)ethyl]-3-D-α-galactose-1,2,3-triazole (F-Gal) with fluoride concentrations of 72 mM, 36 mM, 18 mM, 9 mM, 4.5 mM and 2.25 mM, respectively.

[0182] 2. Transfer the test solution of each concentration to a 10 mm NMR sample tube. Place the NMR sample tube in a 400 M magnetic resonance imaging spectrometer (Bruker BioSpec MRI system) for tuning and shimming. Use the RARE sequence for imaging, repeat sampling 8 times, sampling matrix 32×32, scan time 4 min 16 s. The other sampling parameters are set as follows: acceleration factor RAREfactor = 4, repetition time TR = 4000.0 ms, echo time TE = 3.0 ms.

[0183] Experimental results:

[0184] In vitro test solutions with different fluoride concentrations 19 FMR imaging image as follows Figure 2 As shown, from Figure 2 It can be seen that even at a fluorine concentration as low as 2.2 mM, it is still possible to observe... 19 The fMRI image showed a significant fluorine signal.

[0185] Plotting fluoride concentration on the x-axis and fluoride signal intensity on the y-axis based on the detected data, and then fitting the plot to obtain a standard curve, as shown below. Figure 3 As shown, from Figure 3 It can be seen that within the fluorine concentration range of 2.2-72.0 mM, the fluorine concentration and the corresponding fluorine signal intensity exhibit a good linear relationship, R 2 =0.9999.

[0186] Experiment 3: In vitro testing of the fluorinated monosaccharide derivative of the present invention in living cells. 19 f MRI experiment

[0187] Test method:

[0188] 1. Using 10% FBS in DMEM medium as a solvent, prepare a drug-containing medium with a fluorine concentration of 2 mM for 5-[(perfluorotert-butoxy)ethyl]-3-D-α-glucose-1,2,3-triazole (F-Glc) or 5-[(perfluorotert-butoxy)ethyl]-3-D-α-galactose-1,2,3-triazole (F-Gal);

[0189] 2. Culture HepG2 human liver tumor cells in a 10cm cell culture dish. When the cells grow to about 90% of the total culture dish area (the cells are in the logarithmic growth phase), add 5mL of drug-containing medium to the culture medium and incubate at 37°C for 24 hours. Then, aspirate the drug-containing medium and wash twice with PBS to remove floating dead cells. Digest the human liver tumor cells with trypsin for 2 minutes. Then, disperse the digested human liver tumor cells, centrifuge to collect the cells in a 0.5mL conical EP tube and transfer the EP tube to a sample tube.

[0190] 3. Place the NMR sample tube in a 400M magnetic resonance imaging spectrometer (Bruker BioSpec MRI system) for tuning and shimming. Use the RARE sequence for imaging, repeat sampling 64 times, sampling matrix 32×32, scan time 17 min 4 s, and other sampling parameters are set as follows: acceleration factor RARE factor = 4, repetition time TR = 2000.0 ms, echo time TE = 3.0 ms.

[0191] Experimental results:

[0192] In vitro human liver tumor cells 19 FMR imaging such as Figure 4 As shown, by Figure 4 It can be seen that even at a low drug concentration of 2 mM (compound concentration), a significant fluoride signal can still be observed in the cells, indicating that human liver tumor cells HepG2 can efficiently take up fluorinated monosaccharide derivatives.

Claims

1. A fluorinated monosaccharide derivative, characterized in that: The fluorinated monosaccharide derivative consists of three parts: the first part is a substituted monosaccharide group at the 1-position, the second part is a perfluorotert-butanol group (a fluorine signal source), and the third part is a triazole ring group connecting the two. Its general structural formula is as follows: ， Wherein, aldose is glucose, galactose, mannose, fucose, rhamnose, arabinose, or ribose, n is an integer between 1 and 20, and F is fluorine-19.

2. A method for synthesizing a fluorinated monosaccharide derivative, characterized in that... Includes the following steps: S1. In the presence of a sulfonating agent, n-butyninol undergoes a sulfonation reaction with p-toluenesulfonyl chloride to produce butynyl p-toluenesulfonate, as shown in the following reaction formula: ； S2, butynyl p-toluenesulfonate, undergoes a nucleophilic substitution reaction with perfluorotert-butoxide to generate butynyl perfluorotert-butyl ether, as shown in the following reaction formula: ； Among them, M + It is a metal ion; S3. Under the condition of the presence of a catalyst and a reducing agent, compound (I) undergoes a click reaction with butynyl perfluorotert-butyl ether to generate compound (II), and the reaction formula is as follows: ， The aldose mentioned is glucose, galactose, mannose, fucose, rhamnose, arabinose, or ribose; S4. Under alkaline conditions, the compound of formula (II) loses its acetyl group to generate the fluorinated monosaccharide derivative, as shown in the following reaction formula: 。 3. The method for synthesizing fluorinated monosaccharide derivatives according to claim 2, characterized in that: The fucoidant mentioned is triethylamine or N,N-diisopropylethylamine.

4. The method for synthesizing fluorinated monosaccharide derivatives according to claim 2, characterized in that: The sulfonation reaction is carried out at room temperature, and the molar ratio of n-butyninol, p-toluenesulfonyl chloride and fusible acid agent is 1.0:1.0-1.5:2.0-3.

0.

5. The method for synthesizing fluorinated monosaccharide derivatives according to claim 2, characterized in that: The nucleophilic substitution reaction is carried out at a temperature of 70℃-90℃, and the molar ratio of n-butynol p-toluenesulfonate and perfluorotert-butoxide potassium is 1.0:1.0-1.

5.

6. The method for synthesizing fluorinated monosaccharide derivatives according to claim 2, characterized in that: The catalyst is copper sulfate pentahydrate, the reducing agent is sodium ascorbate, and the reaction solvent is a mixture of tetrahydrofuran and water.

7. The method for synthesizing fluorinated monosaccharide derivatives according to claim 2, characterized in that: The click reaction was carried out under nitrogen protection and at room temperature, with the molar ratio of butynyl perfluorotert-butyl ether, compound (I), catalyst B and reducing agent being 1.0:1.0-1.5:0.25:0.

5.

8. The method for synthesizing fluorinated monosaccharide derivatives according to claim 2, characterized in that: The alkaline conditions used are sodium methoxide, and the deacetylation reaction is carried out at room temperature.

9. The use of the fluorinated monosaccharide derivative of claim 1 in the preparation of fluorine-19 contrast agents.

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